Rectal diazepam gel for treatment of acute repetitive seizures

Rectal Diazepam Gel for Treatment of Acute Repetitive Seizures Robert L. Kriel, MD*, James C. Cloyd, PharmD†, John M. Pellock, MD‡, Wendy G. Mitchell, MD§, James J. Cereghino, MD|, N. Paul Rosman, MD¶, and The North American Diastat Study Group* The purpose of these investigations was to determine from combined data the response to rectal diazepam (DZP) gel (Diastat [Athena Neurosciences, South San Francisco, CA]) in home treatment of children with episodes of acute repetitive seizures (ARS). A subset of patients aged 2-17 years were selected from two prospective placebo-controlled studies of children and adults. In both studies a prospective, double-blind, placebo-controlled design was used. The treatment groups (68 DZP; 65 placebo) did not differ significantly in age, race, seizure type or etiology, or in the median number of ARS episodes per month before study entry. DZP-treated children demonstrated a significant reduction in median seizure frequency compared with the placebo group (0.00 vs 0.25 seizures per hour, P 5 0.001). Significantly more DZP-treated children remained seizure free during the observation period (40 vs 20, P 5 0.001). Somnolence was the only adverse effect present significantly more often in the DZP-treated children (25.0% vs 7.7%, P 5 0.0095). There were no instances of serious respiratory depression. Rectal DZP was demonstrated to be an effective and safe treatment to abort an episode of ARS in a child and, additionally, lessened the likelihood of seizure recurrence within the next 12 hours. © 1999 by Elsevier Science Inc. All rights reserved. Kriel RL, Cloyd JC, Pellock JM, et al. Rectal diazepam gel for treatment of acute repetitive seizures. Pediatr Neurol 1999;20:282-288.

Introduction Some children with recurrent seizures periodically exhibit characteristic episodes of repetitive seizures distinct

Affiliations for the authors of the study can be found on p. 285.

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from their usual seizure pattern. Terms used for this phenomenon in the past century include serial, cluster, recurrent, and repetitive seizures, and most recently, acute repetitive seizures (ARS) [1-4]. Characteristics of ARS are listed in Table 1. These were developed by a panel convened by Athena Neurosciences in 1995. Persons with epilepsy and ARS have predictable episodes of recurrent seizures that occur under particular circumstances. An ARS episode may last from minutes to hours but rarely for more than 1 day. Between episodes of ARS, patients typically return to their baseline seizure frequency and usual level of function. Parents and caregivers frequently recognize the onset of ARS because there are typical features for that particular child. Benzodiazepines (BZDs) are considered the treatment of choice for the acute management of severe seizures [5]. BZDs are active against a wide range of seizure types, have a rapid onset of action once delivered into the central nervous system, and are safe. Oral diazepam (DZP) and lorazepam (LZP), sublingual LZP, rectal solutions of DZP and LZP, and DZP suppositories have been used to treat ARS [6-10]. Oral and sublingual administration is frequently difficult, impossible, or hazardous when the patient is actively having a seizure or is in a postictal state. Also, absorption after oral administration of tablets is usually slower than after rectal administration of solutions [11-13]. DZP when given rectally as a solution possesses most of the aforementioned characteristics. It has high lipid solubility, resulting in prompt absorption after rectal administration, and it rapidly enters the central nervous system [14,15]. In children, peak blood concentrations after rectal administration of DZP solution are usually achieved within 3-30 minutes, and bioavailability averages 80-

Communications should be addressed to: Dr. Kriel; Hennepin County Medical Center; Box 867B; 701 Park Avenue South; Minneapolis, MN, 55415. Received September 2, 1998; accepted December 8, 1998.

© 1999 by Elsevier Science Inc. All rights reserved. PII S0887-8994(98)00156-8 ● 0887-8994/99/$20.00

Table 1.

Defining characteristics of acute repetitive seizures*

Acute repetitive seizures Are severe Are a predictable component of a patient’s seizure disorder Are historically distinct from the patient’s other seizures in either type, frequency, severity, or duration Have an onset that is easily recognized by the family and physician Demonstrate patient recovery between seizures Have a consistent component (such as an aura, prodrome, or characteristic single or multiple seizures) that is predictable and temporally linked to subsequent seizures Are a constellation of seizures also called recurrent, serial, cluster, or crescendo seizures * Consensus statement of an expert panel convened by Athena Laboratories in Houston, Texas, October 2, 1995: F.E. Dreifuss, MD; M. Duchowny, MD; J.A. Ferrendelli, MD; J. French, MD; A. Krumholz, MD; T.A. Pedley, MD; J. Pellock, MD; N. Santilli, MSN, PNP; and S. Shinnar, MD, PhD.

100% [6,15-18]. After rectal administration, DZP in plasma equilibrates with muscle and fat tissue during the absorption phase; this reduces both the peak concentration (limiting the potential for toxicity) and the rapid decline in brain concentration that occurs after intravenous administration [14]. By contrast, DZP suppositories demonstrate slower and more erratic absorption, which limits efficacy in the acute management of severe seizures and ARSs [11]. To assess the value of home treatment of ARS, the National Institute of Neurological Disorders and Stroke and Athena Neurosciences conducted a clinical trial to assess the efficacy and safety of a DZP rectal gel delivery system (Diastat) in children and adults. Subsequently, Athena Neurosciences sponsored a second independent clinical study. The results of these studies have been published in separate reports [19,20]. In the present report the authors summarize the combined data of the children from these two studies. Combining this pediatric data provided a larger sample size and also included adolescents. The larger sample size permitted an analysis of the incidence of adverse reactions, the number of children seizure free, and the relationship of response to the number of doses, which was not possible in the initial reports. Methods Children in this report are a subset of patients enrolled in either the initial NINDS clinical trial (study one) [19] or the subsequent clinical trial sponsored by Athena Neuroscience study (study two) [20]. The study protocols were identical, except as indicated below. Patients. ARS was defined as an episode of multiple seizures of complex partial or generalized type (tonic, clonic, tonic-clonic, atypical absence, or myoclonic) occurring within a 12-hour period and distinguishable by the patient’s caregiver as distinct from the child’s usual seizure pattern. Eligible patients enrolled included males and females who were 2-17 years of age, with a maximal body weight of 111 kg. Patients needed to have had at least four (study one) or two (study two) ARS episodes within the previous year, with one episode within the previous 6 months. Additional inclusion criteria were stable antiepileptic drug (AED) dosage for at least 2 weeks before enrollment; a cranial

computed tomography scan or magnetic resonance imaging study, without evidence of a treatable cause for the seizures; and, for females of childbearing potential, a negative pre-enrollment pregnancy test and on-going contraception. Exclusion criteria were phenobarbital concentrations greater than 30 mg/L; current chronic treatment with drugs other than AEDs; central nervous system depressants, concurrent use of drugs known to alter DZP pharmacokinetics or pharmacodynamics; long-term administration of BZDs (study one); nonepileptic seizures within the past 5 years; habitual progression to status epilepticus; a significant psychiatric disorder; lack of a suitable caregiver; or use of an investigational drug or device within the past 5 months. In study one, previous treatment with rectal DZP was an exclusion criterion, except for a single episode given by someone other than the current caregiver. Once enrolled, all children underwent physical, neurologic, and rectal examinations, as well as laboratory evaluations. The protocol and consent forms were approved by each center’s Institutional Review Board. Parents or legal guardians provided written informed consent and, when appropriate, the child’s assent was also obtained. Study Medication. Active and placebo medications were supplied by the sponsor in prefilled, identically appearing syringes with rectal tips and lubricant. The DZP gel was a viscous solution (Diastat) in a concentration of 5 mg/mL. DZP doses available for patients ranged from 2.5-20 mg in 2.5-mg increments in study one, and 5-20 mg in 5-mg increments in study two. The dose for each patient was based on age and weight. The targeted doses were 0.5 mg/kg for ages 2-5 years, 0.3 mg/kg for ages 6-11 years, and 0.2 mg/kg for those 12 years and older. In study one, children received a second dose 4 hours after the initial treatment. The study medication package for these patients included a replacement dose syringe, containing one half the regular dose. Caregivers were instructed to administer the replacement dose if the initial dose was expelled within 5 minutes of administration. Patients in study two received only one treatment. Study Design. A prospective, double-blind, placebo-controlled design was used in both studies. Patients were randomized by age and site. Investigators, nurse coordinators, patients, caregivers, and clinical monitors were unaware of whether the patient was receiving DZP or placebo. Site pharmacists and statisticians knew what patients were receiving. The blind was not broken until the last patient completed the study, except for one placebo-treated patient who required emergency room treatment for status epilepticus. Study Procedures. When a potential patient was identified by the investigator, the child’s complete seizure history was reviewed with the caregiver. The caregiver and physician characterized the child’s ARS episodes and specified the criteria for treatment. The study nurse instructed the caregiver on study procedures, which included identification of the ARS onset, administration of study medication, and monitoring and recording of respiration, skin color, seizures, and any adverse events. Caregivers also viewed a video that reinforced the nurse’s instructions. Each caregiver received a kit containing the study medications, a booklet with a summary of instructions for drug administration, and data collection forms. A study nurse maintained contact with each caregiver by telephone at 2-week intervals until an ARS episode was treated. Caregivers returned to the study center every 3 months for a brief review of study procedures. The caregiver initiated treatment when an ARS episode was identified. During the treatment period a study nurse or physician was available by pager and for telephone consultation and clinical monitoring. The observation period for seizures and safety assessments began after the first dose and continued for 12 hours. Caregivers and patients returned to the clinic within 72 hours of treatment for reassessment of the child’s clinical and laboratory status. At that time the study nurse reviewed the caregiver’s booklet. All subjects who completed treatment for an ARS episode were eligible to enroll in an open-label, follow-up study. Efficacy Variables. Efficacy variables were selected from those common to both original studies: seizure frequency, time to next seizure, and caregiver’s global evaluation of outcome. Seizure count began 15 minutes after dose administration. In study one, global evaluations were

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based on a three-point scale (better, same, and worse); in study two, global evaluations were based on a 10-cm visual analog scale (0 5 much worse than before and 10 5 much better than before). Safety. At the post-treatment visit the study nurse and caregiver reviewed the caregiver’s booklet. Any adverse events were recorded on the case report forms. Adverse events were reported using the Coding Symbols for Thesaurus of Adverse Reaction Terms preferred terms [21]. Respiratory rates of less than 12 were considered to be below an acceptable limit. Serious adverse events were defined by Food and Drug Administration criteria (death, immediately life threatening, hospitalization required, permanently disabling, causing cancer or congenital anomaly, or drug overdose). Statistical Analysis—Data set. Data from studies one and two were combined. Unless otherwise noted, all analyses were performed with combined data. Statistical analysis— demographic and baseline characteristics. The demographic and baseline variables, sex, age, age group (2-5, 6-11, and 12-17 years), race, weight, seizure etiology, ARS frequency, and seizure type (complex partial vs generalized) were analyzed for comparability between DZP- and placebo-treated groups. Sex, age group, and race were analyzed with a chi-square test. Baseline values of age and weight were analyzed using a two-sample t test. Each seizure etiology was analyzed with a chi-square test. If any of the expected subgroups was less than 5, however, Fisher’s Exact Test was employed. ARS frequency at baseline was analyzed with a Wilcoxon rank-sum test because the data were not normally distributed. The analysis of seizure types was performed with a chi-square test. Efficacy analyses. The seizure count was the number of seizures within an ARS episode after treatment with the study medication. Seizure frequency was reported as the number of seizures per hour. Differences in seizure frequency were analyzed separately for treatment, sex, and age group (2-11 or 12-17 years) with a Wilcoxon rank-sum test because the data were not normally distributed. A chi-square test was used to detect treatment group differences in the number of patients who were seizure free during the observation period. Differences in time to next seizure were graphically presented using Kaplan-Meier curves. The modified Wilcoxon test, stratified by age group (2-11 and 12-17 years), was used to compare time to first seizure between treatment groups. Global assessment was analyzed separately for each of the two studies. In study one an exact test was used to detect treatment differences, in study two the van Elteren extension to the Wilcoxon rank-sum test was used. Safety analysis. Treatment group differences in rates of adverse events were analyzed using Fisher’s Exact Test. Respiratory function in the two groups was assessed by comparing median respiratory rates using the Wilcoxon rank-sum test. In addition, minimal respiratory rates (i.e., less than 12/minute) and all adverse respiratory events were reviewed. Exploratory analyses. Exploratory analyses were performed to detect any benefit from receiving an extra DZP dose 4 hours after the first dose. A Wilcoxon rank-sum test, stratified by sex, was used to analyze differences in seizure frequency rates. Comparisons of the one- vs two-dose groups were made for the 0-3, 4-12, and 0-12 hour periods. Another set of analyses compared the 0-3 hour period with the 4-12 hour period for each child who received a single dose of DZP. NcNemar’s paired test was used to determine whether the proportion of patients experiencing no seizures during the 0-3 hour period was different than the proportion experiencing no seizures during the 4-12 hour period. A Wilcoxon signed rank-sum test was used to assess differences in seizure frequency between the two periods. To detect any effect of chronic BZD administration for children in study two, a Wilcoxon rank-sum test compared seizure frequency rates for children receiving maintenance BZDs with other children. Fisher’s Exact Test compared differences in emergency medical treatment between the DZP and placebo groups.

Results A total of 185 children were enrolled, 96 randomized into the DZP treatment arm and 89 into the placebo

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Table 2.

Demographics of patients

Males Females Age (yr) 2-5 6-11 12-17 Mean age (yr) Race White Black Other

DZP-Treated (n)

Placebo (n)

Total (n)

42 (62) 26 (38)

23 (35)* 42 (65)

65 (49) 68 (51)

14 (21) 25 (37) 29 (43) 10.2

25 (38) 21 (32) 19 (29) 8.6

39 (29) 46 (35) 48 (36) 9.4

48 (71) 14 (21) 6 (8)

55 (84) 5 (8) 5 (8)

103 (77) 19 (14) 11 (9)

Numbers in parentheses are percentages. * Chi-square test, P 5 0.002. Abbreviation: DZP 5 Diazepam

treatment arm. The only demographic difference between the DZP vs placebo groups was the preponderance of males in the DZP-treated group (Table 2). Etiologies of the underlying seizure disorder did not differ in the DZP- vs the placebo-treated children. The median number of ARS episodes at time of enrollment was two per month in the DZP-treated group vs three per month in the placebotreated group; these differences were not statistically significant. There were no differences in the frequency of seizure types seen in the ARS events (i.e., complex partial vs generalized) in the DZP- vs placebo-treated children. Sixty-eight of the children (71%) in the DZP arm completed treatment compared with 65 of the placebotreated children (73%). Two of the DZP group and one of the placebo group did not complete the study because of adverse events. Physical and neurologic examinations, laboratory studies, and hemoccult analysis of fecal specimens were no different after treatment between the two groups. Twenty-three of the DZP group (24%) vs 21 of the placebo group (24%) discontinued without treatment, primarily because an ARS episode did not occur during the study. At the conclusion of the investigation, 76% of DZP-treated and 85% of placebo-treated subjects elected to enroll in the open-label study. There was a significant reduction in seizure frequency in children who received DZP compared with the placebo group (Fig 1). The median number of seizures per hour in the DZP-treated group was 0 vs 0.25 seizures per hour in the placebo group (P 5 0.001). In addition, significantly more DZP-treated children remained seizure free during the 12-hour observation period (59% vs 31%, P 5 0.001). DZP exerted a prompt therapeutic effect that persisted throughout the observation period (Fig 2). Time to the next seizure was significantly longer in DZP-treated than in placebo-treated children (P 5 0.0002; Fig 2). There was no difference in seizure frequency with regard to sex or age. In study one, there was a significant

Figure 1. Seizure frequency (median number per hour) after treatment. Wilcoxon rank-sum test, P 5 0.001.

improvement in the caretaker’s global evaluation in the DZP vs placebo groups (P , 0.001). In study two a significant difference in the global evaluation was not seen (P 5 0.053). Children who received two DZP doses had a lower seizure frequency than those receiving one DZP dose for both the 4-12, and 0-12 hour periods (P , 0.001 and P 5 0.011). The children who received a single DZP dose did not demonstrate a significant difference in remaining seizure free during the 0-4 vs 4-12 hour periods (71% vs

56%). In study two, there was no difference in seizure frequency in children receiving chronic BZDs vs other children (P 5 0.599). Somnolence was the only adverse event that occurred significantly more frequently in the DZP-treated children (P 5 0.0095). Adverse events occurring in more than 3% of subjects are listed in Table 3. Serious adverse events occurred in six children, four of whom were in the DZP-treated group. One of these children received an excessive DZP dose because of a prescribing error, with-

Figure 2. Kaplan-Meier survival curves for time to next seizure. Modified Wilcoxon test stratified by age, P 5 0.0002.

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Table 3.

Adverse events (occurring in 3% or more patients)

Adverse Event

Diazepam (n)

Placebo (n)

P Value*

Somnolence Fever Headache Diarrhea Convulsion† Ataxia Incoordination Skin reaction Pain (rectal) Nervousness Anorexia Rhinitis Otitis media

17 (25) 0 (0) 4 (5.9) 4 (5.9) 1 (1.5) 3 (4.4) 3 (4.4) 3 (4.4) 3 (4.4) 2 (2.9) 1 (1.5) 2 (2.9) 0 (0)

5 (7.7) 4 (6.2) 2 (3.1) 0 (0) 3 (4.6) 1 (1.5) 0 (0) 0 (0) 2 (3.1) 2 (3.1) 2 (3.1) 2 (3.1) 2 (3.1)

0.01 0.05 0.68 0.12 0.36 0.62 0.24 0.24 1.00 1.00 0.61 1.00 0.24

Numbers in parentheses are percentages. * P value is from a treatment comparison using Fisher’s Exact Test. † Reported as adverse events when more severe than expected.

out recognized clinical consequence. According to Food and Drug Administration criteria, that event was a serious adverse event. The other serious adverse events were continuing seizures. One death occurred in a placebotreated child and was determined not to be study related. Fewer DZP- than placebo-treated children received emergency medical treatment during an ARS episode (4.4% vs 15.4% P 5 0.042). There were no reports of severe respiratory depression necessitating emergency medical care in either group. One DZP- and one placebo-treated child had respiratory rates of 11 per minute, but the median respiratory rates did not differ in the DZP- vs placebo-treated children (Table 4). Discussion The authors analyzed the combined pediatric data from two double-blind, randomized, placebo-controlled studies of the efficacy and safety of rectal DZP for ARS. DZP significantly reduced the number of subsequent seizures, with 59% of DZP-treated patients remaining seizure free throughout the 12-hour observation period. Additionally, the rectal DZP was well tolerated. Optimal treatment of ARS has not been previously defined. Before this study the authors’ patients had been Table 4.

Respiratory rates after treatment

Time after Dose (min) 15 30 60 120

Respiratory Rate per Minute Diazepam Placebo Median Minimum Median Minimum 22 22 20 20.5

13 12 12 11

22 22 22 21

12 12 13 11

No significant differences in median respiratory rates were observed.

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treated with any or all of the following: extra doses of their usual AEDs, oral or intravenous BZDs, off-label rectal use of parenteral DZP, expectant observation at home, or management in emergency facilities. These approaches are of unproved efficacy, costly, or disruptive to the family. Risks and costs associated with treatment in emergency facilities are substantial [22]. These disadvantages are obviated with the use of a DZP formulation specifically designed for rectal administration at home. Adverse effects were few, and most were not clinically important. Somnolence, expected with an acute dose of a BZD, was the only adverse effect seen significantly more often in DZP-treated patients. No child experienced serious respiratory compromise after treatment with rectal DZP. Chronic administration of other AEDs, including phenobarbital with serum levels not exceeding 30 mg/mL, and maintenance BZD therapy did not affect the efficacy or safety of rectal DZP. ARS encompass all seizure types. It is a predictable seizure pattern with a definable, predictably repetitive component. ARS need to be carefully described and defined by both medical staff and family. Some children with ARS have relatively good seizure control until intercurrent illness, stress, or other factors cause breakthrough seizures that are recognizable by the family as likely to result in continuing seizure activity (i.e., an episode of ARS). Other children have severe, chronic epilepsy, with periodic exacerbation. Effective home therapy in such cases helps to reduce costs, emergency room visits, and disruption of family activities and empowers the family [22]. Ensuring comparability of the authors’ data from different medical centers required a rigid definition of ARS and intensive training of caregivers. Clinical use will still require instruction of caregivers. Parents must be able to recognize an episode of ARS in their child and then administer the medication. Identification of ARS onset requires discussion and collaboration by family members and physicians, because the definition of ARS is specific to each child. Safe use of rectal DZP will require that the family and the physician also have an established plan for emergency intervention in the event of treatment failure or an adverse event. In addition, patients may need to be assessed after treatment for any precipitating events, such as a febrile illness, intoxication, or head injury. In study one, patients received two doses and in study two a single dose. These studies were not designed to determine efficacy of one vs two DZP doses. Nonetheless, exploratory analysis suggests that for some children a second DZP dose might be beneficial in terminating the ARS episode. The authors suggest that the physician initially instruct the caretaker to use one DZP dose. If experience demonstrates that the ARS episodes are not adequately controlled, a second dose may be administered approximately 4 hours later, because safety of this dose regimen has been demonstrated.

In children, rectally administered DZP solution should reach therapeutic serum concentrations in 3-7 minutes, with peak levels usually within 4-10 minutes after administration [6]. Thus the authors began seizure counts 15 minutes after administration. Parents and physicians should be aware that seizures occurring within the first few minutes after administration are not necessarily an indication of treatment failure. There are several unique benefits to rectal DZP gel (Diastat). Efficacy and safety have been demonstrated in these well-controlled clinical studies. Administration does not require the handling or use of glass ampules, needles, or syringes, and the potential for dose errors or abuse is minimized. These considerations have sharply limited the number of children with ARS for which off-label DZP treatment could be offered. Rectal DZP gel avoids these risks, making home treatment of ARS episodes more accessible to a much larger number of children and adolescents. Although usage of emergency facilities was not a primary efficacy outcome measure, only one third as many DZP-treated patients in the authors’ study required emergency treatment. The increased control and autonomy improves the family’s quality of life. Although not every patient responded to rectal DZP in these studies, most families elected to enroll in the subsequent openlabel study to ensure continued access to the study medication. The authors’ experience adds to that of others who have demonstrated that home therapy can be safe and effective for treatment of acute seizure conditions, reducing the need for more costly emergency medical care [6,22,23]. The studies reported here were supported by contracts from the Epilepsy Branch, National Institute of Neurological Disorders and Stroke, and Athena Neurosciences, Inc. The authors thank Robert Freeman of Upsher Laboratories, Ilo Leppik, MD of MINCEP, and Tom Rector, PhD of United Health Care, Minneapolis, without those contributions and insight this investigation would not have been possible. The authors are grateful to Walter E. Bell, PhD of the Epilepsy Branch of NINDS for his review of the manuscript. In addition the authors wish to acknowledge the following individuals for their participation in various phases of this involved clinical trial: Lee A. Adelman; Peter A. Ahmann, MD; E. Martina Bebin, MD; Marjorie Berg; Carolyn Belz, CRNP; Sarah Borror, RN; Michael N. Boyd, PhD; Patricia L. Bruno, RN, BS; Debbie Carson, RN; Mary Chu, RN; Susan M. Driscoll-Bannister; William R. Garnett, PhD; Lesley Groves, PhD; Cheryl Hall, RN; Christi Harker, RN; Peggy Hugger; Cherri B. Hughes; Carolyn Jones-Saete, RN; Linda Kraemer, LPN; Ruben I. Kuzniecky, MD; Lorraine Lazar, MD; Warren D. Lo, MD; Susan Melamed, RN, MSN, CRNP; Kim M. Merner; Suzanne O’Donnell Murphy, RN, MSN, CRNP; Kathryn A. O’Hara; Betty Y. Ong, MD; Jan L. Paolini, RN, MS; Frank J. Ritter, MD; Nancy Santilli, MSN, PNP; Gloria Schallert; Roberta Homzie Schlesinger; Cathy Schumer, RN; Paulette Snider, RN; Georgia Thompson, RN; Christie Tilton; Edwin Trevathan, MD; and Dana B. Vrcan. From the *Hennepin County Medical Center; †University of Minnesota; Minneapolis, Minnesota; ‡Medical College of Virginia; Richmond, Virginia; §Children’s Hospital of Los Angeles and University of Southern California; Los Angeles, California; \Oregon Health Sciences University Epilepsy Center; Portland, Oregon; ¶New England Medical Center, Boston, Massachusetts; #University of Virginia Health Sciences Center; Charlottesville, Virginia (deceased); **University of Alabama

School of Medicine; Birmingham, Alabama; ††Children’s Mercy Hospital; Kansas City, Missouri; ‡‡Columbus Children’s Hospital; Columbus, Ohio; §§University of British Columbia; Vancouver, British Columbia, Canada; \ \Children’s Medical Center, Dallas, Texas; ¶¶Scottish Rite Children’s Medical Center; Atlanta, Georgia; ##University of Arkansas for Medical Sciences; Little Rock, Arkansas; ***Children’s Hospital and Medical Center; Seattle, Washington; †††Children’s Hospital of Pittsburgh; Pittsburgh, Pennsylvania; ‡‡‡Vanderbilt University; Nashville, Tennessee; §§§New York Hospital-Cornell Medical Center; New York, New York; \ \ \Cleveland Clinic Foundation; Cleveland, Ohio; ¶¶¶International Center for Epilepsy; Miami, Florida; ###Rush/Presbyterian/St. Luke’s Medical Center; Chicago, Illinois; ****Children’s Hospital of Philadelphia; Philadelphia, Pennsylvania; ††††Children’s National Medical Center; Washington, District of Columbia; ‡‡‡‡Colorado Neurological Institute Epilepsy Center, Englewood, Colorado; §§§§Pharmaceutical Research Associates, Inc.; Charlottesville, Virginia.

Appendix: Members of the North American Diastat Study Group *Fritz E. Dreifuss, MD#, Edward Faught, MD**, Jerome Murphy, MD††, Chang-Yong Tsao, MD‡‡, Kevin Farrell, MB§§, Anthony R. Riela, MD\ \, Raymond Cheng, MD¶¶, Gregory B. Sharp, MD##, Jacqueline R. Farwell, MD***, Patricia K. Crumrine, MD†††, Bassel W. Abou-Khalil, MD‡‡‡, Abraham M. Chutorian, MD§§§, Prakash Kotagal, MD\ \ \, R. Eugene Ramsay, MD¶¶¶, Donna C. Bergen, MD###, Lawrence W. Brown, MD****, Joan A. Conry, MD††††, Ronald E. Kramer, MD‡‡‡‡, and P. Christopher Holland, MS§§§§

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