Sevoflurane: The Challenges of Safe Formulation

Evan D. Kharasch, MD, PhD

Sevoflurane is a widely used inhalational anesthetic, first introduced in 1990 by Maruishi Pharmaceuticals in Japan, and subsequently (1995) marketed by Abbott Laboratories in the United States as Ultane® and worldwide as Sevorane®. Beginning in 2006, generic versions of sevoflurane became available, first by Baxter Healthcare and then by Minrad International. Although Ultane® and the generic versions are considered by regulatory agencies to be therapeutically equivalent, there are potentially important differences between them. These include the methods of synthesis, impurities, the containers in which they are sold, and the formulation (sevoflurane itself and any additives).

A recent publication by Dr. Max Baker, professor of anesthesiology at the University of Iowa, thoroughly reviewed the differences in sevoflurane products, and the potential patient safety implications.1 Dr. Baker is an accomplished chemist, holding patents on the synthesis of volatile anesthetics, and has written previously on the challenges of drug formulation.2 The methods for synthesizing sevoflurane differ between manufacturers, resulting in differing impurities and their amounts. The good news is that, as Dr. Baker states, “the quantities of impurities are low and qualitative differences minor” and are “not expected to be of clinical significance, if they remain so” (italics mine).

It is this last caveat that is the focus of the remainder of the Baker paper. Sevoflurane is susceptible to various types of chemical degradation. Most pertinent is the degradation of sevoflurane by Lewis acids (such as metal oxides and metal halides), to hydrofluoric acid, and to other toxic compounds. Hydrofluoric acid (HF), even in minute amounts, is highly reactive, corrosive, profoundly toxic, and can cause respiratory irritation or pulmonary hemorrhage.3,4

An incident of Lewis acid mediated sevoflurane degradation occurred in 1996.5,6 Several bottles of sevoflurane had cloudy drug, a pungent odor, marked acidity (pH <1), and high fluoride (863 ppm), all indicating substantial anesthetic degradation and formation of HF, in quantities far exceeding the safe limits of 3 ppm over an 8 hr average. Abbott subsequently determined that increasing the water content in sevoflurane formulations decreased Lewis acid-dependent sevoflurane degradation.7 They changed the sevoflurane formulation to contain at least 300 ppm water, in order to prevent Lewis acid degradation and formation of toxic degradants. The new “water-enhanced” sevoflurane formulation was approved later that year by the U.S. Food and Drug Administration (FDA), and awarded patent protection.

Why is all this important? Generic sevoflurane formulations do not contain Lewis acid inhibitors, nor can they contain water in concentrations higher than 130 ppm. As Dr. Baker concludes, “a potential remains for sevoflurane instability, . . . therefore some vigilance regarding product integrity remains prudent.”1

Recent information from the European Medicines and Healthcare Products Regulatory Agency,8 and in abstract form,9,10 reinforces the need for such vigilance. The Penlon Sigma Delta sevoflurane vaporizer, distributed by Baxter, was found to interact with lower-water sevoflurane formulations, with the production of certain degradation byproducts. This caused etching of the vaporizer sight glass and partial disintegration of the indicator ball, etching of the metal filling port shoe, corrosion of the plastic keyed-filler stoppers with resulting leakage of anesthetic, and yellow discoloration of the sevoflurane. Sight glass etching made the sevoflurane liquid levels in the vaporizer hard to read. The European Agency recommended that the vaporizers be removed from use. Although the degradants were not identified in the above reports, sight glass etching suggests the potential formation of hydrofluoric acid.

Recent laboratory findings also reinforce the need for vigilance.11-13 Vaporizers from various manufacturers were disassembled and found to contain potential Lewis acids (metal oxides) on surfaces that contact both liquid or vapor sevoflurane. Degradation of lower-water generic sevoflurane by aluminum oxide, a prototypic Lewis acid, was up to 90-fold greater than that of higher-water Ultane® sevoflurane. Lower-water generic sevoflurane, but not higher-water Ultane®, when stored in Penlon Sigma Delta vaporizers under accelerated storage conditions, underwent substantial degradation. There were substantial increases in fluoride (as high as 600 ppm) and reduced pH (as low as 3), as well as sight glass etching and metal filler shoe corrosion. Thus, lower-water generic sevoflurane underwent Lewis-acid mediated degradation to HF. The absence of such degradation with water-added Ultane® sevoflurane is consistent with the known ability of water to prevent Lewis acid-mediated sevoflurane degradation.

Degradation of lower-water sevoflurane to toxic compounds is a potential patient safety issue. The 1996 Lewis acid degradation of original low-water sevoflurane to HF was considered a clinically significant safety issue prompting widespread practitioner notification and reformulation of sevoflurane to contain at least 300 ppm water as a Lewis acid inhibitor. Recent clinical and laboratory reports of new lower-water sevoflurane formulation degradation in Penlon vaporizers to HF recapitulate those of 1996. Patient harm was not needed in 1996 in order to generate safety concerns about degradation of lower-water sevoflurane, and lead to its replacement with higher-water sevoflurane. Therefore, the absence of reports (to date) of patient harm with currently marketed lower-water sevoflurane should not mitigate appropriate concerns about the degradation and safety of lower-water sevoflurane.

The FDA defines drugs as pharmaceutical equivalents if they 1) contain the same active ingredient(s), 2) are of the same dosage form and route of administration, and 3) are identical in strength or concentration.14 The FDA also defines drugs as therapeutic equivalents only if they are pharmaceutical equivalents and if they can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling.15

Although the active ingredient (sevoflurane) in various manufacturers’ formulations is chemically identical, the formulations differ in their water content. Recently approved lower-water sevoflurane formulations do not contain enough water to prevent Lewis acid-mediated degradation and the production of toxic hydrogen fluoride. Nevertheless, low-water sevoflurane is considered therapeutically equivalent (AN rated) to high-water sevoflurane. Recent laboratory and clinical case reports that demonstrate degradation of lower-water sevoflurane to toxic and corrosive hydrogen fluoride, and damage to vaporizers, suggest that the higher- and lower-water sevoflurane formulations may not have the same safety profile. While they may be considered pharmaceutical equivalents, they may not be therapeutic equivalents. Again, vigilance, the maxim of anesthesiology, is warranted.

Dr. Kharasch is the Russell D. and Mary B. Shelden Professor of Anesthesiology, Director, Division of Clinical and Translational Research, Department of Anesthesiology, Washington University, St. Louis, MO.

DISCLOSURE: Dr. Kharasch is also an occasional consultant to Abbott, a manufacturer of sevoflurane.

References

  1. Baker MT. Sevoflurane: are there differences in products? Anesth Analg 2007;104:1447-51.
  2. Baker MT, Naguib M. Propofol: the challenges of formulation. Anesthesiology 2005;103:860-76.
  3. Dalbey W, Dunn B, Bannister R, et al. Acute effects of 10-minute exposure to hydrogen fluoride in rats and derivation of a short-term exposure limit for humans. Regul Toxicol Pharmacol 1998;27:207-16.
  4. Bertolini J. Hydrofluoric acid: a review of toxicity. J Emerg Med 1992;10:163-8.
  5. Leary JP. Contaminated sevoflurane use reported from New York State (Letter to Editor). APSF Newsletter 1996-97;11(4):37, 39.
  6. Callan CM. Sevo manufacturer outlines circumstances, response. (Response) APSF Newsletter 1996-97;11(4):37, 39.
  7. McLeskey CH. Anesthesiologist executive reports how Abbott made sevoflurane safer: water stops formation of highly toxic acid. APSF Newsletter 2000;15(3):39.
  8. Vaporizer – Penlon – Sigma Delta Sevoflurane vaporizer- updated.Available at http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&useSecondary=true&ssDocName=CON2024730&ssTargetNodeId=967. Accessed August 9, 2007.
  9. O’Neill B, Hafiz MA, DeBeer DA. Corrosion of Penlon sevoflurane vaporizers. Anaesthesia 2007;62:421.
  10. Gupta A, Ely J. Faulty sevoflurane vaporizer. Anaesthesia 2007:62:421.
  11. Stephens D, Kharasch E, Cromack K, Shrivastava S, Saltarelli M. Commercially marketed sevoflurane vaporizers contain Lewis acid metal oxides that can potentially degrade sevoflurane containing insufficient protective water content. Anesthesiology, 2007, in press.
  12. Cromack K, Kharasch E, Stephens D, Subbarao G, Saltarelli M. Influence of formulation water content on sevoflurane degradation in vitro by Lewis acids, Anesthesiology, 2007, in press.
  13. Kharasch E, Subbarao G, Stephens D, Cromack K, Saltarelli M. Influence of sevoflurane formulation water content on degradation to hydrogen fluoride in commercial vaporizers. Anesthesiology, 2007, in press.
  14. Glossary of Terms. Available at www.fda.gov/cder/drugsatfda/glossary.htm. Accessed August 9, 2007.
  15. FDA Center for Drug Evaluation and Research: Approved Drug Products with Therapeutic Equivalence Evaluations, 27th edition. Available at www.fda.gov/cder/ob/docs/preface/ecpreface.htm. Accessed August 9, 2007.