Fycompa  / perampanel

1. Fycompa / perampanel Manufacturer: Eisai Group FDA Approval Date: 10/2012

2. Fycompa / perampanelClinical Application • Indications: • Adjunctive treatment of partial-onset seizures with or without secondarily generalized seizures in epileptic patients aged 12 years and older • Place in therapy: • Patients whose seizure activity is not adequately controlled on 2-3 antiepileptic medications

3. Fycompa / perampanelClinical Application • Black Box Warning: • Neuropsychiatric disorders: • Dose-related serious and/or life-threatening neuropsychiatric events (including aggression, anger, homicidal thoughts, hostility, and irritability) have been reported most often in the first 6 weeks of treatment (occurs regardless of preexisting psychiatric disease). • Monitor initially, and throughout dose titration

4. Fycompa / perampanelClinical Application • Warnings: • Suicidal ideation: analysis of trials involving various antiepileptics showed an increased risk of suicidal thoughts/behavior; risk observed as early as 1 week after initiation • CNS effects: dizziness, fatigue, gait disturbances, and somnolence may occur during therapy; caution with driving or performing tasks which require alertness • Precautions: • CNS depressants: concomitant use with CNS depression my increase the risk of CNS depression • Fall risk: use with extreme caution in patients who are at risk of falls • Withdrawal: avoid abrupt discontinuation due to possible increased risk of seizures

5. Fycompa / perampanelClinical Application • Pregnancy: • Category C • Lactation: • Excretion in breast milk unknown; use caution

6. Fycompa / perampanelDrug Facts • Pharmacology • Alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptor antagonist • Non-competitive and highly selective • Attenuates neuronal excitability that characterizes epileptic brain regions by inhibiting AMPA glutamate receptors on postsynaptic neurons

7. Fycompa / perampanelDrug Facts • Pharmacokinetics • A – Tpeak: 0.5-2.5 hours, rapid and complete • D – Protein binding: ~95% • M – Hepatic, extensive CYP3A4/5 primary oxidation, then glucuronidation • E – T ½: 105 hours; Feces (48%); urine (22%)

8. Fycompa / perampanelDrug Interactions • Drug Interactions – Object Drugs • Aripiprazole (serum concentration) • Azelastine (CNS depressant effects) • Buprenorphine (CNS depressant effects) • Contraceptives: progestins (serum concentration) • Methadone (CNS depressant effects) • Mirtazapine (CNS depressant effects) • Oxcarbazepine (serum concentration) • Zolpidem (CNS depressant effects)

9. Fycompa / perampanelDrug Interactions • Drug Interactions – Precipitant Drugs • Ethyl alcohol (negative CNS effects) • Carbamazepine (serum concentration) • Phenytoin (serum concentration) • Oxcarbazepine (serum concentration)

10. Fycompa / perampanelAdverse Effects • Common Adverse Effects

11. Fycompa / perampanelMonitoring Parameters • Efficacy Monitoring • Decrease in seizure frequency and/or duration • Toxicity Monitoring • Suicidality • Weight gain • Somnolence

12. Fycompa / perampanelPrescription Information • Dosing - Initial • NOT receiving enzyme-inducing AED: 2 mg once daily at bedtime • Receiving enzyme-inducing AED: 4 mg once daily at bedtime • Dosing - Usual • May increase dose by 2 mg at weekly intervals depending on response and tolerability • Recommended dose: 8-12 mg once daily at bedtime • Dosing - Max • Max dose: 12 mg once daily at bedtime

13. Fycompa / perampanelLiterature Review: Study 304 • Randomized double-blind, multicenter, placebo- and active-controlled • 4 phases of trial • Baseline: 6 weeks • Titration: 6 weeks • Maintenance: 13 weeks • Follow-up: 4 weeks French JA, et al. Neurology. 2012;79(6):589-96

14. Fycompa / perampanelLiterature Review: Study 304 • 388 patients were randomized 1:1:1 to receive once-daily perampanel 8 mg, 12 mg, or placebo • Patients could be on stable doses of > 3 approved antiepileptic drugs (AEDs) French JA, et al. Neurology. 2012;79(6):589-96

15. Fycompa / perampanelLiterature Review: Study 304 • Most common concomitant AEDs French JA, et al. Neurology. 2012;79(6):589-96

16. Fycompa / perampanelLiterature Review: Study 304 • Inclusion criteria • ≥ 12 years of age • Diagnosed with partial-onset seizures with or without 2°generalization • Failed ≥ 2 AEDs • ≥ 5 partial seizures during baseline period French JA, et al. Neurology. 2012;79(6):589-96

17. Fycompa / perampanelLiterature Review: Study 304 • Primary endpoints French JA, et al. Neurology. 2012;79(6):589-96

18. Fycompa / perampanelLiterature Review: Study 304 • Conclusions • Once-daily, adjunctive perampanel at 8 mg or 12 mg improved seizure control in patients refractory to ≥ 3 approved AEDs • Doses of 8 mg and 12 mg were safe with acceptable tolerability • The efficacy of perampanel in less refractory patients and in other types of seizure syndromes is currently unknown • Targeting AMPA receptors may provide a new mechanism of action to alleviate frequent seizure activity French JA, et al. Neurology. 2012;79(6):589-96

19. Fycompa / perampanelSummary • Fycompa, perampanel, is a novel antiepileptic medication for the adjunctive treatment of partial-onset seizures with or without secondarily generalized seizures in epileptic patients aged 12 years and older • Perampanel is a non-competitive and highly selective glutamatergic AMPA receptor antagonist that reduces neuronal hyperexcitation associated with seizure activity • Use in severe hepatic or renal dysfunction has not been studied and is not recommended • The most common adverse event associated with use of perampanel is somnolence

20. Fycompa / perampanelReferences • http://www.Fycompa.eu • Fycompa package insert. Eisai Group. Oct. 2012. • French JA, Krauss GL, Biton V, Squillacote D, Yang H, Laurenza A, Kumar D, Rogawski MA. Adjunctive perampanel for refractory partial-onset seizures. Neurology 2012;79(6):589-96.