Perampanel Discontinuation Is Not Associated With Self-Reported Withdrawal Symptoms in Patients Completing Phase III Clinical Studies (P1.232)

Abstract

Rationale: Although gradual withdrawal of antiepileptic drugs (AEDs) is generally recommended, abrupt withdrawal may be needed in patients experiencing drug hypersensitivity reactions or in response to other adverse events (AEs). Perampanel (PER), a selective, orally active, noncompetitive AMPA receptor antagonist approved for adjunctive treatment of partial-onset seizures (POS), has a long half-life (~105 h), so blood levels fall gradually even after abrupt withdrawal. We sought to determine if withdrawal of PER is associated with increased self-reports of a diverse set of behavioral symptoms, focusing on symptoms associated with withdrawal of drugs with a likelihood for tolerance or physical dependence. Methods: Patients (aged >12 yrs) with refractory POS receiving 1-3 concomitant AEDs enrolled in 3 Phase III studies were randomized to 19 wks of a once-daily double-blind (DB) treatment (6-wk titration/13-wk maintenance) with PER 2, 4, 8 or 12mg (total PER n=1038) or placebo (n=442). Patients who completed a DB study (Study 304, 305 or 306) were eligible for the open-label extension (OLE) (Study 307). Patients completed a questionnaire where they self-reported as "none," "mild," "moderate" or "severe" 13 symptom clusters typically associated with withdrawal of psychoactive agents including opiates. The questionnaire was administered at baseline, end of treatment (EOT), 8(+/-2) days after last dose and 4 wks after last dose. Patients who discontinued due to AEs or were lost to follow-up were not included in the analyses. Using shift tables we compared the frequency with which the symptoms were reported at each questionnaire administration, particularly focusing on increases at 8 days (withdrawal) compared with EOT (immediately before withdrawal either in DB or OLE). Results: A total of 832 patients treated with PER (n=96 DB studies; n=736 OLE) were included in this analysis. A majority of patients taking low (<8mg/day; n=198) and high (8-12mg/day; n=634) PER doses gave ratings of "none" or "mild" for all symptoms at each questionnaire administration. Few patients (<6) rated any symptom as "severe" at 8 days or 4 wks. Overall we did not detect a clinically meaningful increase in frequency or severity of any of the symptoms (including anxiety/nervousness, irritability, and insomnia/sleep disturbances) at 8 days with respect to EOT. We also did not detect a clinically meaningful increase in fatigue/lethargy/asthenia or irritability at EOT in relation to baseline, suggesting that low dose or high dose PER does not persistently induce symptoms typically associated with sedative agents. At baseline <4% of patients reported craving/drug seeking and this did not increase during or following treatment. Conclusions: Withdrawal of PER treatment was not associated with an increase in the frequency or severity of diverse behavioral symptoms at 8 days following drug discontinuation. Whether withdrawal symptoms would be reported prior to 8 days remains to be determined.