How long is IV lorazepam good for once drawn out of a multidose vial?

Comment by InpharmD Researcher

Studies have found that lorazepam injections, with concentrations between 0.16 to 2 mg/mL, remain stable for 28 hours to 2 days at room temperature when stored in polypropylene syringes. However, after 2 days at 5 ± 3°C, the lorazepam solutions become chemically unstable, losing more than 10% of their concentration. The type of vial (single- or multi-dose) used and the presence of preservatives were unclear. Limited data suggest that undiluted lorazepam solution may remain stable for up to 150 days in clear glass syringes under refrigeration or at ambient temperatures, retaining at least 90% of the original concentration. However, degradation is faster at higher temperatures or when stored in polypropylene syringes.

Background

A 2020 study evaluated the long-term stability of lorazepam in sodium chloride 0.9% in polypropylene syringes stored at 5 ± 3°C and room temperature compared to glass bottles at 5 ± 3°C and at room temperature. Eight polypropylene Becton Dickinson (BD) syringes and 6 glass bottles were prepared under aseptic conditions by diluting 1 mL of lorazepam solution 4 mg/mL in 23 mL of sodium chloride solution to a final concentration of 167 mcg/mL. One mL of solution was withdrawn from each syringe and bottle on day 0 (day of preparation) and after 1, 2, 3, 4, and 7 days to perform physical stability testing. An additional 20 microliters were frozen at 80°C for chemical stability testing. Samples were tested for particle, haze, precipitation, and color change. Optical densities (ODs) were measured with a spectrophotometer to search for subvisible particles and assess turbidity; pH was also measured. After 4 days, crystals were detected in syringes stored at 5 ± 3 °C and decreased OD at 350 nm. Crystallization was also detected after 7 days in syringes at room temperature, 3 days in bottles at 5 ± 3°C, and 2 days in bottles at room temperature. No samples were found to have altered pH, color, or absorbance at 410 nm at any time point during storage. After 2 days, solutions of lorazepam stored in syringes at 5 ± 3°C were considered chemically unstable due to a loss of lorazepam concentration greater than 10%. It was concluded this lack of stability prohibits advance preparation. Storage conditions, including temperature and storage form, did not appear to improve stability. [1]

A 2017 study evaluated the physical stability of injectable lorazepam 0.16 mg/mL prepared in polypropylene syringes and stored at room temperature. Under aseptic conditions, 30-mL syringes were prepared, each containing 4 mg of lorazepam diluted into 23 mL of sodium chloride solution for a total volume of 24 mL (0.16 mg/mL). Syringes were stored at room temperature to mimic the clinical conditions of administration in the intensive care unit. Immediately after the preparation (hour 0) and after 1, 4, 8, 24, and 48 hours, 2 mL of each solution was withdrawn from each syringe and placed in glass tubes to proceed with the stability test. The pH of the solutions was measured at each time by a glass electrode pH meter, and all specimens underwent spectrophotometric measurements at three wavelengths (350, 410, and 550 nm). Measurements of pH at each time showed no significant change during storage. The average pH was 7.30 ± 0.23 (minimum 7.06, maximum 7.54), and average spectrophotometric measurements at 350, 410, and 550 nm were 0.07 ± 0.001, 0.001 ± 0.0007, and 0.00003 ± 0.0001, respectively. Additionally, no color change, turbidity, opacity, or precipitation was observed in the solutions during storage for 48 hours. Microaggregates were not detected by microscope. Based on these results, lorazepam 0.16 mg/mL appears physically stable in 0.9% sodium chloride polypropylene syringes when stored at room temperature for 48 hours. It was unclear if the lorazepam vials used were multi-dose or single-dose vials. [2]

A 1998 stability study evaluates the physical and chemical stability of lorazepam in glass bottles and plastic syringes at concentrations (1 mg/mL and 2 mg/mL) suitable for use in the critical care setting. The solutions to be stored in syringes were prepared with 5% dextrose injection or 0.9% sodium chloride injection at a concentration of 1 mg/ mL; 20 mL of the 2 mg/mL lorazepam preparation and 20 mL of 5% dextrose injection or 0.9% sodium chloride injection (total volume, 40 mL) were placed in 60 mL syringes. All prepared solutions were stored at room temperature at 22 °C under normal room light. Small portions were visually inspected for color, clarity, precipitation, pH, and stability by high-performance liquid chromatography (HPLC) at –80 °C up to 28 hours. No color, clarity, or pH changes during the observation period were noted for the 1 mg/mL solutions stored in syringes. All solutions stored in the syringes at 1 mg/mL maintained more than 90% of their initial lorazepam concentration during the 28-hour observation period. Overall, lorazepam 1 mg/mL in 5% dextrose injection or 0.9% sodium chloride injection was stable for 28 hours at room temperature in polypropylene syringes when the 2 mg/mL lorazepam preparation was used. It was unclear if the study used multi-dose 2 mg/mL vials to prepare studied solutions stored in syringes. [3]

Another older stability study from 1996 investigated the stability of lorazepam when prefilled in polypropylene syringes. Three mL of undiluted lorazepam 2 mg/mL were drawn into syringes under aseptic conditions and stored at 30 °C. Samples were assessed on days 0, 3, 5, and 10 using HPLC, with stability defined as retention of at least 90% of the initial concentration. Lorazepam lost significant drug content by day 3 of storage, suspected to be due to the sorption of the drug to the container. The authors concluded lorazepam 2 mg/mL should not be stored in polypropylene infusion pump syringes. [4]

A study evaluated lorazepam 2 mg/mL injectable solutions in clear glass syringes under refrigeration (4-10 °C), at ambient temperatures (15-30 °C), and oven-heated temperatures (38 °C) for up to 210 days (see Table 1). Results showed lorazepam retained 90% of its original concentration for 150 days at ambient temperature. A similar study measured the stability of lorazepam 4 mg/mL for emergency use under refrigeration, at room temperature, and in a helicopter (mean 11.8 °C) for up to 4 months (see Table 2). At room temperature, the lorazepam solution lost ~22% of its original concentration after 4 months, but the samples under refrigeration and in the helicopter were still stable. This data suggests temperature is the main cause of degradation, and the effect of vibrations is negligible. [5], [6]

References:

[1] Colsoul ML, Breuer A, Goderniaux N, et al. Long-Term Stability of Lorazepam in Sodium Chloride 0.9% Stored at Different Temperatures in Different Containers. Hosp Pharm. 2020;55(3):188-192. doi:10.1177/0018578719836649
[2] Closset M, Hecq JD, Soumoy L, et al. Physical stability of highly concentrated injectable drugs solutions used in intensive care units. Ann Pharm Fr. 2017;75(3):185-188. doi:10.1016/j.pharma.2016.12.004
[3] Share MJ, RD, Folstad J, Fleming RA. Stability of lorazepam 1 and 2 mg/mL in glass bottles and polypropylene syringes. Am J Health Syst Pharm. 1998;55(19):2013-2015. doi:10.1093/ajhp/55.19.2013
[4] Stiles ML, Allen LV Jr, Prince SJ. Stability of deferoxamine mesylate, floxuridine, fluorouracil, hydromorphone hydrochloride, lorazepam, and midazolam hydrochloride in polypropylene infusion-pump syringes. Am J Health Syst Pharm. 1996;53(13):1583-1588. doi:10.1093/ajhp/53.13.1583
[5] Gottwald MD, Akers LC, Liu PK, et al. Prehospital stability of diazepam and lorazepam. Am J Emerg Med. 1999;17(4):333-337. doi:10.1016/s0735-6757(99)90079-7.
[6] De Winter S, Bronselaer K, Vanbrabant P, et al. Stability of Drugs Used in Helicopter Air Medical Emergency Services: An Exploratory Study. Air Med J. 2016;35(4):247-250. doi:10.1016/j.amj.2016.02.001

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the stability of lorazepam solution for injection in polypropylene syringes if drawn up from a multidose vial?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→



Please see Tables 1-2 for your response.


Prehospital Stability of Diazepam and Lorazepam

Design

Stability trial

N= 16

Objective

To evaluate the stability of lorazepam stored in prefilled glass syringes at several different temperatures

Study Groups

Lorazepam (2 mg/mL) injectable solutions in clear glass syringes 

Stored in the refrigerator (4°C to 10°C)

Stored at room temperature in an ambulance (15°C to 30°C)

Stored in an oven (37°C)

Methods

Lorazepam (2 mg/mL) injectable solutions were stored for up to 210 days in clear glass syringes at three conditions: 4°C to 10°C (refrigerated); 15°C to 30°C (on-ambulance ambient temperature); and 37°C (oven heated).

Lorazepam, USP (Wyeth-Ayerst) solutions contained 2 mg lorazepam, 0.18 mL polyethylene glycol 400 in propylene glycol with 2.0% benzyl alcohol as preservative.

Duration

Time 0, 30, 60, 90, 120, 150, 180, and 210 days

Outcome Measures

Stability of lorazepam stored in prefilled glass syringes at several different temperatures

Results

 

 

 

 

 

 

 

 

 

 

Refrigerated (n= 4)

Ambulance 1-ambient  (n= 4)

Ambulance 2-ambient (n= 4)

37ºC oven (n= 4)

0 days

1.97 ± 0.04 mg/mL

98.7%

 ---

 ---  ---

30 days 

2.01 ± 0.04 mg/mL

100.6%

1.94 ± 0.03 mg/mL

97.1%

1.97 ± 0.02 mg/mL

98.7% 

1.78 ± 0.01 mg/mL

89.2.1% 

60 days

2.04 ± 0.03 mg/mL

102.1%

1.99 ± 0.02 mg/mL

99.6%

1.99 ± 0.02 mg/mL

99.6%

1.57 ± 0.04 mg/mL

78.3%

90 days

2.01 ± 0.02 mg/mL

100.7%

1.90 ± 0.02 mg/mL

94.9%

1.89 ± 0.05 mg/mL

94.9%

1.26 ± 0.03 mg/mL

62.9% 

120 days

1.97 ± 0.02 mg/mL

98.3%

1.86 ± 0.02 mg/mL

93.2%

1.89 ± 0.05 mg/mL

94.4%

0.99 ± 0.02 mg/mL

49.3%

150 days

2.00 ± 0.03 mg/mL

100.0%

1.90 ± 0.04 mg/mL

94.9%

1.87 ± 0.02 mg/mL

93.7%

0.77 ± 0.04 mg/mL

38.5%

180 days

1.97 ± 0.06 mg/mL

98.7%

1.81 ± 0.02 mg/mL

90.4%

1.79 ± 0.02 mg/mL

89.6%

0.62 ± 0.02 mg/mL

31.1%

210 days

2.04 ± 0.02 mg/mL

101.9%

1.83 ± 0.03 mg/mL

91.5%

1.81 ± 0.06 mg/mL

90.4%

0.50 ± 0.03 mg/mL

24.8%

Study Author Conclusions

The results suggest that lorazepam can be stored on ambulances. When ambient storage temperatures are 30°C or less, ambulances carrying lorazepam should be restocked every 30 to 60 days. When drug storage temperatures exceed 30°C, more frequent stocking or refrigeration is required.

InpharmD Researcher Critique

Limitations include the small sample size and the fact that samples in the ambulance went above-defined room temperatures.

 
References:

Gottwald MD, Akers LC, Liu PK, et al. Prehospital stability of diazepam and lorazepam. Am J Emerg Med. 1999;17(4):333-337. doi:10.1016/s0735-6757(99)90079-7

Stability of Drugs Used in Helicopter Air Medical Emergency Services: An Exploratory Study

Design

Longitudinal exploratory stability study

Objective

To determine whether or not vibrations caused by a helicopter induce the degradation of three drugs labeled for refrigeration (cisatracurium, lorazepam, and succinylcholine) and two albumin solutions (human albumin 4% and 20%) used in this setting

Study Groups

Stored in the refrigerator

Stored at room temperature

Stored in a helicopter

Methods

Vials of cisatracurium, lorazepam, succinylcholine, and both albumin solutions were stored in a refrigerator, at room temperature, and inside a helicopter. Three samples of each drug and one sample of the albumin products were used for each storage condition.

Room temperature and helicopter ampules were placed into the regular drug box in the portable EMS backpack and stored either in the emergency department or on the floor of the helicopter under the seat of the pilot where they were protected from ultraviolet exposure caused by direct sunlight.

Duration

4 months

Outcome Measures

Stability of the drugs stored in different temperature settings

Results

 

Refrigerator (0 months)

Refrigerator (4 months)

Room Temperature (4 months)

Helicopter (4 months)

Lorazepam 4 mg/mL

102.9% ± 2.1% 97.3% ± 5.5%  77.8% ± 1.8% 9.1% ± 3.8%

Study Author Conclusions

These data suggest that the effect of the degradation of drugs caused by vibrations is negligible; temperature was observed as the main cause of drug degradation.

InpharmD Researcher Critique

The room temperature samples appeared to be stored at a single emergency department in Belgium. All room temperature samples were not stable after 4 months.

 
References:

De Winter S, Bronselaer K, Vanbrabant P, et al. Stability of Drugs Used in Helicopter Air Medical Emergency Services: An Exploratory Study. Air Med J. 2016;35(4):247-250. doi:10.1016/j.amj.2016.02.001