perampanel and Epilepsy--Complex-Partial

Complex-partial seizures are frequently resistant to antiepileptic therapy. Two new medications with mechanisms of action novel within the antiepileptic class have recently received approval for the adjunctive treatment of partial (focal) seizures.. A Medline search was conducted to identify preclinical and clinical studies of ezogabine and perampanel. This was supplemented with additional articles obtained from online sources and information provided by the FDA and the manufacturers. The focus of this review is on the safety profiles of ezogabine (retigabine), a novel antiepileptic that targets voltage-gated potassium channels, and perampanel, a noncompetitive α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate glutamate receptor antagonist.. Central nervous system effects are predominant within the adverse event profiles of both ezogabine and perampanel. In addition, ezogabine exerts its inhibitory effects on potassium channels in the urogenital tract potentially resulting in urinary retention and related outcomes. Recent reports of blue discoloration of the skin and in the retinas of long-term ezogabine users have surfaced. Both drugs have demonstrated the ability to induce neuropsychiatric symptoms. Though both are welcome additions to the antiepileptic drug class, additional monitoring, appropriate counseling, and careful selection of patients are warranted to minimize adverse events.

Topics: Anticonvulsants; Carbamates; Drug Monitoring; Drug Resistance; Epilepsy, Complex Partial; Humans; Nitriles; Patient Selection; Phenylenediamines; Potassium Channels, Voltage-Gated; Pyridones; Receptors, AMPA

Perampanel is a novel antiepileptic drug (AED) used as adjunctive therapy in adolescents and adults with partial-onset seizures (with or without secondarily generalized seizures). It is a selective, noncompetitive antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors on post-synaptic neurons, and is the first in this new class of AED known as AMPA receptor antagonists. In three randomized, double-blind, placebo-controlled, phase III trials in adolescent and adult patients with refractory partial-onset seizures, once-daily administration of perampanel 4, 8 and 12 mg/day (6-week titration phase followed by 13-week maintenance phase), as adjunctive therapy with one to three AEDs, was statistically superior to adjunctive placebo in achieving the key efficacy endpoints of the median percentage change from baseline in seizure frequency and/or the proportion of patients with a ≥50 % reduction in seizure frequency relative to baseline. Adverse events were usually mild or moderate in severity and the most frequent treatment-emergent events reported among perampanel recipients were CNS-related, such as dizziness, somnolence, headache and fatigue. Interim data from a large extension study (16-week blinded conversion period followed by open-label maintenance phase), which enrolled patients who completed the phase III trials, showed a similar group response for the reduction in seizure frequency over at least 1 year of adjunctive treatment with perampanel. Perampanel was generally well tolerated over the longer-term in extension studies, with no unexpected adverse events reported. On the basis of its overall clinical profile and unique mechanism of action, perampanel is a useful adjunctive treatment option in patients with refractory partial-onset seizures.

Topics: Animals; Anticonvulsants; Clinical Trials, Phase III as Topic; Drug Therapy, Combination; Epilepsy, Complex Partial; Humans; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Treatment Outcome

To evaluate the efficacy and safety of perampanel 2, 4, and 8 mg/day added to 1-3 concomitant antiepileptic drugs (AEDs) in patients with uncontrolled partial-onset seizures.. During this double-blind, placebo-controlled trial, patients with persisting seizures on 1-3 AEDs were randomized to perampanel 2, 4, and 8 mg/day or placebo following a 6-week baseline phase. Perampanel was titrated weekly by 2 mg/day and maintained at the dose achieved for 13 weeks. Primary endpoints were median percent change in seizure frequency and 50% responder rate. Analysis of covariance was performed on all treated patients with any seizure data (recorded in daily diaries) in the double-blind phase.. A total of 706 patients were randomized and received trial medication; 623 completed the trial. Median percent change in seizure frequency-the primary efficacy endpoint-was -10.7%, -13.6%, -23.3%, and -30.8% for placebo, perampanel 2, 4, and 8 mg/day, respectively. The difference from placebo was statistically significant for perampanel 4 mg/day (p = 0.0026) and 8 mg/day (p < 0.0001). The corresponding 50% responder rates were 17.9%, 20.6%, 28.5%, and 34.9%. The difference from placebo was statistically significant for perampanel 4 mg/day (p = 0.0132) and 8 mg/day (p = 0.0003). An apparent dose response was suggested for dizziness, which was the most frequent treatment-emergent adverse event.. This trial demonstrated that adjunctive perampanel effectively reduced seizure frequency and possessed a favorable tolerability profile in patients ≥12 years with partial-onset seizures (with or without secondary generalization), with a minimum effective dose of 4 mg/day.. This study provides Class I evidence that 4 and 8 mg/day doses of adjunctive perampanel are effective and tolerated in reducing partial-onset seizures.

Topics: Adolescent; Adult; Anticonvulsants; Child; Dose-Response Relationship, Drug; Drug Administration Schedule; Electroencephalography; Epilepsies, Partial; Epilepsy, Complex Partial; Female; Humans; Intention to Treat Analysis; Male; Nitriles; Pyridones; Young Adult