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NEUROLOGY 1994;44:1830
© 1994 American Academy of Neurology

Flunarizine for treatment of partial seizures

Results of a concentration-controlled trial

G. W. Pledger, PhD, J. C. Sackellares, MD, D. M. Treiman, MD, J. M. Pellock, MD, F. S. Wright, MD, M. Mikati, MD, J. T. Sahlroot, PhD, J. Y. Tsay, PhD, M. E. Drake, MD, L. Olson, MD, C. A. Handforth, MD, W. R. Garnett, PharmD, S. Schachter, MD, H. J. Kupferberg, PhD, M. R. Ashworth, RN, BS, C. McCormick, MD, D. Leiderman, MD, I. M. Kapetanovic, PhD, S. Driscoll, RN, BSN, K. O'Hara, RN, C. D. Torchin, BS, J. Gentile, RN, A. Kay, RN and J. J. Cereghino, MD

NINDS Epilepsy Branch (Drs. Pledger, Sahlroot, Tsay, Kupferberg, McCormick, Leiderman, Kapetanovic, and Cereghino, and M.R. Ashworth and CD. Torchin), Bethesda, MD; the University of Michigan (Drs. Sackellares and Olson), Ann Arbor, MI; the University of California, Los Angeles (Drs. Treiman and Handforth), Los Angeles, CA; the Medical College of Virginia (Drs. Pellock and Garnett, and S. Driscoll and K. O'Hara), Virginia Commonwealth University, Richmond, VA; Children's Hospital Research Foundation (Dr. Wright), Columbus, OH; Children's Hospital Medical Center (Dr. Mikati), Boston, MA; Ohio State University (Dr. Drake and A. Kay), Columbus, OH; and Beth Israel Hospital (Dr. Schachter and J. Gentile), Boston, MA.

The National Institutes of Health sponsored a randomized, double-blind, multicenter, placebo-controlled trial of flunarizine (FNR) in epileptic patients receiving concomitant phenytoin (PHT) or carbamazepine (CBZ). Because of FNR's long half-life (up to 7 weeks), a parallel rather than crossover design was used. Each patient received an individualized loading dose and maintenance dosage targeted at a 60-ng/ml plasma FNR concentration. Of 93 patients randomized, 92 provided seizure data for the full 25-week treatment period; one placebo-treated patient dropped out for personal reasons. Fifty-four patients received CBZ only, nine received PHT only, and 30 received both CBZ and PHT. Eighty-seven patients had a history of complex partial seizures, and 60 had secondarily generalized seizures. Eight patients discontinued FNR prematurely, all because of adverse neurologic or psychiatric signs or symptoms; depression was the specific cause in three cases. Calculated maintenance dosages, based on single-dose pharmacokinetic profiles, ranged from 7 to 138 mg/day (mean, 40 mg/day). Plasma FNR concentrations generally exceeded the target, with the highest concentrations observed immediately after loading; excluding the first three treatment weeks and all concentrations after a FNR dosage change, the median plasma FNR concentration was 71.7 ng/ml. The percent reduction from baseline seizure rate was statistically greater (p = 0.002) in the FNR-treated group (mean, 24.4%) than in the placebo-treated group (mean, 5.7%).

Address correspondence and reprint requests to Dr. Gordon Pledger, The R.W. Johnson Pharmaceutical Research Institute, Route 202, Box 300, Raritan, NJ 08869.

Received May 25, 1993. Accepted in final form March 24, 1994.






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