The most recent warning from the FDA, issued May 2005 is as follows:
Patient Information Sheet
Misoprostol (marketed as Cytotec)
This is a summary of the most important information about misoprostol. For details, talk to your healthcare professional.
FDA ALERT: – Risks of Use in Labor and Delivery
This Patient Information Sheet is for pregnant women who may receive misoprostol to soften their cervix or induce contractions to begin labor. Misoprostol is sometimes used to decrease blood loss after delivery of a baby. These uses are not approved by the FDA. No company has sent the FDA scientific proof that misoprostol is safe and effective for these uses.
There can be rare but serious serious side effects, including a torn uterus (womb), when misoprostol is used for labor and delivery. A torn uterus may result in severe bleeding, having the uterus removed (hysterectomy), and death of the mother or baby. These side effects are more likely in women who have had previous uterine surgery, a previous Cesarean delivery (C-section), or several previous births.
What Is Misoprostol?
Who Should Not Take Misoprostol for Labor and Delivery?
How is Misoprostol Used?
Misoprostol comes as a tablet. Sometimes the tablets are split, and you will be given only a piece of a tablet. You may be asked to take misoprostol by mouth, or it may be placed in your vagina or rectum.
Is There Anything Else I Need To Know?
Questions? Call Drug Information, 1-888-INFO-FDA (automated) or 301-827-4570
IN SPITE OF THESE WARNINGS
THE PROFESSIONAL ORGANIZATION OF OBSTETRICIANS CLING TO CYTOTEC:
For Release: October 27, 2000
ACOG Writes FDA on Safety of Misoprostol
WASHINGTON, DC -- Yesterday, The American College of Obstetricians and Gynecologists (ACOG) delivered the following letter on the safety of the drug misoprostol to the US Food and Drug Administration (FDA), for their consideration during FDA review of the labeling of misoprostol.
The drug has been used for many years during labor and delivery for labor induction and treatment of postpartum hemorrhage. ACOG addresses issues raised in a letter from the drug's manufacturer that warned physicians against the use of misoprostol for pregnant women.
October 26, 2000
Janet Woodcock, MD, Director
Food and Drug Administration
Center for Drug Evaluation and Research
Woodmont Building 2, Room 6027
1451 Rockville Pike
Rockville, MD 20852
Dear Dr. Woodcock:
The American College of Obstetricians and Gynecologists Committee on Obstetric Practice has met regarding Cytotec (misoprostol). We are expediting the transmittal of the content of their review to the Food and Drug Administration so that the agency can consider it during its review of the labeling of misoprostol.
"On August 23, 2000, G.D. Searle & Co. issued a letter entitled "Important Drug Warning Concerning Unapproved Use of Intravaginal or Oral Misoprostol in Pregnant Women for Induction of Labor or Abortion." This letter cautions that Cytotec (misoprostol) is indicated for prevention of non-steroidal-antiinflammatory-drug-induced gastric ulcers and states, "…Cytotec administration by any route is contraindicated in women who are pregnant because it can cause abortion." The letter further states that Searle has become aware of the drug's use for induction of labor or as a cervical ripening agent prior to termination of pregnancy. Moreover, the letter notes serious adverse events, including uterine hyperstimulation and uterine rupture, which have resulted in fetal and maternal death. Finally, the company cautions, "In addition to the known and unknown acute risks to the mother and fetus, the effect of Cytotec on the later growth, development, and functional maturation of the child when Cytotec is used for induction of labor or cervical ripening has not been established."
The American College of Obstetricians and Gynecologists (ACOG) is concerned by the content, timing, and tone of this letter. Given that misoprostol is commonly employed in conjunction with mifepristone (RU 486) to achieve nonsurgical early pregnancy terminations, the arrival of the Searle letter within weeks of the U.S. Food and Drug Administration's (FDA) approval of mifepristone could limit the use of this new option for reproductive choice. Also, although the letter correctly points out the potentially serious, but relatively rare, risks of misoprostol when employed for cervical ripening and labor induction, it fails to comment on the extensive clinical experience with this agent and the large body of published reports supporting its safety and efficacy when used appropriately. A recent review of the Cochrane Pregnancy and Childbirth group trials registry identified 26 clinical trials of misoprostol for cervical ripening or induction of labor or both (1). These studies indicate misoprostol is more effective than prostaglandin E2 in achieving vaginal deliveries within 24 hours and reduces the need for and total amount of oxytocin augmentation. Although these studies do suggest misoprostol is associated with a higher incidence of uterine hyperstimulation and meconium-stained amniotic fluid, these complications were more common with higher doses (> 25 µg) of misoprostol. Other recent reviews and clinical trials support these conclusions (2-4). No studies indicate that intrapartum exposure to misoprostol (or other prostaglandin cervical ripening agents) has any long-term adverse health consequences to the fetus in the absence of fetal distress, nor is there a plausible biological basis for such a concern.
A review of published reports and of MedWatch, the FDA medical products reporting program, indicates the vast majority of adverse maternal and fetal outcomes associated with misoprostol therapy resulted from the use of doses greater than 25 µg, dosing intervals more frequent than 3-6 hours, addition of oxytocin less than 4 hours after the last misoprostol dose, or use of the drug in women with prior cesarean delivery or major uterine surgery. Grand multiparity also appears to be a relative risk factor for uterine rupture.
Thus, based on recently published series and a detailed review of adverse outcomes reported to the FDA, the ACOG Committee on Obstetric Practice strongly endorses its previous conclusions, published in Committee Opinion Number 228 (November 1999), Induction of Labor with Misoprostol, which states, "Given the current evidence, intravaginal misoprostol tablets appear effective in inducing labor in pregnant women who have unfavorable cervices" (5). Nonetheless, the Committee would like to emphasize that the following clinical practices appear to minimize the risk of uterine hyperstimulation and rupture in patients undergoing cervical ripening or induction in the third trimester:
- If misoprostol is to be used for cervical ripening or labor induction in the third trimester, one quarter of a 100µg tablet (i.e., approximately 25µg) should be considered for the initial dose.
- Doses should not be administered more frequently than every 3-6 hours.
- Oxytocin should not be administered less than 4 hours after the last misoprostol dose.
- Misoprostol should not be used in patients with a previous cesarean delivery or prior major uterine surgery.
The use of higher doses of misoprostol (e.g., 50 µg every 6 hours) to induce labor may be appropriate in some situations, although there are reports that such doses increase the risk of complications, including uterine hyperstimulation and uterine rupture (6). There is insufficient clinical evidence to address the safety or efficacy of misoprostol in patients with multifetal gestations or suspected fetal macrosomia.
In conclusion, the ACOG Committee on Obstetric Practice reaffirms that misoprostol is a safe and effective agent for cervical ripening and labor induction when used appropriately. Moreover, misoprostol also contributes to the obstetrician-gynecologist's resources as an effective treatment for serious postpartum hemorrhage in the presence of uterine atony (7-12)."
Stanley Zinberg, MD, MS, FACOG
- Hofmeyr GJ, Gulmezoglu AM. Vaginal misoprostol for cervical ripening and labour induction in late pregnancy (Cochrane Review). In: The Cochrane Library, Issue 3, 2000. Oxford: Update Software
- Wing DA. Labor induction with misoprostol. Am J Obstet Gynecol 1999;181:339- 345
- Nunes F, Rodrigues R, Meirinho M. Randomized comparison between intravaginal misoprostol and dinoprostone for cervical ripening and induction of labor. Am J Obstet Gynecol 1999;181:626-629
- Blanchette HA, Nayak S, Erasmus S. Comparison of the safety and efficacy of intravaginal misoprostol (prostaglandin E1) with those of dinoprostone (prostaglandin E2) for cervical ripening and induction of labor in a community hospital. Am J Obstet Gynecol 1999;180:1551-1559
- American College of Obstetricians and Gynecologists. Induction of labor with misoprostol. ACOG Committee Opinion 228. Washington, DC: ACOG, 1999
- American College of Obstetricians and Gynecologists. Induction of labor. ACOG Practice Bulletin 10. Washington, DC: ACOG, 1999
- El-Refaey H, O'Brien P, Morafa W, Walder J, Rodeck C. Use of oral misoprostol in the prevention of postpartum haemorrhage. Br J Obstet Gynaecol 1997;104:336-339
- O'Brien P, El-Refaey H, Gordon A, Geary M, Rodeck CH. Rectally administered misoprostol for the treatment of postpartum hemorrhage unresponsive to oxytocin and ergometrine: a descriptive study. Obstet Gynecol 1998;92:212-214
- Bamigboye AA, Hofmeyr GJ, Merrell DA. Rectal misoprostol in the prevention of postpartum hemorrhage: a placebo-controlled trial. Am J Obstet Gynecol 1998;179:1043-1046
- Surbek DV, Fehr PM, Hosli I, Holzgreve W. Oral misoprostol for third stage of labor: a randomized placebo-controlled trial. Obstet Gynecol 1999;94:255-258
- Hofmeyr GJ, Nikodem VC, de Jager M, Gelbart BR. A randomised placebo controlled trial of oral misoprostol in the third stage of labour. Br J Obstet Gynaecol 1998;105:971-975
- Bamigboye AA, Merrell DA, Hofmeyr GJ, Mitchell R. Randomized comparison of rectal misoprostol with Syntometrine for management of third stage of labor. Acta Obstet Gynecol Scand 1998;77:178-181
The American College of Obstetricians and Gynecologists is the national medical organization representing nearly 40,000 physicians who provide health care for women.
THE ORIGINAL FDA WARNING from 2000:
FDA posts safety alerts, public health advisories, press releases and other notices from companies as a service to health professionals, consumers and other interested parties. Although FDA approves medical products, FDA does not endorse either the product or the company.
Following is the retyped text of a letter from Searle, the original manufacturer.
Contact the company for a copy of any referenced enclosures.
August 23, 2000
IMPORTANT DRUG WARNING
CONCERNING UNAPPROVED USE OF INTRAVAGINAL
OR ORAL MISOPROSTOL IN PREGNANT WOMEN
FOR INDUCTION OF LABOR OR ABORTION
Dear Health Care Provider:
The purpose of this letter is to remind you that Cytotec administration by any route is contraindicated in women who are pregnant because it can cause abortion. Cytotec is not approved for the induction of labor or abortion.
Cytotec is indicated for the prevention of NSAID (nonsteroidal anti-inflammatory drugs, including aspirin)-induced gastric ulcers in patients at high risk of complications from gastric ulcer, e.g., the elderly and patients with concomitant debilitating disease, as well as patients at high risk of developing gastric ulceration, such as patients with a history of ulcer.
The uterotonic effect of Cytotec is an inherent property of prostaglandin E1(PGE1), of which Cytotec is stable, orally active, synthetic analog. Searle has become aware of some instances where Cytotec, outside of its approved indication, was used as a cervical ripening agent prior to termination of pregnancy, or for induction of labor, in spite of the specific contraindications to its use during pregnancy.
Serious adverse events reported following off-label use of Cytotec in pregnant women include maternal or fetal death; uterine hyperstimulation, rupture or perforation requiring uterine surgical repair, hysterectomy or salpingo-oophorectomy; amniotic fluid embolism; severe vaginal bleeding, retained placenta, shock, fetal bradycardia and pelvic pain.
Searle has not conducted research concerning the use of Cytotec for cervical ripening prior to termination of pregnancy or for induction of labor, nor does Searle intend to study or support these uses. Therefore, Searle is unable to provide complete risk information for Cytotec when it is used for such purposes. In addition to the known and unknown acute risks to the mother and fetus, the effect of Cytotec on the later growth, development and functional maturation of the child when Cytotec is used for induction of labor or cervical ripening has not been established.
Searle promotes the use of Cytotec only for its approved indication. Please read the enclosed updated complete Prescribing Information for Cytotec.
Further information may be obtained by calling 1-800-323-4204.
Michael Cullen, MD
Medical Director, U.S.
5200 Old Orchard Road
Skokie, Illinois, 60077
Phone: (847) 982-7000
Fax: (847) 470-1480