Degradation of Benzodiazepines after 120 Days of EMS Deployment

Abstract

Introduction EMS treatment of status epilepticus improves outcomes, but the benzodiazepine best suited for EMS use is unclear, given potential high environmental temperature exposures. Objective To describe the degradation of diazepam, lorazepam, and midazolam as a function of temperature exposure and time over 120 days of storage on active EMS units. Methods Study boxes containing vials of diazepam, lorazepam, and midazolam were distributed to 4 active EMS units in each of 2 EMS systems in the southwestern United States during May–August 2011. The boxes logged temperature every minute and were stored in EMS units per local agency policy. Two vials of each drug were removed from each box at 30-day intervals and underwent high-performance liquid chromatography to determine drug concentration. Concentration was analyzed as mean (and 95%CI) percent of initial labeled concentration as a function of time and mean kinetic temperature (MKT). Results 192 samples were collected (2 samples of each drug from each of 4 units per city at 4 time-points). After 120 days, the mean relative concentration (95%CI) of diazepam was 97.0% (95.7–98.2%) and of midazolam was 99.0% (97.7–100.2%). Lorazepam experienced modest degradation by 60 days (95.6% [91.6–99.5%]) and substantial degradation at 90 days (90.3% [85.2-95.4%]) and 120 days (86.5% [80.7–92.3%]). Mean MKT was 31.6°C (95%CI 27.1–36.1). Increasing MKT was associated with greater degradation of lorazepam, but not midazolam or diazepam. Conclusions Midazolam and diazepam experienced minimal degradation throughout 120 days of EMS deployment in high-heat environments. Lorazepam experienced significant degradation over 120 days and appeared especially sensitive to higher MKT exposure.

Persistence of alprazolam in river water according to forced and non‐forced degradation assays: adsorption to sediment and long‐term degradation products

“…Alprazolam is a relatively stable benzodiazepine in comparison with other pharmaceutical drugs, and human metabolites, of the same family according to the results of some forced assays reported on several aqueous matrixes. Thus, the half-life of alprazolam in solution was notably higher than those of diazepam, oxazepam, nordiazepam, temazepam, and mainly midazolam and lorazepam, when they were irradiated with simulated sunlight, [16][17][18][19] which is coherent with the stability observed for alprazolam in the wileyonlinelibrary.com/journal/dta photodegradation assays carried out in this work. In the same way, although the different assays are not totally comparable, it can be stated that the acidic or alkaline hydrolysis of lorazepam, oxazepam, diazepam and bromazepam is easier than for alprazolam [12,[20][21][22][23][24][25] ; conversely, midazolam and clonazepam seem to be more resistant to hydrolysis than alprazolam.…”

“…Thus, the half-life of alprazolam in solution was notably higher than those of diazepam, oxazepam, nordiazepam, temazepam, and mainly midazolam and lorazepam, when they were irradiated with simulated sunlight, [16][17][18][19] which is coherent with the stability observed for alprazolam in the photodegradation assays carried out in this work. Thus, the half-life of alprazolam in solution was notably higher than those of diazepam, oxazepam, nordiazepam, temazepam, and mainly midazolam and lorazepam, when they were irradiated with simulated sunlight, [16][17][18][19] which is coherent with the stability observed for alprazolam in the photodegradation assays carried out in this work.…”

Pre-hospital midazolam for benzodiazepine-treated seizures before and after the Rapid Anticonvulsant Medication Prior to Arrival Trial: A national observational cohort study

“…The increasing use of midazolam could be explained by growing acknowledgment of the benefits of midazolam for the treatment of pre-hospital status epilepticus. Midazolam is not only as effective as alternative intravenous medications [ 3 ], but is also easier to administer[ 8 ], has better pharmacodynamics than diazepam [ 9 ], is cheaper [ 10 – 12 ] and has a longer shelf life than lorazepam [ 13 ]. Furthermore, midazolam is subject to far fewer shortages, with diazepam and lorazepam making up 2 of the 10 most susceptible drugs to national shortages [ 14 ].…”

Pre-Hospital Midazolam for Treatment of Status Epilepticus Before and After the Rapid Anticonvulsant Medication Prior to Arrival Trial: A National Observational Cohort Study

“…The increasing use of midazolam could be explained by growing acknowledgement of the benefits of midazolam for the treatment of pre-hospital status epilepticus. Midazolam is not only as effective as alternative intravenous medications [3, 5], but is also easier to administer[8], has better pharmacodynamics than diazepam [9], is cheaper [10-12] and has a longer shelf life than lorazepam [13]. Furthermore, midazolam is subject to far fewer shortages, with diazepam and lorazepam making up 2 of the 10 most susceptible drugs to national shortages [14].…”