Perampanel for Focal Epilepsy

1. Perampanel
for
Focal Epilepsy
Ade Wijaya, MD – November 2019

2. Rudzinski LA, Vélez-Ruiz NJ, Gedzelman ER, Mauricio EA, Shih JJ, Karakis I. New antiepileptic drugs: focus on ezogabine, clobazam, and perampanel. Journal of Investigative Medicine. 2016 Aug 1;64(6):1087-101.

3. Perampanel
• A selective non-competitive AMPA (a-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid) receptor antagonist
• Adjunctive therapy for focal seizures with or without secondarily
generalized seizures in patients >12 years with epilepsy
• Initial dose: 2 mg/day can be titrated to optimal dose with maxium dose 12
mg/day
• Once daily
Trinka E, Steinhoff BJ, Nikanorova M, Brodie MJ. Perampanel for focal epilepsy: insights from early clinical experience. Acta Neurologica Scandinavica. 2016 Mar;133(3):160-72.

4. Pharmacokinetics
• Rapid and complete absorption with negligible first-pass metabolism.
• The median time to reach peak concentration varies between 0.5 to 2.5 hours
fasting (delayed by two to three hours when taken with food).
• Peak plasma concentration is reached in approximately one hour (decreased
by 40% when taken with food).
• It is worth noting that the extent of absorption is not affected by food
Fycompa (perampanel) prescribing information. Woodcliff Lake, New Jersey: Eisai R&D Management (Eisai Ltd.); 2016.
Franco V, Crema F, Iudice A, et al. Novel treatment options for epilepsy: focus on perampanel.Pharmacol Res. 2013;70(1):35–40.

5. Pharmacokinetics
• 95% to 96% protein-bound in the concentration range of 20 ng/mL to 2,000 ng/mL
• Mediated by cytochrome P450 (CYP) 3A4/5, CYP1A2, and CYP2B6, perampanel is
metabolized extensively through oxidation followed by glucuronidation
• Approximately 30% and 70% of oxidative and conjugated metabolites being
found in urine and feces, respectively
Fycompa (perampanel) prescribing information. Woodcliff Lake, New Jersey: Eisai R&D Management (Eisai Ltd.); 2016.
Franco V, Crema F, Iudice A, et al. Novel treatment options for epilepsy: focus on perampanel.Pharmacol Res. 2013;70(1):35–40.

6. Pregnancy and Lactation
• pregnancy category C, indicating it may cause fetal harm based on animal
studies; however, due to the lack of well-controlled studies in pregnant
women, the risk is uncertain.
• Administration of perampanel during organogenesis in rats and rabbits
resulted in diverticulum of the intestine, reduced fetal body weight, and
embryo lethality
• Caution is advised when considering the use of perampanel in women who
are of child-bearing age or who may be pregnant or nursing
Fycompa (perampanel) prescribing information. Woodcliff Lake, New Jersey: Eisai R&D Management (Eisai Ltd.); 2016.
Fycompa (perampanel) product monograph. Mississauga, Ontario: Eisai Ltd; 2013

7. Adverse Effects
• Dizziness (10.0–47.9%) and somnolence (9.3–18.2%)] and were dose
dependent.
• Headache, fall, irritability, ataxia, and fatigue also occurred in ≥10% of
patients in any treatment group.
• Aggression, ataxia, blurred vision, convulsion, dizziness, dysarthria, fatigue,
headache, hypersomnia, somnolence, and vertigo most frequently resulted in
the discontinuation, reduction, or interruption of perampanel dosing
Krauss GL, perucca E, ben-Menachem E, et al. Longterm safety of perampanel and seizure outcomes in refractory partial-onset seizures and secondarily generalized seizures: results from phase III extension study 307. Epilepsia 2014;55:1058–68.

8. Perampanel and The Elderly
• The efficacy and tolerability in elderly patients was good
• Slowet titration rate (less than 2 mg per 2 weeks)
Trinka E, Steinhoff BJ, Nikanorova M, Brodie MJ. Perampanel for focal epilepsy: insights from early clinical experience. Acta Neurologica Scandinavica. 2016 Mar;133(3):160-72.

9. Perampanel and The Adolescents
• Behavioral problems
• Slower titration rate (every 3 or 4 weeks)
Trinka E, Steinhoff BJ, Nikanorova M, Brodie MJ. Perampanel for focal epilepsy: insights from early clinical experience. Acta Neurologica Scandinavica. 2016 Mar;133(3):160-72.

10. Drug Interactions
• Enzyme-inducing antiepileptic agents such as carbamazepine,
oxcarbazepine, and phenytoin – increased perampanel clearance leading to a
reduction of serum levels of up to 30%
• The concomitant use of central nervous system depressants such as alcohol,
benzodiazepines, narcotics, barbiturates, and sedating antihistamines may
cause additive central nervous system depression
• Perampanel can reduce levonorgestrel serum levels by 40%, thus rendering
contraceptives containing levonorgestrel less effective.
LAURENZA A, FERRY J, HUSSEIN Z. Population pharmacokinetics and pharmacodynamics of perampanel: a pooled analysis of three phase III trials. Epilepsy Curr 2012;12(Suppl 1):216–7
Fycompa (perampanel) prescribing information. Woodcliff Lake, New Jersey: Eisai R&D Management (Eisai Ltd.); 2016.
Fycompa (perampanel) product monograph. Mississauga, Ontario: Eisai Ltd; 2013

11. Dose Modifications
• Coadministration with enzyme inducing antiepileptic drugs: initial dose 4
mg / day oncrease by 2 mg in weekly interval
• Hepatic impairment: mild (maximum 6 mg/day), moderate (maximum 4
mg/day), severe (not recommended)
• Not recommended for patients with severe renal impairmen or hemodialysis
Emedicine.com

12. Summary
• Safe and effective adjunctive treatment option for patients with focal epilepsy
• The most frequently reported adverse events are dizziness, fatigue, and
somnolence
• Careful monitoring of the patient’s clinical status, concomitant medications,
and comorbid conditions is essential when initiating and titrating
perampanel

13. THANK YOU