Article abstract ~
Clonazepam, a chlorinated derivativeof nitrazepam,was administeredto 10 children with absence seizures. Serum concentrationswere measured after 8 weeks of treatment, at steady state. Seizure frequency reports and the 12-hour telemetered electroencephalogramwere studied before and after 8 weeks of treatment to determine the frequency and duration of generalized spike-wave paroxysms. The clonazepam dosage ranged from 0.028 to 0.111 mg per kilogram and was reflected in serum levels ranging from 13 to 72 ng per milliliter, with an excellent correlation between dose and serum level. Eight of the 10 patients showed a significant decrease in seizure frequency, with three experiencing no seizures at all. Six patients had side effects, predominantlydrowsiness and ataxia. This preliminarystudy shows clonazepam to be useful in the treatment of absence seizures in children and to merit further study.
Serum clonazepam concentrations in children with absence seizures FRITZ E. DREIFUSS, M.B., M.R.C.P., F.R.A.C.P., J. KlFFlN PENRY, M.D., STEPHEN W. ROSE, M.D., HARVEY J. KUPFERBERG, PH.D., PAUL DYKEN, M.D., and S. SATO, M.D.
C
lonazepam, 5-(2-chlorophenyl)- 1,3-dihydro-7nitro-2H- 1,4-benzodiazepine-2-0ne, a chlorinated derivative of nitrazepam, is currently undergoing testing as an antiepileptic drug.'-'' In the United States, it is now listed as an investigational new drug in phase I11 testing. To date, there has been only one published report'* on human plasma levels of clonazepam in relation to dosage and on half-life determinations, and none on serum levels in relation to efficacy and toxicity. The present study addresses these points in a report on 10 patients taking part in a 17-week double-blind study designed to compare the efficacy of clonazepam with ethosuximide in the treatment of absence seizures. Final conclusions concerning the clinical value of clonazepam in the treatment of absence seizures will be deferred until completion of the study in about 100 patients. From the Section on Epilepsy, Applied Neurologic Research Branch, Collaborative and Field Research, National Institute of Neurological Diseases and Stroke, Bethesda, Maryland: the Department of Neurology, University of Virginia School of Medicine, Charlottesville; and the Department of Neurology, University of Georgia School of Medicine, Augusta. This paper was read at the twenty-sixth annual meeting of the American Academy of Neurology, San Francisco, April 1974. This work was supported by NINDS contracts NIH-69-2169 and NIH-69-2196 and by grant RR-304 from the General Clinical Research Centers Program of the NIH Division of Research Resources. Received for pubficatjonAugust 13, 1974. Dr. Penry's address is Building 36, Room 5D-10, National Institutes of Health, Bethesda, MD 20014.
Methods. Patient selection. The 10 patients selected for measurement of serum concentrations were those who first completed the 17-week study and who were taking only clonazepam. The patients ranged in age from 6 to 13 years (mean 9.8 years). All patients exhibited absence seizures as defined by the International Classification. l 3 None had taken benzodiazepines previously. Study protocol. The 17-week study included three hospital observation periods and one outpatient visit. During the first observation period, the patients were admitted to the hospital for 7 days. On the first 2 days, a complete evaluation was carried out, including history, physical examination, routine electroencephalogram (EEG), complete neuropsychologic test battery, 12-hour telemetered EEG, and blood studies with base-line antiepileptic drug levels. Treatment was started on the third day of hospitalization, with the drug selected being number-coded by the coordinating pharmacist. The patients were given either clonazepam and placebo ethosuximide or ethosuximide and placebo clonazepam. The code was broken after the 17 weeks of study. Clonazepam was initially administered in a dose of 0.05 mg per kilogram in three divided doses per day. The clonazepam dosage was increased to 0. I mg per kilogram if the patient was tolerating the test drug on the fourth treatment day. If the patient did not have a 50 percent reduction in seizures at the end of the first treatment week, NEUROLOGY 25: 255-258, March 1975 255
Serum clonazepam concentrations in children with absence seizures the clonazepam dosage was increased to 0.3 mg per kilogram. If toxicity developed, the dosage was decreased to 0.2 mg per kilogram. Each patient returned during the fourth treatment week for an outpatient visit. The second and third hospital observation periods occurred on the eighth and seventeenth treatment weeks. Blood was drawn for serum level determinations of antiepileptic drugs 3 hours after the last dose except in those periods in which the drug was being delayed for half-life determinations. In order to maintain the double-blind design, determinations of the serum clonazepam levels were not completed until the patients finished the study. Clonazepurn assay method. The serum clonazepam levels were determined by a modified method of de Silva, Puglisi, and Munno,14 using electron-capture gas-liquid chromatography. The procedure is capable of measuring 3 ng per milliliter of clonazepam with a precision of about 5 percent in a 2 milliliter serum sample. Telemetry. Four 12-hour telemetered EEGs were recorded from each patient during the course of the study. The recordings were made before treatment and again during the first, eighth, and seventeenth treatment weeks. The 12-hour telemetry method has been described by Porter, Wolf, and Penry. l 5 Seizure index. A seizure index, as described by Penry, Porter, and Dreifuss,I6 was developed in an effort to quantitate clinical control. The index utilized four sources of data. The first was the physician’s observation of seizures occurring at the time of physical examinations before treatment and during the first, eighth, and seventeenth treatment weeks. The second source was the observation by nurses during the hospitalization periods for 5 minutes every hour for the awake patient and for 1 minute each hour when the patient was asleep. The third
data source was each patient’s history, usually taken from the mother, who observed the patient in the home environment. The data were completed by the presence or absence of spike-wave bursts on the routine EEG, which was performed before treatment and during the first, eighth, and seventeenth treatment weeks. Thus, the index is a n u m b e r d e r i v e d f r o m t h e s e o b s e r v a t i o n s that approximates the average number of absence seizures occurring daily. Toxicity. A number of modes for measuring toxicity were employed. The toxic side effects noted by the physician, laboratory tests, and serial body weights were monitored during the period of study. Complete psychologic test batteries were administered both before and after eight weeks of treatment. The Idestrom ataxia test” was employed as a measure of ataxia and drowsiness. A history of generalized tonic-clonic seizures before treatment was compared with their occurrence during the study.
Results. The relationship of serum clonazepam concentrations to dosage, efficacy, and toxicity is summarized in the table. Dosage. The relationship between serum levels and dosage is shown in figure I . Serum levels ranged from 13 to 72 ng per milliliter. These were eighth-treatment-week serum levels obtained 3 hours after the last oral dose of the drug. Serum half-life determinations (figure 2) were completed on four of the 10 patients and ranged from 22 to 33 hours (mean 28.7 hours). Half-life determinations were based on four serum levels obtained over a 40-hour period while administration of the drug was delayed. EfSiicacy . The 12-hour telemetered EEGs indicated that by the eighth treatment week seven patients had experienced a seizure reduction of 75 percent or greater
Serum clonazepam concentrations related to dosage, efficacy, and toxicity
256
NEUROLOGY March 1975
--
-
-z
60-
E \
0
-
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a z W
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V
fIf:
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.93
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I
0.02
I
I
0.04
I
I
0.06
I
I
I
0.08
I
0.10
I
F i g u r e 1 . R e l a t i o n s h i p of s e r u m concentration (nanograms per milliliter) to clonazepam dose (milligrams per kilogram) for 10 children.
I
0.12
CLONAZEPAM DOSE ( mg 1 k g )
and one had a 30 percent reduction in seizures. Two patients had no seizures on the telemetered EEGs before treatment. The duration of seizures was increased in only one patient, from 4.5 to 15.6 seconds; the others had a decrease in seizure duration. The value of the seizure index as an independent measure of efficacy was apparent in the two patients whose telemetered EEGs did not demonstrate seizure discharges before treatment. By the eighth treatment week, eight patients had a 50 percent or greater reduction in seizures, and one patient's seizures were reduced by 10 percent, according to the seizure index. The patient who showed a 30 percent reduction in telemetered EEG discharges, however, showed a 6 percent increase in seizure index. Toxicity. Five of the 10 patients developed drowsiness during the first 8 weeks on clonazepam. Other side effects were ataxia, hyperactivity, and personality change.
The Idestrom ataxia scores increased in five patients between the pretreatment week and the eighth treatment week. There was no direct relationship between drowsiness and an increase in the ataxia scores. All patients showed a gain in body weight by the eighth week of treatment, with a maximum of 16 percent and a median of 5 percent. Two patients had histories of generalized tonic-clonic seizures and one patient had a history of two febrile seizures. None of these had a generalized tonicclonic convulsion during the first 8 weeks on the drug. Results of psychologic test batteries will be reported when the study is completed.
Discussion. There has been only one previous report relating dosage of clonazepam to plasma levels. Naestoft and co-workers12 measured plasma levels after daily oral doses of 2 to 4 mg of clonazepam and found plasma concentrations in the range of 10 to 50 ng per milliliter. These findings are comparable with our range of serum levels of 13 to 72 ng per milliliter with dosages ranging from 1.5 to 4.0 mg per day. The serum levels in our study were determined at the eighth treatment week and obtained 2 to 3 hours after the last oral dose of the drug. This level was selected to represent steady state the best because it was felt that the levels would fluctuate during the first treatment week as a result of alteration in dosage schedules and that compliance could not be assured during the outpatient period. Naestoft and colleagues also reported half-life determinations in the range of 22 to 38 hours. These closely approximate the half-life range of 22 to 33 hours in our study. There are a number of reports discussing the efficacy of clonazepam in both tonic-clonic and absence seizures and some in relation to absence alone. These show the drug to be effective in reducing seizure frequency. In our study, seven of the 10 patients had a definite reduction in seizure frequency, as measured by 12-hour telemetered EEGs and the seizure index. One patient with a serum level of 18 ng per milliliter showed a 30 percent reduction in seizures by telemetered EEG, but the seizure index showed an increase in seizure frequency. Another patient, with a NEUROLOGY March 1975 257
Serum clonazepam concentrations in children with absence seizures
T 50%
28.8 Hours (pt.2) o 22.1 Hours(pt.7) 32.7 Hours (pt.6) A 3 I .O Hours(pt.10)
0
Figure 2. Serum half-life values (hours) for four children. Four serum concentrations for each patient were determined within a 40-hour period while the dosage of clonazepam was delayed.
9\
0
I
I
I
I
I
J
10
20
30
40
50
60
TIME (Hours)
serum level of 38 ng per milliliter, showed an 80 percent reduction in seizures by telemetered EEG and a 70 percent reduction in seizure index, but the average duration of his seizures increased from 4.5 to 15.6 seconds. Finally, one patient had no seizures on telemetered EEG and had only a 10 percent reduction in seizure index. As this child had rare absence attacks, it was difficult to determine drug efficacy. Hanson and Menkes6 described the side effects of clonazepam at therapeutic doses in 8 1 patients. Ataxia, drowsiness, and weight gain of 20 percent or more of the original body weight were the most frequently noted side effects. None of our patients experienced a weight gain of 20 percent, although two showed a gain of 16 percent in 8 weeks. Hanson and Menkes also mentioned hyperactivity as a side effect of clonazepam, and this was exhibited by two of our patients. These authors also described the appearance of a new seizure type in two of their patients, but in none of our patients was this a feature.
Conclusions. There is a linear relationship between serum clonazepam levels (nanograms per milliliter) and dosage (milligrams per kilogram). The half-life of the drug ranges from 22 to 33 hours. Clonazepam appears to be effective in reducing the frequency of absence seizures at serum levels of 13 to 72 ng per milliliter. Drowsiness is a prominent side effect at a wide range of serum levels. REFERENCES 1. Lund M (Editor): Symposium on the therapeutic use of the anti-convulsant Ro 5-4023 (clonazepam) in different forms of epilepsy; Copenhagen, May 26, 1972. Acta Neurol Scand, Suppl 53, 49:l-143,
1973 2. Chandra 6:Rivotril Ro 5-4023 in the treatment of petit ma1in 14 patients:
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A preliminary study. Asian J Med 8:249-250, 1972 3. Gastaut H: The exceptional antiepileptic properties of a new benzodiazepine. 9th International Congress of Neurology, Excerpta Medica International Congress Series 1935, 1969 4. Gastaut H, Catier J, Dravet C, et al: Demonstration by a screening method of the exceptional anti-convulsant properties of a new benzodiazepine. (Abstr) ElectroencephalogrClin Neurophysiol27:l05, 1969 5. Gastaut H, Courjon J, Poire'R,et al: Treatmentofstatusepi/ep~icus with a new benzodiazepine more active than diazepam. Epilepsia 12:197-214, 1971 6. Hanson RA. Menkes JH: A new anticonvulsant in the management of minor motor seizures. Dev Med Child Neurol 14:3-14, 1972 7. Hooshmand H: Intractable seizures: Treatment with a new benzodiazepine anticonvulsant. Arch Neurol 27:205-208, 1972 8. Lechat P, Boismare F, Streichenberger G, et al: Evaluation experimentale des proprietes anti-epileptiques d'une nouvelle benzodiazepine: le Ro-05-4023.Therapie 25:893-905, 1970 9. Poire'R,Royer J: Etude electrographiqueexperimentale comparee des proprietes antiepileptiques dun nouveau derive'des benzodiazepines le Ro 05-4023. Rev Neurol 120:408-411, 1969 10. Turner M, Corder0 Funes JR, Aspinwall R, et al: Ensayo de valoracion clinicoelectroencefalograficade un nuevo derivado benzodiazepinico (Ro 05-4023) por administracion oral en pacientes epilepticos con tecnica de doble ceguera. Acta Neurol Lat Am 16:158-169, 1970 11. Turner M. Fejerman N, Schugurensky E, et al: Evaluacion clinicoelectroencefalografica de la accion antiepileptica de una nueva serie de derivados benzodiazepinicos. Acta Neurol Lat Am 16:97-109, 1970 12. Naestofi J, Lund M, Larsen N-E, et al: Assay and pharmacokineticsof clonazepam in humans. Acta Neurol Scand, Suppl 53, 49:103-108, 1973 13. Gastaut H: Clinical and electroencephalographical classification of epileptic seizures. Epilepsia 11:102-113, 1970 14. de Silva JAF, Puglisi CV, Munno N: Determination of clonazepam and flunitrazepam in blood and urine by electron-capture GLC. J Pharm Sci 63520-527, 1974 15. Porter RJ, Wolf AA Jr, Penry JK: Human electroencephalographic telemetry. Am J EEG Techno1 11:I 45-1 59, 1971 16. Penry JK, Porter RJ, Dreifuss FE: Ethosuximide: Relation of plasma levels to clinical control. In: Woodbury DM, Penry JK, Schmidt RP (Editors): Antiepileptic Drugs. New York, Raven Press, 1972, pp 431-441 17. ldestrom CM: The effect of gamma-phenyl-propylcarbarnatecompared with meprobamate and placebo: An experimental psychological study. Psychopharmacologia 335-22, 1962
Serum clonazepam concentrations in children with absence seizures FRITZ E. DREIFUSS, J. KIFFIN PENRY, STEPHEN W. ROSE, et al. Neurology 1975;25;255 DOI 10.1212/WNL.25.3.255 This information is current as of March 1, 1975 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1975 by the American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Clonazepam, a chlorinated derivativeof nitrazepam,was administeredto 10 children with absence seizures. Serum concentrationswere measured after 8 weeks of treatment, at steady state. Seizure frequency reports and the 12-hour telemetered electroencephalogramwere studied before and after 8 weeks of treatment to determine the frequency and duration of generalized spike-wave paroxysms. The clonazepam dosage ranged from 0.028 to 0.111 mg per kilogram and was reflected in serum levels ranging from 13 to 72 ng per milliliter, with an excellent correlation between dose and serum level. Eight of the 10 patients showed a significant decrease in seizure frequency, with three experiencing no seizures at all. Six patients had side effects, predominantlydrowsiness and ataxia. This preliminarystudy shows clonazepam to be useful in the treatment of absence seizures in children and to merit further study.
Serum clonazepam concentrations in children with absence seizures FRITZ E. DREIFUSS, M.B., M.R.C.P., F.R.A.C.P., J. KlFFlN PENRY, M.D., STEPHEN W. ROSE, M.D., HARVEY J. KUPFERBERG, PH.D., PAUL DYKEN, M.D., and S. SATO, M.D.
C
lonazepam, 5-(2-chlorophenyl)- 1,3-dihydro-7nitro-2H- 1,4-benzodiazepine-2-0ne, a chlorinated derivative of nitrazepam, is currently undergoing testing as an antiepileptic drug.'-'' In the United States, it is now listed as an investigational new drug in phase I11 testing. To date, there has been only one published report'* on human plasma levels of clonazepam in relation to dosage and on half-life determinations, and none on serum levels in relation to efficacy and toxicity. The present study addresses these points in a report on 10 patients taking part in a 17-week double-blind study designed to compare the efficacy of clonazepam with ethosuximide in the treatment of absence seizures. Final conclusions concerning the clinical value of clonazepam in the treatment of absence seizures will be deferred until completion of the study in about 100 patients. From the Section on Epilepsy, Applied Neurologic Research Branch, Collaborative and Field Research, National Institute of Neurological Diseases and Stroke, Bethesda, Maryland: the Department of Neurology, University of Virginia School of Medicine, Charlottesville; and the Department of Neurology, University of Georgia School of Medicine, Augusta. This paper was read at the twenty-sixth annual meeting of the American Academy of Neurology, San Francisco, April 1974. This work was supported by NINDS contracts NIH-69-2169 and NIH-69-2196 and by grant RR-304 from the General Clinical Research Centers Program of the NIH Division of Research Resources. Received for pubficatjonAugust 13, 1974. Dr. Penry's address is Building 36, Room 5D-10, National Institutes of Health, Bethesda, MD 20014.
Methods. Patient selection. The 10 patients selected for measurement of serum concentrations were those who first completed the 17-week study and who were taking only clonazepam. The patients ranged in age from 6 to 13 years (mean 9.8 years). All patients exhibited absence seizures as defined by the International Classification. l 3 None had taken benzodiazepines previously. Study protocol. The 17-week study included three hospital observation periods and one outpatient visit. During the first observation period, the patients were admitted to the hospital for 7 days. On the first 2 days, a complete evaluation was carried out, including history, physical examination, routine electroencephalogram (EEG), complete neuropsychologic test battery, 12-hour telemetered EEG, and blood studies with base-line antiepileptic drug levels. Treatment was started on the third day of hospitalization, with the drug selected being number-coded by the coordinating pharmacist. The patients were given either clonazepam and placebo ethosuximide or ethosuximide and placebo clonazepam. The code was broken after the 17 weeks of study. Clonazepam was initially administered in a dose of 0.05 mg per kilogram in three divided doses per day. The clonazepam dosage was increased to 0. I mg per kilogram if the patient was tolerating the test drug on the fourth treatment day. If the patient did not have a 50 percent reduction in seizures at the end of the first treatment week, NEUROLOGY 25: 255-258, March 1975 255
Serum clonazepam concentrations in children with absence seizures the clonazepam dosage was increased to 0.3 mg per kilogram. If toxicity developed, the dosage was decreased to 0.2 mg per kilogram. Each patient returned during the fourth treatment week for an outpatient visit. The second and third hospital observation periods occurred on the eighth and seventeenth treatment weeks. Blood was drawn for serum level determinations of antiepileptic drugs 3 hours after the last dose except in those periods in which the drug was being delayed for half-life determinations. In order to maintain the double-blind design, determinations of the serum clonazepam levels were not completed until the patients finished the study. Clonazepurn assay method. The serum clonazepam levels were determined by a modified method of de Silva, Puglisi, and Munno,14 using electron-capture gas-liquid chromatography. The procedure is capable of measuring 3 ng per milliliter of clonazepam with a precision of about 5 percent in a 2 milliliter serum sample. Telemetry. Four 12-hour telemetered EEGs were recorded from each patient during the course of the study. The recordings were made before treatment and again during the first, eighth, and seventeenth treatment weeks. The 12-hour telemetry method has been described by Porter, Wolf, and Penry. l 5 Seizure index. A seizure index, as described by Penry, Porter, and Dreifuss,I6 was developed in an effort to quantitate clinical control. The index utilized four sources of data. The first was the physician’s observation of seizures occurring at the time of physical examinations before treatment and during the first, eighth, and seventeenth treatment weeks. The second source was the observation by nurses during the hospitalization periods for 5 minutes every hour for the awake patient and for 1 minute each hour when the patient was asleep. The third
data source was each patient’s history, usually taken from the mother, who observed the patient in the home environment. The data were completed by the presence or absence of spike-wave bursts on the routine EEG, which was performed before treatment and during the first, eighth, and seventeenth treatment weeks. Thus, the index is a n u m b e r d e r i v e d f r o m t h e s e o b s e r v a t i o n s that approximates the average number of absence seizures occurring daily. Toxicity. A number of modes for measuring toxicity were employed. The toxic side effects noted by the physician, laboratory tests, and serial body weights were monitored during the period of study. Complete psychologic test batteries were administered both before and after eight weeks of treatment. The Idestrom ataxia test” was employed as a measure of ataxia and drowsiness. A history of generalized tonic-clonic seizures before treatment was compared with their occurrence during the study.
Results. The relationship of serum clonazepam concentrations to dosage, efficacy, and toxicity is summarized in the table. Dosage. The relationship between serum levels and dosage is shown in figure I . Serum levels ranged from 13 to 72 ng per milliliter. These were eighth-treatment-week serum levels obtained 3 hours after the last oral dose of the drug. Serum half-life determinations (figure 2) were completed on four of the 10 patients and ranged from 22 to 33 hours (mean 28.7 hours). Half-life determinations were based on four serum levels obtained over a 40-hour period while administration of the drug was delayed. EfSiicacy . The 12-hour telemetered EEGs indicated that by the eighth treatment week seven patients had experienced a seizure reduction of 75 percent or greater
Serum clonazepam concentrations related to dosage, efficacy, and toxicity
256
NEUROLOGY March 1975
--
-
-z
60-
E \
0
-
I-
a z W
V
2 0
V
fIf:
40-
20-
.93
I
I
0.02
I
I
0.04
I
I
0.06
I
I
I
0.08
I
0.10
I
F i g u r e 1 . R e l a t i o n s h i p of s e r u m concentration (nanograms per milliliter) to clonazepam dose (milligrams per kilogram) for 10 children.
I
0.12
CLONAZEPAM DOSE ( mg 1 k g )
and one had a 30 percent reduction in seizures. Two patients had no seizures on the telemetered EEGs before treatment. The duration of seizures was increased in only one patient, from 4.5 to 15.6 seconds; the others had a decrease in seizure duration. The value of the seizure index as an independent measure of efficacy was apparent in the two patients whose telemetered EEGs did not demonstrate seizure discharges before treatment. By the eighth treatment week, eight patients had a 50 percent or greater reduction in seizures, and one patient's seizures were reduced by 10 percent, according to the seizure index. The patient who showed a 30 percent reduction in telemetered EEG discharges, however, showed a 6 percent increase in seizure index. Toxicity. Five of the 10 patients developed drowsiness during the first 8 weeks on clonazepam. Other side effects were ataxia, hyperactivity, and personality change.
The Idestrom ataxia scores increased in five patients between the pretreatment week and the eighth treatment week. There was no direct relationship between drowsiness and an increase in the ataxia scores. All patients showed a gain in body weight by the eighth week of treatment, with a maximum of 16 percent and a median of 5 percent. Two patients had histories of generalized tonic-clonic seizures and one patient had a history of two febrile seizures. None of these had a generalized tonicclonic convulsion during the first 8 weeks on the drug. Results of psychologic test batteries will be reported when the study is completed.
Discussion. There has been only one previous report relating dosage of clonazepam to plasma levels. Naestoft and co-workers12 measured plasma levels after daily oral doses of 2 to 4 mg of clonazepam and found plasma concentrations in the range of 10 to 50 ng per milliliter. These findings are comparable with our range of serum levels of 13 to 72 ng per milliliter with dosages ranging from 1.5 to 4.0 mg per day. The serum levels in our study were determined at the eighth treatment week and obtained 2 to 3 hours after the last oral dose of the drug. This level was selected to represent steady state the best because it was felt that the levels would fluctuate during the first treatment week as a result of alteration in dosage schedules and that compliance could not be assured during the outpatient period. Naestoft and colleagues also reported half-life determinations in the range of 22 to 38 hours. These closely approximate the half-life range of 22 to 33 hours in our study. There are a number of reports discussing the efficacy of clonazepam in both tonic-clonic and absence seizures and some in relation to absence alone. These show the drug to be effective in reducing seizure frequency. In our study, seven of the 10 patients had a definite reduction in seizure frequency, as measured by 12-hour telemetered EEGs and the seizure index. One patient with a serum level of 18 ng per milliliter showed a 30 percent reduction in seizures by telemetered EEG, but the seizure index showed an increase in seizure frequency. Another patient, with a NEUROLOGY March 1975 257
Serum clonazepam concentrations in children with absence seizures
T 50%
28.8 Hours (pt.2) o 22.1 Hours(pt.7) 32.7 Hours (pt.6) A 3 I .O Hours(pt.10)
0
Figure 2. Serum half-life values (hours) for four children. Four serum concentrations for each patient were determined within a 40-hour period while the dosage of clonazepam was delayed.
9\
0
I
I
I
I
I
J
10
20
30
40
50
60
TIME (Hours)
serum level of 38 ng per milliliter, showed an 80 percent reduction in seizures by telemetered EEG and a 70 percent reduction in seizure index, but the average duration of his seizures increased from 4.5 to 15.6 seconds. Finally, one patient had no seizures on telemetered EEG and had only a 10 percent reduction in seizure index. As this child had rare absence attacks, it was difficult to determine drug efficacy. Hanson and Menkes6 described the side effects of clonazepam at therapeutic doses in 8 1 patients. Ataxia, drowsiness, and weight gain of 20 percent or more of the original body weight were the most frequently noted side effects. None of our patients experienced a weight gain of 20 percent, although two showed a gain of 16 percent in 8 weeks. Hanson and Menkes also mentioned hyperactivity as a side effect of clonazepam, and this was exhibited by two of our patients. These authors also described the appearance of a new seizure type in two of their patients, but in none of our patients was this a feature.
Conclusions. There is a linear relationship between serum clonazepam levels (nanograms per milliliter) and dosage (milligrams per kilogram). The half-life of the drug ranges from 22 to 33 hours. Clonazepam appears to be effective in reducing the frequency of absence seizures at serum levels of 13 to 72 ng per milliliter. Drowsiness is a prominent side effect at a wide range of serum levels. REFERENCES 1. Lund M (Editor): Symposium on the therapeutic use of the anti-convulsant Ro 5-4023 (clonazepam) in different forms of epilepsy; Copenhagen, May 26, 1972. Acta Neurol Scand, Suppl 53, 49:l-143,
1973 2. Chandra 6:Rivotril Ro 5-4023 in the treatment of petit ma1in 14 patients:
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Serum clonazepam concentrations in children with absence seizures FRITZ E. DREIFUSS, J. KIFFIN PENRY, STEPHEN W. ROSE, et al. Neurology 1975;25;255 DOI 10.1212/WNL.25.3.255 This information is current as of March 1, 1975 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1975 by the American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
