ORIGINAL CONTRIBUTION. Rectal Diazepam Gel for Treatment of Acute Repetitive Seizures in Adults

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1 ORIGINAL CONTRIBUTION Rectal Diazepam Gel for Treatment of Acute Repetitive Seizures in Adults James J. Cereghino, MD; James C. Cloyd, PharmD; Ruben I. Kuzniecky, MD; for the North American Diastat Study Group Objective: To evaluate the efficacy and tolerability of diazepam (DZP) rectal gel (Diastat; Elan Pharmaceuticals, Dublin, Ireland) for the treatment of acute repetitive seizures in adult patients in 2 multicenter, doubleblind, placebo-controlled parallel studies. Methods: Ninety-six adults 18 years or older with acute repetitive seizures, 70 of whom received treatment, were randomized into the 2 studies. Active and placebo medications were supplied in prefilled, identical-appearing delivery systems. In study 001, patients received a second dose 4 hours after the initial treatment. Patients in study 003 received only 1 treatment. Patients were observed for 12 hours after the first dose. Results: There was a significant reduction in seizure frequency in patients who received DZP compared with the placebo group. The median number of seizures per hour in the group treated with DZP rectal gel was 0.00, vs 0.13 in the placebo group (P=.002). In addition, significantly more DZP rectal gel treated patients remained seizurefree during the 12-hour observation period (71% [22/31] vs 28% [11/39]). Using Kaplan-Meier life-table analysis, time to the next seizure was found to be significantly longer in DZP rectal gel treated than placebo-treated patients (P.001). Global assessment as provided by the caregivers was in favor of DZP rectal gel for both study 001 (P=.17) and study 003 (P=.02). Dizziness and somnolence were the only central nervous system adverse events that occurred more frequently in patients receiving DZP rectal gel than in those receiving placebo. Conclusion: In adults, rectal DZP formulated as Diastat significantly reduced the likelihood of seizure recurrence during an episode of acute repetitive seizures, with minimal safety concerns. Arch Neurol. 2002;59: Author affiliations are listed at the end of the article. A list of the members of the North American Diastat Study Group appears in a box on page SOME ADULTS with epilepsy periodically exhibit characteristic episodes of repetitive seizures distinct from their usual seizure pattern. Terms used for this seizure phenomenon in the past century include serial, cluster, recurrent, and repetitive, and most recently, acute repetitive seizures (ARS). 1-4 Characterized as a severe, predictable component of a patient s seizure disorder, ARS as defined jointly by the physician and caregiver is easily recognized. It is historically distinct from the patient s other seizures in either type, frequency, severity, or duration. An ARS episode may last from minutes to hours but rarely for more than 1 day. Its onset may have a consistent predictable component (eg, aura or prodrome) temporally linked to subsequent seizures. 5 This condition may diminish the function and quality of life for the patient and family. Benzodiazepines are considered the treatment of choice for the short-term management of severe seizures. 6 This class of drugs is active against a wide range of seizure types, has a rapid onset of action once delivered into the central nervous system, and is relatively safe. Diazepam (DZP), oral or rectal, and lorazepam (oral, sublingual, and rectal) have been used to treat ARS Midazolam hydrochloride by intramuscular administration has been used in hospital settings; it has also been used intranasally. However, midazolam is not formulated for this route, the solution may be irritating, and the required dose of several milliliters has not been fully explored for the potential for aspiration Oral, buccal, and sublingual administration are frequently difficult, impossible, or hazardous when the patient is in the middle of a seizure or in a postictal state. In addition, drug absorption after oral administration of tablets is substantially slower than after rectal administration of solutions When given rectally as a solution, DZP has several attractive properties relevant to the treatment of ARS. It is highly lipid soluble, resulting in prompt absorption, and 1915

2 it rapidly enters the central nervous system. 19,20 Peak blood concentrations after rectal administration of a DZP solution are usually achieved within 3 to 30 minutes, and bioavailability averages 80% to 100%. 7,20-23 After absorption from rectal administration, plasma DZP levels equilibrate with levels in the brain, muscle, and fat tissues. This process reduces both the peak concentration (limiting the potential for toxicity) and the rapid decline in brain concentration that occurs after intravenous administration. 19 Diazepam suppositories display slower and more erratic absorption, limiting efficacy and reliability in this setting. 16 In an effort to provide effective therapy that can be administered by a nonmedical caregiver, a viscous formulation of DZP has been developed for rectal use (Diastat; Elan Pharmaceuticals, Dublin, Ireland). The rectal delivery system includes a plastic applicator with a flexible, molded tip available in pediatric and adult lengths and a dosage range suitable for small children to large adults. In a clinical pharmacokinetic study, Diastat produced a rapid, consistent absorption of DZP and was well tolerated.minimallyeffectiveconcentrationswereachievedwithin 15 minutes, and maximum concentrations within 45 minutes. The absolute bioavailability of rectally administered DZP gel was 90.4%, with a range of 70.8% to 110.0%. 19 To assess the value of home treatment of ARS, the National Institute of Neurological Disorders and Stroke (Bethesda, Md) conducted a clinical trial to assess the efficacy and safety of the DZP rectal gel delivery system in adults and children. Subsequently, the manufacturer sponsored a second independent clinical trial. The results of these studies have been published in separate reports. 24,25 In this article, we summarize the combined data of the adults from these 2 studies; combining the data provided a larger sample size. Although the methods were somewhat different, the definitions of the main end points were sufficiently similar to allow us to compare the effects of DZP rectal gel with placebo. The larger sample size permitted an analysis of the incidence of adverse effects and the number of seizure-free adults, which was not possible in the initial reports. METHODS This article contains a subset of patients enrolled in both the initial clinical trial by the National Institute of Neurological Disorders and Stroke (study 001: Rectal Administration of Diastat for Acute Repetitive Seizures) 25 and the subsequent clinical trial (study 003) sponsored by Athena Neurosciences, Inc, South San Francisco, Calif (now Elan Pharmaceuticals). 24 Adult patients were considered to be those 18 years or older; this is slightly different from the original reports, in which the cutoff was 15 years or older for study 001 and 12 years or older for study 003. Data from the pediatric subset of these patients (aged 2-17 years) were reported separately. 5 The 2 study protocols were identical except as indicated in this section. The methods for these studies may be found in detail in the previous reports. 24,25 A brief summary of the methods is presented as follows. Both studies were prospective, multicenter, doubleblind, placebo-controlled parallel trials. Patients were randomized by age and site using a computer-generated code at the time of admission to the study. We defined ARS as an episode of multiple seizures of a complex partial or generalized type (tonic, clonic, tonicclonic, atypical absence, or myoclonic) occurring within the observation period and distinct from the patient s usual seizure pattern as determined by the caregiver. Patients must have had at least 4 (study 001) or 2 (study 003) ARS episodes within the previous year, and 1 episode within the previous 6 months. All patients were refractory and continued to have seizures even though most received polytherapy at optimal doses of each antiepileptic drug. The protocol and consent forms were approved by each center s institutional review board. Patients or legal guardians provided written informed consent. Active and placebo medications were supplied by the manufacturer in prefilled, identical-appearing delivery systems with rectal tips and lubricant. Two tip sizes were made: 4.4 cm and 6.0 cm. The targeted dose was 0.2 mg/kg. In study 001, patients received a second dose 4 hours after the initial treatment; patients 15 years or older received a third dose 12 hours later. Patients in study 003 received only 1 treatment. 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 in study 001 for 12 hours for children younger than 15 years, and for 24 hours for those 15 years and older. The observation period for all patients in study 003 was 12 hours. Efficacy variables were selected from those common to both original studies: seizure frequency, time to next seizure, and caregiver s global evaluation of outcome. In study 001, caregivers began recording seizures immediately following administration of the study medication, whereas in study 003, this began 15 minutes following administration. When data from the 2 studies were combined, however, data collected during the first 15 minutes in study 001 were not included. In study 001, global evaluations were based on a 3-point scale (better, same, or worse); in study 003, global evaluations were based on a 10-cm visual analog scale (0=much worse than before; 10=much better than before). At the posttreatment visit, the study nurse and caregiver recorded adverse events. Respiratory rates of less than 10 respirations per minute were considered to be lower than the 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). Categorical demographic measures were analyzed for comparability between treatment groups with a 2 test, whereas continuous measures were analyzed using a 2-sample t test. Seizure count was defined as the number of seizures within an ARS episode starting 15 minutes after treatment with the study medication. Seizure frequency was reported as the number of seizures per hour and was analyzed with a Wilcoxon rank sum test because the data were not normally distributed. A 2 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. A modified Wilcoxon test was used to compare time to first seizure between treatment groups. Because of differences in measurement systems, probability for global assessment was measured in study 001 with a Fisher exact test and in study 003 with a van Elteren extension to the Wilcoxon rank sum test. RESULTS We enrolled 96 adults; 42 were randomized into the DZP rectal gel treatment arm, and 54 into the placebo treatment arm. Of these 96 patients, 70 experienced an ARS episode and were treated with the test medication (DZP rectal gel: 74% [31/42]; placebo: 72% [39/54]). The de- 1916

3 Table 1. Demographics of Randomized Patients* Characteristic Diazepam (n = 31) Placebo (n = 39) All (N = 70) P Value Age, y.73 Mean ± SD 29.1 ± ± ± 10.9 Range Sex.40 F 15 (48.4) 15 (38.5) 30 (42.9) M 16 (51.6) 24 (61.5) 40 (57.1) Race.31 White 25 (80.7) 36 (92.3) 61 (87.1) African American 4 (5.7) 2 (5.1) 6 (8.6) Hispanic... 1 (2.6) 1 (1.4) Asian American 1 (3.2)... 1 (1.4) Other 1 (3.2)... 1 (1.4) *Data are presented as number (percentage) unless otherwise indicated. Ellipses indicate not applicable. P values were determined using a t test for continuous measures and a 2 test for categorical measures. mographics of the treated patients are presented in Table 1. There were no statistically significant differences between treatment groups according to these measures (sex: P=.34; race: P=.43; age: P=.61). There was a significant reduction in seizure frequency in patients who received DZP rectal gel compared with the placebo group (Table 2). The median number of seizures per hour in the DZP rectal gel treated group was 0.00, vs 0.13 in the placebo group (P=.002). In addition, significantly more DZP rectal gel treated patients remained seizure-free during the 12- hour observation period (71% [22/31] vs 28% [11/39]). The DZP rectal gel exerted a prompt therapeutic effect that persisted throughout the observation period (Figure). Time to the next seizure as measured using Kaplan-Meier life-table analysis was significantly longer in DZP rectal gel treated than placebo-treated patients (P.001). Global assessment as provided by the caregivers was in favor of DZP rectal gel for both study 001 (P=.17) and study 003 (P=.02) (Table 3). The proportion of patients who remained seizurefree in study 001 (multiple dose) was 73% (8/11) vs 15% (3/20) in the DZP rectal gel and placebo groups, respectively. Thus, the treatment effect (DZP rectal gel minus placebo) was 58%. The proportion of patients who remained seizure-free in study 003 (single dose) was 70% (14/20) vs 42% (8/19) in the DZP rectal gel and placebo groups, respectively, for a treatment effect of 38% (Table 2). The proportion of patients experiencing at least 1 adverse event was higher (32% [10/31]) in the DZP rectal gel treated group than in the placebo-treated group (23% [9/39]). Somnolence and dizziness were the only central nervous system adverse events that occurred more frequently in the patients receiving DZP rectal gel than in those receiving placebo (Table 4). The only serious adverse events occurred in 2 patients in the DZP rectal gel group who inadvertently received more than 180% of the intended doses. These resolved without incident. Two patients in the placebo group discontinued the study because of adverse events: Seizure-Free Patients, % Table 2. Median Seizures per Hour During Postdose Observation Period Diazepam Placebo P Value* Both studies Sample size Mean Median (range) 0.00 (0-1.8) 0.13 (0-11.8) Seizure-free, No. (%) 22 (71) 11 (28).001 Study 001 Sample size Mean Median (range) 0.00 (0-1.8) 0.13 (0-11.8) Seizure-free, No. (%) 8 (73) 3 (15).001 Study 003 Sample size Mean Median (range) 0.00 (0-1.3) 0.08 (0-0.83) Seizure-free, No. (%) 14 (70) 8 (42).08 *P values for mean seizures per hour were determined using a Wilcoxon 2-sample test, and for percent seizure-free using a 2 test Diazepam Placebo Time Postdose, h Kaplan-Meier survival curves for time to next seizure. P.001 using the 2 test. one patient was taken to the emergency department and did not receive all prescribed doses, and a second patient continued to have seizures during the observation period, became cyanotic, was treated with lorazepam at home, and had to discontinue the study prematurely. The only anorectal event occurred in 1 placebo-treated patient who reported rectal burning for approximately 1 minute. This patient had a history of prostate hypertrophy. The median respiratory rates were similar in the DZP rectal gel and placebo groups, and the minimum observed was lower in the placebo-treated group (Table 5). No DZP rectal gel treated patient had a respiratory rate lower than the criterion( 10 per minute) in either study. At least 2 placebo-treated patients (both in study 001) reached this criterion several times. There were no reports of severe respiratory depression necessitating emergency medical care in either treatment group. 1917

4 Table 3. Global Assessment Study 001* A B C Total Treatment Diazepam Placebo Study 003 Sample Size Median Mean Minimum Maximum Treatment Diazepam Placebo *In study 001, the overall evaluation was either A (better), B (same), or C (worse) (P =.17 using a Wilcoxon 2-sample test). Data are presented as number of patients. In study 003, global assessment was based on a visual analog scale from 0 to 10 (0 = much worse than before; 10 = much better than before) (P =.02). Table 4. Adverse Events* Diazepam (n = 31) Placebo (n = 39) All (N = 70) Subjects reporting at least 1 adverse event 10 (32) 9 (23) 19 (27) Body as a whole 1 (3) 5 (13) 6 (9) Abdominal pain 0 1 (3) 1 (1) Headache 1 (3) 2 (5) 3 (4) Pain 0 2 (5) 2 (3) Cardiovascular 0 1 (3) 1 (1) Palpitation 0 1 (3) 1 (1) Digestive 0 1 (3) 1 (1) Nausea 0 1 (3) 1 (1) Vomiting 0 1 (3) 1 (1) Hematic and lymphatic 0 1 (3) 1 (1) Cyanosis 0 1 (3) 1 (1) Nervous 7 (23) 4 (10) 11 (16) Agitation 1 (3) 0 1 (1) Dizziness 2 (6) 1 (3) 3 (4) Euphoria 1 (3) 0 1 (1) Hyperkinesia 1 (3) 1 (3) 2 (3) Somnolence 4 (13) 3 (8) 7 (10) Tremor 0 1 (3) 1 (1) Skin and appendages 1 (3) 0 1 (1) Sweating 1 (3) 0 1 (1) Urogenital 1 (3) 0 1 (1) Urinary tract infection 1 (3) 0 1 (1) *Subjects are counted only once in each event category per treatment and only once in each body system summary per treatment. Data are presented as number (percentage). Table 5. Respiratory Rates After Treatment* Diazepam Placebo Time After Dose, min Sample Size Median Minimum Sample Size Median Minimum *If the patient had more than 1 reading per time point, the mean value was obtained. Data are presented as respirations per minute. COMMENT When given intravenously to treat seizure emergencies, DZP is associated with a higher rate of adverse events in adults than seen in children. 26 Previous controlled clinical trials involving both adults and children have demonstrated that DZP rectal gel is safe and effective. 24,25 Given the differential response to DZP rectal gel in children and 1918

5 North American Diastat Study Group B. Abou-Khalil, MD; W. E. Bell, PhD; D. C. Bergen, MD; L. Brown, MD; R. Burgerman, MD; J. J. Cereghino, MD; R. Cheng, MD; J. C. Cloyd, PharmD; A. Chutorian, MD; J. A. Conry, MD; J. Cooper, MD; P. K. Crumrine, MD; F. E. Dreifuss, MD (deceased); K. Farrell, MB; J. Farwell, MD; E. Faught, MD; R. Finkel, MD; L. Groves, PhD; P. Kotagal, MD; R. Kramer, MD; R. L. Kriel, MD; R. I. Kuzniecky, MD; C. W. Lai, MD; R. Lesser, MD; W. D. Lo, MD; F. Matsuo, MD; W. G. Mitchell, MD; J. Murphy, MD; B. Parks, Jr, PhD; J. M. Pellock, MD; R. E. Ramsay, MD; A. R. Riela, MD; W. E. Rosenfeld, MD; N. P. Rosman, MD; G. B. Sharp, MD; M. K. Shellenberger, PhD; A. Spiegel, MD; E. Trevathan, MD; C. Y. Tsao, MD. adults, it is important to examine the outcomes associated with its use separately in adults. The treatment reduced the number of subsequent seizures, with 71% (22/ 31) of DZP rectal gel treated patients remaining seizurefree throughout the 12- to 24-hour observation period relative to 28% (11/39) of placebo-treated patients. This treatment effect was clinically and statistically significant. Considering the stratification by study, in which one used a single dose and the other used multiple doses, the evidence suggests that multiple doses may be more effective than a single dose. Additionally, DZP rectal gel was well tolerated. Adverse events were few, and most were not clinically important. Somnolence and dizziness, which are expected with the immediate administration of a benzodiazepine, were the only adverse events seen significantly more often in DZP rectal gel treated patients. No patient treated with DZP rectal gel experienced respiratory depression according to the study criterion ( 10 respirations per minute). We do point out, however, that these studies were not designed to evaluate the elderly population specifically and that the inclusion of elderly patients was only incidental to the general population. There are several unique benefits of a rectal DZP gel in the treatment of ARS. 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. The rectal DZP gel fills a need for more convenient and comfortable delivery systems. Home treatment of ARS episodes thus becomes accessible to a much larger number of patients. The increased control and autonomy provided by home treatment may improve both the patient s and family s quality of life. Our experience adds to that of others who have demonstrated that home therapy can be safe and effective for the treatment of acute seizure conditions, reducing the need for more costly emergency medical care. 7,27,28 Other controlled clinical trials with rectal DZP gel have demonstrated the value of this therapy in treating seizure emergencies. In summary, rectal DZP, formulated into a viscous gel as Diastat, is an effective and safe treatment to abort episodes of ARS in adults and additionally lessens the likelihood of seizure recurrence within the next 12 hours. The efficacy and safety of DZP rectal gel in adults was similar to that previously reported in children. 5 Accepted for publication June 6, From the Epilepsy Center, Oregon Health and Science University, Portland (Dr Cereghino); College of Pharmacy, University of Minnesota, Minneapolis (Dr Cloyd); and University of Alabama Epilepsy Center, Department of Neurology, University of Alabama at Birmingham (Dr Kuzniecky). Drs Cereghino, Cloyd, and Kuzniecky have served as consultants and speakers for Xcel Pharmaceuticals (San Diego, Calif) and/or Elan Pharmaceuticals (Dublin, Ireland). Dr Cereghino was an employee of the National Institute of Neurological Disorders and Stroke (Bethesda, Md) until Dr Cloyd has received research funding from Elan Pharmaceuticals and has stock options in Xcel Pharmaceuticals. Author contributions: Study concept and design (Drs Cereghino, Cloyd, and Kuzniecky); acquisition of data (Drs Cereghino, Cloyd, and Kuzniecky); analysis and interpretation of data (Drs Cereghino, Cloyd, and Kuzniecky); drafting of the manuscript (Drs Cereghino and Cloyd); critical revision of the manuscript for important intellectual content (Drs Cereghino, Cloyd, and Kuzniecky); administrative, technical, and material support (Drs Cereghino, Cloyd, and Kuzniecky); study supervision (Drs Cereghino and Kuzniecky). The studies mentioned in this article were supported by contracts from the Epilepsy Branch, National Institute of Neurological Disorders and Stroke, and Athena Neurosciences, Inc (now part of Elan Pharmaceuticals). Support for additional analyses was provided by Xcel Pharmaceuticals. Presented in part at the Annual Meeting of the American Epilepsy Society, San Diego, Calif, December 8, We acknowledge the contributions of Gary D. Novack, PhD, and Shawki Salem, PhD. Corresponding author and reprints: James J. Cereghino, MD, Oregon Health and Science University, Epilepsy Center CDW 3, 3181 SW Sam Jackson Park Rd, Portland, OR ( cereghin@ohsu.edu). REFERENCES 1. Aicardi J. Epilepsy in children. In: Epilepsy in Patients. New York, NY: Raven Press; 1994: Mitchell WG. Status epilepticus and acute repetitive seizures in children, adolescents, and young adults: etiology, outcome, and treatment. Epilepsia. 1996; 37(suppl 1):S74-S Malkowicz DE, Legido A, Jackel RA, Sussman NM, Eskin BA, Harner RN. Prolactin secretion following repetitive seizures. Neurology. 1995;45: Wallis W, Kutt H, McDowell F. Intravenous diphenylhydantoin in treatment of acute repetitive seizures. Neurology. 1968;18: Kriel RL, Cloyd JC, Pellock JM, et al. Rectal diazepam gel for treatment of acute repetitive seizures. Pediatr Neurol. 1999;20: Working Group on Status Epilepticus. Treatment of convulsive status epilepticus: recommendations of the Epilepsy Foundation of America s Working Group on Status Epilepticus. JAMA. 1993;270: Lombroso CT. Intermittent home treatment of status and clusters of seizures. Epilepsia. 1989;30(suppl 2):S11-S Schroeder MC, Wolff DL, Maister BH, et al. Lorazepam intensol for the management of hospitalized pediatric patients with epilepsy. Epilepsia. 1996;37:S Yager JY, Seshia SS. Sublingual lorazepam in childhood serial seizures. AJDC. 1988;142:

6 10. Garofalo EA, Hirschorn KA, Komarynski MA. Improved control of seizures clusters with rectal diazepam and lorazepam. Cleve Clin J Med. 1989;56: S Milligan NM, Dhillon S, Griffiths A, Oxley J, Richens A. A clinical trial of single dose rectal and oral administration of diazepam for the prevention of serial seizures in adult epileptic patients. J Neurol Neurosurg Psychiatry. 1984;47: Hanley DF, Kross JF. Use of midazolam in the treatment of refractory status epilepticus. Clin Ther. 1998;20: Rey E, Treluyer JM, Pons G. Pharmacokinetic optimization of benzodiazepine therapy for acute seizures: focus on delivery routes. Clin Pharmacokinet. 1999; 36: Towne AR, DeLorenzo RJ. Use of intramuscular midazolam for status epilepticus. J Emerg Med. 1999;17: Malinovsky JM, Lejus C, Servin F, et al. Plasma concentrations of midazolam after iv, nasal or rectal administration in children. Br J Anaesth. 1993;70: Moolenaar F, Bakker S, Visser J, Huizinga T. Biopharmaceutics of rectal administration of drugs in man IX: comparative biopharmaceutics of diazepam after single rectal, oral, intramuscular and intravenous administration in man. Int J Pharm. 1980;5: Greenblatt DJ, Divoll M, Harmatz JS, Shader RI. Pharmacokinetic comparison of sublingual lorazepam with intravenous, intramuscular, and oral lorazepam. J Pharm Sci. 1982;71: Graves NM, Kriel RL. Rectal administration of antiepileptic drugs in children. Pediatr Neurol. 1987;3: Cloyd JC, Lalonde R, Beniak TE, Novack GD. A single blind, crossover comparison of the pharmacokinetics and cognitive effects of a new rectal diazepam gel with intravenous diazepam. Epilepsia. 1998;39: Agurell S, Berlin A, Ferngren H, Hellstrom B. Plasma levels of diazepam after parenteral and rectal administration in children. Epilepsia. 1975;16: Dulac O, Aicardi J, Rey E, Olive G. Blood levels of diazepam after single rectal administration in infants and children. J Pediatr. 1978;93: Langslet A, Meberg A, Bredesen JE, Lunde PK. Plasma concentrations of diazepam and N-desmethyldiazepam in newborn infants after intravenous, intramuscular, rectal and oral administration. Acta Paediatr Scand. 1978;67: Knudsen FU. Plasma-diazepam in infants after rectal administration in solution and by suppository. Acta Paediatr Scand. 1977;66: Cereghino JJ, Mitchell WG, Murphy J, et al. Treating repetitive seizures with a rectal diazepam formulation: a randomized study. Neurology. 1998;51: Dreifuss FE, Rosman NP, Cloyd JC, et al. A comparison of rectal diazepam gel and placebo for acute repetitive seizures. N Engl J Med. 1998;338: Painter MJ. Benzodiazepines and the barbiturates in the treatment of childhood epilepsy. In: Dodson WE, Pellock JM, eds. Pediatric Epilepsy: Diagnosis and Therapy. New York, NY: Demos Publications; 1993: Kriel RL, Cloyd JC, Hadsall RS, Carlson AM, Floren KL, Jones-Saete CM. Home use of rectal diazepam for cluster and prolonged seizures: efficacy, adverse reactions, quality of life, and cost analysis. Pediatr Neurol. 1991;7: Camfield CS, Camfield PR, Smith E, Dooley JM. Home use of rectal diazepam to prevent status epilepticus in children with convulsive disorders. J Child Neurol. 1989;4: CME Announcement Online CME to Begin in Mid-2003 I n mid-2003, online CME will be available for JAMA/ARCHIVES and will offer many enhancements: Article-specific questions Hypertext links from questions to the relevant content Online CME questionnaire Printable CME certificates and ability to access total CME credits We apologize for the interruption in CME and hope that you will enjoy the improved online features that will be available in mid