Diazepam autoinjector intramuscular delivery system versus diazepam rectal gel: A pharmacokinetic comparison

Garnett, William R.; Barr, William H.; Edinboro, Leslie E.; Karnes, H. Thomas; Mesa, Mike; Wannarka, Gerald L.

doi:10.1016/j.eplepsyres.2010.10.001

Cited by 29 publications

(37 citation statements)

References 15 publications

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“…There was a numerically greater decline in mean respiration rate for the active treatment group compared with the placebo group; however, the mean rates in the two treatment groups were similar at all postdose time points (Table ). This lack of respiratory effect with diazepam AI is consistent with its pharmacokinetic profile, which parallels that of rectally administered diazepam (Garnett et al., ; Lamson et al., ). Rectal diazepam has been shown to have a low incidence of respiratory depression (Pellock & Shinnar, ), in contrast to rapid i.v.…”

Section: Discussionsupporting

confidence: 73%

“…administration of diazepam may be associated with slow and inconsistent absorption, diazepam AI i.m. absorption has been demonstrated to be reliable and consistent (Lehman & Wannarka, ; Garnett et al., ; Lamson et al., ), suggesting that the injection site and method and speed of AI may influence absorption. In a crossover study of 24 healthy volunteers, the diazepam AI resulted in higher average exposure (mean area under the curve for diazepam) than rectal administration (Garnett et al., ).…”

Section: Discussionmentioning

confidence: 98%

“…absorption has been demonstrated to be reliable and consistent (Lehman & Wannarka, ; Garnett et al., ; Lamson et al., ), suggesting that the injection site and method and speed of AI may influence absorption. In a crossover study of 24 healthy volunteers, the diazepam AI resulted in higher average exposure (mean area under the curve for diazepam) than rectal administration (Garnett et al., ). This may be a consequence of greater variability of rectal administration in individual pharmacokinetic values, possibly due to lower average diazepam plasma concentrations related to drug expulsion, defecation, or oozing.…”

Section: Discussionmentioning

confidence: 98%

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A double‐blind, randomized, placebo‐controlled trial of a diazepam auto‐injector administered by caregivers to patients with epilepsy who require intermittent intervention for acute repetitive seizures

Abou‐Khalil

Wheless

Rogin³

et al. 2013

Epilepsia

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SUMMARYPurpose: A diazepam auto-injector (AI) has been developed for intramuscular administration to treat acute repetitive seizures (ARS). The objective of this study was to evaluate the efficacy and safety of the diazepam AI when administered by caregivers to control an episode of ARS. Methods: In this phase III, randomized, double-blind, parallel-group, placebo-controlled, multicenter study, subjects with epilepsy on a stable antiepileptic drug regimen who required intermittent medical intervention to control ARS were randomized 1:1 to the placebo AI or the diazepam AI group. Subjects were stratified according to age (2-5, 6-11, ≥12 years). Dose (5, 10, 15, or 20 mg) was based on age and weight. A single dose of study medication was dispensed to be administered by caregivers in an outpatient setting when required. The primary end point was time to next seizure or rescue from 15 min to 12 h postdose. Secondary end points included rescue medication use, number of seizures postdose, caregiver and physician treatment assessments, and safety measures. Key Findings: Of 234 subjects randomized, 81/110 in the placebo AI group and 82/124 in the diazepam AI group were included in the intent-to-treat analysis. Baseline characteristics were similar for both groups. Time to next seizure or rescue was significantly longer in the diazepam AI group compared with the placebo AI group, with a hazard ratio of 0.55 (95% confidence interval (CI) 0.34-0.88; p = 0.012) for diazepam AI versus placebo AI, adjusted for age group. The 25th percentile for time to the next seizure or rescue was 1.18 h (95% CI 0.38-2.03) for placebo AI and 2.70 h (95% CI 0.48-11.42) for diazepam AI; the median was 5.9 h for placebo AI and was inestimable for diazepam AI due to the low number of events experienced by subjects in that group. The proportion of subjects using rescue medication postdose was 30% (24/81) placebo AI versus 17% (14/82) diazepam AI (p = 0.066). An event (seizure or rescue) occurred in 55.6% of subjects in the placebo AI group and 35.4% in the diazepam AI group. The number of seizures experienced during the 12-h postdose period was significantly lower for diazepam AI (median 0.0) compared with placebo AI (median 1.0; p = 0.010). Treatment-emergent adverse events (TEAEs) were reported in 44% (35/79) of subjects in the placebo AI group and 42% (34/81) in the diazepam AI group. The most common TEAEs reported were injection site pain (15% placebo AI, 17% diazepam AI) and injection site hemorrhage (6% placebo AI, 5% diazepam AI). Significance: The diazepam AI was significantly more effective than placebo AI at delaying the next seizure or rescue. Secondary efficacy end points were generally supportive of the primary outcome. Diazepam AI administered by trained caregivers was effective for the treatment of ARS and was well-tolerated, with a safety profile similar to placebo.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

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A double‐blind, randomized, placebo‐controlled trial of a diazepam auto‐injector administered by caregivers to patients with epilepsy who require intermittent intervention for acute repetitive seizures

Abou‐Khalil

Wheless

Rogin³

et al. 2013

Epilepsia

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“…Intramuscular diazepam administered by autoinjector as shown efficacy in the treatment of ARS [9,10] (Table 1) and appears to be rapidly absorbed [24,25]. Two studies in healthy volunteers demonstrated that intramuscular autoinjection was bioequivalent to intramuscular injection with a conventional syringe [24].…”

Section: Consider Alternative Formulations If Necessarymentioning

confidence: 96%

“…Two studies in healthy volunteers demonstrated that intramuscular autoinjection was bioequivalent to intramuscular injection with a conventional syringe [24]. Other studies found that diazepam administered intramuscularly by autoinjector was absorbed more rapidly than rectal diazepam [25], with slightly higher bioavailability [26].…”

Section: Consider Alternative Formulations If Necessarymentioning

confidence: 99%

Quick treatment with the most appropriate benzodiazepine formulation is vital when treating acute repetitive seizures in the outpatient setting

Writers

2015

Drugs Ther Perspect

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Acute repetitive seizures are a serious epilepsy condition that may progress to status epilepticus. Prompt out-of-hospital treatment is vital and usually involves oral, rectal, intramuscular or intranasal administration of benzodiazepines (e.g. diazepam, midazolam, lorazepam) by nonmedical caregivers. The choice of benzodiazepine and mode of administration should take into account disease severity, patient age, physical condition, individual factors and patient preference.

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Consistent safety and tolerability of Valtoco^® (diazepam nasal spray) in relationship to usage frequency in patients with seizure clusters: Interim results from a phase 3, long‐term, open‐label, repeat‐dose safety study

et al. 2021

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Objective Need for rescue therapy differs among patients with seizure clusters. Diazepam nasal spray is approved to treat seizure clusters in patients with epilepsy ≥6 years of age. This analysis used interim data from a phase 3 safety study to assess safety profile and effectiveness of diazepam nasal spray using average number of doses/month as a proxy measurement. Methods This phase 3, open‐label, repeat‐dose, safety study of diazepam nasal spray enrolled patients (6‐65 years) with epilepsy and need of benzodiazepine rescue. Patients were stratified by average number of doses/month (<2, moderate frequency; 2‐5, high frequency; >5, very‐high frequency). Safety was evaluated based on treatment‐emergent adverse events (TEAEs), assessed nasal irritation, and olfaction. The proportion of treatments given as a second dose was used as an exploratory proxy for effectiveness. Results Of 175 enrolled patients (data cutoff, October 31, 2019), 158 received ≥1 dose of diazepam nasal spray. Frequency of use was moderate in 43.7% of patients, high in 50.6% of patients, and very high in 5.7% of patients. Patients treated 3397 seizure episodes (moderate frequency, 14.2%; high frequency, 59.9%; very high frequency, 25.8%). Nasal discomfort was the most common treatment‐related TEAE in all groups. No notable changes in nasal irritation or olfaction were observed. Second doses represented only 2.5%, 7.5%, and 17.2% of all doses in the moderate‐, high‐, and very‐high‐frequency groups, respectively. Overall retention rate was 82.9%, without an observed relationship to frequency of use. Significance Frequency of dosing diazepam nasal spray had little impact on the safety/tolerability profile across a range of <2 to >5 doses/month. Effectiveness was suggested for all dosing frequencies by the high proportion of seizure clusters not treated with a second dose. These results support the utility, safety profile, and effectiveness of diazepam nasal spray across frequencies of seizure cluster burden.

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Diazepam autoinjector intramuscular delivery system versus diazepam rectal gel: A pharmacokinetic comparison

Cited by 29 publications

References 15 publications

A double‐blind, randomized, placebo‐controlled trial of a diazepam auto‐injector administered by caregivers to patients with epilepsy who require intermittent intervention for acute repetitive seizures

A double‐blind, randomized, placebo‐controlled trial of a diazepam auto‐injector administered by caregivers to patients with epilepsy who require intermittent intervention for acute repetitive seizures

Quick treatment with the most appropriate benzodiazepine formulation is vital when treating acute repetitive seizures in the outpatient setting

Consistent safety and tolerability of Valtoco^® (diazepam nasal spray) in relationship to usage frequency in patients with seizure clusters: Interim results from a phase 3, long‐term, open‐label, repeat‐dose safety study

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Diazepam autoinjector intramuscular delivery system versus diazepam rectal gel: A pharmacokinetic comparison

Cited by 29 publications

References 15 publications

A double‐blind, randomized, placebo‐controlled trial of a diazepam auto‐injector administered by caregivers to patients with epilepsy who require intermittent intervention for acute repetitive seizures

A double‐blind, randomized, placebo‐controlled trial of a diazepam auto‐injector administered by caregivers to patients with epilepsy who require intermittent intervention for acute repetitive seizures

Quick treatment with the most appropriate benzodiazepine formulation is vital when treating acute repetitive seizures in the outpatient setting

Consistent safety and tolerability of Valtoco® (diazepam nasal spray) in relationship to usage frequency in patients with seizure clusters: Interim results from a phase 3, long‐term, open‐label, repeat‐dose safety study

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Product

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Consistent safety and tolerability of Valtoco^® (diazepam nasal spray) in relationship to usage frequency in patients with seizure clusters: Interim results from a phase 3, long‐term, open‐label, repeat‐dose safety study