SHORT COMMUNICATION
Stability of Generic Meropenem Solutions for Administration by Continuous Infusion at Normal and Elevated Temperatures Loretta Franceschi, BSc, Piergiorgio Cojutti, MD, Massimo Baraldo, MD, and Federico Pea, MD
Abstract: Administration by continuous infusion may represent an effective tool for the treatment of multidrug-resistant gram-negative related infections with meropenem. Currently, no data on chemical stability of generic bioequivalent versions of meropenem over time are available. Triplicate samples of 5 mg/mL solutions of a generic meropenem formulation, Hospira, were evaluated for chemical stability at increasing temperatures (258C, 308C, 358C, and 408C) by means of a high-performance liquid chromatography technique over 4 separate days. Degradation of generic meropenem was both time and temperature dependent, and the aqueous solutions were stable for up to 8 hours in the temperature range between 258C and 358C, and for up to 5 hours at 408C. Continuous infusion of generic meropenem Hospira may be applied in clinical settings with ambient temperature below 358C, provided that the 5 mg/mL aqueous solution is reconstituted at most after 6–8 hours. Key Words: meropenem, continuous infusion, stability, elevated temperature, concentrated solutions (Ther Drug Monit 2014;36:674–676)
INTRODUCTION The increasing prevalence of infections caused by multidrug-resistant (MDR) gram-negative bacterial pathogens challenges clinicians to adopt new administration strategies with the intent of maximizing the time-dependent antibacterial activity of beta-lactams.1 Several studies have documented that administration of meropenem by continuous infusion may represent an effective tool for the treatment of MDR gram-negative related infections.1–3 Interestingly, it has been suggested that this approach may be worthwhile even in the presence of carbapenemase-producing Enterobacteriaceae, with a minimum inhibitory concentration up to 4 mg/L, provided that Received for publication September 11, 2013; accepted January 15, 2014. From the Institute of Clinical Pharmacology, Azienda OspedalieroUniversitaria Santa Maria della Misericordia; Department of Experimental and Clinical Medical Sciences, Medical School, University of Udine, Italy. F. Pea has been on the speakers’ bureau of and has been a board membership of AstraZeneca. The remaining authors declare no conflict of interest. Correspondence: Federico Pea, MD, Institute of Clinical Pharmacology, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia and Department of Experimental and Clinical Medical Sciences, University of Udine, P.le S. Maria della Misericordia 3, Udine 33100, Italy (e-mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins
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meropenem is used in combination therapy with other active antibacterial agents.4 These facts encouraged us to validate dosing nomograms based on creatinine clearance estimates for attaining optimum meropenem concentrations by continuous infusion in the treatment of severe gram-negative infections in critically ill patients.5 Unfortunately, meropenem is a semi-synthetic drug that is quite unstable when in concentrated aqueous solutions, and it has been demonstrated with the originator meropenem brand (AstraZeneca) that significant time-dependent degradation may occur under these circumstances.6 According to the European Pharmacopoeia, beta-lactam solutions may be considered stable only when containing at least 90% of intact molecule. This means that continuous infusion of brand meropenem may be attained only through the reconstitution of the solution every 6–8 hours maximum.5 Brand meropenem came off patent protection recently, and several generic bioequivalent versions became available. Upon their arrival in the market, originator brand meropenem was then replaced in several hospitals by these generic versions. However, considering the health care providers’ concerns and suspicions about generic drugs,7 it would be helpful to confirm whether or not the stability in an aqueous solution of these generic formulations may be long enough to make continuous infusion feasible. The aim of this study was to test the stability of a generic meropenem formulation, Hospira, in concentrated aqueous solutions at normal room temperatures and at elevated temperatures, to assess the feasibility of prolonged continuous infusion.
MATERIALS AND METHODS Four commercially available 500-mg vials of generic meropenem (Hospira) that came from the same batch were used for this test. The stability of the solutions at increasing temperatures was assessed in an air-thermostated oven during 4 separate days (day 1 at 258C, day 2 at 308C, day 3 at 358C, and day 4 at 408C). On each study day, 1 fresh solution was reconstituted from a single vial with 100 mL of sterile water to produce a 5 mg/mL solution. For each of the 10 scheduled exposure times that were tested daily (1, 2, 3, 4, 5, 6, 7, 8, 9, and 24 hours), triplicate samples were collected from the solution immediately after reconstitution, subsequently incubated at the set temperature for the appropriate time, and finally frozen at 2808C until assayed. Chromatographic Ther Drug Monit Volume 36, Number 5, October 2014
Ther Drug Monit Volume 36, Number 5, October 2014
Stability of Generic Meropenem Solutions
FIGURE 1. Stability of generic meropenem, Hospira, 5 mg/mL aqueous solutions upon incubation for up to 24 hours at increasing temperatures. Data are presented as mean 6 SD of triplicate samples at each time set.
analysis was carried out by means of a previously validated method,8 with some modifications and using cefepime (provided by Sigma-Aldrich) as the internal standard, as previously reported.9 Assay reference material was purchased from Sigma-Aldrich. Briefly, the high-performance liquid chromatography equipment (Beckman 126 Solvent Module) was connected with a UV detector (Beckman 168 Detector) set at 296 nm, and an Ultrasphere C18 column (ODS, 250 · 4.6 mm, 5 mm; Beckman Instruments) with isocratic elution [phosphate buffer/acetonitrile (91/9 vol/vol), pH 3, flow rate 1.2 mL/min, range 0.2–50 mg/L, coefficient of variation , 10%] was used. Each test was performed in triplicate, and data are presented as mean 6 SD. The solution was considered stable as long as the percentage of degradation of the parent molecule was #10% (or until there was ,90% parent compound).
RESULTS Figure 1 shows the stability of generic meropenem in concentrated aqueous solutions upon incubation for up to 24 hours at 258C (ambient temperature) and at elevated temperatures. The degradation of generic meropenem was both time and temperature dependent, and the aqueous solutions were stable for up to 8 hours in the range of temperature between 258C and 358C, and for up to 5 hours at 408C.
DISCUSSION Various studies have assessed the stability of the originator brand meropenem in concentrated aqueous solutions. Viaene et al10 showed that the degradation of brand meropenem in concentrated aqueous solutions (6.4 g/100 mL) resulted in a 10% degradation after 5.15 hours of incubation at 258C. Berthoin et al6 confirmed that the degradation of the 4 g/100 mL solution was both time and temperature dependent (10% in 12 hours at 258C, in 6 hours at 378C), and highlighted that it was also concentration dependent 2014 Lippincott Williams & Wilkins
(10% for the 4 g/100 mL solution and .20% for the 9 g/100 mL solution after 12 hours of incubation at 258C). Finally, Keel et al11 showed recently that the time to reach ,90% of the initial concentration with the 5 mg/mL aqueous solution of brand meropenem was of 12, 8, and 6 hours at temperatures of 30, 35 and 408C, respectively. Our findings show that the stability of the Hospira formulation in a concentrated aqueous solution of 5 mg/mL is similar to that of the originator brand meropenem under similar conditions of concentration and temperature. This is in agreement with the fact that this formulation does not change in the addition of new buffers or salts and suggests that in clinical settings with ambient temperatures below 358C, continuous infusion of meropenem may be applied even for this generic version of the drug, provided that the 5 mg/mL aqueous solution is reconstituted at most after 6–8 hours. We recognize that our study might have 2 limitations that could limit the application of our findings. First, direct assessment of the stability of the originator meropenem was not carried out; comparison was based on historical data. Second, all the tests were performed on vials coming from a single batch. However, we believe that this mode of administration, by maximizing the time-dependent bactericidal activity of meropenem, could be helpful both to improve the clinical outcome of MDR gram-negative infections in critically ill patients and to limit the spread of carbapenemases among Enterobacteriaceae.1,5 REFERENCES 1. Dulhunty JM, Roberts JA, Davis JS, et al. Continuous infusion of Beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial. Clin Infect Dis. 2013;56:236–244. 2. Chytra I, Stepan M, Benes J, et al. Clinical and microbiological efficacy of continuous versus intermittent application of meropenem in critically ill patients: a randomized open-label controlled trial. Crit Care. 2012;16:R113. 3. Lorente L, Lorenzo L, Martin MM, et al. Meropenem by continuous versus intermittent infusion in ventilator-associated pneumonia due to gram-negative bacilli. Ann Pharmacother. 2006;40:219–223.
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4. Daikos GL, Markogiannakis A. Carbapenemase-producing Klebsiella pneumoniae: (when) might we still consider treating with carbapenems? Clin Microbiol Infect. 2011;17:1135–1141. 5. Pea F, Viale P, Cojutti P, et al. Dosing nomograms for attaining optimum concentrations of meropenem by continuous infusion in critically ill patients with severe gram-negative infections: a pharmacokinetics/ pharmacodynamics-based approach. Antimicrob Agents Chemother. 2012;56:6343–6348. 6. Berthoin K, Le Duff CS, Marchand-Brynaert J, et al. Stability of meropenem and doripenem solutions for administration by continuous infusion. J Antimicrob Chemother. 2010;65:1073–1075. 7. Venkatesh M, Bairavi VG, Sasikumar KC. Generic antibiotic industries: challenges and implied strategies with regulatory perspectives. J Pharm Bioallied Sci. 2011;3:101–108.
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8. Mendez AS, Steppe M, Schapoval EE. Validation of HPLC and UV spectrophotometric methods for the determination of meropenem in pharmaceutical dosage form. J Pharm Biomed Anal. 2003;33:947–954. 9. Pea F, Cojutti P, Sbrojavacca R, et al. TDM-guided therapy with daptomycin and meropenem in a morbidly obese, critically ill patient. Ann Pharmacother. 2011;45:e37. 10. Viaene E, Chanteux H, Servais H, et al. Comparative stability studies of antipseudomonal beta-lactams for potential administration through portable elastomeric pumps (home therapy for cystic fibrosis patients) and motor-operated syringes (intensive care units). Antimicrob Agents Chemother. 2002;46:2327–2332. 11. Keel RA, Sutherland CA, Crandon JL, et al. Stability of doripenem, imipenem and meropenem at elevated room temperatures. Int J Antimicrob Agents. 2011;37:184–185.
2014 Lippincott Williams & Wilkins
Stability of Generic Meropenem Solutions for Administration by Continuous Infusion at Normal and Elevated Temperatures Loretta Franceschi, BSc, Piergiorgio Cojutti, MD, Massimo Baraldo, MD, and Federico Pea, MD
Abstract: Administration by continuous infusion may represent an effective tool for the treatment of multidrug-resistant gram-negative related infections with meropenem. Currently, no data on chemical stability of generic bioequivalent versions of meropenem over time are available. Triplicate samples of 5 mg/mL solutions of a generic meropenem formulation, Hospira, were evaluated for chemical stability at increasing temperatures (258C, 308C, 358C, and 408C) by means of a high-performance liquid chromatography technique over 4 separate days. Degradation of generic meropenem was both time and temperature dependent, and the aqueous solutions were stable for up to 8 hours in the temperature range between 258C and 358C, and for up to 5 hours at 408C. Continuous infusion of generic meropenem Hospira may be applied in clinical settings with ambient temperature below 358C, provided that the 5 mg/mL aqueous solution is reconstituted at most after 6–8 hours. Key Words: meropenem, continuous infusion, stability, elevated temperature, concentrated solutions (Ther Drug Monit 2014;36:674–676)
INTRODUCTION The increasing prevalence of infections caused by multidrug-resistant (MDR) gram-negative bacterial pathogens challenges clinicians to adopt new administration strategies with the intent of maximizing the time-dependent antibacterial activity of beta-lactams.1 Several studies have documented that administration of meropenem by continuous infusion may represent an effective tool for the treatment of MDR gram-negative related infections.1–3 Interestingly, it has been suggested that this approach may be worthwhile even in the presence of carbapenemase-producing Enterobacteriaceae, with a minimum inhibitory concentration up to 4 mg/L, provided that Received for publication September 11, 2013; accepted January 15, 2014. From the Institute of Clinical Pharmacology, Azienda OspedalieroUniversitaria Santa Maria della Misericordia; Department of Experimental and Clinical Medical Sciences, Medical School, University of Udine, Italy. F. Pea has been on the speakers’ bureau of and has been a board membership of AstraZeneca. The remaining authors declare no conflict of interest. Correspondence: Federico Pea, MD, Institute of Clinical Pharmacology, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia and Department of Experimental and Clinical Medical Sciences, University of Udine, P.le S. Maria della Misericordia 3, Udine 33100, Italy (e-mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins
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meropenem is used in combination therapy with other active antibacterial agents.4 These facts encouraged us to validate dosing nomograms based on creatinine clearance estimates for attaining optimum meropenem concentrations by continuous infusion in the treatment of severe gram-negative infections in critically ill patients.5 Unfortunately, meropenem is a semi-synthetic drug that is quite unstable when in concentrated aqueous solutions, and it has been demonstrated with the originator meropenem brand (AstraZeneca) that significant time-dependent degradation may occur under these circumstances.6 According to the European Pharmacopoeia, beta-lactam solutions may be considered stable only when containing at least 90% of intact molecule. This means that continuous infusion of brand meropenem may be attained only through the reconstitution of the solution every 6–8 hours maximum.5 Brand meropenem came off patent protection recently, and several generic bioequivalent versions became available. Upon their arrival in the market, originator brand meropenem was then replaced in several hospitals by these generic versions. However, considering the health care providers’ concerns and suspicions about generic drugs,7 it would be helpful to confirm whether or not the stability in an aqueous solution of these generic formulations may be long enough to make continuous infusion feasible. The aim of this study was to test the stability of a generic meropenem formulation, Hospira, in concentrated aqueous solutions at normal room temperatures and at elevated temperatures, to assess the feasibility of prolonged continuous infusion.
MATERIALS AND METHODS Four commercially available 500-mg vials of generic meropenem (Hospira) that came from the same batch were used for this test. The stability of the solutions at increasing temperatures was assessed in an air-thermostated oven during 4 separate days (day 1 at 258C, day 2 at 308C, day 3 at 358C, and day 4 at 408C). On each study day, 1 fresh solution was reconstituted from a single vial with 100 mL of sterile water to produce a 5 mg/mL solution. For each of the 10 scheduled exposure times that were tested daily (1, 2, 3, 4, 5, 6, 7, 8, 9, and 24 hours), triplicate samples were collected from the solution immediately after reconstitution, subsequently incubated at the set temperature for the appropriate time, and finally frozen at 2808C until assayed. Chromatographic Ther Drug Monit Volume 36, Number 5, October 2014
Ther Drug Monit Volume 36, Number 5, October 2014
Stability of Generic Meropenem Solutions
FIGURE 1. Stability of generic meropenem, Hospira, 5 mg/mL aqueous solutions upon incubation for up to 24 hours at increasing temperatures. Data are presented as mean 6 SD of triplicate samples at each time set.
analysis was carried out by means of a previously validated method,8 with some modifications and using cefepime (provided by Sigma-Aldrich) as the internal standard, as previously reported.9 Assay reference material was purchased from Sigma-Aldrich. Briefly, the high-performance liquid chromatography equipment (Beckman 126 Solvent Module) was connected with a UV detector (Beckman 168 Detector) set at 296 nm, and an Ultrasphere C18 column (ODS, 250 · 4.6 mm, 5 mm; Beckman Instruments) with isocratic elution [phosphate buffer/acetonitrile (91/9 vol/vol), pH 3, flow rate 1.2 mL/min, range 0.2–50 mg/L, coefficient of variation , 10%] was used. Each test was performed in triplicate, and data are presented as mean 6 SD. The solution was considered stable as long as the percentage of degradation of the parent molecule was #10% (or until there was ,90% parent compound).
RESULTS Figure 1 shows the stability of generic meropenem in concentrated aqueous solutions upon incubation for up to 24 hours at 258C (ambient temperature) and at elevated temperatures. The degradation of generic meropenem was both time and temperature dependent, and the aqueous solutions were stable for up to 8 hours in the range of temperature between 258C and 358C, and for up to 5 hours at 408C.
DISCUSSION Various studies have assessed the stability of the originator brand meropenem in concentrated aqueous solutions. Viaene et al10 showed that the degradation of brand meropenem in concentrated aqueous solutions (6.4 g/100 mL) resulted in a 10% degradation after 5.15 hours of incubation at 258C. Berthoin et al6 confirmed that the degradation of the 4 g/100 mL solution was both time and temperature dependent (10% in 12 hours at 258C, in 6 hours at 378C), and highlighted that it was also concentration dependent 2014 Lippincott Williams & Wilkins
(10% for the 4 g/100 mL solution and .20% for the 9 g/100 mL solution after 12 hours of incubation at 258C). Finally, Keel et al11 showed recently that the time to reach ,90% of the initial concentration with the 5 mg/mL aqueous solution of brand meropenem was of 12, 8, and 6 hours at temperatures of 30, 35 and 408C, respectively. Our findings show that the stability of the Hospira formulation in a concentrated aqueous solution of 5 mg/mL is similar to that of the originator brand meropenem under similar conditions of concentration and temperature. This is in agreement with the fact that this formulation does not change in the addition of new buffers or salts and suggests that in clinical settings with ambient temperatures below 358C, continuous infusion of meropenem may be applied even for this generic version of the drug, provided that the 5 mg/mL aqueous solution is reconstituted at most after 6–8 hours. We recognize that our study might have 2 limitations that could limit the application of our findings. First, direct assessment of the stability of the originator meropenem was not carried out; comparison was based on historical data. Second, all the tests were performed on vials coming from a single batch. However, we believe that this mode of administration, by maximizing the time-dependent bactericidal activity of meropenem, could be helpful both to improve the clinical outcome of MDR gram-negative infections in critically ill patients and to limit the spread of carbapenemases among Enterobacteriaceae.1,5 REFERENCES 1. Dulhunty JM, Roberts JA, Davis JS, et al. Continuous infusion of Beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial. Clin Infect Dis. 2013;56:236–244. 2. Chytra I, Stepan M, Benes J, et al. Clinical and microbiological efficacy of continuous versus intermittent application of meropenem in critically ill patients: a randomized open-label controlled trial. Crit Care. 2012;16:R113. 3. Lorente L, Lorenzo L, Martin MM, et al. Meropenem by continuous versus intermittent infusion in ventilator-associated pneumonia due to gram-negative bacilli. Ann Pharmacother. 2006;40:219–223.
675
Franceschi et al
4. Daikos GL, Markogiannakis A. Carbapenemase-producing Klebsiella pneumoniae: (when) might we still consider treating with carbapenems? Clin Microbiol Infect. 2011;17:1135–1141. 5. Pea F, Viale P, Cojutti P, et al. Dosing nomograms for attaining optimum concentrations of meropenem by continuous infusion in critically ill patients with severe gram-negative infections: a pharmacokinetics/ pharmacodynamics-based approach. Antimicrob Agents Chemother. 2012;56:6343–6348. 6. Berthoin K, Le Duff CS, Marchand-Brynaert J, et al. Stability of meropenem and doripenem solutions for administration by continuous infusion. J Antimicrob Chemother. 2010;65:1073–1075. 7. Venkatesh M, Bairavi VG, Sasikumar KC. Generic antibiotic industries: challenges and implied strategies with regulatory perspectives. J Pharm Bioallied Sci. 2011;3:101–108.
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Ther Drug Monit Volume 36, Number 5, October 2014
8. Mendez AS, Steppe M, Schapoval EE. Validation of HPLC and UV spectrophotometric methods for the determination of meropenem in pharmaceutical dosage form. J Pharm Biomed Anal. 2003;33:947–954. 9. Pea F, Cojutti P, Sbrojavacca R, et al. TDM-guided therapy with daptomycin and meropenem in a morbidly obese, critically ill patient. Ann Pharmacother. 2011;45:e37. 10. Viaene E, Chanteux H, Servais H, et al. Comparative stability studies of antipseudomonal beta-lactams for potential administration through portable elastomeric pumps (home therapy for cystic fibrosis patients) and motor-operated syringes (intensive care units). Antimicrob Agents Chemother. 2002;46:2327–2332. 11. Keel RA, Sutherland CA, Crandon JL, et al. Stability of doripenem, imipenem and meropenem at elevated room temperatures. Int J Antimicrob Agents. 2011;37:184–185.
2014 Lippincott Williams & Wilkins
