Epilepsia, 32(3):398406, 1991 Raven Press, Ltd., New York 0 International League Against Epilepsy
Discontinuation of Phenytoin and Carbamazepine in Patients Receiving Felbamate *$M. L. Wagner, "N. M. Graves, TK. Marienau, 8G. B . Holmes, *R. P. Remmel, and *?$I. E. Leppik *College of Pharmacy, and fDepartment of Neurology, University of Minnesota; 2MINCEP Epilepsy Care, P.A., Minneapolis, Minnesota; and 9Pharmaco Dynamics Research, Austin, Texas, U . S . A .
Summary: Five patients participated in a controlled discontinuation of phenytoin (PHT) and carbamazepine (CBZ) after a study in which all subjects had felbamate (FBM) added to both PHT and CBZ. Four subjects (three women and 1 man aged 23-36 years) completed the protocol. Mean total seizure frequency per day with PHT and CBZ was 1.33 ? 0.93 (mean ? SEM), decreasing to 0.87 0.71 with addition of FBM, and 0.82 2 0.78 after discontinuation of PHT. Only one subject tolerated discontinuation of CBZ; the other three had dosage reduc-
tions of 33, 54, and 63%. Toxicity attributable to FBM was not observed, and patients often described less severe seizures. Results from four refractory patients indicated that FBM was able to replace PHT and reduce the need for CBZ. In addition, as PHT dosages were reduced, FBM clearance decreased 21%. As the CBZ dosages were reduced, FBM clearance decreased an additional 16.5%. Key Words: Anticonvulsants-FelbarnateEpilepsy-Drug interactions-Phenytoin-Carbarnazepine.
Felbamate (FBM, 2-phenyl- 1,3 propanediol dicarbamate) is a promising investigational drug for epilepsy. Previous pharmacologic and toxicologic studies in laboratory animals suggest that FBM is an effective anticonvulsant with a high margin of safety (Swinyard et al., 1986). Results from several human studies (Wilensky et al., 1985; Nice et al., 1986; Sheridan et al., 1986; Leppik et al., 1989) indicate that FBM may be an effective antiepileptic drug (AED). In all these studies, however, FBM was added to standard AEDs. We wished to determine if patients responding favorably to FBM could undergo a systematic discontinuation of phenytoin (PHT) and carbamazepine (CBZ). Patients selected had successfully completed a National Institutes of Health (N1H)sponsored study in which FBM was prescribed to patients who were still having four or more seizures a month while receiving both CBZ and PHT (Leppik et al., 1989). The primary goal was to decrease three-drug therapy (CBZ, PHT, and FBM) to FBM monotherapy.
The addition of FBM is reported to affect the concentrations of other AEDs. FBM increases PHT concentrations, necessitating a 1&30% reduction in PHT dose (Wilensky et al., 1985; Sheridan et al., 1986; Fuerst et al., 1988; Graves et al., 1989~).On the other hand, FBM consistently decreases CBZ concentrations (Fuerst et al., 1988; Graves et al., 1989~).Because PHT and CBZ are inducers of drug-metabolizing enzymes, discontinuation of PHT or CBZ may alter FBM concentrations. Thus, the second goal of this study was to assess FBM clearance as PHT and CBZ were discontinued.
*
METHODS Patient characteristics Five patients from the University of Minnesota elected to continue receiving FBM after completing an NIH-sponsored safety and efficacy trial and were willing to participate in this study. Patient characteristics of the four patients who completed the study are shown in Table 1 . All participants were able to report their own seizures adequately. None had a history of drug abuse, status epilepticus within 3 months of initiating the study, psychiatric or medical disorders, concurrent medication, poor compliance, or abnormal blood chemistries. When
Received February 1990; revision accepted September 1990. Address correspondence and reprint requests to Dr. N. M. Graves at College of Pharmacy, Department of Pharmacy Practice, Health Science Unit F, 308 Harvard St., Minneapolis, MN 55455, U . S . A .
398
FBM AS A N AED
399
TABLE 1. Patient characteristics when starting discontinuation phase
- .-
Seizure frequency (Seizureslday)
Dose (mglday)
CP (mdL)
Dose (mglday)
CP (mdL)
-
230 200 300 260
13.5 13.3 11.3 17.9
900 800 600 1,300
2.4 4.4 2.5 3.6
3,000 3,000 2,600 2,200
35.2 38.5 31.4 20.1
0.91
248
14.0
900
3.2
2,700
31.3
CP
SP
0.30
-
0.02 0.06 0 0.35
2.67 0.04 0.017
4
Fl29155.9 Fl35l70.0 Ml23168.6 Fl36155.7
Mean
29.5
0.16
0.11
62.6
0.011
_________
CP (mg/L)
GTC
I 2 3
FBM
CBZ
Dose (mglday)
Sex/age(yr)/weight(kg)
Patient
PHT
GTC, generalized tonic-clonic; CP, complex partial; SP, simple partial; PHT, phenytoin; CBZ, carbamazepine; FBM, felbamate; Cp, plasma concentration.
they began participating in the discontinuation study, patients were receiving FBM in addition to CBZ and PHT. Study design Because of the small number of patients, discontinuation of PHT and CBZ was not randomized. The first drug withdrawn was PHT because of the significant interaction between FBM and PHT. Patients were seen monthly during both the PHT and CBZ taper. This protocol was similar to that used for tapering concurrent AEDs in patients who had been treated with progabide (Leppik et al., 1986). At each visit, AED concentrations, seizure frequency, and adverse effects were assessed. AED concentrations were reviewed by a clinical pharmacist to assess patient compliance, drug toxicity, and drug interactions. Patients recorded the time, date, and estimated duration for each of their seizures on a calendar. Patients had been trained to recognize occurrence of seizures in a previous study that included estimation of duration. Although duration is difficult to measure and subjective, each patient was asked to be consistent and patient reports were reviewed by a nurse clinician at each clinic visit. Adverse effects were evaluated by clinical judgment, physical examination, neurologic examination, and blood chemistries. A short neuropsychologic test (SNT) assessed cognitive function and fine motor movement. In addition, a semiannual electrocardiogram (ECG) and annual chest roentgenogram were obtained. The PHT dose during taper was calculated by the Bayesian technique (Vozeh et al., 1981). At each monthly visit, the PHT dosage was modified so that plasma concentration would decrease by approximately one third of the previous concentration. An additional step was added to the PHT taper if it appeared that discontinuation of PHT from one third of the baseline concentration to zero was associated with a transient increase in seizure frequency or a higher than anticipated PHT concen-
tration. If an additional step was needed, the PHT dose was modified so that the PHT concentration would decrease by one sixth and again by one sixth the following month. Successful drug discontinuation was defined as cessation of treatment with the AED for 1 month without an increase in seizure frequency. After completing the PHT taper, the patient was stabilized with CBZ and FBM for 4 weeks. The following month, the dosage of CBZ was decreased by one third at each monthly visit. If the patient’s seizures worsened as PHT or CBZ was tapered, the FBM dosage was increased by 400 mg per day every 3 days to a maximum of 3,600 mg/day. If the increased dosage of FBM did not control the patient’s seizures or if the patient developed side effects, the PHT or CBZ dosage was increased by one third. AED serum concentrations PHT and CBZ were measured by a high-pressure liquid chromatography (HPLC) assay (Sawchuk and Cartier, 1980). The coefficients of variation of PHT and CBZ over the range of concentrations observed in the study were
Discontinuation of Phenytoin and Carbamazepine in Patients Receiving Felbamate *$M. L. Wagner, "N. M. Graves, TK. Marienau, 8G. B . Holmes, *R. P. Remmel, and *?$I. E. Leppik *College of Pharmacy, and fDepartment of Neurology, University of Minnesota; 2MINCEP Epilepsy Care, P.A., Minneapolis, Minnesota; and 9Pharmaco Dynamics Research, Austin, Texas, U . S . A .
Summary: Five patients participated in a controlled discontinuation of phenytoin (PHT) and carbamazepine (CBZ) after a study in which all subjects had felbamate (FBM) added to both PHT and CBZ. Four subjects (three women and 1 man aged 23-36 years) completed the protocol. Mean total seizure frequency per day with PHT and CBZ was 1.33 ? 0.93 (mean ? SEM), decreasing to 0.87 0.71 with addition of FBM, and 0.82 2 0.78 after discontinuation of PHT. Only one subject tolerated discontinuation of CBZ; the other three had dosage reduc-
tions of 33, 54, and 63%. Toxicity attributable to FBM was not observed, and patients often described less severe seizures. Results from four refractory patients indicated that FBM was able to replace PHT and reduce the need for CBZ. In addition, as PHT dosages were reduced, FBM clearance decreased 21%. As the CBZ dosages were reduced, FBM clearance decreased an additional 16.5%. Key Words: Anticonvulsants-FelbarnateEpilepsy-Drug interactions-Phenytoin-Carbarnazepine.
Felbamate (FBM, 2-phenyl- 1,3 propanediol dicarbamate) is a promising investigational drug for epilepsy. Previous pharmacologic and toxicologic studies in laboratory animals suggest that FBM is an effective anticonvulsant with a high margin of safety (Swinyard et al., 1986). Results from several human studies (Wilensky et al., 1985; Nice et al., 1986; Sheridan et al., 1986; Leppik et al., 1989) indicate that FBM may be an effective antiepileptic drug (AED). In all these studies, however, FBM was added to standard AEDs. We wished to determine if patients responding favorably to FBM could undergo a systematic discontinuation of phenytoin (PHT) and carbamazepine (CBZ). Patients selected had successfully completed a National Institutes of Health (N1H)sponsored study in which FBM was prescribed to patients who were still having four or more seizures a month while receiving both CBZ and PHT (Leppik et al., 1989). The primary goal was to decrease three-drug therapy (CBZ, PHT, and FBM) to FBM monotherapy.
The addition of FBM is reported to affect the concentrations of other AEDs. FBM increases PHT concentrations, necessitating a 1&30% reduction in PHT dose (Wilensky et al., 1985; Sheridan et al., 1986; Fuerst et al., 1988; Graves et al., 1989~).On the other hand, FBM consistently decreases CBZ concentrations (Fuerst et al., 1988; Graves et al., 1989~).Because PHT and CBZ are inducers of drug-metabolizing enzymes, discontinuation of PHT or CBZ may alter FBM concentrations. Thus, the second goal of this study was to assess FBM clearance as PHT and CBZ were discontinued.
*
METHODS Patient characteristics Five patients from the University of Minnesota elected to continue receiving FBM after completing an NIH-sponsored safety and efficacy trial and were willing to participate in this study. Patient characteristics of the four patients who completed the study are shown in Table 1 . All participants were able to report their own seizures adequately. None had a history of drug abuse, status epilepticus within 3 months of initiating the study, psychiatric or medical disorders, concurrent medication, poor compliance, or abnormal blood chemistries. When
Received February 1990; revision accepted September 1990. Address correspondence and reprint requests to Dr. N. M. Graves at College of Pharmacy, Department of Pharmacy Practice, Health Science Unit F, 308 Harvard St., Minneapolis, MN 55455, U . S . A .
398
FBM AS A N AED
399
TABLE 1. Patient characteristics when starting discontinuation phase
- .-
Seizure frequency (Seizureslday)
Dose (mglday)
CP (mdL)
Dose (mglday)
CP (mdL)
-
230 200 300 260
13.5 13.3 11.3 17.9
900 800 600 1,300
2.4 4.4 2.5 3.6
3,000 3,000 2,600 2,200
35.2 38.5 31.4 20.1
0.91
248
14.0
900
3.2
2,700
31.3
CP
SP
0.30
-
0.02 0.06 0 0.35
2.67 0.04 0.017
4
Fl29155.9 Fl35l70.0 Ml23168.6 Fl36155.7
Mean
29.5
0.16
0.11
62.6
0.011
_________
CP (mg/L)
GTC
I 2 3
FBM
CBZ
Dose (mglday)
Sex/age(yr)/weight(kg)
Patient
PHT
GTC, generalized tonic-clonic; CP, complex partial; SP, simple partial; PHT, phenytoin; CBZ, carbamazepine; FBM, felbamate; Cp, plasma concentration.
they began participating in the discontinuation study, patients were receiving FBM in addition to CBZ and PHT. Study design Because of the small number of patients, discontinuation of PHT and CBZ was not randomized. The first drug withdrawn was PHT because of the significant interaction between FBM and PHT. Patients were seen monthly during both the PHT and CBZ taper. This protocol was similar to that used for tapering concurrent AEDs in patients who had been treated with progabide (Leppik et al., 1986). At each visit, AED concentrations, seizure frequency, and adverse effects were assessed. AED concentrations were reviewed by a clinical pharmacist to assess patient compliance, drug toxicity, and drug interactions. Patients recorded the time, date, and estimated duration for each of their seizures on a calendar. Patients had been trained to recognize occurrence of seizures in a previous study that included estimation of duration. Although duration is difficult to measure and subjective, each patient was asked to be consistent and patient reports were reviewed by a nurse clinician at each clinic visit. Adverse effects were evaluated by clinical judgment, physical examination, neurologic examination, and blood chemistries. A short neuropsychologic test (SNT) assessed cognitive function and fine motor movement. In addition, a semiannual electrocardiogram (ECG) and annual chest roentgenogram were obtained. The PHT dose during taper was calculated by the Bayesian technique (Vozeh et al., 1981). At each monthly visit, the PHT dosage was modified so that plasma concentration would decrease by approximately one third of the previous concentration. An additional step was added to the PHT taper if it appeared that discontinuation of PHT from one third of the baseline concentration to zero was associated with a transient increase in seizure frequency or a higher than anticipated PHT concen-
tration. If an additional step was needed, the PHT dose was modified so that the PHT concentration would decrease by one sixth and again by one sixth the following month. Successful drug discontinuation was defined as cessation of treatment with the AED for 1 month without an increase in seizure frequency. After completing the PHT taper, the patient was stabilized with CBZ and FBM for 4 weeks. The following month, the dosage of CBZ was decreased by one third at each monthly visit. If the patient’s seizures worsened as PHT or CBZ was tapered, the FBM dosage was increased by 400 mg per day every 3 days to a maximum of 3,600 mg/day. If the increased dosage of FBM did not control the patient’s seizures or if the patient developed side effects, the PHT or CBZ dosage was increased by one third. AED serum concentrations PHT and CBZ were measured by a high-pressure liquid chromatography (HPLC) assay (Sawchuk and Cartier, 1980). The coefficients of variation of PHT and CBZ over the range of concentrations observed in the study were
