Highlights
- •This report analyzed the safety of perampanel in different disorders and doses with a meta-analysis.
- •Dizziness, ataxia, fatigue, and somnolence showed a clear dose-response relationship.
- •Psychiatric adverse events significantly associated with perampanel occurred more frequently in patients with epilepsy than in other diseases.
- •Dose discontinuation rates due to adverse events were lower in patients with epilepsy patients with epilepsy than in patients with other disorders.
Abstract
Purpose
To investigate the safety of perampanel in different disorders and doses.
Methods
Embase, the Cochrane Library, Medline, and ClinicalTrials.gov were searched from inception
to July 2022 for randomized controlled trials (RCTs). The meta-analysis was performed
by using Review Manager 5.3 and R 4.2.1 software.
Results
A total of 17 RCTs with 5711 subjects were included in the final analysis. The double-blind
treatment phase was from 12 weeks to 48 weeks. Our results showed that 11 adverse
events (aggression, ataxia, balance disorder, dizziness, fall, fatigue, irritability,
rash, somnolence, vertigo, and weight increase) were statistically significantly associated
with perampanel, and 4 of them (ataxia, dizziness, fatigue, and somnolence) showed
a clear dose-response relationship. Psychiatric adverse events occurred most frequently
among serious treatment-emergent adverse events (TEAEs). At 8 mg/day, seven adverse
events (aggression, balance disorder, dizziness, fatigue, irritability, vertigo, and
weight increase) occurred more frequently in patients with epilepsy than in patients
with other disorders, whereas dose discontinuation rates due to adverse events were
lower in patients with epilepsy than in patients with other disorders.
Conclusion
The safety profile of perampanel is dependent on diseases and dose. The risk of adverse
events was statistically significantly higher, with doses exceeding 4 mg/day. Despite
a higher risk of adverse events, patients with epilepsy had a lower perampanel discontinuation
rate than patients with other disorders.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Seizure - European Journal of EpilepsyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options.Pharmacol Rev. 2020; 72: 606-638https://doi.org/10.1124/pr.120.019539
- Epilepsy in adults.The Lancet. 2019; 393: 689-701https://doi.org/10.1016/S0140-6736(18)32596-0
- What has been the impact of new drug treatments on epilepsy?.Curr Opin Neurol. 2020; 33: 185-190https://doi.org/10.1097/WCO.0000000000000803
- Modulation of AMPA Receptor Gating by the Anticonvulsant Drug, Perampanel.Acs Med Chem Lett. 2018; 10: 237-242https://doi.org/10.1021/acsmedchemlett.8b00322
- Ionotropic Glutamate Receptors in Epilepsy: A Review Focusing on AMPA and NMDA Receptors.Biomolecules. 2020; 10: 464https://doi.org/10.3390/biom10030464
- Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy.Neurology. 2018; 91: 82-90https://doi.org/10.1212/WNL.0000000000005756
FDA. Fycompa®(perampanel): highlights of prescribing information, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202834s016,208277s004lbl.pdf; 2019 [accessed 15 September 2022].
EMA. Fycompa®(perampanel): summary of product characteristics, https://www.ema.europa.eu/en/documents/product-information/fycompa-epar-product-information_en.pdf; 2022 [accessed 15 September 2022].
- Randomized phase 2 study of perampanel for sporadic amyotrophic lateral sclerosis.J Neurol. 2022; 269: 885-896https://doi.org/10.1007/s00415-021-10670-y
- Safety and efficacy of perampanel in advanced Parkinson's disease: A randomized, placebo-controlled study.Movement Disord. 2010; 25 (896-05)https://doi.org/10.1002/mds.22974
- Perampanel, an AMPA antagonist, found to have no benefit in reducing “off” time in Parkinson's disease.Movement Disord. 2012; 27: 284-288
- Perampanel in Parkinson disease fluctuations: a double-blind randomized trial with placebo and entacapone.Clin Neuropharmacol. 2012; 35: 15-20https://doi.org/10.1097/WNF.0b013e318241520b
- Efficacy and safety of perampanel in Parkinson's disease. A systematic review with meta-analysis.J Neurol. 2018; 265: 733-740https://doi.org/10.1007/s00415-017-8681-y
- The adverse event profile of perampanel: meta-analysis of randomized controlled trials.Eur J Neurol. 2013; 20: 1204-1211https://doi.org/10.1111/ene.12170
- The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.BMJ. 2021; 372: n71https://doi.org/10.1136/bmj.n71
- The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.BMJ. 2011; 343: d5928https://doi.org/10.1136/bmj.d5928
- Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304.Neurology. 2012; 79: 589-596https://doi.org/10.1212/WNL.0b013e3182635735
- Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: Results of randomized global phase III study 305.Epilepsia. 2013; 54: 117-125https://doi.org/10.1111/j.1528-1167.2012.03638.x
- Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy.Neurology. 2015; 85: 950-957https://doi.org/10.1212/WNL.0000000000001930
- Tolerability and safety of perampanel: two randomized dose-escalation studies.Acta Neurol Scand. 2012; 125: 8-15https://doi.org/10.1111/j.1600-0404.2011.01588.x
- Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures.Neurology. 2012; 78: 1408-1415https://doi.org/10.1212/WNL.0b013e318254473a
- Cognitive effects of adjunctive perampanel for partial-onset seizures: A randomized trial.Epilepsia. 2016; 57: 243-251https://doi.org/10.1111/epi.13279
- Adjunctive perampanel in partial-onset seizures: Asia-Pacific, randomized phase III study.Acta Neurol Scand. 2018; 137: 392-399https://doi.org/10.1111/ane.12883
The National Institutes of Health Clinical trial registry. An evaluation of the efficacy and safety of E2007 in patients with painful diabetic neuropathy, https://clinicaltrials.gov/ct2/show/NCT00505284; 2013 [accessed 15 September 2022].
The National Institutes of Health Clinical trial registry. Efficacy and safety of E2007 in migraine prophylaxis, https://clinicaltrials.gov/ct2/show/NCT00154063; 2015 [accessed 15 September 2022].
The National Institutes of Health Clinical trial registry. A study to explore the safety and tolerability of dose of E2007 up to a maximum of 8 mg in patients with Parkinson's disease who experience end-of-dose wearing off motor fluctuations, https://clinicaltrials.gov/ct2/show/NCT00165789; 2015 [accessed 15 September 2022].
The National Institutes of Health Clinical trial registry. Study of perampanel as adjunctive treatment for inadequately controlled seizures associated with Lennox-Gastaut Syndrome, https://clinicaltrials.gov/ct2/show/NCT02834793; 2022 [accessed 15 September 2022].
- Adjunctive perampanel in adolescents with inadequately controlled partial-onset seizures: Arandomized study evaluating behavior, efficacy, and safety.Epilepsia. 2016; 57: 1120-1129https://doi.org/10.1111/epi.13417
- Efficacy, safety, and tolerability of perampanel in Asian and non-Asian patients with epilepsy.Epilepsia. 2019; 60: 37-46https://doi.org/10.1111/epi.14642
- The adverse event profile of pregabalin: A systematic review and meta-analysis of randomized controlled trials.Epilepsia. 2011; 52: 826-836https://doi.org/10.1111/j.1528-1167.2010.02966.x
- The adverse event profile of lacosamide: A systematic review and meta-analysis of randomized controlled trials.Epilepsia. 2013; 54: 66-74https://doi.org/10.1111/j.1528-1167.2012.03589.x
- The adverse event profile of zonisamide: a meta-analysis.Acta Neurol Scand. 2013; 128: 297-304https://doi.org/10.1111/ane.12147
- The adverse event profile of levetiracetam: A meta-analysis on children and adults.Seizure. 2015; 31: 49-55https://doi.org/10.1016/j.seizure.2015.07.004
- Systematic Review and Meta-Analysis of the Efficacy and Safety of Perampanel in the Treatment of Partial-Onset Epilepsy.Cns Drugs. 2013; 27: 817-827https://doi.org/10.1007/s40263-013-0091-9
- Sleep quality and daytime sleepiness in patients treated with adjunctive perampanel for focal seizures.Epilepsy Behav. 2016; 63: 57-62https://doi.org/10.1016/j.yebeh.2016.08.004
- Effect of adjunctive perampanel on the quality of sleep and daytime somnolence in patients with epilepsy.Epilepsy Behav Case Rep. 2016; 7: 13-15https://doi.org/10.1016/j.ebcr.2016.10.002
- Effects of adjunctive perampanel on sleep quality, daytime somnolence and cognition in refractory focal epilepsy: further data.Epilepsy Behav. 2017; 67: 137-138https://doi.org/10.1016/j.yebeh.2016.10.033
- Perampanel effect on sleep architecture in patients with epilepsy.Seizure. 2020; 76: 137-142https://doi.org/10.1016/j.seizure.2020.01.021
- Insomnia is less prevalent and less severe, independent of depressive symptoms, in patients with epilepsy treated with perampanel as an adjuvant.Epilepsy Behav. 2020; 112107384https://doi.org/10.1016/j.yebeh.2020.107384
- Does a psychiatric history play a role in the development of psychiatric adverse events to perampanel… and to placebo?.Epilepsy Behav. 2021; 125108380https://doi.org/10.1016/j.yebeh.2021.108380
- Cerebrospinal fluid glutamate concentration correlates with impulsive aggression in human subjects.J Psychiatr Res. 2013; 47: 1247-1253https://doi.org/10.1016/j.jpsychires.2013.05.001
- Pharmacokinetics and brain uptake study of novel AMPA receptor antagonist perampanel in SD rats using a validated UHPLC-QTOF-MS method.J Pharmaceut Biomed. 2018; 149: 234-241https://doi.org/10.1016/j.jpba.2017.11.008
- Analysis of falls in patients with epilepsy enrolled in the perampanel phase III randomized double-blind studies.Epilepsia. 2017; 58: 51-59https://doi.org/10.1111/epi.13600
- Impact of Antiseizure Medications on Appetite and Weight in Children.Pediatr Drugs. 2022; 24: 335-363https://doi.org/10.1007/s40272-022-00505-2
- Perampanel-induced weight gain depends on level of intellectual disability and its serum concentration.Epilepsy Res. 2019; 152: 1-6https://doi.org/10.1016/j.eplepsyres.2019.02.011
- Glucagon-Like Peptide-1 Receptor Activation in the Nucleus Accumbens Core Suppresses Feeding by Increasing Glutamatergic AMPA/Kainate Signaling.J Neurosci. 2014; 34: 6985-6992https://doi.org/10.1523/JNEUROSCI.0115-14.2014
- Valproic acid after five decades of use in epilepsy: time to reconsider the indications of a time-honoured drug.Lancet Neurol. 2016; 15: 210-218https://doi.org/10.1016/S1474-4422(15)00314-2
- Lamotrigine add-on for drug-resistant partial epilepsy.Cochrane Database Syst Rev. 2016; 2016 (CD001909)https://doi.org/10.1002/14651858.CD001909.pub2
- The clinical pharmacology profile of the new antiepileptic drug perampanel: A novel noncompetitive AMPA receptor antagonist.Epilepsia. 2015; 56: 12-27https://doi.org/10.1111/epi.12865
- Perampanel efficacy and tolerability with enzyme-inducing AEDs in patients with epilepsy.Neurology. 2015; 84: 1972-1980https://doi.org/10.1212/WNL.0000000000001558
- Perampanel monotherapy for the treatment of epilepsy: Clinical trial and real-world evidence.Epilepsy Behav. 2022; 136108885https://doi.org/10.1016/j.yebeh.2022.108885
Article info
Publication history
Accepted:
January 19,
2023
Received in revised form:
January 17,
2023
Received:
September 22,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
