How long is lorazepam stable out of the refrigerator?

Comment by InpharmD Researcher

There are variable data regarding the stability of lorazepam solution at room temperature. Evidence from the manufacturer suggests unopened lorazepam vials are stable for up to six weeks at room temperature, while an older newsletter states lorazepam may be stable for up to 60 days at room temperature. Other pharmacokinetic studies have found lorazepam to be stable for up to 210 days at room temperature.

Background

A newsletter from the Institute for Safe Medication Practices (ISMP) suggests lorazepam injection vial is both physically and chemically stable for up to 60 days at room temperature. However, ISMP does not make recommendations regarding the extension of beyond-use dates outside of manufacturer-approved recommendations. [1], [2]

Communication with Wyeth Pharmaceuticals (a subsidiary of Pfizer, Inc.), the original manufacturer of Ativan (lorazepam) provided unpublished data that found unopened vials remained stable for up to 6 weeks at room temperature (25°C). Although the product remained within specification, the manufacturer does not advocate the use of these products past expiration. [3]

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 at oven-heated temperatures (38 °C) for up to 210 days (see Table 2). 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 4). 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 suggest temperature is the main cause of degradation and the effect of vibrations is negligible. [4], [5]

Prefilled disposable single-use glass syringes with lorazepam 2 mg/mL were studied in instrumented boxes in an emergency medicine environment (variations in ambient temperature). After 60 days, lorazepam maintained a clinically acceptable concentration. This study (See Table 3) had a large variability in temperatures and the authors failed to report the amount (percentage) of degradation observed. [6]

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 as well as a decrease in 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 to be 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. [7]

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 in order 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 were 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. [8]

References:

[1] Institute for Safe Medication Practices. Results of our survey on drug storage, stability, compatibility, and beyond use dating. ISMP Medication Safety Alert. 2012; 17(6):1-4.
[2] Jahns BE, et al. Extension of expiration time for lorazepam injection at room temperature. Am J Hosp Pharm. 1993;50:1134.
[3] Pfizer Medical Communication. Lorazepam Injection, USP - Stability Stored Above Recommended Temperatures [provided document]. Updated April 26, 2019. Accessed July 18, 2022.
[4] 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.
[5] 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
[6] McMullan JT, Pinnawin A, Jones E, et al. The 60-day temperature-dependent degradation of midazolam and Lorazepam in the prehospital environment. Prehosp Emerg Care. 2013;17(1):1-7. doi:10.3109/10903127.2012.722177
[7] 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
[8] 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

Relevant Prescribing Information

Lorazepam injection:
Storage: Refrigerate between 2° to 8°C (36° to 46°F).
PROTECT FROM LIGHT.
Use carton to protect contents from light.

References:

Lorazepam injection [prescribing information]. Akorn, Inc.; 2022.

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

How long is lorazepam stable out of the refrigerator?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→



Please see Tables 1-4 for your response.


 

Stability of Lorazepam 1 and 2 mg/mL in Glass Bottles and Polypropylene Syringes

Design

Single-center stability study

Objective

To evaluate the physical and chemical stability of lorazepam in glass bottles and plastic syringes at concentrations suitable for use in the critical care setting

Study Groups

Glass bottles

Lorazepam 1 mg/mL in 5% dextrose (n=3)

Lorazepam 2 mg/mL in 5% dextrose (n=3)

Syringes

Lorazepam 1 mg/mL in 5% dextrose (n=3)

Lorazepam 1 mg/mL in 0.9% sodium chloride (n=3)

Methods

Solutions of lorazepam 1 and 2 mg/mL in glass bottles and polypropylene syringes were prepared. For the 1 mg/mL solution, 20 mL of the 2 mg/mL lorazepam preparation and 20 mL of 5% dextrose injection were added to a 250 mL evacuated bottle. For the 2 mg/mL solution, 20 mL of the 4 mg/mL lorazepam preparation and 20 mL of 5% dextrose injection were added to a 250 mL evacuated bottle.

Syringe solutions were prepared with 5% dextrose injection or 0.9% sodium chloride (NaCl) injection at a concentration of 1 mg/ mL.

Bottles and syringes were stored at 22°C under normal room light. 

Duration

Followup:  At 0, 1, 2, 4, 8, and 28 hours

Outcome Measures

Solution color, clarity, precipitation, and pH

Results

Stability of Lorazepam at 22°C

Nominal Initial Concentration

Initial Concentration

Diluent

% Initial Concentration Remaining (n= 6)   
1 hr 2 hr 4 hr 8 hr 28 hr

Glass Bottles

1 mg/mL

2 mg/mL

 

0.89 ± 0.01

1.66 ± 0.06

 

5% dextrose injection

5% dextrose injection

 

99.5 ± 1.6

103.4 ± 1.2

 

100.6 ± 0.5

103.0 ± 1.5

 

101.4 ± 1.8

101.1 ± 2.0

 

100.4 ± 3.0

101.4 ± 3.0

 

98.3 ± 0.7

100.0 ± 1.6

Syringes

1 mg/mL

1 mg/mL

 

1.02 ± 0.01

1.02 ± 0.03

 

5% dextrose injection

0.9% NaCl injection

 

99.1 ± 0.8

98.3 ± 2.5

 

98.3 ± 1.3

100.6 ± 0.9

 

97.8 ± 1.5

97.3 ± 1.8

 

97.8 ± 0.6

97.3 ± 3.8

 

97.3 ± 1.4

97.2 ± 1.5

There was no substantial change in color or clarity, and pH changed by ​​​​<0.2 pH unit in all solutions; all solutions retained >90% initial lorazepam concentration at 28 hours.

Study Author Conclusions

Lorazepam 1 and 2 mg/mL in 5% dextrose injection was stable for 28 hours at room temperature in glass bottles when the 2 mg/mL and 4 mg/mL lorazepam preparations, respectively, were used.

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.

InpharmD Researcher Critique

This had a small sample size and was conducted at a single institution.



References:

Share MJ, Harrison RD, Folstad J, Fleming RA. Stability of lorazepam 1 and 2 mg/mL in glass bottles and polypropylene syringes. American Journal of Health-System Pharmacy. 1998;55(19):2013–2015. https://doi.org/10.1093/ajhp/55.19.2013

 

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 a 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 et. al. Prehospital stability of diazepam and lorazepam. American Journal of Emergency Medicine. 1999;17(4):333-337

 

The 60-Day Temperature-Dependent Degradation of Midazolam and Lorazepam in the Prehospital Environment

Design

Multicenter, randomized, controlled trial 

N= 229

Objective

To evaluate temperature-dependent degradation of lorazepam and midazolam after 60 days in the EMS environment

Study Groups

Midazolam 5 mg/mL glass cartridge autoinjector (n= 122)

Lorazepam 2 mg/mL prefilled disposable single-use glass syringe (n= 107)

Methods

Lorazepam or midazolam samples were collected prior to or after 60 days of emergency medical services (EMS) deployment during spring-summer months in 14 metropolitan areas across the United States. Medications were stored in study boxes that logged temperature every minute and were stored in EMS units per local agency policy.

Mean kinetic temperature (MKT) exposure was derived for each sample. Drug concentrations were determined in a central laboratory by high-performance liquid chromatography. Concentration as a function of MKT was analyzed by linear regression.

Duration

60 days

Outcome Measures

Relative reduction in medication concentration from the labeled concentration

Results

  Lorazepam Midazolam

Baseline relative concentration

Baseline

After 60 days

 

1.00 (95% CI 1.00 to 1.00)

0.99 (95% CI 0.98 to 0.99)

 

0.99 (95% CI 0.98 to 0.99)

1.00 (95% CI 1.00 to 1.00)

Mean kinetic temperature: 22.1°C (95% CI 21.6°C–22.5°C)

Midazolam showed no significant degradation over time, while lorazepam experienced some degradation.

Study Author Conclusions

Lorazepam experiences small but statistically significant temperature-dependent degradation after 60 days in the EMS environment. Additional study is needed to evaluate whether clinically significant deterioration occurs after 60 days.

The regression analysis found a slight correlation with increasing temperature, suggesting that the degree of degradation is affected by the degree of exposure to higher temperatures.

InpharmD Researcher Critique

This was a purely kinetic study that had an uneven sample distribution among varying environments.



References:

McMullan JT et. al. The 60-day temperature dependent degradation of midazolam and lorazepam in the prehospital environment. Prehospital Emergency Care. 2013;17(1):1-7.

 

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):247-50.