Rectal Diazepam Gel for Treatment of Acute Repetitive Seizures in Adults

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, double-blind, 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 seizure-free 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.

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.^7-11 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.^12-15 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.^16-18

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 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. Minimally effective concentrations were achieved within 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.

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, double-blind, 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, tonic-clonic, 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 χ² 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 χ² 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.

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 demographics 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 1). 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 seizure-free 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: 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.

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 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 seizure-free 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, 2002.

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, 1998.

We acknowledge the contributions of Gary D. Novack, PhD, and Shawki Salem, PhD.

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.

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 97239 (e-mail: cereghin@ohsu.edu).