- Email: [email protected]
Stability of diazepam rectal gel in ambulance-like environments
Stability of Diazepam Rectal Gel in AmbulanceLike Environments BRIAN K. ALLDREDGE, PHARMD,* ROBERT VENTEICHER, PHD,† AND THOMAS S. CALDERWOOD, PHD† The objective of the present study was to evaluate the stability of diazepam rectal gel (Diastat) in various conditions of temperature and light exposure as might be found in ambulances. Three lots of Diastat (Xcel Pharmaceuticals, San Diego, CA) in various fill/syringe configurations were evaluated in controlled conditions of a freeze-thaw cycle, hard freeze (ⴚ30°C for 72 hours), extreme light exposure (1,000 ft candles for 1 month), and long-term evaluation at either 30°C or 40°C. In the various configurations and tests, diazepam concentration always exceeded 95% of label, with no changes of note in excipients or physicochemical properties. The estimated shelf-life at 30°C exceeds 48 months. Based on the results of the present study, the restocking frequency of Diastat in ambient storage conditions (eg, ambulances), could be up to 48 months in nonfreezing environments, as long as this does not exceed the labeled expiration date on the product. (Am J Emerg Med 2002;20:88-91. Copyright 2002, Elsevier Science (USA). All rights reserved.)
In many emergency medical service (EMS) systems, paramedics and emergency medical personnel administer diazepam for the out-of-hospital treatment of seizures. A gel formulation of diazepam for rectal administration (Diastat; Xcel Pharmaceuticals, San Diego, CA) was recently added to the armamentarium of products available in the U.S. for the acute management of seizures. This product is a specially formulated viscous diazepam gel, provided in a prefilled, unit-dose, rectal delivery system. The rectal delivery system includes a plastic applicator with a flexible, molded tip available in “pediatric” and “adult” lengths. Diastat is formulated specifically for use in nonhospital settings for the management of patients who require intermittent treatment to control bouts of increased seizure activity (eg, acute repetitive seizures, also known as cluster, serial, or crescendo seizures and similar acute seizure episodes). In a
controlled comparison to intravenous diazepam, Diastat was found to provide rapid, consistent absorption.1 A practical concern in the prehospital use of medications is the effect of ambulance storage conditions on product potency. Most drugs are recommended for storage at 15°C to 30°C (59°F to 85°F).2 However, drugs carried on ambulances for emergency use can be exposed to more extreme temperature conditions. For example, on-ambulance drug storage temperatures in Salt Lake City were reported to frequently exceed 38°F (100°F) and to reach as high as 60°C (140 °F). This is a concern for diazepam which is also recommended for storage at temperatures of 15 °C to 30°C. Stability limits for diazepam under the specific storage conditions dictate the frequency for restocking ambulances.3 Stored in its original vial, parenteral diazepam is stable for prolonged periods under severe conditions.4 Recently, the prehospital stability of diazepam in glass syringes was reported.5 Significant reductions in diazepam potency were found when this configuration was stored at 37°C. Those investigators concluded that at storage conditions above 30°C, diazepam in glass syringes should be restocked every 30 to 60 days. The objective of the present study was to evaluate the stability of diazepam rectal gel (Diastat) in various conditions of temperature and light exposure as might be found in ambulances. The stability of the product at a range of temperatures and light exposure is clinically relevant, as Diastat may be stored in ambulances or other locations where there is prolonged exposure to ambient conditions METHODS Materials
From *Department of Clinical Pharmacy, University of California, San Francisco, CA. and †Elan Pharmaceuticals, Inc., South San Francisco, CA. Supported by Elan Pharmaceuticals, Inc., South San Francisco, CA. Dr Alldredge has consulted for Elan Pharmaceuticals, but has no proprietary interest in the company or this product. At the time this work was conducted, Drs. Venteicher and Calderwood were employees of Elan Pharmaceuticals, the manufacturer of Diastat. Manuscript received February 28, 2001, returned March 22, 2001, revision received September 21, 2001, accepted September 28, 2001. Address reprint requests to Brian K. Alldredge, PharmD, Professor of Clinical Pharmacy and Clinical Professor of Neurology, Departments of Clinical Pharmacy and Neurology, 521 Parnassus Avenue, C-152, San Francisco, CA 94143-0622. E-mail: bka@ itsa.ucsf.edu Key Words: Diazepam, stability, Diastat, prehospital treatment, seizures. Copyright 2002, Elsevier Science (USA). All rights reserved. 0735-6757/02/2002-0005$35.00/0 doi:10.1053/ajem.2002.31573 88
Diastat contains a nonsterile diazepam gel provided in a prefilled, unit-dose, rectal delivery system. Diastat contains 5 mg/mL diazepam, propylene glycol, ethyl alcohol (10%), hydroxypropyl methylcellulose, sodium benzoate, benzyl alcohol (1.5%), benzoic acid and water. Diastat is clear to slightly yellow and has a pH between 6.5 to 7.2. Storage Conditions As shown in Table 1, 3 lots of Diastat in various typical marketing configurations (0.5 mL in 3 cc syringe, 2.0 mL in 3 cc syringe, and 4.0 mL in 5 cc syringe) were evaluated in several conditions. Each amount/container size is referred to as a sublot. Two separate syringes were used for each assay. Stability chambers were environmentally-controlled, 5.4 cubic feet chambers. Refrigeration (nominal 5°C) was regulated between 2 and 8°C, and the 30°C and 40 °C chambers regulated within 2°C.
ALLDREDGE, VENTEICHER, AND CALDERWOOD ■ DIASTAT STABILITY
TABLE 1.
Temperature and Light Stability Studies Conducted Lot
Conditions Extreme light Extreme low temperature Freeze-thaw Hard freeze 30°C 40°C
#1
#2
#3
24 months 9 months
24 months 8 months
1 month 3 days 3 days 24 months 8 months
For the freeze-thaw cycle, syringes were taken from the 5°C chamber, placed in white low density polyethylene (LDPE) shrouds, and then at ⫺30°C for 24 hours, then at ambient temperature for 24 hours for 3 total cycles. For the hard freeze, syringes were also taken from the 5°C chamber and placed in shrouds, then placed at⫺30°C for 72 hours, and at ambient temperature for 24 hours. For the extreme light exposure, samples were placed in white LDPE shrouds, and exposed to intense light (1,000 ft candles) at 25°C for 1 month. Samples were taken after 1, 2, and 4 weeks of exposure. For the longer term accelerated stability, sample were placed at either 30°C or 40°C, and samples taken regularly. As a sealed delivery system, Diastat would not be expected to be affected by relative humidity. Analytical methods A high performance liquid chromatography (HPLC) method was used to quantify diazepam, diazepam degradants and benzyl alcohol (the preservative) in the samples. This method is equivalent to the diazepam injectable method in the monograph in the USP (USP 24, page 539, United State Pharmacopeial Convention, Inc., Rockville, MD). Diazepam and its degradants, 3-amino-6-chloro-1methyl-4-phenylcarbostryil (3-ACMP), and 2-methyl-amino5-chlorobenzophenone (2-MACB) were extracted with methanol. An aliquot of the sample solution was diluted with methanol. After separation by HPLC, diazepam, degradants and benzyl alcohol were detected by ultraviolet (UV) spectrophotometry at 254 nm, and quantified by external standards. The identity of diazepam, pH, viscosity, and volume were determined according to USP standards.
89
The shelf life was determined as the time at which the lower one-sided 95% confidence interval for the regression mean reaches 90% of label strength. Additionally, for 2-MACB, the shelf life was calculated as the time until the upper one-sided 95% confidence interval intersected with a concentration of 2-MACB with 2%. The regression mean and confidence interval were constructed for the appropriate regression model (either common slope and common intercept, common slope and worst case intercept, or worst case individual regression). All regressions were unweighted, using the means of the replicate measurements from each of the sublots at each time (ie, a single value for each batch*sublot*month combination.) SAS JMP for Windows (Version 3.1.6.2, SAS Institute, Cary, NC), and Excel (Version 7.0, Microsoft Corporation, Redmond, WA) were used for all regressions and statistical analyses. RESULTS The stability of diazepam in Diastat tested in a freezethaw cycle is shown in Fig 1. At initial test, the concentration of diazepam ranged from 101% to 102% of labeled strength. After 3 freeze-thaw cycles, the concentration of diazepam ranged from 99% to 103% of labeled strength. The 2 degredants, 3-ACMP and 2-MACB were not detected at any time. Also shown in Fig 1 is the stability of diazepam in Diastat tested in a hard freeze cycle. At initial test, the concentration of diazepam ranged from 101% to 102% of labeled strength. After hard freeze, the proportion of diazepam in light exposed containers ranged from 100% to 102% of labeled strength. The 2 degredants, 3-ACMP and 2-MACB were not detected at any time. The stability of diazepam in Diastat stored at 30°C was evaluated for 24 months in 3 lots. At initial test, the concentration of diazepam ranged from 101% to 102% of labeled strength. After storage at 30°C for up to 24 months, the proportion of diazepam ranged from 96% to 102% of labeled strength. The results for one of these lots is shown in Fig 2. The degradant, 3-ACMP, was detected beginning at months 6 to 12, and ranged up to 0.2% of labeled strength. The degradant 2-MACB was detected beginning at 3 months, and ranged up to 0.9% of labeled strength.
Statistical Analysis ANOVA was performed on percent label strength and 2-MACB to examine homogeneity of sublots. The ANOVA included terms for LOT, MONTH, LOT*MONTH, SLTBLOT, and SUBLOT*MONTH. This is consistent with FDA and ICH guidelines6 which describe testing for common slope and intercept among batches using a P-value cutoff of 0.25. This test was applied first for SUBLOT and SUBLOT*MONTH to test for their poolability. If both p-values were greater than 0.25 then testing proceeded as usual, with the regression model with terms for LOT, MONTH, and LOT*MONTH, testing for common slope and intercept. If that test failed, then the test for common slope was applied. If that test also failed, then the worst case regression was used as the basis for shelf life estimation.
FIGURE 1. Stability profile of diazepam in a freeze-thaw cycle and hard freeze (Lot #1). No 3-ACMP or 2-MACB were detected (⬍.05%). Zero suppressed on chart.
90
AMERICAN JOURNAL OF EMERGENCY MEDICINE ■ Volume 20, Number 2 ■ March 2002
FIGURE 2. Stability profile of diazepam stored at 30°C (Lot #1). Abbreviations:Syringe size and fill: 0.5/3 ⫽ 0.5 mL/3 cc; 1/3 ⫽ 1.0 mL/3 cc; 2/3 ⫽ 2.0 mL/3 cc; 2/5 ⫽ 2.0 mL/5 cc;3/5 ⫽ 3.0 mL/5 cc; 4/5 ⫽ 4.0 mL/5 cc. 3-ACMP was detected beginning at months 6-12 and ranged up to 0.2% of labeled strength. 2-MACP was detected beginning at 3 months and ranged up to 0.9% of labeled strength.
The stability of diazepam in Diastat stored at 40°C was evaluated for 8 months in 3 lots. At initial test, the concentration of diazepam ranged from 102% to 103% of labeled strength. After storage at 40°C for up to 8 months, the proportion of diazepam ranged from 96% to 101% of labeled strength. The results for one of these lots is shown in Fig 3. The degredants profile was similar to that seen for the samples stored at 30°C. The other 2 lots had similar stability. Because of heterogeneity among the fill size/syringe size configurations, slopes in the ANOVA analysis, each container configuration was analyzed independently. The estimated shelf-lives at 30°C for the various configurations ranged from 49 to 93 months. The lower limit of 95% confidence interval for one container configuration is shown in Fig 4. The estimated shelf life for 2-MACB to exceed 2% ranged from 69 to 111 months.
FIGURE 3. Stability profile of diazepam stored at 40°C (Lot #1). Abbreviations as in Figure 2. Degradant concentrations (3-ACMP and 2-MACB) similar to those obtained during 30°C storage.
FIGURE 4. Stability profile of diazepam stored at 30°C with 95% lower confidence interval: Three lots of 2.0 mL/3 cc. The regression line is shown in solid black. The lower limit of the 95% confidence interval is shown as a dashed line. Shelf life (90% of label) was calculated to be 84 months.
The stability of the diazepam in Diastat when stored under extreme light conditions for 1 month is shown in Fig 5. At initial test, the concentration of diazepam ranged from 100 to 101% of labeled strength. After extreme light exposure, the proportion of diazepam ranged from 98% to 103% of labeled strength. The 2 degredants, 3-ACMP and 2-MACB were not detected at any time. For each of the assays of diazepam and its degredants, the pH, viscosity, volume, and benzyl alcohol preservative was also measured. For each test, values were well within ⫾ 10% of labeled values. There were no changes in the mechanical functioning of the device (eg, integrity of plastic, plunger, and so on) With long-term storage at accelerated conditions, there was a slight yellowing of the solution. DISCUSSION The objective of the present study was to evaluate the stability of Diastat under extreme conditions as might be experienced in out-of-hospital settings. The conditions of
FIGURE 5. Stability of diazepam stored under extreme light conditions (1,000 foot-candles). Abbreviations as in Figure 2. No 3-ACMP or 2-MACB were detected (⬍.05%).
ALLDREDGE, VENTEICHER, AND CALDERWOOD ■ DIASTAT STABILITY
extreme heat, light exposure and cold (freezing) used in this study likely exaggerate actual exposure conditions in ambulances or in airplanes where Diastat for emergency use might be stored. Under these test conditions the product was both physically and chemically stable for at least 30 days. Under conditions of extreme heat (30 and 40°C), the product was stable in excess of 48 months for both percent label strength and degredants. The product does not seem sensitive to extreme cold or freezing and thawing. Such conditions could be experienced during airplane storage or transport of Diastat, or if an ambulance were parked in extremely cold conditions for prolonged periods of time and subsequently warmed. Under no conditions did the concentration of the 2-MACB degradant reach the 2% critical value. In a previous study of injectable diazepam in glass syringes, percent label strength decreased to 91% at 1 month at 37°C, and further declined to 75% at 7 months.5 The magnitude of decrement with Diastat stored under similar conditions was much less, having at least 96% of labeled strength at 8 months. The Diastat product has advantages over rectal administration of diazepam parenteral solution that are relevant to its use by emergency medical systems. It has a lower potential for calculation error in emergency situations. Diastat is easy-to-use, and has less preparation time for personnel than preparing a parenteral solution for rectal use. Diastat is easy to administer, and has a lowered potential for leakage. These features may shorten the time interval between initial patient contact and completion of drug administration, a critical issue in treating patients in seizures. There is concern regarding the stability of drugs used in emergency care situations when these agents are stored (before use) in uncontrolled conditions. Temperature fluctuations on ambulances exposed to ambient conditions can be considerable depending on local climate conditions.2 Also, drugs are usually stored on ambulances in containers that are not temperature-controlled.7 Although many drugs for emergency use have been shown to be stable after exposure to temperature extremes,7 changes in the chemical stability and drug concentrations have been reported for some drugs following actual or simulated on-ambulance storage.2,5 For these reasons, it is important to evaluate the stability of drug products under a variety of storage conditions before their use by prehospital settings. The present results show that Diastat is an extremely stable product under conditions of extreme cold, heat, and
91
light. These results are consistent with other studies which show long-term stability of diazepam.4 Within the error of the testing, the stability of Diastat and the stability of the parental solution are essentially equivalent. It may be possible that the added light protection in Diastat with the shroud, might attenuate light exposure and physical stress relative to the parenteral solution, and thus provide some nominal additional protection. One might be tempted to extrapolate these results to the use and restocking of Diastat in other emergency care situations (eg, airline flight kits, and so on). However, as no tests were specifically performed in these conditions, it is difficult to speculate. Furthermore, we evaluated the stability of Diastat under freezing and freeze-thaw conditions over relatively short time periods. Although no meaningful degradation occurred, we cannot confirm the long-term stability of the product under these conditions. Based on the results of the present study, the restocking frequency of Diastat in ambient storage conditions (eg, ambulances), could be up to 48 months in nonfreezing environments. Although long-term storage at freezing conditions was not performed in this study, it appears that Diastat is not sensitive to freezing. Of course, the distribution time from manufacturer to pharmacy may vary, and personnel should not exceed the labeled expiration date on the product. The authors acknowledge the contributions of Gary D. Novack, PhD.
REFERENCES 1. Cloyd JC, Lalonde R, Beniak TE, et al: A single blind, crossover comparison of the pharmacokinetics and cognitive effects of a new rectal diazepam gel with intravenous diazepam. Epilepsia 1998;39: 520-6 2. Valenzuela TD, Criss EA, Hammargren WM, et al: Thermal stability of prehospital medications. Ann Emerg Med 1989;18:173-6 3. Physicians’ Desk Reference (ed 54). Montvale, NJ, Medical Economics Data, 2000, pp 1012-7 4. Fyllingen G, Kristiansen F, Roksvaag PO: Long-term stability of diazepam injections. Pharm Acta Helv 1991;66:44-6 5. Gottwald MD, Akers LC, Liu PK, et al: Prehospital stability of diazepam and lorazepam. Am J Emerg Med 1999;17:333-7 6. FDA Center for Drugs and Biologics: Guideline for Submitting Documentation for the Stability of Human Drugs and Biologics, Washington, DC, Author, 1987 7. Johansen RB, Schafer NC, Brown PI: Effect of extreme temperatures on drugs for prehospital ACLS. Am J Emerg Med 1993; 11:450-2
In many emergency medical service (EMS) systems, paramedics and emergency medical personnel administer diazepam for the out-of-hospital treatment of seizures. A gel formulation of diazepam for rectal administration (Diastat; Xcel Pharmaceuticals, San Diego, CA) was recently added to the armamentarium of products available in the U.S. for the acute management of seizures. This product is a specially formulated viscous diazepam gel, provided in a prefilled, unit-dose, rectal delivery system. The rectal delivery system includes a plastic applicator with a flexible, molded tip available in “pediatric” and “adult” lengths. Diastat is formulated specifically for use in nonhospital settings for the management of patients who require intermittent treatment to control bouts of increased seizure activity (eg, acute repetitive seizures, also known as cluster, serial, or crescendo seizures and similar acute seizure episodes). In a
controlled comparison to intravenous diazepam, Diastat was found to provide rapid, consistent absorption.1 A practical concern in the prehospital use of medications is the effect of ambulance storage conditions on product potency. Most drugs are recommended for storage at 15°C to 30°C (59°F to 85°F).2 However, drugs carried on ambulances for emergency use can be exposed to more extreme temperature conditions. For example, on-ambulance drug storage temperatures in Salt Lake City were reported to frequently exceed 38°F (100°F) and to reach as high as 60°C (140 °F). This is a concern for diazepam which is also recommended for storage at temperatures of 15 °C to 30°C. Stability limits for diazepam under the specific storage conditions dictate the frequency for restocking ambulances.3 Stored in its original vial, parenteral diazepam is stable for prolonged periods under severe conditions.4 Recently, the prehospital stability of diazepam in glass syringes was reported.5 Significant reductions in diazepam potency were found when this configuration was stored at 37°C. Those investigators concluded that at storage conditions above 30°C, diazepam in glass syringes should be restocked every 30 to 60 days. The objective of the present study was to evaluate the stability of diazepam rectal gel (Diastat) in various conditions of temperature and light exposure as might be found in ambulances. The stability of the product at a range of temperatures and light exposure is clinically relevant, as Diastat may be stored in ambulances or other locations where there is prolonged exposure to ambient conditions METHODS Materials
From *Department of Clinical Pharmacy, University of California, San Francisco, CA. and †Elan Pharmaceuticals, Inc., South San Francisco, CA. Supported by Elan Pharmaceuticals, Inc., South San Francisco, CA. Dr Alldredge has consulted for Elan Pharmaceuticals, but has no proprietary interest in the company or this product. At the time this work was conducted, Drs. Venteicher and Calderwood were employees of Elan Pharmaceuticals, the manufacturer of Diastat. Manuscript received February 28, 2001, returned March 22, 2001, revision received September 21, 2001, accepted September 28, 2001. Address reprint requests to Brian K. Alldredge, PharmD, Professor of Clinical Pharmacy and Clinical Professor of Neurology, Departments of Clinical Pharmacy and Neurology, 521 Parnassus Avenue, C-152, San Francisco, CA 94143-0622. E-mail: bka@ itsa.ucsf.edu Key Words: Diazepam, stability, Diastat, prehospital treatment, seizures. Copyright 2002, Elsevier Science (USA). All rights reserved. 0735-6757/02/2002-0005$35.00/0 doi:10.1053/ajem.2002.31573 88
Diastat contains a nonsterile diazepam gel provided in a prefilled, unit-dose, rectal delivery system. Diastat contains 5 mg/mL diazepam, propylene glycol, ethyl alcohol (10%), hydroxypropyl methylcellulose, sodium benzoate, benzyl alcohol (1.5%), benzoic acid and water. Diastat is clear to slightly yellow and has a pH between 6.5 to 7.2. Storage Conditions As shown in Table 1, 3 lots of Diastat in various typical marketing configurations (0.5 mL in 3 cc syringe, 2.0 mL in 3 cc syringe, and 4.0 mL in 5 cc syringe) were evaluated in several conditions. Each amount/container size is referred to as a sublot. Two separate syringes were used for each assay. Stability chambers were environmentally-controlled, 5.4 cubic feet chambers. Refrigeration (nominal 5°C) was regulated between 2 and 8°C, and the 30°C and 40 °C chambers regulated within 2°C.
ALLDREDGE, VENTEICHER, AND CALDERWOOD ■ DIASTAT STABILITY
TABLE 1.
Temperature and Light Stability Studies Conducted Lot
Conditions Extreme light Extreme low temperature Freeze-thaw Hard freeze 30°C 40°C
#1
#2
#3
24 months 9 months
24 months 8 months
1 month 3 days 3 days 24 months 8 months
For the freeze-thaw cycle, syringes were taken from the 5°C chamber, placed in white low density polyethylene (LDPE) shrouds, and then at ⫺30°C for 24 hours, then at ambient temperature for 24 hours for 3 total cycles. For the hard freeze, syringes were also taken from the 5°C chamber and placed in shrouds, then placed at⫺30°C for 72 hours, and at ambient temperature for 24 hours. For the extreme light exposure, samples were placed in white LDPE shrouds, and exposed to intense light (1,000 ft candles) at 25°C for 1 month. Samples were taken after 1, 2, and 4 weeks of exposure. For the longer term accelerated stability, sample were placed at either 30°C or 40°C, and samples taken regularly. As a sealed delivery system, Diastat would not be expected to be affected by relative humidity. Analytical methods A high performance liquid chromatography (HPLC) method was used to quantify diazepam, diazepam degradants and benzyl alcohol (the preservative) in the samples. This method is equivalent to the diazepam injectable method in the monograph in the USP (USP 24, page 539, United State Pharmacopeial Convention, Inc., Rockville, MD). Diazepam and its degradants, 3-amino-6-chloro-1methyl-4-phenylcarbostryil (3-ACMP), and 2-methyl-amino5-chlorobenzophenone (2-MACB) were extracted with methanol. An aliquot of the sample solution was diluted with methanol. After separation by HPLC, diazepam, degradants and benzyl alcohol were detected by ultraviolet (UV) spectrophotometry at 254 nm, and quantified by external standards. The identity of diazepam, pH, viscosity, and volume were determined according to USP standards.
89
The shelf life was determined as the time at which the lower one-sided 95% confidence interval for the regression mean reaches 90% of label strength. Additionally, for 2-MACB, the shelf life was calculated as the time until the upper one-sided 95% confidence interval intersected with a concentration of 2-MACB with 2%. The regression mean and confidence interval were constructed for the appropriate regression model (either common slope and common intercept, common slope and worst case intercept, or worst case individual regression). All regressions were unweighted, using the means of the replicate measurements from each of the sublots at each time (ie, a single value for each batch*sublot*month combination.) SAS JMP for Windows (Version 3.1.6.2, SAS Institute, Cary, NC), and Excel (Version 7.0, Microsoft Corporation, Redmond, WA) were used for all regressions and statistical analyses. RESULTS The stability of diazepam in Diastat tested in a freezethaw cycle is shown in Fig 1. At initial test, the concentration of diazepam ranged from 101% to 102% of labeled strength. After 3 freeze-thaw cycles, the concentration of diazepam ranged from 99% to 103% of labeled strength. The 2 degredants, 3-ACMP and 2-MACB were not detected at any time. Also shown in Fig 1 is the stability of diazepam in Diastat tested in a hard freeze cycle. At initial test, the concentration of diazepam ranged from 101% to 102% of labeled strength. After hard freeze, the proportion of diazepam in light exposed containers ranged from 100% to 102% of labeled strength. The 2 degredants, 3-ACMP and 2-MACB were not detected at any time. The stability of diazepam in Diastat stored at 30°C was evaluated for 24 months in 3 lots. At initial test, the concentration of diazepam ranged from 101% to 102% of labeled strength. After storage at 30°C for up to 24 months, the proportion of diazepam ranged from 96% to 102% of labeled strength. The results for one of these lots is shown in Fig 2. The degradant, 3-ACMP, was detected beginning at months 6 to 12, and ranged up to 0.2% of labeled strength. The degradant 2-MACB was detected beginning at 3 months, and ranged up to 0.9% of labeled strength.
Statistical Analysis ANOVA was performed on percent label strength and 2-MACB to examine homogeneity of sublots. The ANOVA included terms for LOT, MONTH, LOT*MONTH, SLTBLOT, and SUBLOT*MONTH. This is consistent with FDA and ICH guidelines6 which describe testing for common slope and intercept among batches using a P-value cutoff of 0.25. This test was applied first for SUBLOT and SUBLOT*MONTH to test for their poolability. If both p-values were greater than 0.25 then testing proceeded as usual, with the regression model with terms for LOT, MONTH, and LOT*MONTH, testing for common slope and intercept. If that test failed, then the test for common slope was applied. If that test also failed, then the worst case regression was used as the basis for shelf life estimation.
FIGURE 1. Stability profile of diazepam in a freeze-thaw cycle and hard freeze (Lot #1). No 3-ACMP or 2-MACB were detected (⬍.05%). Zero suppressed on chart.
90
AMERICAN JOURNAL OF EMERGENCY MEDICINE ■ Volume 20, Number 2 ■ March 2002
FIGURE 2. Stability profile of diazepam stored at 30°C (Lot #1). Abbreviations:Syringe size and fill: 0.5/3 ⫽ 0.5 mL/3 cc; 1/3 ⫽ 1.0 mL/3 cc; 2/3 ⫽ 2.0 mL/3 cc; 2/5 ⫽ 2.0 mL/5 cc;3/5 ⫽ 3.0 mL/5 cc; 4/5 ⫽ 4.0 mL/5 cc. 3-ACMP was detected beginning at months 6-12 and ranged up to 0.2% of labeled strength. 2-MACP was detected beginning at 3 months and ranged up to 0.9% of labeled strength.
The stability of diazepam in Diastat stored at 40°C was evaluated for 8 months in 3 lots. At initial test, the concentration of diazepam ranged from 102% to 103% of labeled strength. After storage at 40°C for up to 8 months, the proportion of diazepam ranged from 96% to 101% of labeled strength. The results for one of these lots is shown in Fig 3. The degredants profile was similar to that seen for the samples stored at 30°C. The other 2 lots had similar stability. Because of heterogeneity among the fill size/syringe size configurations, slopes in the ANOVA analysis, each container configuration was analyzed independently. The estimated shelf-lives at 30°C for the various configurations ranged from 49 to 93 months. The lower limit of 95% confidence interval for one container configuration is shown in Fig 4. The estimated shelf life for 2-MACB to exceed 2% ranged from 69 to 111 months.
FIGURE 3. Stability profile of diazepam stored at 40°C (Lot #1). Abbreviations as in Figure 2. Degradant concentrations (3-ACMP and 2-MACB) similar to those obtained during 30°C storage.
FIGURE 4. Stability profile of diazepam stored at 30°C with 95% lower confidence interval: Three lots of 2.0 mL/3 cc. The regression line is shown in solid black. The lower limit of the 95% confidence interval is shown as a dashed line. Shelf life (90% of label) was calculated to be 84 months.
The stability of the diazepam in Diastat when stored under extreme light conditions for 1 month is shown in Fig 5. At initial test, the concentration of diazepam ranged from 100 to 101% of labeled strength. After extreme light exposure, the proportion of diazepam ranged from 98% to 103% of labeled strength. The 2 degredants, 3-ACMP and 2-MACB were not detected at any time. For each of the assays of diazepam and its degredants, the pH, viscosity, volume, and benzyl alcohol preservative was also measured. For each test, values were well within ⫾ 10% of labeled values. There were no changes in the mechanical functioning of the device (eg, integrity of plastic, plunger, and so on) With long-term storage at accelerated conditions, there was a slight yellowing of the solution. DISCUSSION The objective of the present study was to evaluate the stability of Diastat under extreme conditions as might be experienced in out-of-hospital settings. The conditions of
FIGURE 5. Stability of diazepam stored under extreme light conditions (1,000 foot-candles). Abbreviations as in Figure 2. No 3-ACMP or 2-MACB were detected (⬍.05%).
ALLDREDGE, VENTEICHER, AND CALDERWOOD ■ DIASTAT STABILITY
extreme heat, light exposure and cold (freezing) used in this study likely exaggerate actual exposure conditions in ambulances or in airplanes where Diastat for emergency use might be stored. Under these test conditions the product was both physically and chemically stable for at least 30 days. Under conditions of extreme heat (30 and 40°C), the product was stable in excess of 48 months for both percent label strength and degredants. The product does not seem sensitive to extreme cold or freezing and thawing. Such conditions could be experienced during airplane storage or transport of Diastat, or if an ambulance were parked in extremely cold conditions for prolonged periods of time and subsequently warmed. Under no conditions did the concentration of the 2-MACB degradant reach the 2% critical value. In a previous study of injectable diazepam in glass syringes, percent label strength decreased to 91% at 1 month at 37°C, and further declined to 75% at 7 months.5 The magnitude of decrement with Diastat stored under similar conditions was much less, having at least 96% of labeled strength at 8 months. The Diastat product has advantages over rectal administration of diazepam parenteral solution that are relevant to its use by emergency medical systems. It has a lower potential for calculation error in emergency situations. Diastat is easy-to-use, and has less preparation time for personnel than preparing a parenteral solution for rectal use. Diastat is easy to administer, and has a lowered potential for leakage. These features may shorten the time interval between initial patient contact and completion of drug administration, a critical issue in treating patients in seizures. There is concern regarding the stability of drugs used in emergency care situations when these agents are stored (before use) in uncontrolled conditions. Temperature fluctuations on ambulances exposed to ambient conditions can be considerable depending on local climate conditions.2 Also, drugs are usually stored on ambulances in containers that are not temperature-controlled.7 Although many drugs for emergency use have been shown to be stable after exposure to temperature extremes,7 changes in the chemical stability and drug concentrations have been reported for some drugs following actual or simulated on-ambulance storage.2,5 For these reasons, it is important to evaluate the stability of drug products under a variety of storage conditions before their use by prehospital settings. The present results show that Diastat is an extremely stable product under conditions of extreme cold, heat, and
91
light. These results are consistent with other studies which show long-term stability of diazepam.4 Within the error of the testing, the stability of Diastat and the stability of the parental solution are essentially equivalent. It may be possible that the added light protection in Diastat with the shroud, might attenuate light exposure and physical stress relative to the parenteral solution, and thus provide some nominal additional protection. One might be tempted to extrapolate these results to the use and restocking of Diastat in other emergency care situations (eg, airline flight kits, and so on). However, as no tests were specifically performed in these conditions, it is difficult to speculate. Furthermore, we evaluated the stability of Diastat under freezing and freeze-thaw conditions over relatively short time periods. Although no meaningful degradation occurred, we cannot confirm the long-term stability of the product under these conditions. Based on the results of the present study, the restocking frequency of Diastat in ambient storage conditions (eg, ambulances), could be up to 48 months in nonfreezing environments. Although long-term storage at freezing conditions was not performed in this study, it appears that Diastat is not sensitive to freezing. Of course, the distribution time from manufacturer to pharmacy may vary, and personnel should not exceed the labeled expiration date on the product. The authors acknowledge the contributions of Gary D. Novack, PhD.
REFERENCES 1. Cloyd JC, Lalonde R, Beniak TE, et al: A single blind, crossover comparison of the pharmacokinetics and cognitive effects of a new rectal diazepam gel with intravenous diazepam. Epilepsia 1998;39: 520-6 2. Valenzuela TD, Criss EA, Hammargren WM, et al: Thermal stability of prehospital medications. Ann Emerg Med 1989;18:173-6 3. Physicians’ Desk Reference (ed 54). Montvale, NJ, Medical Economics Data, 2000, pp 1012-7 4. Fyllingen G, Kristiansen F, Roksvaag PO: Long-term stability of diazepam injections. Pharm Acta Helv 1991;66:44-6 5. Gottwald MD, Akers LC, Liu PK, et al: Prehospital stability of diazepam and lorazepam. Am J Emerg Med 1999;17:333-7 6. FDA Center for Drugs and Biologics: Guideline for Submitting Documentation for the Stability of Human Drugs and Biologics, Washington, DC, Author, 1987 7. Johansen RB, Schafer NC, Brown PI: Effect of extreme temperatures on drugs for prehospital ACLS. Am J Emerg Med 1993; 11:450-2