Correspondence

Manufacturer's Warning Regarding Unapproved Uses of Misoprostol

N Engl J Med 2001; 344:61January 4, 2001

Article

The review article in this issue by Goldberg et al. and the accompanying editorial by Hale and Zinberg were sent to G.D. Searle, the manufacturer of misoprostol, which offers the following:

To the Editor: The article by Goldberg et al. on misoprostol and pregnancy1, the accompanying editorial by Hale and Zinberg,2 and the events surrounding the approval by the Food and Drug Administration (FDA) of mifepristone for the termination of pregnancy raise important issues. Searle has been invited to clarify its position and actions in this regard. We at Searle share the overriding concern of Hale and Zinberg that physicians be supported in providing the most appropriate care for their patients. We also wish to emphasize our commitment to working collegially with all relevant parties.

Our product, Cytotec (misoprostol), was approved by the FDA in 1988 for the prevention of gastric ulcers associated with the use of nonsteroidal antiinflammatory drugs. This is the only approved indication for Cytotec, and we are prohibited by FDA regulations from promoting or even suggesting its use for any other purpose. Since 1988, the Cytotec label has always carried a “black box” warning against its use in pregnant women because of its potential to cause serious adverse events, including miscarriage.

Our letter of August 23, 2000, to health care professionals was, therefore, an elaboration of this long-standing warning, consistent with our continuing duty to inform health care professionals about possible risks. It resulted from lengthy discussions between Searle and the FDA after reports were received of uterine rupture in connection with the off-label use of Cytotec in pregnant women. The FDA requested that we make a labeling change to clarify further the serious risks and to consider sending a letter to health care professionals. Our August 23 letter was a result of this dialogue and was developed in consultation with the FDA. We continue to work with the FDA to resolve issues related to the language in the label regarding the risk of adverse events. However, these discussions have not included consideration of any alteration to Cytotec's approved indication.

We particularly wish to clarify the timing of the letter dated August 23. The fact that it was distributed just over a month before the FDA approval of mifepristone was entirely coincidental. We had no specific knowledge about the status of regulatory action on mifepristone, which had been pending for several years.

With regard to the article by Goldberg et al., the authors find evidence of efficacy when misoprostol is used in pregnant women. However, as the authors correctly note, “misoprostol is not approved for any of these indications in the United States.” We fully support the role of physicians, using their professional judgment, to prescribe an approved pharmaceutical product for a use outside of its FDA-approved indication in the best interest of their patients, on the basis of published research, expert clinical opinion, or their own clinical experience.

In conclusion, as a company, we have been guided in these matters by regulatory requirements, by our desire for the safe use of our products, and by our respect for health caregivers and their patients. Nonetheless, we fully recognize the importance of a better dialogue with the American College of Obstetricians and Gynecologists, and with caregivers, on the issues and concerns reflected in the editorial by Hale and Zinberg. We are committed to engaging in this dialogue and likewise to continued close cooperation with the FDA.

Michael A. Friedman, M.D.
Searle, Skokie, IL 60077

2 References

1. 1

   Goldberg AB, Greenberg MB, Darney PD. Misoprostol and pregnancy. N Engl J Med 2001;344:38-47
   Full Text | Web of Science | Medline

2. 2

   Hale RW, Zinberg S. Use of misoprostol in pregnancy. N Engl J Med 2001;344:59-60
   Full Text | Web of Science | Medline

Citing Articles (16)

Citing Articles

1. 1

   Elke Krause, Simona Malorgio, Annette Kuhn, Corina Schmid, Marc Baumann, Daniel Surbek. (2011) Off-label use of misoprostol for labor induction: a nation-wide survey in Switzerland. European Journal of Obstetrics & Gynecology and Reproductive Biology
   CrossRef

2. 2

   Hajo Wildschut, Marieke I Both, Suzanne Medema, Eeke Thomee, Mark F Wildhagen, Nathalie Kapp, Hajo Wildschut. 2011. Medical methods for mid-trimester termination of pregnancy. .
   CrossRef

3. 3

   FJ Willmott, C Scherf, SM Ford, K Lim. (2008) Rupture of uterus in the first trimester during medical termination of pregnancy for exomphalos using mifepristone/misoprostol. BJOG: An International Journal of Obstetrics & Gynaecology 115:12, 1575-1577
   CrossRef

4. 4

   Daniel V. Surbek. (2007) Misoprostol for labor induction in term pregnancy. European Clinics in Obstetrics and Gynaecology 3:1, 25-29
   CrossRef

5. 5

   Andrew D. Weeks, Christian Fiala, Peter Safar. (2005) Misoprostol and the debate over off-label drug use. BJOG: An International Journal of Obstetrics and Gynaecology 112:3, 269-272
   CrossRef

6. 6

   Marsden Wagner. (2005) Off-label use of misoprostol in obstetrics: a cautionary tale. BJOG: An International Journal of Obstetrics and Gynaecology 112:3, 266-268
   CrossRef

7. 7

   Marsden Wagner. (2005) From caution to certainty: hazards in the formation of evidence-based practice - a case study on evidence for an association between the use of uterine stimulant drugs and amniotic fluid embolism. Paediatric and Perinatal Epidemiology 19:2, 173-176
   CrossRef

8. 8

   Yap-Seng Chong, Lin-Lin Su, Sabaratnam Arulkumaran. (2004) Misoprostol: A Quarter Century of Use, Abuse, and Creative Misuse. Obstetrical & Gynecological Survey 59:2, 128-140
   CrossRef

9. 9

   S SHARMA, H ELREFAEY. (2003) Prostaglandins in the prevention and management of postpartum haemorrhage. Best Practice & Research Clinical Obstetrics & Gynaecology 17:5, 811-823
   CrossRef

10. 10

    G JUSTUSHOFMEYR. (2003) Induction of labour with an unfavourable cervix. Best Practice & Research Clinical Obstetrics & Gynaecology 17:5, 777-794
    CrossRef

11. 11

    B. B. Matonhodze, L. C. Katsoulis, G. Justus Hofmeyr. (2002) Labor induction and meconium: in vitro effects of oxytocin, dinoprostone and misoprostol on rat ileum relative to myometrium. Journal of Perinatal Medicine 30:5, 405-410
    CrossRef

12. 12

       . (2002) Misoprostol en zwangerschapsafbreking. Medisch-Farmaceutische Mededelingen 40:2, 36-36
    CrossRef

13. 13

    G. Justus Hofmeyr. (2001) Induction of labour with misoprostol. Current Opinion in Obstetrics and Gynecology 13:6, 577-581
    CrossRef

14. 14

    G.J. Hofmeyr, Z. Alfirevic, B. Matonhodze, P. Brocklehurst, E. Campbell, V.C. Nikodem. (2001) Titrated oral misoprostol solution for induction of labour: a multi-centre, randomised trial. BJOG: An International Journal of Obstetrics and Gynaecology 108:9, 952-959
    CrossRef

15. 15

    (2001) Current Awareness. Pharmacoepidemiology and Drug Safety 10:3, 263-278
    CrossRef

16. 16

    &NA;. (2001) Confusion concerning the use of misoprostol in pregnancy. Inpharma Weekly &NA;:1270, 3
    CrossRef