Perampanel is a first-in-class antagonist of postsynaptic AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid) glutamate receptors. Glutamate is the main excitatory neurotransmitter in the central nervous system and appears to play a significant role in the initiation and spread of seizure activity. Perampanel is currently subsidised on the Pharmaceutical Benefits Scheme (PBS) for the treatment of partial epileptic seizures. The Pharmaceutical Benefits Advisory Committee (PBAC) recently made a positive recommendation to also list perampanel for the treatment of primary generalised tonic-clonic (PGTC) seizures in patients with idiopathic generalised epilepsy.

Efficacy in the management of PGTC seizures was demonstrated in a double-blind, randomised clinical trial. Perampanel reduced median PGTC seizure frequency per 28 days by 76.5% compared to 38.4% for placebo. During the 13-week maintenance period, 30.9% of patients in the perampanel group achieved freedom from PGTC seizures compared to 12.3% of the placebo group.

As perampanel is not recommended for monotherapy, drug interactions are of particular importance. Perampanel is extensively metabolised, primarily by cytochrome P450 (CYP) 3A4. Antiepileptic drugs that induce this enzyme include carbamazepine, oxcarbazepine, phenytoin, and topiramate. Coadministration of these agents with perampanel may increase perampanel clearance and reduce plasma levels. Conversely, strong inhibitors of CYP 3A4 such as clarithromycin and diltiazem may increase perampanel plasma concentrations.

Most adverse effects appear to be dose-related and include drowsiness, dizziness, weight gain, and paraesthesia. Psychiatric and behavioural effects were commonly reported during clinical trials. These reactions may be serious and include anxiety, aggression, hostility, confusion, euphoria, and paranoia. Caution should be exercised in patients with pre-existing psychiatric disorders, although these effects can occur in patients with no history of psychiatric illness. Patients should avoid alcohol as it produces additive sedation and can worsen psychiatric and behavioural reactions.

References:

  1. Chapman AG. Glutamate and epilepsy. J Nutr. 2000; 130(4): 10435-55.
  2. French JA, Krauss GL, Wechsler RT, Wang XF, DiVentura B, Brandt C, et al. Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy. Neurology. 2015; 85(11): 950-7.
  3. Fycompa® (perampanel) Australian approved product information. Melbourne: Eisai Australia Pty Ltd. Approved May 2016.

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