When asked about RU486, keep these notes handy
Pharmacists should know the basics
Now that the Food and Drug Administration has approved mifepristone (RU486, or Mifeprex) for the termination of early pregnancy, pharmacists should expect questions from colleagues and patients alike. While pharmacists will not dispense the drug — it will be available only to physicians who meet specific criteria and establish an account with the manufacturer, Danco Laboratories in New York City — they should be prepared to answer those questions.
Keep in mind that the mifepristone package insert calls for the use of misoprostol (Cytotec) in women whose pregnancies continue two days after taking mifepristone, but misoprostol’s manufacturer, G.D. Searle & Co. in Skokie, IL, "promotes the use of Cytotec only for its approved indication," according to an August letter from Searle to health care providers. The letter states that the approved indication is "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 American College of Obstetricians and Gynecologists (ACOG) stands by the use of misoprostol for purposes other than the treatment of gastric ulcer. In an Oct. 11 letter to Rep. Tom Coburn (R-OK) and Sen. Tim Hutchinson (R-AZ), co-sponsors of a bill that would restrict the use of RU486 and misoprostol in combination, ACOG reiterated its strong belief in the safety and efficacy of the drug combination. (Visit ACOG’s Web site for a copy of the letter, www.acog.org.)
"Misoprostol has many uses of importance to women," the letter stated, citing the drug’s longstanding use to induce labor and its use with mifepristone for the termination of very early pregnancies. "Without misoprostol, mifepristone cannot be employed for this purpose in the U.S. regardless of its recent approval by the FDA," the letter stated.
DUR will provide updates on the controversy in future issues. For now, here are some basic facts pharmacists can use to answer questions about RU486:
Mifepristone is a synthetic steroid that inhibits the activity of endogenous or exogenous progesterone at progesterone receptor sites. Doses of 1 mg/kg or greater antagonize the endometrial and myometrial effects of progesterone in women. During pregnancy, mifepristone sensitizes the myometrium to the contraction-inducing activity of prostaglandins.
Prior to initiating the drug regimen, the patient must read the medication guide and then sign the patient agreement, which states, among other things, that she believes she is no more than 49 days, or seven weeks, pregnant, counting from the beginning of the last menstrual period. The pregnancy is then terminated with the use of mifepristone in the following manner, according to the mifepristone package insert:
• Day 1 — Patient takes three mifepristone 200 mg tablets (600 mg total) as a single oral dose in health care provider’s office.
• Day 3 — Patient returns to provider’s office to learn if the pregnancy has ended. If she is still pregnant, she takes two misoprostol 200 mcg tablets (400 mcg total) orally in provider’s office.
• Day 14 — Patient returns to provider’s office to confirm by clinical examination or ultrasonography that the pregnancy has been terminated.
Patients should expect vaginal bleeding for nine to 16 days. Up to 8% of patients may experience bleeding for 30 days or more. However, neither bleeding alone nor as accompanied by cramping is necessarily evidence that the pregnancy has been terminated. Lack of bleeding after treatment typically indicates drug failure. Patients who have an ongoing pregnancy at day 14 run the risk of fetal malformation. According to the drug labeling, medical abortion failures should be managed with surgical termination.
Mifepristone use will cause vaginal bleeding and cramping. In some patients, bleeding may be heavy and may require surgery. Other possible side effects include diarrhea, nausea, vomiting, headache, dizziness, back pain, fatigue, fever, viral infection, vaginitis, rigors, dyspepsia, insomnia, asthenia, leg pain, anxiety, anemia, leukorrhea, sinusitis, and syncope.
The FDA has restricted the use of mifepristone, stating that it must be provided by or under the supervision of a physician who meets the following qualifications:
• has the ability to assess the duration of pregnancy accurately;
• has the ability to diagnose ectopic pregnancies;
• has the ability to provide surgical intervention in cases of incomplete abortion or severe bleeding, or has made plans to provide such care through other qualified physicians, and is able to assure patient access to medical facilities equipped to provide blood transfusions and resuscitation, if necessary;
• has read and understood the prescribing information for mifepristone;
• provides each patient with a medication guide, fully explains the procedure to each patient, provides her with a copy of the patient agreement, gives her an opportunity to read and discuss both documents, obtains her signature on the patient agreement, and signs the agreement as well;
• notifies the sponsor or its designate (Danco Laboratories) in writing — as discussed in the package insert under the heading "Dosage and Administration" — in the event of an ongoing pregnancy that is not terminated subsequent to the conclusion of the treatment procedure;
• reports any hospitalization, transfusion, or other serious events to the sponsor or its designate;
• records the mifepristone package serial number in each patient’s record.
Providers must sign and submit to the distributor a prescriber’s agreement prior to receiving mifepristone. By doing so, providers indicate that they meet the criteria and will follow the dictated guidelines.
The FDA also requires that a cohort-based study of safety outcomes be performed, comparing patients having medical abortion under the care of physicians who have surgical intervention skills with patients whose physicians refer them for surgical intervention. An audit of signed patient agreement forms also will be incorporated, along with a surveillance study on outcomes of ongoing pregnancies.
The final printed labeling the FDA requires for mifepristone includes more documents than does labeling for most prescription medications, including the package insert, a medication guide, a patient agreement form, and a prescriber’s agreement form.
For more details
For immediate consultation with an expert in mifepristone, you may call Danco Laboratories at (877) 432-7596. Information also is available at the manufacturer’s Web site: www.earlyoptionpill.com. In addition, the FDA mifepristone page at www.fda.gov/cder/drug/infopage/mifepristone/default.htm includes links to:
• FDA press release on mifepristone approval;
• Mifepristone approval letter;
• Mifepristone MedGuide;
• Questions and answers about mifepristone;
• Patient agreement form;
• Prescriber’s agreement form;
• Mifepristone review;
• Office memo to Population Council;
• Federal Register Final Rule, Restrictions on Use After Marketing.