New Insights into the Efficacy and Safety of Perampanel

New Insights into the Efficacy and Safety of Perampanel

Michelle Bell, MD

The Neurological Institute of New York, Columbia University Medical Center, New York, New York

The unique mechanism of action of perampanel may help patients with epilepsy who present with particular therapeutic challenges. Data presented at the 2014 Annual Meeting of the American Epilepsy Society reflected on the efficacy of perampanel therapy among young and older patients, men and women, and individuals diagnosed with primary generalized epilepsy and partial seizures. Researchers focused on the value of the drug in treating epilepsy and its potential adverse effects on growth and development of adolescents, renal function, aggression, and neuropsychiatric events. The data provided prompted interest and offered answers to a number of important questions related to the use of this novel drug alone and with other antiepileptic drugs.

Michelle Bell, MDThe antiepileptic drug (AED) perampanel has attracted great interest since it was approved for marketing by the US Food and Drug Administration (FDA) in October 2012. Perampanel's unique mechanism of action—noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate-receptor antagonism—has spurred hope that it will be effective in patients with epilepsy who respond inadequately to other AEDs.

PIVOTAL CLINICAL TRIALS
Efficacy results from three double-blinded, placebo-controlled trials in patients with refractory partial-onset seizures were not unlike those of other previously approved AEDs. In all three studies, perampanel or placebo was added to one to three other AEDs the patients were already taking. In Study 304, French et al1 reported that the median percent change in seizure frequency was –26.3% (P = 0.0261) and –34.5% (P = 0.0158) among patients who received 8 or 12 mg/d of perampanel, compared with –21.0% for those who received placebo. In Study 305, French and others2 noted that the median percent change from baseline seizure frequency was −30.5% (P < 0.001) and −17.6% (P = 0.011) for patients receiving 8 or 12 mg/d of perampanel versus −9.7% for those given placebo. Finally, in Study 306, Krauss and colleagues3 demonstrated a median percent change in seizure frequency of –13.6% (P = not significant [NS]), –23.3% (P = 0.0026), and –30.8% (P < 0.0001) among patients taking 2, 4, or 8 mg/d of perampanel versus –10.7% for those who received placebo. Observed side effects in these three studies included dizziness, ataxia, somnolence, fatigue, irritability, and headache.

Since publication of these trials, various subgroup analyses have aimed to tease out potential differential effects of perampanel in specific patient groups. With the exception of falls, which not surprisingly were more frequent in the elderly, no significant differences in the safety and efficacy of perampanel were found between the following groups: patients ≥ 65 years of age and younger patients; males and females; patients in different regions of the world; patients with or without structural epileptogenic lesions; and patients with or without preexisting neurologic and psychiatric comorbidities.4

Many of the new studies on perampanel presented at the 68th Annual Meeting of the American Epilepsy Society reflected both ongoing interest in possible dissimilarities in efficacy and safety among different groups of patients and the rising concern about perampanel's neuropsychiatric side effects, specifically the risk of suicidality.5 The data presented at the meeting can be grouped along two axes: (1) its efficacy in controlling generalized tonic-clonic seizures in patients with primary generalized epilepsy, in controlling partial-onset seizures in adolescents, in improving patient quality of life (QOL), and in comparison with placebo; and (2) its safety in regard to suicidality, aggression, renal toxicity, withdrawal symptoms, growth and development in adolescents, and cognitive function in adolescents.

EFFICACY OF PERAMPANEL

Placebo-Adjusted Treatment Effect of Perampanel
Placebo effect varies greatly across randomized clinical trials. Even among the three cornerstone perampanel trials, significant variability was noted—the median percent reduction in seizure frequency for patients receiving placebo was –21.0% in Study 304 and –9.7% and –10.7% in Studies 305 and 306, respectively. Consequently, Wechsler and colleagues6 used the Hodges-Lehmann method to account for this variability in placebo effect and reanalyze the relative efficacy of perampanel at various doses.

As shown in Figure 1, daily administration of 4, 8, and 12 mg of perampanel produced a significant reduction in seizure frequency, even when the data were adjusted for the placebo effect. In this analysis, the reduction in seizure frequency observed in patients receiving a subtherapeutic dose of 2 mg/d of perampanel was not statistically different from that in the placebo arm. Interestingly, it appears that there may be a waning benefit and even possibly diminishing returns by administering 12 mg/d of the drug compared with 8 mg/d. In Study 304, administration of 12 mg/d added only a 0.7% placebo-adjusted reduction in seizure frequency compared with 8 mg/d.1 In Study 305, the reduction in seizure frequency actually was lower in patients receiving 12 mg/d (13.7%) versus those receiving 8 mg/d (19.1%).2

Figure 1

FIGURE 1 Placebo-adjusted estimation of perampanel treatment effect in each of the three pivotal clinical trials (Studies 304, 305, and 306). Adapted, with permission, from Wechsler et al.6

Figure 2 illustrates the placebo-adjusted perampanel response based on dose and concomitant use of enzyme-inducing AEDs.6 Perampanel's primary route of metabolism is cytochrome P3A4; thus, it is not surprising that the placebo median percentage reduction from baseline in seizure frequency is higher when enzyme-inducing AEDs are not being taken concomitantly.

Figure 2

FIGURE 2 Placebo-adjusted estimation of perampanel treatment effect by dose and concomitant enzyme-inducing antiepileptic drug (AED) use. Adapted, with permission, from Wechsler et al.6

Effect of Perampanel on QOL
Epileptologists and patients alike maintain that health-related QOL is at least as important as reduction in seizure frequency in treating epilepsy. In addition, these two outcomes are significantly related, as reduction in seizure frequency probably impacts QOL. Tsong and colleagues7 administered the Quality of Life in Epilepsy Inventory 31 (QOLEI-31-P) at the inception and completion of the three pivotal phase 3 clinical trials of perampanel (Studies 304, 305, and 306) to assess the impact of the drug on patient QOL. Clinically significant improvement was determined using Boughs' and Wiebe's analyses.

The results showed a clinically significant improvement in QOLEI-31-P scores among patients given perampanel who experienced a ≥ 50% reduction in seizure frequency. The domains most affected included seizure worry, mood, and distress. Patients who experienced an improvement in seizure control also showed enhancements in energy, daily activities, and overall QOL and health status.

In addition, regardless of its effect on seizure control, treatment with perampanel was associated with a lower incidence of cognitive decline when compared with placebo (Wiebe analysis, 19.3% vs 27.0%).

Effect of Perampanel on Drug-Resistant Primary Tonic-Clonic Seizures
French et al8 reported on the first study on the efficacy of perampanel in patients with primary generalized epilepsy. The investigators focused on the drug's ability to reduce the frequency of primary generalized tonic-clonic seizures. Patients were > 12 years of age and on a fixed dose of one to three concomitant AEDs for > 30 days before study entry. All patients had a history of primary generalized epilepsy (as confirmed by external Epilepsy Study Consortium review and consistent electroencephalographic [EEG] findings) and had experienced at least three primary generalized tonic-clonic seizures over an 8-week baseline period. Only one concomitant inducer AED was allowed; no non-AED inducers could be used. Any vagal-nerve stimulator had to be in place for at least 5 months.

Patients were excluded if they experienced status epilepticus during the previous 12 months or needed rescue benzodiazepine therapy more than twice over the previous 30 days. Patients with Lennox-Gastaut syndrome, partial-onset seizures, or a progressive neurologic disorder also were excluded (Table 1).8

Table 1

In all, 163 patients were randomized 1:1 to receive perampanel or placebo. The median baseline frequency of generalized tonic-clonic seizures over the previous 30 days was 2.6 among patients who were treated with perampanel and 2.5 among those who received placebo. The baseline period was followed by a 4-week titration period, when the dose of perampanel was increased by 2 mg/wk to either 8 mg/d or the maximum tolerated dose; the median dose was 8 mg/d.

When compared with the placebo group, patients taking perampanel (Figure 3) exhibited a higher median improvement in seizure frequency (76.5% vs 38.4%; P < 0.0001), higher responder rate (64.2% vs 39.5%; P < 0.01), and higher seizure-free rate (30.9% vs 12.3%; P = NS).8 Importantly, these changes represented only a change in generalized tonic-clonic seizures and not a change in absence or myoclonic seizures, which was not reported.

Figure 3a Figure 3b Figure 3c

FIGURE 3 Antiepileptic efficacy of perampanel for primary generalized tonic-clonic seizures. Seizure-free rates expressed as a percentage of the full analysis set. To achieve "seizure-free" status, patients had to complete the maintenance period with no seizures. Non-completers were considered not to be seizure-free. Adapted, with permission, from French et al.8

Two suicidality-related serious adverse events (suicide attempt and suicidal ideation) were noted in the perampanel-treatment group. Suicidality also was noted among three patients in the placebo group, but these events were not categorized as "serious" by the authors. Increased irritability also was noted more frequently in the perampanel group (11.1%) than in the placebo group (2.4%). Other "non-serious" treatment-emergent side effects were similar to those seen in patients with partial-onset epilepsy (Table 2).8

Table 2

FYDATA Study: Retrospective Analysis of Perampanel in a Real-Life Setting
Villanueva and others9 conducted a multicenter, retrospective, 1-year observational study that examined the efficacy and safety of adjunctive perampanel therapy in patients ≥ 12 years of age with pharmacoresistant epilepsy across 13 tertiary hospital centers in Spain. This is one of two studies that reviewed real-life experience with perampanel.

Patients were treated with 2, 4, 6, or 8 mg/d of perampanel in addition to their current AED regimen and assessed for freedom from seizures, > 50% seizure reduction, and retention at 12 months. Secondary outcomes measures included the same endpoints at 3 and 6 months. Safety endpoints were adverse events or intolerable adverse effects after 3, 6, and 12 months of therapy.

The mean age of the patient population was 38.5 ± 13 years, the median time since diagnosis was 24 years (range, 13–35.5 years), the median monthly frequency of seizures was 6 (range, 2.7–20), and the median number of previous AEDs used was 8 (range, 2–18). The concomitant AEDs most commonly used were lacosamide (36.9%), levetiracetam (36.0%), carbamazepine (29.7%), lamotrigine (28.8%), and eslicarbazepine (27.9%).

The mean daily dose of perampanel used was 5.4 ± 1.7 mg. Just 21.6% of patients reached a dose of 8 mg/d. At 3 months after initiation of therapy, 61.3% of patients showed some improvement in seizure frequency, with 9.0% being seizure-free and 44.1% having a > 50% response. Data on seizure frequency at 6 or 12 months were not reported.

The side-effect profile of perampanel in this study was similar to that noted during the initial trials of perampanel for partial-onset seizures. The incidence of specific adverse effects occurring in two or more patients was 13.5% for irritability; 10.8% for somnolence; 9.9% for dizziness; 5.4% for aggression; 3.6% each for headache and weakness/fatigue; and 1.8% each for anxiety, psychosis, and insomnia.

Psychiatric adverse events were monitored closely. A psychiatric history conferred a 3.5-fold increased risk of an adverse psychiatric effect occurring while the patient was taking perampanel (9.1% for patients without a psychiatric history and 32.4% for those with a psychiatric history). The incidence of aggression and irritability seemed to be most closely linked to a personality disorder or history of hyperactivity. To a lesser degree, it was associated with a history of depression, psychosis, or anxiety (Table 3).9

Table 3

In patients with psychiatric histories, the emergence of psychiatric side effects also appeared to be closely linked to the rate of upward dosage titration (Figure 4).9 Psychiatric adverse effects were not reported among patients without psychiatric histories whose daily perampanel dose was titrated upward at a rate of 2 mg over a period of 3 weeks or slower (Figure 5).9 There was no mention of suicidality in this study.

Figure 4

FIGURE 4 Incidence of psychiatric adverse events by speed of dose titration in patients with prior psychiatric comorbidities. Adapted, with permission, from Villanueva et al.9

Figure 5

FIGURE 5 Incidence of psychiatric adverse events by speed of dose titration in patients without prior psychiatric comorbidities. Adapted, with permission, from Villanueva et al.9

Adjunctive Perampanel for Focal-Onset Seizures
Kelly et al10 reported on a prospective study performed at the Western Infirmary Epilepsy Unit in Scotland from 2012 to 2014; data on 45 patients treated with perampanel were included in this interim analysis.

In all, 48% of patients benefited from perampanel therapy; 2 remained seizure free, 5 had a > 50% reduction in seizures, and 15 reported marginal benefits. Perampanel was withdrawn in 48.9% of the patients, in 4 cases due to lack of efficacy and in 19 secondary to side effects. Similar to the side effects described in other reported studies, the side effects that most commonly prompted withdrawal were depression and ataxia (three cases each) and nausea/vomiting, sedation, irritability, aggression, and dizziness (two cases each).

Perampanel in Adolescents with Inadequately Controlled Partial Seizures
Adolescents were included in the three pivotal double-blind, randomized, placebo-controlled, phase 3 studies but did not comprise a large proportion of the patients studied in those trials.1–3 Renfroe and others11 conducted a phase 2 study (Study 235) that focused specifically on 133 adolescents 12–18 years of age; 85 were treated with perampanel, and 48 were given placebo. Perampanel was started at 2 mg/d and titrated upward in weekly 2-mg increments to reach target doses of 8–12 mg/d over a period of 6 weeks. The maintenance treatment phase lasted 13 weeks.

The placebo-adjusted effect was higher than that noted in Studies 304, 305, and 306,1–3 but the relative treatment effect was comparable. Specifically, the median percentage change in seizure frequency was –18.0% in the placebo group compared with –34.8% in patients given 8 mg/d of perampanel and –35.6% in those receiving 12 mg/d. The higher placebo effect in this population may be explained by the adolescents' lower baseline seizure frequency and, by extension, less drug resistance.

This study also assessed adverse effects among adolescents. It was not powered to assess differences in side effects between the placebo group and the perampanel group. Emergent trends were similar to those reported in Studies 304, 305, and 306 (Tables 4 and 5).11

Table 4


Table 5

Racial Differences in Response to Perampanel
Laurenza and others12 presented the racial identities of patients participating in Studies 304, 305, 306 and assessed racial differences in seizure reduction and adverse events.

The vast majority of study participants were Caucasian (75.4%) or Asian/Pacific Islanders (19.6%). Blacks or African-Americans constituted 2.1% of the group; the remaining 3.0% of patients were of other racial origins (namely, Hispanic/Latino/Cuban/Mexican, American Indian, Asian Indian, North African, or mixed origin). Given the small number of patients in the Black/African-American and other racial subgroups, the analysis only compared Caucasians with Asian/Pacific Islanders.

Major differences between Asian/Pacific Islanders and Caucasians emerged at the higher doses of perampanel (8 and 12 mg/d) . When compared with Caucasian subjects, at the higher doses, Asian/Pacific Islanders exhibited a greater reduction in seizure frequency and a higher responder rate. The relative rate of treatment discontinuation at 12 mg/d (25.9% for Caucasians vs 11.1% for Asian/Pacific Islanders) and the relative incidence of adverse events given as a reason for treatment discontinuation (20.4% vs 5.6%, respectively) suggested that the 12-mg daily dose of perampanel may be more effective and better tolerated among Asian/Pacific Islanders than among Caucasians. The perampanel plasma concentration did not vary significantly between the two racial groups and, therefore, did not explain the observed differences in therapeutic efficacy or rate of treatment discontinuation.

Reported side effects varied between Caucasians and Asian/Pacific Islander subjects. In all, 10.8% of the Asian/Pacific Islanders developed symptoms of upper respiratory tract infection or nasopharyngitis, whereas none of the Caucasian patients reported these side effects. These findings suggest that these races mount different immune responses to perampanel. Overall, imbalance, ataxia, vertigo, and dysarthria were relatively prevalent in the Caucasian group (14.3%). Only gait disturbance was reported in the Asian/Pacific Islander group (2.8%).

SAFETY OF PERAMPANEL

Suicidality in Perampanel Clinical Studies
Is suicidality more frequent in patients treated with perampanel than with other AEDs? According to Ettinger et al,13 the answer is murky. Among 1,651 perampanel-treated patients with partial epilepsy, 18 (1.1%) experienced suicidality-related adverse effects (suicide ideation and attempts) as compared with 2 (0.4%) of the placebo group. Similarly, among 2,013 non-epilepsy patients who received perampanel, 5 (0.2%) experienced treatment-emergent, suicidality-related adverse events, as compared with none of the placebo group.

According to the authors, however, this view falsely overrepresented the suicidality-related events in the perampanel group, since the overall extent of exposure was much greater in the perampanel group than in the placebo group. After analysis of data considering the duration of exposure, the suicidality-related adverse events were comparable between the perampanel and placebo groups, both among patients with epilepsy and those without.

To assess better which approach (raw numbers vs exposure-adjusted) is more appropriate, it may be helpful to have a sense of how quickly these adverse effects emerge. Do they appear immediately? If so, raw numbers are more relevant. Are they exposure-dependent? If so, the exposure-adjusted analysis may be more appropriate. Data in this study did not specify when suicidality symptoms emerged.

Among the 18 perampanel-treated epilepsy patients with suicidality-related adverse effects, 12 experienced suicidal ideation, 4 attempted suicide, and 2 had taken an intentional overdose (Table 6).13 Among the five patients in the non-epilepsy populations who exhibited suicidality, two had suicide ideation and three made suicide attempts (Table 7).13 Both suicidality-related events in the placebo-treated epilepsy group were suicidal ideation (no suicide attempt), and none of the placebo-treated non-epilepsy group had suicidality-related adverse events.

Table 6


Table 7

The majority of perampanel-treated epilepsy patients who developed suicidality (11/18) did not have a psychiatric medical history. Three patients who developed suicidality had no other concurrent related psychiatric adverse events during the course of perampanel therapy, including the two patients who attempted suicide.

Aggression in Patients Taking Perampanel and Levetiracetam Concurrently
Aggression has been reported in 12%–20% of patients given perampanel. In the pivotal phase 3 clinical trials, patients used up to three AEDs concomitantly, in addition to perampanel. One of the more commonly used AEDs was levetiracetam. Fain et al14 assessed whether patients taking levetiracetam and perampanel concurrently had a higher incidence of hostility and aggression than did those taking perampanel without levetiracetam.

The results showed a slight increase in irritability, aggression, and anger among patients taking both AEDs together compared with perampanel alone (Table 8). The report did not discuss whether any of these differences was statistically significant.

Table 8

Renal Studies of Perampanel
Leppik et al15 investigated the effects of perampanel therapy on blood urea nitrogen and serum creatinine levels, treatment-emergent adverse renal events, and the effect of renal impairment on perampanel clearance.

No consistent link between perampanel therapy and abnormal renal laboratory parameters was observed. Mild and moderate renal impairment was associated with an apparent decrease in the clearance of oral perampanel; however, the decrease was less for those with moderate renal impairment (14%) than for those with mild renal impairment (27%). No patients with severe renal impairment were included in the study.

Although the incidence of treatment-emergent renal events was similar in patients treated with perampanel and those receiving placebo, some adverse events were unique to the use of permapanel. Four patients (0.4%) in the perampanel group had abnormally frequent urination, two (0.2%) each had enuresis and nephrolithiasis , and one (0.1%) had hemorrhagic cystitis. One case of urinary incontinence was so severe that it prompted discontinuation of the drug.

Perampanel Discontinuation Not Associated with Self-Reported Withdrawal
Rogawski and colleagues16 studied 832 patients who had been randomized to treatment with perampanel in the three pivotal phase 3 clinical trials, later entered an open-label extension study (Study 307), and completed a treatment-withdrawal questionnaire. This questionnaire was administered at visit 2 to obtain baseline symptoms, at the end of the extension treatment period, 6–10 days after taking their last dose, and again 4 weeks later. Patients were asked about fatigue, irritability, anxiety, craving/drug seeking, mood swings, nausea/stomach discomfort/vomiting, change in appetite, worsening in mood, insomnia, muscle pain/stiffness, changes in weight, and rhinorrhea/lacrimation.

No appreciable increase in withdrawal symptoms was noted at any of the time points after drug discontinuation. Presumably, perampanel's long half-life (105 hours) is responsible for this lack of withdrawal symptoms, because after abrupt withdrawal of the drug, blood levels fall gradually.

Effect of Perampanel on Growth and Development in Adolescents
Pina-Garza et al17 assessed the effect of adjunctive perampanel therapy on growth and development markers in adolescents with inadequately controlled partial-onset seizures despite treatment with one to three other AEDs (see description of Study 235 above).

Weight gain occurred in 5.9% of 85 perampanel-treated patients but none of the 48 patients receiving placebo. No significant differences in thyroid function, height, bone age, or Tanner staging was noted between the two groups, although it is unclear whether changes in the latter three parameters would be expected within the 19-week observation time. There was, however, a significant difference between the two groups in insulin-like growth factor-1 (IGF-1) levels; the IGF-1 level decreased to a greater extent in the placebo group (–13.9 µg/L) than it did in the perampanel group (–1.1 µg/L). This finding would suggest that perampanel provides some protection against growth impairment, but why this would be so is unclear.

Perampanel's Pharmacokinetic, Pharmacodynamic, and Cognitive Effects
The primary goal of Study 235 (see above) was to assess the effects of adjunctive perampanel therapy on cognition in adolescents with inadequately controlled partial seizures. Increasing exposure to perampanel resulted in a small, but significant, increase in power of attention (95% confidence interval [CI] = 0.108–0.210) and quality of episodic secondary memory (95% CI = 0.0241–0.845) counterbalanced by a decrease in continuity of attention (from –0.00729 to –0.000390). There also was a slight decrease in global cognitive function, but the change in the global cognitive scale was not significant.

The secondary goal of this study was to assess the pharmacokinetics and pharmacodynamics of perampanel in adolescents. As with adults, the pharmacokinetics were linear. Clearance of perampanel was affected by coadministration of CYP3A4- enzyme inducers (clearance increased by a factor of 2.64 with carbamazepine and 1.78 with oxcarbazepine or phenytoin) and not by renal function, liver function, age, or race. Clearance was 17.5% lower in adolescent girls.18

CONCLUSION
These studies provide robust data on the differential efficacy and side effects of perampanel and clarify answers to several unanswered clinical questions regarding its use. Specifically, perampanel appears to be effective in controlling generalized seizures in patients with primary generalized epilepsy, as well as those with refractory partial-onset seizures; higher daily doses (8 and 12 mg) of perampanel may be more effective in Asian/Pacific Islanders than in Caucasians; the median seizure frequency reduction rate is 15%–20% for higher perampanel doses after adjusting for placebo; and perampanel therapy can improve patient QOL as it decreases seizure frequency.

Data on the adverse effects of this relatively new AED further our understanding of these effects. They suggest that psychiatric side effects may be more common among patients with psychiatric histories; aggression and irritability can be mollified by slowing the rate of dosage uptitration; and concurrent treatment with levetiracetam and perampanel slightly increases the risk of aggression compared with perampanel therapy alone. Additionally, perampanel therapy does not appear to have short-term, clinically appreciable side effects on the growth, development, and cognitive function of adolescents. It does not seem to alter renal laboratory parameters or cause withdrawal symptoms when it is abruptly discontinued. Renal side effects are virtually absent, although abnormally frequent urination has been reported in < 1% of patients taking it. Lastly, Caucasian patients are more likely to experience nausea, ataxia, lethargy, irritability, and aggression than the other studied racial or ethnic groups.

Although these studies have increased our understanding of the many questions regarding perampanel, there continue to be unanswered questions: Does perampanel therapy reduce the frequency of other types of primary generalized seizures (namely, absence, myoclonic, atonic, and tonic seizures)? What is the most accurate way to analyze the perampanel suicidality data—by comparing raw incidence values or by applying the exposure-adjusted calculations? Finally, does the increased rate of nasopharyngitis and upper respiratory tract infection among Asian/Pacific Islander patients actually represent a mild hypersensitivity reaction and, by extension, a race-based variability in the immune response to perampanel? As these and other questions are answered, clinicians will become more confident prescribing perampanel and will be better able to find a place for this novel drug in the ever-growing armamentarium of AEDs.

REFERENCES

  1. French JA, Krauss GL, Biton V, et al. Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304. Neurology. 2012;79:589–596.
  2. French JA, Krauss GL, Steinhoff BJ, et al. Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of randomized global phase III study 305. Epilepsia. 2013;54:117–125.
  3. Krauss GL, Serratosa JM, Villanueva V, et al. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology. 2012;78:1408–1415.
  4. Wabulya A. Update on perampanel: a novel anti-epileptic drug for partial-onset seizures. Neurol Rep. 2013;6:26–36.
  5. Huber B. Increased risk of suicidality on perampanel (Fycompa®)? Epilepsy Behav. 2014; 31:71–72.
  6. Wechsler R, Mintzer S, Yang H, Williams B, Xing D, Laurenza A. Placebo-adjusted estimation of treatment effect of perampanel. Presented at the 68th Annual Meeting of the American Epilepsy Society; December 5–9, 2014; Seattle, WA. Poster 2.291.
  7. Tsong W, Hudgens S, Forsythe A, Muniz R. Impact of adding perampanel to existing anti-epileptic drug therapy on health-related quality of life as measured by the quality of life in epilepsy inventory (QOLIE-31-P) in a pooled population of patients with partial-onset seizures from 3 phase III trials. Presented at the 68th Annual Meeting of the American Epilepsy Society; December 5–9, 2014; Seattle, WA. Poster 3.301.
  8. French J, Krauss G, Wechsler R, et al. Adjunctive perampanel for treatment of drug-resistant primary generalized tonic-clonic seizures in patients with idiopathic generalized epilepsy: a double-blind, randomized, placebo-controlled phase III trial. Presented at the 68th Annual Meeting of the American Epilepsy Society; December 5–9, 2014; Seattle, WA. Poster 2.389.
  9. Villanueva V, Garces M, Lopez-Gonzalez FJ, et al. FYDATA study: retrospective analysis of perampanel in a real-life setting. Presented at the 68th Annual Meeting of the American Epilepsy Society; December 5–9, 2014; Seattle, WA. Poster 1.332.
  10. Kelly K, Stephen L, Parker P, Brodie M. Adjunctive perampanel for focal-onset seizures—an interim analysis. Presented at the 68th Annual Meeting of the American Epilepsy Society; December 5–9, 2014; Seattle, WA. Poster 1.331.
  11. Renfroe B, Lagae L, Williams B, Yang H, Kumar D, Laurenza A. Adjunctive perampanel in adolescents with inadequately controlled partial seizures: efficacy and safety results from study 235. Presented at the 68th Annual Meeting of the American Epilepsy Society; December 5–9, 2014; Seattle, WA. Poster 2.294.
  12. Laurenza A, Yang H, Williams B, Ma T, Sperling M. Subgroup analysis by race in perampanel phase III clinical studies. Presented at the 68th Annual Meeting of the American Epilepsy Society; December 5–9, 2014; Seattle, WA. Poster 2.289.
  13. Ettinger A, Dobrinsky C, Yang H, et al. Review of suicidality events in perampanel clinical studies. Presented at the 68th Annual Meeting of the American Epilepsy Society; December 5–9, 2014; Seattle, WA. Poster 2.276.
  14. Fain R, Chung S, Yang H, Ma T, Williams B, Laurenza A. Aggression adverse events with concomitant levetiracetam use in perampanel phase III partial seizure clinical studies. Presented at the 68th Annual Meeting of the American Epilepsy Society; December 5–9, 2014; Seattle, WA. Poster 2.288.
  15. Leppik Il, Yang H, Williams B, Ma T, Laurenza A. Assessment of renal toxicity in perampanel-treated subjects: pooled results from phase III clinical studies. Presented at the 68th Annual Meeting of the American Epilepsy Society; December 5–9, 2014; Seattle, WA. Poster 1.325.
  16. Rogawski M, Yang H, Fant R, et al. Perampanel discontinuation is not associated with self-reported withdrawal symptoms. Presented at the 68th Annual Meeting of the American Epilepsy Society; December 5–9, 2014; Seattle, WA. Poster 2.279.
  17. Pina-Garza J, Yang H, Williams B, Kumar D, Laurenza A. Effect of adjunctive perampanel on growth and development in adolescents with inadequately controlled partial seizures. Presented at the 68th Annual Meeting of the American Epilepsy Society; December 5–9, 2014; Seattle, WA. Poster 2.293.
  18. Hussein Z, Gidal B, Yang H, et al. Pharmacokinetics, pharmacodynamic, and cognitive effects of adjunctive perampanel in adolescents with inadequately controlled partial seizures. Presented at the 68th Annual Meeting of the American Epilepsy Society; December 5–9, 2014; Seattle, WA. Poster 2.295.

Dr. Bell is a Clinical Fellow in Clinical Neurophysiology (Epilepsy) at The Neurological Institute of New York, Columbia University Medical Center, New York, New York.

View/download a PDF version of this article