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Published Online, 28 March 2006, www.theannals.com, DOI 10.1345/aph.1G481e.
 The Annals of Pharmacotherapy: Vol. 40, No. 4, pp. 786. DOI 10.1345/aph.1G481e
© 2006 Harvey Whitney Books Company.
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Authors' Reply

Donna J Harrison, MD

Chairperson, Subcommittee on Mifeprex, American Association of Prolife Obstetricians and Gynecologists, PO Box 414, Eau Claire, Michigan 49111-0414. djharrison{at}juno.com

Margaret M Gary, MD

Obstetrician/Gynecologist, Virginia Beach, Virginia

Published Online, March 28, 2006. www.theannals.com, DOI 10.1345/aph.1G481e

AUTHORS' REPLY: First, the Food and Drug Administration's (FDA's) recently published guidance document on adverse events states: "Typical reasons to suspect causality for an event include (1) timing of onset or termination with respect to drug use, (2) plausibility in light of a drug's known pharmacology, (3) occurrence at a frequency above that expected in the treated population, and (4) occurrence of an event typical of drug-induced adverse reactions."1 Consider these reasons in the fatalities that followed mifepristone use: (1) all of the deaths occurred within 7 days of taking mifepristone, (2) mifepristone-induced suppression of the innate immune system is plausible,2 and (3) the frequency of fatalities from Clostridium sordellii after mifepristone far exceeds the frequency of this infection prior to mifepristone availability. Based on the FDA's guidance, there are multiple reasons to infer a causal link between mifepristone and these deaths.

Second, we believe that pregnancy is in most instances a benign, selflimited condition as evidenced by the statistic cited by Hausknecht: 99 992.9/100 000 women survive pregnancy.

Third, the clinical picture of medically induced abortion can mimic the symptoms of ectopic pregnancy. If these symptoms are incorrectly ascribed to the medical abortion, then delay in diagnosis of the ectopic pregnancy can be lethal. This contraindication to the use of mifepristone has been acknowledged by Danco Laboratories.3

Fourth, given the incomplete nature of the Medwatch adverse event report (AER) 3943786-2,4 we believe our assessment remains plausible. While acetaminophen overdose can be associated with hepatic toxicity, renal failure, and disseminated intravascular coagulation, it is also plausible that this scenario is caused by sepsis with multiorgan failure. Hausknecht infers causality from empty pill bottles but has left out crucial information in his depiction of both the adverse event and its AER. In his letter, he states that the event was related to drug overdose with alcohol. Rather, this AER stated that "current thinking was that this event was related to some sort of drug overdose (Tylenol)" and does not mention alcohol toxicity. One of the cases of fatal mifepristone-associated sepsis syndrome also had no evidence of infection initially, then progressed rapidly to multiorgan failure and death.5 Hausknecht's assertion that "there are many similar errors of omission and exaggeration" is incorrect. Our review was based on the limited information available in the reports submitted to the FDA by Hausknecht.

Finally, this AER illustrates the lack of documentation provided by Danco. The Medwatch AER 3943786-2 contained no emergency department records, no hospital records, and no white blood cell count or acetaminophen levels.4 The report appears to reflect an initial conversation between the reporting physician and Danco but the report language is Danco's. It is curious that such an opportunity failed to produce a detailed, clear summary of the hospital course and laboratory findings or even a final diagnosis. It is the ethical responsibility of Danco to seek complete and accurate documentation for these AERs. Failure to do so thwarts postmarketing safety monitoring.

Footnotes

Drs. Gary and Harrison are members of the Subcommittee on Mifeprex of the American Association of Prolife Obstetricians and Gynecologists (AAPLOG), the largest interest group of the American College of Obstetricians and Gynecologists. AAPLOG has filed a Citizen Petition with the Food and Drug Administration requesting withdrawal of approval for mifepristone based on safety considerations.

References

  1. Food and Drug Administration. Office of Training and Communications, Division of Drug Information, HFD-240 Center for Drug Evaluation and Research. Guidance for industry. Adverse reactions section of labeling for human prescription drug and biological products—content and format. January 2006. www.fda.gov/cder/guidance/5537fnl.htm (accessed 2006 Jan 20).
  2. Miech RP. Pathophysiology of mifepristone-induced septic shock due to Clostridium sordellii. Ann Pharmacother 2005;39: 1483-8. Epub 26 Jul 2005. DOI 10.1345/aph.1G189[Abstract/Free Full Text]
  3. Open letter to health care providers ("Dear Doctor Letter"). April 19, 2002. New York, NY: Danco Laboratories.
  4. Medwatch Adverse Event Reports. Individual Safety Report no. 3943786-2. Rockville, MD: Office of Postmarketing Drug Risk Assessment, Food and Drug Administration.
  5. Fischer M, Bhatnagar J, Guarner J, et al. Fatal toxic shock syndrome associated with Clostridium sordellii after medical abortion. N Engl J Med 2005;353:2352-60.[Abstract/Free Full Text]




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