1. What has happened that made the FDA work with Danco to issue a Dear Doctor Letter?

FDA has been informed of postmarketing adverse events occurring in women treated with Mifeprex and misoprostol. The reports are cases of ectopic pregnancy, which is a pregnancy lodged outside of the womb such as in the tubes, (including one case of ectopic pregnancy resulting in death), severe systemic infection (also called sepsis), and a single case of heart attack. At this time, it is unknown whether there is a causal relationship between any of these events and the use of Mifeprex and misoprostol.

In all of these cases, misoprostol was given vaginally, not orally, which is the approved regimen. FDA has not reviewed data on the safety and effectiveness of vaginal administration of misoprostol.

When FDA receives and reviews new information, the agency routinely provides updates to doctors and their patients so that they have information on how to use a drug safely.

2. What is a ruptured ectopic pregnancy and how often does this happen?

An ectopic pregnancy is any pregnancy that develops outside of the womb. It occurs in 2% of all pregnancies. The ectopic pregnancy is usually in the fallopian tube. As it grows, it damages the tube causing it to rupture (burst) and bleed. Unless it is discovered and treated early, almost 40% of ectopic pregnancies rupture suddenly, causing pain and dangerous bleeding in the abdominal cavity. The other 60% usually cause slow bleeding in the abdomen. Ruptured ectopic pregnancies can be fatal. According to data gathered from death certificates in the U.S. by the National Center for Heath Statistics (NCHS) in 1999, 19 women were reported to have died of ectopic pregnancies.

The Mifeprex label states uses of Mifeprex and misoprostol for the termination of pregnancy is contraindicated in patients with confirmed or suspected ectopic pregnancy. Mifeprex is not an effective treatment for an ectopic pregnancy.

3. What is a serious systemic bacterial infection and how often does this occur?

Serious systemic bacterial infection is a severe life-threatening infection that spreads throughout the body and can cause death.

It has been reported that the rate of serious infection as a complication of pregnancy is 3.5 per 1000 pregnancies. Uterine infection occurs in 0.1-4.7% of first trimester surgical abortions and in 0.0-6.1% of medical abortions. In the past, it was most often associated with illegal abortions. It rarely occurs with pelvic surgery or even with otherwise normal childbirth.

4. Did the mifepristone treatment regimen cause the death or infection in any of the reported cases? Did it cause the heart attack?

Ectopic pregnancy occurs in 2% of all pregnancies. It happens before the woman knows that she is pregnant and is not caused by the mifepristone and misoprostol regimen. Ectopic pregnancies will rupture and cause bleeding. In the case of the reported death, this bleeding led to the patient’s death.

Infection can result from normally growing bacteria in the vagina, which, in rare cases causes serious infections. Such serious infections occur in two out of every 1000 surgical abortions and rarely occur following pelvic surgery or otherwise normal childbirth. We do not know what role, if any, Mifeprex and "off-label" use of vaginal misoprostol may have in developing serious infections.

The single heart attack occurred in a 21-year old. A heart attack in very young women is extremely rare. This is the only case of heart attack reported with Mifeprex and misoprostol use. The rate of acute heart attack increases with age. In 1997, the rate among US women aged 20-24 years was 0.19 per 100,000 women. From the information available it cannot be known whether the drugs contributed to this event.

5. Are there any reports of heart attacks following use of mifepristone with drugs other than misoprostol?

In other countries, in the early 1990’s, three prostaglandins, misoprostol, sulprostone, and gemeprost, were used with mifepristone to terminate pregnancy. Heart attacks due to coronary spasm, one of them fatal, have occurred in three of the more than 60,000 women given sulprostone (an injected prostaglandin) with mifepristone. As a result, sulprostone is no longer used for abortion with mifepristone. Two cases of coronary spasm, one resulting in a heart attack, were reported for gemeprost used with mifepristone. Neither sulprostone or gemeprost are approved drugs in the U.S.

6. Is the treatment regimen safe?

On the basis of scientific data from clinical trials, FDA concluded in 2000 that mifepristone used in combination with oral administration of misoprostol, is safe and effective for the termination of early pregnancy. Patients should also understand that safe does not mean risk free; FDA will approve a drug if it determines that the benefits exceed the risks for the approved use.

The conclusion that benefits exceed risk is based on using the drug as directed by the labeling. When FDA approves a drug, the labeling includes information on benefits and risks and the appropriate dosing regimens.

The approved dosing regimen includes administration of 600 mg of Mifeprex in a single oral dose. On day three of the regimen, the patient returns to her doctor and, unless abortion has occurred, she takes two-200 mcg tablets of misoprostol orally.

7. Why is the dear doctor letter being issued without the labeling being changed?

This information is new and both FDA and the manufacturer want it to be disseminated as quickly as possible. The dear doctor letter also reminds physicians using Mifeprex and misoprostol about their responsibilities to report adverse events to Danco and to provide patient counseling.

8. Will the Mifeprex labeling be changed?

The labeling has not changed at this time. As with all drugs, FDA and the manufacturer continue to work to evaluate case reports and other information to determine if changes are needed to the labeling.

9. Why are physicians using misoprostol "off-label," in other words, using misoprostol vaginally at different doses?

There are published studies of the use of mifepristone with vaginal administration of misoprostol for abortion. The misoprostol doses used in these studies are higher than those described in the Mifeprex labeling. These studies were not part of the clinical trials that FDA reviewed when FDA approved mifepristone, nor have they been submitted for review, therefore, FDA has had no opportunity to evaluate the safety or efficacy of this regimen. Because physicians exercise their judgment in prescribing what they feel is best for the patient, they may decide to use an "off-label" regimen, rather than the approved regimen.

In order to change or add a new dosing regimen to the labeling, the sponsor must submit data to FDA from clinical trials that show the new regimen is safe and effective.

10. Are there risks with vaginal use of misoprostol?

FDA has not reviewed clinical trials using misoprostol in the vagina for early termination of pregnancy and cannot offer a conclusion about the safety and efficacy of this route of administration of misoprostol.

11. What is FDA’s view or position on how misoprostol should be used in a regimen with mifepristone for early termination of pregnancy?

FDA believes that the drug should only be used according to the approved regimen because the drug was determined to be safe and effective based on clinical trials that used that regimen.

12. Is FDA going to take regulatory action against physicians who are using a mifepristone treatment regimen that differs from that in the labeling?

The Agency strongly encourages the use of mifepristone according to the approved regimen. To convey its expectation and promote safe use of Mifeprex, the Agency has ensured that the approved regimen is clearly described in the labeling of the drug, including the Medication Guide and Patient Agreement Form, both of which must be provided to the patient, and in the case of the latter, signed by the patient and physician. There is also a Prescriber’s Agreement Form that includes an acknowledgement by the prescriber of having read and understood the prescribing information for Mifeprex. The agency will work with the manufacturer and distributors of the drug to continue to promote its safe use. Providers acknowledge that if they do not follow the agreement, the distributor may discontinue distribution of the drug to them.

13. What should physicians do? What should patients do?

Physicians who prescribe Mifeprex (mifepristone) are familiar with the available methods of abortion. All abortion methods have risks and benefits. Health care providers should explain the procedure, answer questions, provide women with the approved Medication Guide, and review and sign a Patient Agreement Form with the patient before giving these medications to cause abortion. They should also provide information about an emergency contact to call if there are problems. The patient should read and understand the Medication Guide, sign the Patient Agreement Form, and be sure that all of her questions are answered. She should call her emergency contact if she gets severe pain, heavy bleeding, bad-smelling discharge, or fever.

14. Is FDA considering withdrawing mifepristone from the market?

As it does with all prescription drugs, FDA continues to monitor the safety and effectiveness of mifepristone.

Physicians who sign the Physician Agreement Form to receive this drug also agree to report serious adverse events and on-going pregnancies to the manufacturer. In addition, the postmarketing monitoring study, which the sponsor agreed to conduct, will provide further data on the drug. Finally, MedWatch will collect adverse event reports from the public.

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