Epilepsy & Behavior 41 (2014) 193–196
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Clinical experience with perampanel: Focus on psychiatric adverse effects Helen Coyle a, Peter Clough a, Paul Cooper a,b, Rajiv Mohanraj a,b,⁎ a b
Greater Manchester Neurosciences Centre, Salford Royal Hospital, UK University of Manchester, Manchester, UK
a r t i c l e
i n f o
Article history: Received 29 August 2014 Revised 23 September 2014 Accepted 26 September 2014 Available online xxxx Keywords: Perampanel Suicidality Epilepsy
a b s t r a c t Background: Perampanel (PER) is a novel antiepileptic drug that inhibits the AMPA class of glutamate receptors. It has been available in the UK since September 2012. We undertook a retrospective analysis of efficacy and tolerability of PER in 47 patients with drug-refractory epilepsy attending a regional epilepsy service in the UK. Methods: Demographic and clinical data of patients with refractory epilepsy prescribed PER were collected by review of records. Efficacy, as measured by responder rates (N 50% reduction in seizure frequency), retention rates, and adverse effects, was analyzed. Results: Of the 47 patients prescribed PER, 39 (87%) had focal epilepsy, four (9%) had idiopathic generalized epilepsy, 3 (6%) had symptomatic generalized epilepsy, and 1 had unclassified epilepsy. Patients were taking a median of 2 AEDs (range: 1–5) when starting on PER. The median dose of PER was 8 mg (range: 2–12 mg). Thirteen (28%) patients were classed as responders, but no patients experienced sustained seizure freedom. Twenty-one (45%) patients had withdrawn from PER during the study period, with 16 (76%) of them withdrawing due to intolerable adverse effects, 4 due to inadequate seizure control, and 1 due to the combination of both. The most frequent adverse effects requiring withdrawal from PER were behavioral reactions including suicidal ideation (n = 2), aggressive behavior (n = 2), and both (n = 1). Conclusion: In our experience, PER had a retention rate of 55% and a responder rate of 28%. Psychiatric adverse effects, including suicidal ideation, were the most common reasons for withdrawal. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Perampanel (PER) is a noncompetitive α-amino-3-hydroxy-5methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist licensed for the treatment of partial-onset seizures. Efficacy in partialonset seizures was demonstrated in 3 randomized controlled trials [1–3]. In total, 1480 patients were randomized in the 3 pivotal studies. Overall, 50% responder rates were 28.5% (PER 4 mg); 35.3% (PER 8 mg) and 35.0% (PER 12 mg); all of which were statistically superior to the responder rate to placebo (19.3%) [4]. The proportions of patients in each randomized dose group who discontinued the trials prematurely were as follows: 11.3% (placebo), 14.4% (PER: 2 mg), 8.1% (PER: 4 mg), 14.8% (PER: 8 mg), and 24.3% (PER: 12 mg) [5]. The most frequently reported treatment emergent adverse effects from the 3 RCTs were dizziness, somnolence, fatigue, irritability, nausea, and falls, which were mild in severity in the majority of patients [6]. In the psychiatric domain, irritability, aggression, and depression were
⁎ Corresponding author at: Department of Neurology, Greater Manchester Neurosciences Centre, Salford Royal Hospital, Salford M6 8HD, UK. Tel.: +44 161 2064626; fax: +44 161 2062993. E-mail address: [email protected] (R. Mohanraj).
http://dx.doi.org/10.1016/j.yebeh.2014.09.072 1525-5050/© 2014 Elsevier Inc. All rights reserved.
more frequently reported by patients on PER compared with those taking placebo. Depression was seen in 2.4% of patients taking PER 12 mg/day and in 1.6% of patients taking placebo. Aggression was reported in 3.1% of patients on PER 12 mg/day and in 0.5% of patients taking placebo [4]. However, rates of depression and aggression in patients taking PER 4 mg/day were lower than those seen in the placebo group. A larger pooled analysis of adverse effects occurring in all patients treated with PER during its development, including phase 2 studies in epilepsy, as well as in Parkinson's disease, also identified dizziness, ataxia, somnolence, irritability, and weight gain as the most frequent adverse effects [7]. Although rates of depression appeared low in the subjects in the RCTs since licensing, concern has been raised regarding the potential of PER to cause suicidality, including a recent report of 3 patients experiencing suicidal ideation after the initiation of PER [8]. Perampanel has been available to be prescribed in the UK since September 2012. Data from regulatory RCTs of AEDs may not be matched by ‘real life’ clinical experience, as RCTs employ rigid dosing schedules and rarely permit significant alterations in concomitant AEDs. Data from open-label postmarketing studies of AEDs can complement those from regulatory trials and help inform the use of newer drugs. In addition, important safety information can emerge from such studies. We, therefore, examined the outcomes from our use of PER in patients attending the Regional Epilepsy Clinic at the Greater
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Manchester Neurosciences Centre, which serves a population of 3.2 million in the north west of England. 2. Methods All patients prescribed PER between September 2012 and March 2014 were identified from the clinical database at the Greater Manchester Neurosciences Centre. Epidemiological and clinical data were collected by review of case records. In addition to demographic details, data on seizure types and frequency, epilepsy classification, imaging and electroencephalography (EEG) results, details of previous and current AED treatment, doses and titration schedules of PER used, and treatment emergent adverse effects were collated on a spreadsheet for analysis. Responder rate, defined as the proportion of patients experiencing N50% reduction in seizure frequency, retention on treatment, and adverse effects leading to withdrawal, was examined.
Table 1 Demographic and clinical details of 47 patients prescribed perampanel. (JME = Juvenile Myoclonic Epilepsy; LGS = Lennox–Gastaut syndrome; SPS = simple partial seizures, CPS = complex partial seizures, GTCS = generalized tonic–clonic seizures, MJ = myoclonic jerks, AED = antiepileptic drugs). Age
Range Median Range Median
Duration of epilepsy Learning disability Number of previous AEDs Number of concomitant AEDs Epilepsy type n (%)
3. Results
Seizure types n (%)
AED withdrawn n (%)
7 (15%) 5 (11%) 2 (4%) 7 (15%) 4 (9%) 3 (6%) 1 (2%) 24 (51%) 12 (26%) 3 (6%) 3 (6%) 2 (4%) 1 (2%) 1 (2%) 1 (2%) 7 (47%) 4 (27%) 2 (13%) 1 (7%) 1 (7%)
Case 1 was a 52-year-old female who had undergone previous left temporal lobectomy for mesial temporal sclerosis. She had continued to experience monthly clusters of auras, and complex partial seizures recurred 7 years postsurgery. At the time of the initiation of PER, she was experiencing monthly clusters of simple partial seizures and 1 complex partial seizure per month. She was taking gabapentin and lacosamide, which were substituted with PER. She had a previous history of suicidality following temporal lobectomy with two drug overdoses,
Proportion continuing on perampanel
During the 19-month period between September 2012 and February 2014, PER was prescribed for 47 patients attending the epilepsy clinic. Twenty-four (51%) were female, and the median age was 31 years (range: 18–61). Learning disability was present in 8 (17%) patients. The median duration of epilepsy was 9 years (range: 0.5–36 years). Patients were taking a median dose of 2 AEDs (range: 1–5) when starting on PER. Details of previous AED treatment were available for 46 patients. Patients had been treated with a median dose of 8 AEDs prior to commencing PER (range: 2–11). Of the 47 patients prescribed PER, 39 (87%) had focal epilepsy, four (9%) had idiopathic generalized epilepsy, 3 (6%) had symptomatic generalized epilepsy, and 1 had unclassified epilepsy. The use of PER in patients with epilepsies other than focal epilepsy was outside its current product license in the EU. The majority had simple or complex partial seizures with or without secondary generalization. Another AED was replaced with PER in 15 patients, and PER was an add-on AED in the remaining 32 patients. A list of the AED withdrawn is included in Table 1. Demographic and clinical details of patients prescribed PER are summarized in Table 1. The initial dose of PER was 2 mg/day, which was titrated by 2 mg every 2 weeks in 37 (79%) patients. Three patients had dose increases made at 3-weekly intervals and one patient at monthly intervals. The average frequency of the most common seizure type in the 3 months leading up to the introduction of PER for each patient was compared with the seizure frequency in the best 3-month period during treatment with PER to identify responders (those with N 50% improvement in seizure frequency). Thirteen (28%) patients were classed as responders by this criterion. One patient became seizure-free for 4 months but had a relapse of seizure on reduction of dose due to adverse effects. Twenty-one (45%) patients had withdrawn from PER during the study period. The actuarial analysis of time to withdrawal is shown in Fig. 1. Sixteen (76%) of the 21 patients had withdrawn from PER because of intolerable adverse effects, 4 because of inadequate seizure control, and 1 because of the combination of both. Doses taken by responders and patients withdrawing due to intolerable treatment emergent adverse effects are shown in Fig. 2. The median dose in either group was 8 mg/day. Behavioral disturbance including suicidal ideation was the most common adverse effect requiring withdrawal from PER. Dizziness and somnolence were other commonly reported adverse effects (Table 2). Behavioral changes were ‘mood swings’ and ‘irritability’ (6 patients) and aggression (3 patients) as well as thoughts of self-harm in one patient and actual self-harm in another patient. Aggressive behavior took the form of verbal aggression in 2 patients and verbal aggression and physical aggression in the case of one patient. Details of 3 patients who developed suicidal ideation are described below.
Range Median Range Median Focal epilepsies Cryptogenic focal epilepsy Hippocampal sclerosis (4 postepilepsy surgery patients) Cortical malformation (1 patient with tuberous sclerosis) Acquired brain injury (trauma/encephalitis) Low-grade tumor Generalized epilepsies Idiopathic generalized epilepsy (3 patients with JME) Symptomatic generalized epilepsy (1 patient with LGS) Unclassified epilepsy SPSs/CPSs SPSs/CPSs + GTCSs GTCSs GTCSs + MJs GTCSs + MJs + absences GTCSs + absences MJs MJs + atonic Retigabine Lacosamide Zonisamide Levetiracetam Valproate
18–63 years 31 years 0.5–36 years 9 years 8 2 to 11 3 (mean: 8) 1 to 5 2 39 (83%) 15 (32%) 10 (21%)
10 0 90 80 70 60 50 40 30 20 10
0 Weeks 0
4
8
12
16
20
24
28
32
36
40
44
48
52
No. at risk 47
46
43
39
37
30
26
17
13
8
5
4
2
1
No. 1 withdrawn
0
3
4
2
3
0
2
1
2
2
0
1
0
Fig. 1. Retention on treatment with PER in 47 patients.
H. Coyle et al. / Epilepsy & Behavior 41 (2014) 193–196
195
in situ. He was experiencing 4 generalized tonic–clonic seizures per month, and the frequency of complex partial seizures was unknown as he spent much time unsupervised. PER had been introduced at a rate of 2 mg per week up to a maximum dose of 8 mg daily. Perampanel was initially well tolerated (taken for a total of 225 days), but once increased to 8 mg daily, marked behavioral changes were noted. Intermittent confusion, aggression, and suicidal ideation were observed by family members ultimately requiring admission and treatment with benzodiazepines. This patient had no previous history of aggression or psychosis. Symptoms resolved upon withdrawal from PER.
12 mg
10 mg
8 mg
6 mg
4 mg
2 mg
4. Discussion
0 mg Maximum doses taken by 13 patients withdrawing due to intolerable adverse effects
Maintenance doses taken by 13 patients who experienced >50% seizure reduction
Fig. 2. Doses taken by responders and those withdrawing from PER due to intolerable adverse effects. The median dose was 8 mg in either group.
but no psychotic features had been identified. Perampanel was titrated at 2 mg every two weeks up to a dose of 4 mg daily. Shortly after PER was introduced, her mood was described as ‘extremely low’. She left her home at night having left a note for her husband with the intention of drowning herself in a canal. Fortunately, a passerby intervened and talked her out of proceeding. Once reported, PER was withdrawn, and her mood improved. She had taken PER for a total of 138 days with no reported reduction in seizure frequency. Case 2 was a 29-year-old female with a 28-year history of difficultto-treat focal epilepsy and had tried at least 10 previous antiepileptic drugs. She declined presurgical investigations for treatment of her left MTS. She also had a diagnosis of Asperger's syndrome and was thought to be experiencing some nonepileptic seizures. There was no documented psychiatric history. At the time of introduction of PER, she was taking oxcarbazepine and clobazam. Seizure frequency at the time of introduction was up to 10 complex and simple partial seizures per day. Perampanel was introduced at 2 mg every 2 weeks up to a dose of 6 mg daily. A slight reduction in the frequency of complex partial seizures was noted. Her family noticed that she was spending increased amounts of time alone in her bedroom, crying inappropriately. This culminated with her taking an overdose of paracetamol. She took PER for 130 days and had withdrawn from the drug following the overdose. Her mood stabilized following withdrawal, and she was started on fluoxetine. Case 3 was a 51-year-old male with drug-refractory focal epilepsy. He also had a history of nonepileptic seizures. He was taking retigabine (which was stopped), clobazam, and levetiracetam (4000 mg daily) at the time PER was introduced. He also had a vagal nerve stimulator Table 2 Adverse effects reported by 17 patients withdrawing from PER due to intolerable treatment emergent adverse effects. Some patients experienced more than one adverse effect. Mood/behavioral changea Dizziness Sedation Slurred speech Confusion Unsteadiness Sensory symptoms Double vision Weight gain Hallucination Headache Memory Skin irritation a
Includes 3 patients with suicidal ideation.
12 9 7 5 4 4 3 2 2 1 1 1 1
Data from randomized controlled trials of AEDs alone are inadequate to inform the most appropriate dosing and titration schedules of AEDs in clinical practice because of the rigid treatment protocols used in RCTs. Moreover, regulatory RCTs are short-term studies and may miss important treatment emergent adverse effects. Postmarketing review of the use of AEDs can help identify optimum dosing and titration schedules, as well as previously unreported treatment emergent adverse effects. In our series, the majority of patients had refractory focal epilepsy, but PER was also used off license in 8 patients with generalized and unclassified epilepsy. Overall, the responder rate was 28% which compares favorably with that observed in the pivotal RCTs. However, no patient experienced sustained seizure freedom. Retrospective observational studies have an inherent bias towards overestimating benefit due to regression to the mean. This needs to be factored into interpretation of efficacy data from this study. A longer period of follow-up will be required to identify true efficacy in improving seizure control. The withdrawal rate of PER was 45%, which is higher than that reported in the regulatory trials. The FDA lists ‘serious psychiatric and behavioral reactions’ as a potential adverse effect of PER. Aggression, both physical and verbal, was displayed by 3 patients in our cohort. The most striking finding was the high rates of behavioral and mood-related side effects requiring withdrawal from PER. In particular, 3 patients experienced significant suicidal ideation. As in the cohort of patients described by Huber, all 3 patients reporting suicidal ideation on treatment with PER had refractory focal epilepsy [8], and one had a previous history of depression and suicide attempt. The other 2 patients were both thought to also have nonepileptic attacks in addition to epilepsy, and one also had a diagnosis of Asperger's syndrome. The third patient was also taking a high dose of levetiracetam, which is also known to cause psychiatric adverse effects, when PER was introduced. However, it is not possible to determine risk factors for suicidality due to PER from a small retrospective study such as ours. In Huber's series, the dose of PER taken in those patients with suicidal thoughts ranged between 4 and 10 mg, whereas our patients were taking comparatively low doses (4–8 mg) when problems were identified. The dose at which mood changes started to occur is not clear from these retrospective data, but Case 1 only took a dose of 4 mg, while in Case 3, psychiatric adverse effects emerged at a dose of 8 mg but did not resolve upon dose reduction. As with Huber's case studies, the addition of PER did not result in any significant improvement in seizure control in these 3 patients. This was an observational study, and treatment was neither randomized nor blinded, which could introduce bias with regard to efficacy data. However, our intention was to draw attention to psychiatric adverse effects, primarily suicidal ideation. In the pivotal RCTs, only one patient, who was taking PER 8 mg/day, reported suicidal ideation, and it was felt that there was no increase in suicidal ideation overall [6]. However, other psychiatric adverse effects including depression and aggression were more common in patients taking higher doses of PER than in those on placebo. Considering this, alongside our cases and those of Huber, we suggest that patients should be counseled regarding
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the potential for psychiatric adverse effects and suicidal ideation at the time of commencing treatment with PER. Disclosure This study was supported by an unrestricted educational grant from Eisai. HC, RM, and PNC have accepted conference hospitality and speaker fees from Eisai. Conflict of interest No conflict of interest to declare. References [1] Krauss GL, Serratosa JM, Villanueva V, Endziniene M, Hong Z, French J, et al. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology 2012;78:1408–15.
[2] French JA, Krauss GL, Biton V, Squillacote D, Yang H, Laurenza A, et al. Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304. Neurology 2012;79:589–96. [3] French JA, Krauss GL, Steinhoff BJ, Squillacote D, Yang H, Kumar D, et al. Evaluation of adjuvant perampanel in patients with refractory partial-onset seizures: results of randomized global phase III study 305. Epilepsia 2013;54:117–25. [4] Steinhoff BJ, Ben-Menachem E, Ryvlin P, Shorvon S, Kramer L, Satlin A, et al. Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: a pooled analysis of three phase III studies. Epilepsia 2013;54:1481–9. [5] Kramer LD, Satlin A, Krauss GL, French J, Perucca E, Ben-Menachem E, et al. Perampanel for adjunctive treatment of partial-onset seizures: a pooled dose–response analysis of phase III studies. Epilepsia 2014;55:423–31. [6] Rugg-Gunn F. Adverse effects and safety profile of perampanel: a review of pooled data. Epilepsia 2014;55(Suppl. 1):13–5. [7] Zaccara G, Giovannelli F, Cincotta M, Verrotti A, Grillo E. The adverse event profile of perampanel: meta-analysis of randomized controlled trials. Eur J Neurol 2013;20: 1204–11. [8] Huber B. Increased risk of suicidality on perampanel (Fycompa®)? Epilepsy Behav 2014;31:71–2.
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Clinical experience with perampanel: Focus on psychiatric adverse effects Helen Coyle a, Peter Clough a, Paul Cooper a,b, Rajiv Mohanraj a,b,⁎ a b
Greater Manchester Neurosciences Centre, Salford Royal Hospital, UK University of Manchester, Manchester, UK
a r t i c l e
i n f o
Article history: Received 29 August 2014 Revised 23 September 2014 Accepted 26 September 2014 Available online xxxx Keywords: Perampanel Suicidality Epilepsy
a b s t r a c t Background: Perampanel (PER) is a novel antiepileptic drug that inhibits the AMPA class of glutamate receptors. It has been available in the UK since September 2012. We undertook a retrospective analysis of efficacy and tolerability of PER in 47 patients with drug-refractory epilepsy attending a regional epilepsy service in the UK. Methods: Demographic and clinical data of patients with refractory epilepsy prescribed PER were collected by review of records. Efficacy, as measured by responder rates (N 50% reduction in seizure frequency), retention rates, and adverse effects, was analyzed. Results: Of the 47 patients prescribed PER, 39 (87%) had focal epilepsy, four (9%) had idiopathic generalized epilepsy, 3 (6%) had symptomatic generalized epilepsy, and 1 had unclassified epilepsy. Patients were taking a median of 2 AEDs (range: 1–5) when starting on PER. The median dose of PER was 8 mg (range: 2–12 mg). Thirteen (28%) patients were classed as responders, but no patients experienced sustained seizure freedom. Twenty-one (45%) patients had withdrawn from PER during the study period, with 16 (76%) of them withdrawing due to intolerable adverse effects, 4 due to inadequate seizure control, and 1 due to the combination of both. The most frequent adverse effects requiring withdrawal from PER were behavioral reactions including suicidal ideation (n = 2), aggressive behavior (n = 2), and both (n = 1). Conclusion: In our experience, PER had a retention rate of 55% and a responder rate of 28%. Psychiatric adverse effects, including suicidal ideation, were the most common reasons for withdrawal. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Perampanel (PER) is a noncompetitive α-amino-3-hydroxy-5methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist licensed for the treatment of partial-onset seizures. Efficacy in partialonset seizures was demonstrated in 3 randomized controlled trials [1–3]. In total, 1480 patients were randomized in the 3 pivotal studies. Overall, 50% responder rates were 28.5% (PER 4 mg); 35.3% (PER 8 mg) and 35.0% (PER 12 mg); all of which were statistically superior to the responder rate to placebo (19.3%) [4]. The proportions of patients in each randomized dose group who discontinued the trials prematurely were as follows: 11.3% (placebo), 14.4% (PER: 2 mg), 8.1% (PER: 4 mg), 14.8% (PER: 8 mg), and 24.3% (PER: 12 mg) [5]. The most frequently reported treatment emergent adverse effects from the 3 RCTs were dizziness, somnolence, fatigue, irritability, nausea, and falls, which were mild in severity in the majority of patients [6]. In the psychiatric domain, irritability, aggression, and depression were
⁎ Corresponding author at: Department of Neurology, Greater Manchester Neurosciences Centre, Salford Royal Hospital, Salford M6 8HD, UK. Tel.: +44 161 2064626; fax: +44 161 2062993. E-mail address: [email protected] (R. Mohanraj).
http://dx.doi.org/10.1016/j.yebeh.2014.09.072 1525-5050/© 2014 Elsevier Inc. All rights reserved.
more frequently reported by patients on PER compared with those taking placebo. Depression was seen in 2.4% of patients taking PER 12 mg/day and in 1.6% of patients taking placebo. Aggression was reported in 3.1% of patients on PER 12 mg/day and in 0.5% of patients taking placebo [4]. However, rates of depression and aggression in patients taking PER 4 mg/day were lower than those seen in the placebo group. A larger pooled analysis of adverse effects occurring in all patients treated with PER during its development, including phase 2 studies in epilepsy, as well as in Parkinson's disease, also identified dizziness, ataxia, somnolence, irritability, and weight gain as the most frequent adverse effects [7]. Although rates of depression appeared low in the subjects in the RCTs since licensing, concern has been raised regarding the potential of PER to cause suicidality, including a recent report of 3 patients experiencing suicidal ideation after the initiation of PER [8]. Perampanel has been available to be prescribed in the UK since September 2012. Data from regulatory RCTs of AEDs may not be matched by ‘real life’ clinical experience, as RCTs employ rigid dosing schedules and rarely permit significant alterations in concomitant AEDs. Data from open-label postmarketing studies of AEDs can complement those from regulatory trials and help inform the use of newer drugs. In addition, important safety information can emerge from such studies. We, therefore, examined the outcomes from our use of PER in patients attending the Regional Epilepsy Clinic at the Greater
194
H. Coyle et al. / Epilepsy & Behavior 41 (2014) 193–196
Manchester Neurosciences Centre, which serves a population of 3.2 million in the north west of England. 2. Methods All patients prescribed PER between September 2012 and March 2014 were identified from the clinical database at the Greater Manchester Neurosciences Centre. Epidemiological and clinical data were collected by review of case records. In addition to demographic details, data on seizure types and frequency, epilepsy classification, imaging and electroencephalography (EEG) results, details of previous and current AED treatment, doses and titration schedules of PER used, and treatment emergent adverse effects were collated on a spreadsheet for analysis. Responder rate, defined as the proportion of patients experiencing N50% reduction in seizure frequency, retention on treatment, and adverse effects leading to withdrawal, was examined.
Table 1 Demographic and clinical details of 47 patients prescribed perampanel. (JME = Juvenile Myoclonic Epilepsy; LGS = Lennox–Gastaut syndrome; SPS = simple partial seizures, CPS = complex partial seizures, GTCS = generalized tonic–clonic seizures, MJ = myoclonic jerks, AED = antiepileptic drugs). Age
Range Median Range Median
Duration of epilepsy Learning disability Number of previous AEDs Number of concomitant AEDs Epilepsy type n (%)
3. Results
Seizure types n (%)
AED withdrawn n (%)
7 (15%) 5 (11%) 2 (4%) 7 (15%) 4 (9%) 3 (6%) 1 (2%) 24 (51%) 12 (26%) 3 (6%) 3 (6%) 2 (4%) 1 (2%) 1 (2%) 1 (2%) 7 (47%) 4 (27%) 2 (13%) 1 (7%) 1 (7%)
Case 1 was a 52-year-old female who had undergone previous left temporal lobectomy for mesial temporal sclerosis. She had continued to experience monthly clusters of auras, and complex partial seizures recurred 7 years postsurgery. At the time of the initiation of PER, she was experiencing monthly clusters of simple partial seizures and 1 complex partial seizure per month. She was taking gabapentin and lacosamide, which were substituted with PER. She had a previous history of suicidality following temporal lobectomy with two drug overdoses,
Proportion continuing on perampanel
During the 19-month period between September 2012 and February 2014, PER was prescribed for 47 patients attending the epilepsy clinic. Twenty-four (51%) were female, and the median age was 31 years (range: 18–61). Learning disability was present in 8 (17%) patients. The median duration of epilepsy was 9 years (range: 0.5–36 years). Patients were taking a median dose of 2 AEDs (range: 1–5) when starting on PER. Details of previous AED treatment were available for 46 patients. Patients had been treated with a median dose of 8 AEDs prior to commencing PER (range: 2–11). Of the 47 patients prescribed PER, 39 (87%) had focal epilepsy, four (9%) had idiopathic generalized epilepsy, 3 (6%) had symptomatic generalized epilepsy, and 1 had unclassified epilepsy. The use of PER in patients with epilepsies other than focal epilepsy was outside its current product license in the EU. The majority had simple or complex partial seizures with or without secondary generalization. Another AED was replaced with PER in 15 patients, and PER was an add-on AED in the remaining 32 patients. A list of the AED withdrawn is included in Table 1. Demographic and clinical details of patients prescribed PER are summarized in Table 1. The initial dose of PER was 2 mg/day, which was titrated by 2 mg every 2 weeks in 37 (79%) patients. Three patients had dose increases made at 3-weekly intervals and one patient at monthly intervals. The average frequency of the most common seizure type in the 3 months leading up to the introduction of PER for each patient was compared with the seizure frequency in the best 3-month period during treatment with PER to identify responders (those with N 50% improvement in seizure frequency). Thirteen (28%) patients were classed as responders by this criterion. One patient became seizure-free for 4 months but had a relapse of seizure on reduction of dose due to adverse effects. Twenty-one (45%) patients had withdrawn from PER during the study period. The actuarial analysis of time to withdrawal is shown in Fig. 1. Sixteen (76%) of the 21 patients had withdrawn from PER because of intolerable adverse effects, 4 because of inadequate seizure control, and 1 because of the combination of both. Doses taken by responders and patients withdrawing due to intolerable treatment emergent adverse effects are shown in Fig. 2. The median dose in either group was 8 mg/day. Behavioral disturbance including suicidal ideation was the most common adverse effect requiring withdrawal from PER. Dizziness and somnolence were other commonly reported adverse effects (Table 2). Behavioral changes were ‘mood swings’ and ‘irritability’ (6 patients) and aggression (3 patients) as well as thoughts of self-harm in one patient and actual self-harm in another patient. Aggressive behavior took the form of verbal aggression in 2 patients and verbal aggression and physical aggression in the case of one patient. Details of 3 patients who developed suicidal ideation are described below.
Range Median Range Median Focal epilepsies Cryptogenic focal epilepsy Hippocampal sclerosis (4 postepilepsy surgery patients) Cortical malformation (1 patient with tuberous sclerosis) Acquired brain injury (trauma/encephalitis) Low-grade tumor Generalized epilepsies Idiopathic generalized epilepsy (3 patients with JME) Symptomatic generalized epilepsy (1 patient with LGS) Unclassified epilepsy SPSs/CPSs SPSs/CPSs + GTCSs GTCSs GTCSs + MJs GTCSs + MJs + absences GTCSs + absences MJs MJs + atonic Retigabine Lacosamide Zonisamide Levetiracetam Valproate
18–63 years 31 years 0.5–36 years 9 years 8 2 to 11 3 (mean: 8) 1 to 5 2 39 (83%) 15 (32%) 10 (21%)
10 0 90 80 70 60 50 40 30 20 10
0 Weeks 0
4
8
12
16
20
24
28
32
36
40
44
48
52
No. at risk 47
46
43
39
37
30
26
17
13
8
5
4
2
1
No. 1 withdrawn
0
3
4
2
3
0
2
1
2
2
0
1
0
Fig. 1. Retention on treatment with PER in 47 patients.
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in situ. He was experiencing 4 generalized tonic–clonic seizures per month, and the frequency of complex partial seizures was unknown as he spent much time unsupervised. PER had been introduced at a rate of 2 mg per week up to a maximum dose of 8 mg daily. Perampanel was initially well tolerated (taken for a total of 225 days), but once increased to 8 mg daily, marked behavioral changes were noted. Intermittent confusion, aggression, and suicidal ideation were observed by family members ultimately requiring admission and treatment with benzodiazepines. This patient had no previous history of aggression or psychosis. Symptoms resolved upon withdrawal from PER.
12 mg
10 mg
8 mg
6 mg
4 mg
2 mg
4. Discussion
0 mg Maximum doses taken by 13 patients withdrawing due to intolerable adverse effects
Maintenance doses taken by 13 patients who experienced >50% seizure reduction
Fig. 2. Doses taken by responders and those withdrawing from PER due to intolerable adverse effects. The median dose was 8 mg in either group.
but no psychotic features had been identified. Perampanel was titrated at 2 mg every two weeks up to a dose of 4 mg daily. Shortly after PER was introduced, her mood was described as ‘extremely low’. She left her home at night having left a note for her husband with the intention of drowning herself in a canal. Fortunately, a passerby intervened and talked her out of proceeding. Once reported, PER was withdrawn, and her mood improved. She had taken PER for a total of 138 days with no reported reduction in seizure frequency. Case 2 was a 29-year-old female with a 28-year history of difficultto-treat focal epilepsy and had tried at least 10 previous antiepileptic drugs. She declined presurgical investigations for treatment of her left MTS. She also had a diagnosis of Asperger's syndrome and was thought to be experiencing some nonepileptic seizures. There was no documented psychiatric history. At the time of introduction of PER, she was taking oxcarbazepine and clobazam. Seizure frequency at the time of introduction was up to 10 complex and simple partial seizures per day. Perampanel was introduced at 2 mg every 2 weeks up to a dose of 6 mg daily. A slight reduction in the frequency of complex partial seizures was noted. Her family noticed that she was spending increased amounts of time alone in her bedroom, crying inappropriately. This culminated with her taking an overdose of paracetamol. She took PER for 130 days and had withdrawn from the drug following the overdose. Her mood stabilized following withdrawal, and she was started on fluoxetine. Case 3 was a 51-year-old male with drug-refractory focal epilepsy. He also had a history of nonepileptic seizures. He was taking retigabine (which was stopped), clobazam, and levetiracetam (4000 mg daily) at the time PER was introduced. He also had a vagal nerve stimulator Table 2 Adverse effects reported by 17 patients withdrawing from PER due to intolerable treatment emergent adverse effects. Some patients experienced more than one adverse effect. Mood/behavioral changea Dizziness Sedation Slurred speech Confusion Unsteadiness Sensory symptoms Double vision Weight gain Hallucination Headache Memory Skin irritation a
Includes 3 patients with suicidal ideation.
12 9 7 5 4 4 3 2 2 1 1 1 1
Data from randomized controlled trials of AEDs alone are inadequate to inform the most appropriate dosing and titration schedules of AEDs in clinical practice because of the rigid treatment protocols used in RCTs. Moreover, regulatory RCTs are short-term studies and may miss important treatment emergent adverse effects. Postmarketing review of the use of AEDs can help identify optimum dosing and titration schedules, as well as previously unreported treatment emergent adverse effects. In our series, the majority of patients had refractory focal epilepsy, but PER was also used off license in 8 patients with generalized and unclassified epilepsy. Overall, the responder rate was 28% which compares favorably with that observed in the pivotal RCTs. However, no patient experienced sustained seizure freedom. Retrospective observational studies have an inherent bias towards overestimating benefit due to regression to the mean. This needs to be factored into interpretation of efficacy data from this study. A longer period of follow-up will be required to identify true efficacy in improving seizure control. The withdrawal rate of PER was 45%, which is higher than that reported in the regulatory trials. The FDA lists ‘serious psychiatric and behavioral reactions’ as a potential adverse effect of PER. Aggression, both physical and verbal, was displayed by 3 patients in our cohort. The most striking finding was the high rates of behavioral and mood-related side effects requiring withdrawal from PER. In particular, 3 patients experienced significant suicidal ideation. As in the cohort of patients described by Huber, all 3 patients reporting suicidal ideation on treatment with PER had refractory focal epilepsy [8], and one had a previous history of depression and suicide attempt. The other 2 patients were both thought to also have nonepileptic attacks in addition to epilepsy, and one also had a diagnosis of Asperger's syndrome. The third patient was also taking a high dose of levetiracetam, which is also known to cause psychiatric adverse effects, when PER was introduced. However, it is not possible to determine risk factors for suicidality due to PER from a small retrospective study such as ours. In Huber's series, the dose of PER taken in those patients with suicidal thoughts ranged between 4 and 10 mg, whereas our patients were taking comparatively low doses (4–8 mg) when problems were identified. The dose at which mood changes started to occur is not clear from these retrospective data, but Case 1 only took a dose of 4 mg, while in Case 3, psychiatric adverse effects emerged at a dose of 8 mg but did not resolve upon dose reduction. As with Huber's case studies, the addition of PER did not result in any significant improvement in seizure control in these 3 patients. This was an observational study, and treatment was neither randomized nor blinded, which could introduce bias with regard to efficacy data. However, our intention was to draw attention to psychiatric adverse effects, primarily suicidal ideation. In the pivotal RCTs, only one patient, who was taking PER 8 mg/day, reported suicidal ideation, and it was felt that there was no increase in suicidal ideation overall [6]. However, other psychiatric adverse effects including depression and aggression were more common in patients taking higher doses of PER than in those on placebo. Considering this, alongside our cases and those of Huber, we suggest that patients should be counseled regarding
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the potential for psychiatric adverse effects and suicidal ideation at the time of commencing treatment with PER. Disclosure This study was supported by an unrestricted educational grant from Eisai. HC, RM, and PNC have accepted conference hospitality and speaker fees from Eisai. Conflict of interest No conflict of interest to declare. References [1] Krauss GL, Serratosa JM, Villanueva V, Endziniene M, Hong Z, French J, et al. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology 2012;78:1408–15.
[2] French JA, Krauss GL, Biton V, Squillacote D, Yang H, Laurenza A, et al. Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304. Neurology 2012;79:589–96. [3] French JA, Krauss GL, Steinhoff BJ, Squillacote D, Yang H, Kumar D, et al. Evaluation of adjuvant perampanel in patients with refractory partial-onset seizures: results of randomized global phase III study 305. Epilepsia 2013;54:117–25. [4] Steinhoff BJ, Ben-Menachem E, Ryvlin P, Shorvon S, Kramer L, Satlin A, et al. Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: a pooled analysis of three phase III studies. Epilepsia 2013;54:1481–9. [5] Kramer LD, Satlin A, Krauss GL, French J, Perucca E, Ben-Menachem E, et al. Perampanel for adjunctive treatment of partial-onset seizures: a pooled dose–response analysis of phase III studies. Epilepsia 2014;55:423–31. [6] Rugg-Gunn F. Adverse effects and safety profile of perampanel: a review of pooled data. Epilepsia 2014;55(Suppl. 1):13–5. [7] Zaccara G, Giovannelli F, Cincotta M, Verrotti A, Grillo E. The adverse event profile of perampanel: meta-analysis of randomized controlled trials. Eur J Neurol 2013;20: 1204–11. [8] Huber B. Increased risk of suicidality on perampanel (Fycompa®)? Epilepsy Behav 2014;31:71–2.
