Espresso: Update to the Mifespristone REMS Requirements

Reading: ACOG Practice Advisory: Updated Mifepristone REMS Requirements

Background 

• What is mifepristone? 

• As you probably know, mife is used in combination with misoprostol as part of medication abortion 

• This method is safe, effective, and FDA-approved 

• Can also be used for early pregnancy loss 

• Check out our medication abortion and telehealth abortion episodes! 

• However: 

• Starting in 2011, the FDA implemented the Mifepristone REMS (risk evaluation and mitigation strategy) Program placed several restrictions on mifepristone distribution 

• There needed to be an in-person dispensing requirement 

• Needed to be dispensed in a clinic, medical office, or hospital by or under direct supervision of a certified clinician 

• So patients could not get the mifepristone in a retail pharmacy or by mail 

• ACOG has long advocated for removal of this restriction 

• Doesn’t make care safer 

• Not based on medical evidence 

• Creates barriers to clinician and patient access to medication abortion and medical management of early pregnancy loss 

• Disproportionately burdens communities already facing structural barriers to care 

Why are we making this episode? 

• Timeline 

• During COVID-19, with advocacy, the FDA halted enforcement of the REMS in-person dispensing requirement due to public health emergency

• This allowed telehealth provision of mifepristone and also by mail in some states  

• December 2021 - FDA completed a review of the Mifepristone REMS Program and determined that modifications were warranted to reflect long-standing safety data, improve patient access, and reduce burden on health care delivery 

• January 3, 2023 - Drug manufacturer’s submission of updated prescribing information, etc. and was approved by FDA 

• Updates 

• Permanent removal of in-person dispensing requirement 

• So in addition to clinics, medical offices, hospital: certified pharmacies can now dispense mifepristone to patients with prescription from certified prescriber 

• Mifepristone can be dispensed in-person or by mail 

• Addition of a pharmacy certification requirement 

• Retail pharmacies that meet certain requirements and complete a Pharmacy Agreement Form can now dispense mifepristone to patients to patients who have a prescription from a certified prescriber 

• Find the documents can be found on the FDA website.

What does this mean for us and for our patients? 

• Increase access to medication abortion 

• Maybe – can still be dependent on state-specific laws and ability and willingness of retail pharmacies to achieve REMS certification 

• Some states restrict abortion

• Some states restrict telehealth access, may still require in-person dispensing of mifepristone, and regulation of medications by mail 

• So… the REMS requirements still remain as a medically unnecessary barrier to obtaining this medication 

Medication Abortion

Epidemiology of Abortion

In 2017:

• 60% of abortions occured prior to 10 weeks gestation;

• Medication abortion comprised 39% of all abortions.

Medication abortion may be more attractive than procedural abortion because it can be done safely, effectively, and discretely, at the patient’s preference. 

Who is eligible for medication abortion?

Most patients at 70 days gestation or less are eligible for medical abortions. Patients with distorting fibroids, uterine anomalies, or scarring of the introitus due to FGM may benefit (versus aspiration). Multiple gestation is not a contraindication, and can use the same regimen as singleton gestations. 

Gestational age should be confirmed prior to initiating a medication abortion, by certain LMP within the past 56 days in patients with regular cycles and no symptoms or signs of ectopic pregnancy. Clinical or sonographic exam are not required before medication abortion.

Rh status should be verified, with RhoGam administered if indicated for Rh negative patients. Research here is continuing, but RhoGam is recommended by ACOG for all Rh negative patients. Some situations may call for shared decision-making on this front, and some institutions and professional groups do not recommend RhoGam prior to 10 weeks gestation. 

Additional laboratories, counseling, or evaluation may be required by local or state laws prior to proceeding with medication abortion.

Finally, medication abortion may not be an appropriate choice for patients: 

• with suspected or confirmed ectopic pregnancies, 

• patients with an IUD that remains in situ, 

• patients with chronic medical conditions: 

  • long-term steroid use, 

  • coagulopathy or anticoagulation use, 

  • adrenal insufficiency.

  • Anemia or hemoglobinopathy: 

    • Transfusion rates are higher with medication abortion versus aspiration (0.1 to 0.01%); patients in this category may benefit from aspiration or closer monitoring but are likely reasonable candidates. 

• Finally, patients should be willing to follow up completely and have good contact information, understand that medication abortion may take some time for completion, and be able to understand instructions to ensure success. 

Counseling:

Clear instructions on what to expect should be provided to patients who undergo medication abortion:

• Bleeding and cramping, with bleeding much heavier than menses.

  • Bleeding heavier than two maxi pads per hour for 2 hours should prompt patients to contact their clinician.

  • Patients should be counselled that additional intervention may be needed in the event of excess bleeding or suspected failure; however this is rare (less than 1%, and transfusion rates less than 0.1%). 

• Rate of ongoing pregnancy is low, and the risk increases at later gestational ages.

  • The risk of ongoing pregnancy at 64-70 days gestation is around 3%.

  • Teratogenicity is associated with the use of both mifepristone and misoprostol, so patients should be counseled about this in the event of medication failure, or if patients attempt to use high-dose progestins for unsanctioned “abortion reversal.”

  • There is no regimen that has been demonstrated to reverse abortion after administration of medications, and this has been shown in small studies to increase risk of complications.

• Side effects of misoprostol use are commonly GI upset, hot flushes, fever or chills. Mifepristone is generally well tolerated with few side effects.

• Risk of infection is overall very low, so there is no indication for antibiotic prophylaxis.

What medications are used for medication abortion?

There are a number of approved regimens, but the most successful and preferred is a combination of mifepristone and misoprostol.

• Mifepristone is a selective progesterone receptor modulator.

  • Binds progesterone receptor with greater affinity than progesterone, but does not activate it, thus acting as an antiprogestin.

  • The provision of mifepristone in the USA is dependent on a “risk evaluation and mitigation strategy,” or REMS program, facilitated by the FDA. ACOG and other professional organizations oppose the ongoing use of the REMS program as it does not make care safer and creates a barrier to the most effective form of medication abortion. 

• Misoprostol is a prostaglandin E1 analog.

  • Causes cervical softening and uterine contractions. 

The FDA approved combination is mifepristone 200mg orally, followed 24-48hrs later by 800 mcg of buccal misoprostol.

The WHO suggests misoprostol can be administered vaginally, buccally, or sublingually at the same dose and interval. 

Success rates range from 93% to 98% (lower success rate at more advanced gestational age). The rate of ongoing pregnancy in the highest gestational age range (64-70 days) was small at 3.1%. 

Misoprostol alone may also be used at 800 mcg vaginally, sublingually, or buccally, every 3 hours for up to 3 doses. However, mife-miso is a much more effective method and should be used if available. 

What clinical follow up is recommended after medication abortion?

Follow up can be performed clinically or remotely via telemedicine. Clinicians are able to successfully determine if pregnancy expulsion has occurred with 96-99% accuracy based on symptomatology alone. The use of pregnancy tests can also be a helpful adjunct to confirm expulsion, but are not absolutely necessary.

Sonography can be used as well, but may also predispose patients to additional unnecessary procedures. The measurement of endometrial thickness does not predict need for subsequent aspiration or complications. 

If abortion is suspected to be incomplete, the patient can be counseled about aspiration versus a repeat dose of misoprostol or expectant management. Surprisingly, studies have shown that even with a gestational sac is retained at 2 weeks after initial medication use, expulsion will usually occur spontaneously in the coming weeks! Ongoing symptoms such as irregular bleeding can persist in this case though, so many patients opt for intervention. 

What about contraception after medication abortion?

Most contraceptive methods are safe to start immediately or soon after abortion. Complete abortion should be ensured before placement of an IUD; usually a week after medication administration. 

Progestin-based contraceptives have a theoretical risk of interfering with mifepristone efficacy; this has been demonstrated with DMPA use on day 1 of the medication abortion, and thus patients should be counseled that risk of ongoing pregnancy may be greater in this scenario. This has not been observed with etonogestrel implants.