To the Editor:
I write to express my strong concern that many unsuspecting anesthesiologists and CRNAs in the U.S. may soon unwittingly expose their patients to a “generic” propofol emulsion that is not the same formulation we have been using for a number of years. Recently, anesthesiologists received a letter from Zeneca announcing that the company had taken the very unusual step of filing a lawsuit against the FDA. Zeneca also did a widespread mailing of relevant public documents; I base much of this letter on these. A new alternative formulation, manufactured by a different company, uses sodium metabisulfite, at a relatively low pH, as an antimicrobial, whereas Zeneca’s Diprivan® brand of propofol that we are accustomed to using is formulated with EDTA as an antimicrobial.
These two “propofols” are not equivalent – for the following reasons:
Sulfite allergies are common. I myself am an asthmatic and must avoid sulfites. Chardonnay and other white wines, for example, with sulfites will place me at risk for a severe asthma attack. Even if packaging for a newly formulated product has a “caution” about sulfites, a busy anesthesiologist, who has used Zeneca’s Diprivan® brand of propofol for years, may suddenly find that a hospital or facility pharmacy has supplied a new sulfite-containing propofol. There is no reason the anesthesia personnel would necessarily know of the important differences in formulation. Anesthesiologists are excellent clinical pharmacologists, but are not knowledgeable about pharmacy, nor should they be. When a “generic” drug is substituted for a trusted brand name, we have every right to expect that the generic drug, and its formulation, will be exactly the same. Incidentally, because of the likelihood that asthmatics will react to sulfites, are we now required to keep a supply of the Zeneca Diprivan® just for asthmatics and others known to be allergic to sulfites if our pharmacies choose a new sulfite-containing product?
EDTA, the antimicrobial in Diprivan’s® current formulation, was in fact tested thoroughly in patients, under FDA control, by Zeneca. Addition of EDTA is in fact a considerable improvement because of its efficacy at preventing microbial growth in Diprivan® without changing other characteristics of the drug or the emulsion. Sulfite-containing propofol has apparently not been tested in humans. My information is that sulfite is not as effective as EDTA as an antimicrobial in this emulsion. The documents filed with the court indicate that sulfite additives were considered and rejected during Zeneca’s search for a microbial growth inhibitor that would be safe and would not affect the emulsion or other properties of Diprivan® (see below).
Emulsions are definitely tricky forms in which to deliver drugs. They either “crack,” i.e., separate, or they don’t. Diprivan® has proven stable in this regard over many years of heavy operating room/ICU use. Addition of metabisulfite requires a considerable lowering of the pH of a newly formulated version of propofol in order to employ the sulfite as an antimicrobial. The court documents indicate that Zeneca made up some propofol using a sulfite-containing product description on file with FDA. That test product using the new sulfite-containing specifications not only “cracked” under standard emulsion shaking stress testing, but also turned yellow! The “cracking” resulted in a layer of clear oil on top of the milky white suspension, a layer not readily visible to a casual glance. Further, upon mild agitation of the “cracked” emulsion, the oil rapidly disappeared, only to reappear rapidly. This means we won’t see the oil, but we could be giving it to our patients (see below regarding fat embolism). Zeneca also tested the yellow color and found it to be a linkage of two molecules of propofol (a dimer). The safety/toxicity of this dimer is unknown to me and to Zeneca. The above information comes from the sworn affidavit of Christopher Jones, PhD, a Zeneca drug development scientist who tested the sulfite-containing formula for Zeneca and reported his findings as part of the court documents filed against the FDA to try to stop release of this new formulation of propofol until/unless proper testing is done.
Is fat embolism possible with the infusion of a “cracked” propofol emulsion? Fat emboli probably occur more often than we suspect during orthopaedic and other surgery. It is accepted however, that fat emboli are additive, i.e. fat seeking to join fat, and coalescing. We have no valid way of monitoring for small “doses” of fat emboli in the OR (nor large emboli either until/unless cardiovascular compromise occurs). A new sulfite-containing version of propofol is apparently intended to be marketed at quite a low pH (4.5 – 6.4) relative to Zeneca’s Diprivan® (7-8.5). This raises the possibility of lipid droplet “rain out” once the new formulation suspension comes in contact with the 7.4 pH of blood.
Propofol has become widely used in ICU settings for sedation in ventilated critically ill patients. In the intensive care literature, there is extensive documentation about broncho-dilating drug formulations that produced “paradoxical bronchoconstriction.” This phenomenon has been clearly shown to be related to sulfites, and these have been removed from such preparations. In an ICU patient, increasing airway resistance might not readily be connected to a new additive in the propofol! The stability of the emulsion is also a particular issue in the ICU due to the longer-term infusions.
Another new development in labeling rules and regulations is relevant to the propofol issue. Under a proposed new FDA rule, believe it or not, brand names apparently could be used on generic drugs manufactured by a competing company in the sense that the new formulation could say on it “equivalent to Diprivan®.” That means sulfite-containing propofol could eventually be marketed as equivalent to the EDTA-propofol, which it is not.
Perhaps most important of all, my understanding of the court documents indicates that the FDA simply approved a potentially clinically different sulfite-containing formulation without requiring human testing. We physicians assume adequate testing on all newly introduced drug products, because we are under the impression that the FDA is very strict and stringent. Indeed, having testified before the FDA several times, I know they normally are indeed very stringent, as they must be to safeguard the public. The FDA is, however, constantly under public (and Congressional) pressure to reduce drug costs. Perhaps this particular “fast track” approval resulted in part from that pressure. Perhaps changing a “preservative” is usually OK, but not to sulfite, especially if the emulsion is not stable. A new sulfite-containing version of propofol is a different formulation, with a different additive, and therefore should be subjected to the same rigorous testing requirements that Zeneca was required to go through to get its EDTA propofol version of Diprivan® through FDA approval.
There is also an issue of fairness here. Zeneca’s EDTA propofol formulation was granted a three-year “Waxman” exclusive right to market, in recognition of the additional investment to bring the improved EDTA version of propofol to us. The FDA’s subsequent approval of a new sulfite propofol preparation does seem to abrogate FDA’s prior agreement. In my many years as a consultant to other pharmaceutical firms, I have never heard of such a reneging on a commitment by the FDA. This issue is important to anesthesiology because we need new drugs to be developed for us by pharmaceutical firms. If these firms cannot protect their enormous investments, anesthesiology could rapidly become a pharmacologic backwater, with little development and improvement of medications. We cannot afford to let that happen. There are still numerous areas in which we need new drug development. The original propofol was in development for many years before a suitable vehicle was discovered. After FDA initial approval, it had a relatively short exclusive marketing life (1989-1996) in the first place.
For all the above reasons, I urge the FDA to reconsider its approval of the sulfite-propofol version until an appropriate testing and approval pathway has been completed and this formulation has been determined to be genuinely equivalent to Zeneca’s EDTA-propofol. I also ask that the FDA Anesthesiology Drug Advisory Committee be shown all relevant data and asked for a formal recommendation about the introduction of sulfite-containing propofol.
Please note that I am neither employed by nor being paid by Zeneca in this matter. The views expressed above are my own, after study of the public documents referred to above.
John H. Tinker, M.D.
Professor and Chair
University of Nebraska Medical Center, Omaha, NE