Abbott Addresses Sevoflurane Formulation

Mario Saltarelli, MD, PhD

To the Editor:

The article “Sevoflurane: The Challenges of Safe Formulation” by Evan Kharasch examines the potential patient safety implications of sevoflurane formulation differences. This letter outlines the safety measures taken by Abbott regarding its sevoflurane product, Ultane® 9also known as Sevorane® ([ex-US]).

Following a voluntary recall in 1996 due to physical changes of sevoflurane, Abbott identified several degradation products, including hydrogen fluoride (863 ppm). Abbott determined that the cause of degradation was a Lewis Acid-mediated reaction that occurred during shipping and transport. This reaction was inhibited by water.1 Abbott subsequently reformulated Ultane® to contain >300 ppm water.

Recent studies confirmed the role of Lewis acids in the degradation of sevoflurane.2, 3 Another experiment investigated the potential breakdown of sevoflurane products in vaporizers.4 Three sevoflurane formulations with differing water content (Ultane® [357 ppm water], Baxter sevoflurane [U.S.] ]57 ppm water], and Minrad sevoflurane [19 ppm water]) were tested in 3 commercial vaporizers (GE Tec 7, Dräger 2000, and Penlon Sigma Delta). Each sevoflurane formulation was stored in each vaporizer type for 3 weeks using an accelerated stability model (simulating 3 month storage at room temperature). In the Penlon vaporizers, marked increases in hydrogen fluoride were measured in both low-water formulations [U.S. Baxter (444 ppm); Minrad (600 ppm)], indicative of sevoflurane degradation. However, no hydrogen fluoride was detected in the high-water sevoflurane formulation [Ultane® (<0.4 ppm)]. Additionally, degradation and hydrogen fluoride production associated with the low water sevoflurane formulations were accompanied by physical corrosion of the vaporizers, specifically etching of the sight glass and degradation of the metal filler port shoe. In early 2007, Abbott shared the results of these experiments with Penlon, Baxter, Minrad, and many regulatory agencies worldwide (including FDA [U.S], TGA [Australia], and MHRA [U.K]), as well as several academic experts. Abbott is conducting further studies.

Shortly after the completion of the Abbott studies, notices issued by the European Medicines and Healthcare Products Regulatory Agency5, 6 and a report in the journal Anaesthesia7 revealed that some units of the Penlon Sigma Delta sevoflurane vaporizer (distributed by Baxter) were found to interact with low-water sevoflurane formulations, resulting in “degradation in some of the materials in use. This degradation [location] has notably been the filling port shoe and the Sight glass. It has made, in some cases, it difficult to establish the drug level in the vaporizer.”5 In both European Agency notices,5, 6 it was recommended that the vaporizers be removed from use.

Historically, Abbott has acted responsibly throughout the years to investigate potential problems with its sevoflurane product in order to ensure patient safety. These studies reflect our continuing commitment to product quality and patient safety.

Mario Saltarelli, MD, PhD
Divisional Vice-President
Neuroscience and Anesthesia Development
Global Pharmaceutical Research and Development
Abbott
Abbott Park, IL 60064

References

  1. Cromack KR, Meinhold JM. Lewis acid chemistry and the effect of water content in sevoflurane. 2007 ASHP Midyear Clinical Meeting. Poster # P457E.
  2. Cromack KR, Kharasch ED, et al. Influence of formulation water content on sevoflurane degradation in vitro by Lewis acids. 2007 ASA Annual Meeting, Poster #A1593, October 16, 2007. http://www.asaabstracts.com
  3. Stephens DA, Kharasch ED, et al. Commercially marketed sevoflurane vaporizers contain Lewis acid metal oxides that can potentially degrade sevoflurane containing insufficient protective water content. 2007 ASA Annual Meeting, Poster #A1597, October 16, 2007. http://www.asaabstracts.com
  4. Kharasch ED, Subbarao G, et al. Influence of sevoflurane formulation water content on degradation to hydrogen fluoride in commercial vaporizers. 2007 ASA Annual Meeting, Poster #A1591, October 16, 2007. http://www.asaabstracts.com
  5. http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&useSecondary=true&ssDocName=CON2024730&ssTargetNodeId=967. Accessed November 13, 2007
  6. http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&useSecondary=true&ssDocName=CON2025389&ssTargetNodeId=967. Accessed November 13, 2007.
  7. O’Neill B, Hafiz MA, DeBeer DA. Corrosion of Penlon sevoflurane vaporizers. Anaesthesia 2007; 62: 421.

Editor’s Note:

The issues regarding the stability and formulation of sevoflurane are complex and controversial. The APSF Newsletter has endeavored to allow all interested parties to share their perspectives and respond to Dr. Kharasch’s prior article.