Continuing Education Activity

Mifepristone, also called RU-486, is a synthetic steroid with dual FDA-approved applications. Firstly, it is utilized in combination with misoprostol for pregnancy termination up to 10 weeks of gestation, offering a medical alternative to surgical procedures for induced abortions. Secondly, mifepristone is employed in managing and treating hyperglycemia associated with Cushing syndrome. As a low-dose competitive binder, mifepristone obstructs progesterone action by binding to its intracellular receptor. Higher doses impede cortisol activity at the glucocorticoid receptor, concurrently elevating circulating cortisol levels to regulate hyperglycemia in individuals with Cushing syndrome. Apart from its predominant use in medically induced abortions, mifepristone proves valuable in addressing Cushing syndrome and uterine leiomyomas.

This activity focuses on elucidating the mechanism of action, adverse event profile, and other crucial aspects, such as dosing, pharmacodynamics, pharmacokinetics, monitoring, and relevant interactions of mifepristone. Healthcare professionals treating patients with mifepristone gain insights into its multifaceted roles, facilitating informed decision-making within the healthcare team. Noteworthy adverse reactions associated with mifepristone include bacterial infections and prolonged, heavy menstrual bleeding, underscoring the importance of comprehensive understanding and vigilance in its clinical use.

Objectives:

• Identify appropriate indications for mifepristone use in elective abortion procedures and other medical conditions.

• Screen patients to assess their eligibility for mifepristone therapy, considering medical history, contraindications, and potential drug interactions.

• Assess patient response to mifepristone treatment and monitor for adverse reactions or complications.

• Develop effective communication with patients, providing clear instructions and addressing their concerns regarding mifepristone treatment.

Indications

FDA-Approved Indications

Mifepristone, also known as RU-486, has 2 main FDA-approved indications. These are pregnancy termination combined with misoprostol through 10 weeks gestation and the management and treatment of hyperglycemia in patients exhibiting signs of Cushing syndrome.[1][2][3] 

Off-Label Uses

In addition to the above indications, mifepristone has shown efficacy with off-label uses for postcoital emergency contraception, cervical maturation, and adjunct therapy for uterine leiomyomas.[2][4][5][6]

Mechanism of Action

Mifepristone works by antagonism of glucocorticoid and progesterone receptors. At low doses, mifepristone works by being a selective antagonist of progesterone. The drug does so by binding to the intracellular progesterone receptor. At high doses, mifepristone blocks cortisol at the glucocorticoid receptor. This action causes an effect on the hypothalamic-pituitary-adrenal axis, leading to an increase in circulating cortisol, thus controlling hyperglycemia in some patients. Mifepristone has a higher affinity for the glucocorticoid II receptor than the glucocorticoid I receptor. 

For use in pregnancy termination, mifepristone works by interrupting progesterone. Progesterone is the primary hormone in preparing the endometrium for implantation and sensitizing the body to the effects of prostaglandins by increasing their synthesis and decreasing their metabolism. It causes the release of endogenous prostaglandins and an increase in the sensitivity of the myometrium to the contractile effects of prostaglandins. The increase in prostaglandins results in menstrual bleeding, disruption of the endometrium, and then termination.[1][7]

Pharmacokinetics

Absorption: Mifepristone is rapidly absorbed, and peak plasma concentrations are attained 90 minutes after administration.

Distribution: Mifepristone has high plasma protein binding (approximately 98%); it binds to albumin and alpha-1-acid glycoprotein. Mifepristone can cross the blood-brain barrier.[8]

Metabolism: Mifepristone is metabolized by CYP3A4, CY2C8, CYP2C9, and CYP2B6; it forms pharmacologically active metabolites.[9][10]

Elimination: The average elimination half-life of mifepristone is 18 hours (single dose). The primary route of elimination is through feces.[11][12]

Administration

Available Dosage Forms

Mifepristone is generally available as an oral tablet in 200 mg and 300 mg preparations.

Adult Dosing

Clinicians should be enrolled in the REMS program. According to the American College of Obstetricians and Gynecologists (ACOG) guidelines for medication abortion, mifepristone can be used in the first 70 days (10 weeks) of gestation; clinicians should confirm pregnancy and estimate gestational age. Any intrauterine device present must be removed before initiating mifepristone. The regimen for termination of pregnancy involves a single mifepristone dose of 200 mg orally and misoprostol 800 μg buccally.

Initially, a 200 mg tablet of mifepristone is administered in a single oral dose. On days 2 or 3, misoprostol should be placed in the buccal pouch as 4 200 μg tablets (total 800 μg). Misoprostol should be taken within 24 to 48 hours after taking mifepristone. Misoprostol should be kept in cheek pouches for at least 30 minutes. The efficacy decreases when misoprostol is administered <24 hours or >48 hours after the administration of mifepristone.[13]

To manage and treat hyperglycemia in patients with Cushing syndrome, an initial dose of 300 mg should be given orally once daily with a meal. That dose may be increased by 300 mg every 2 to 4 weeks up to a maximum of 1200 mg daily. According to the Endocrine Society Guidelines, the quick onset of action of mifepristone is helpful in life-threatening hypercortisolism.[14][15] 

For emergent postcoital contraception, 600 mg should be given orally in a single dose within 72 hours of intercourse. For uterine leiomyomas, 25 to 50 mg once daily by mouth can help reduce the size of the fibroids.[1][3]

Specific Patient Populations

Hepatic impairment: In patients with hyperglycemia with Cushing syndrome, the maximum dose of mifepristone is 600 mg daily for mild to moderate hepatic impairment; use is not recommended in severe hepatic impairment. According to product labeling, no studies have been conducted for mifepristone in hepatic impairment for termination of intrauterine pregnancy; caution is advised.

Renal impairment: In patients with hyperglycemia with Cushing syndrome, the maximum dose is 600 mg daily. According to product labeling, no studies have been conducted for mifepristone in renal impairment for termination of intrauterine pregnancy; caution is advised.

Pregnancy considerations: Mifepristone use for hypercortisolism is contraindicated in pregnancy due to the risk of abortion. As mifepristone is the standard medication in abortion regimens, clinicians must be aware of potential associated teratogenicity (limb defects and Moebius syndrome).[13]

Breastfeeding considerations: Mifepristone is distributed in human milk. Available medical information suggests that breastfeeding need not be discontinued after a single dose of mifepristone, as in medical abortion. However, long-term breastfeeding should be avoided during long-term therapy for hyperglycemia in patients with Cushing syndrome. Product labeling indicates that the decision should be based on a risk-benefit evaluation of the infant and mother.[16]

Pediatric patients: The safety and effectiveness of mifepristone for the termination of intrauterine pregnancy have been demonstrated in pediatric patients.

Older patients: Clinical trials of mifepristone for endogenous Cushing syndrome did not have a sufficient sample size to detect a statistically significant difference.

Adverse Effects

Severe reactions include fetal death, anaphylactic reactions, toxic epidermal necrolysis, angioedema, and teratogenesis.

Moderate reactions may present as hypokalemia, peripheral edema, hypertension, dyspnea, constipation, hypoglycemia, vaginal bleeding, uterine contractions, stomatitis, hot flashes, endometrial hyperplasia, anemia, adrenocortical insufficiency, palpations, and hypotension.[17][4]

Mild reactions include nausea, abdominal pain, fever, vomiting, fatigue, headache, diarrhea, dizziness, sinusitis, pharyngitis, GERD, malaise, insomnia, maculopapular rash, pruritis, pelvic pain, chills, menstrual irregularity, emotional lability, and syncope.[3][18][19]

Drug-Drug Interactions

• CYP3A4 inhibitors: Strong inhibitors of CYP3A, such as itraconazole, ketoconazole, ritonavir, atazanavir, clarithromycin, conivaptan, saquinavir, telithromycin, and voriconazole can increase the concentration of mifepristone.[20][21] The maximum dose of mifepristone should not exceed 600 mg per day.

• CYP3A4 inducers: Strong CYP3A4 inducers such as carbamazepine, phenytoin, rifampin, phenobarbital, and St. John's wort can reduce concentrations of mifepristone. Concurrent use with mifepristone should be avoided.[22]

• Drugs metabolized by CYP2C8/CYP2C9: Fluvastatin, warfarin, and repaglinide are metabolized by CYP2C8/CYP2C9. Use the lowest dose possible during concurrent administration with mifepristone.[23][24]

• Drugs metabolized by CYP2B6: Mifepristone is an inhibitor of CYP2B6 and may increase the concentration of drugs metabolized by CYP2B6, such as bupropion and efavirenz. Use with caution.[10][25]

Contraindications

When using mifepristone to terminate a pregnancy or conception, caution is necessary to test out the patient populations with contraindications to mifepristone. Patients who have previously had a hypersensitivity reaction to mifepristone or prostaglandin therapy should not have mifepristone therapy. Hypersensitivity reactions include symptoms of anaphylaxis, angioedema, rash, hives, and pruritus. Additional contraindications include inherited porphyria, bleeding disorders, and adrenal failure. Clinicians must exclude ectopic pregnancy according to product labeling.[26]

The use of mifepristone in patients with Cushing syndrome is contraindicated with concurrent administration of simvastatin, lovastatin, and CYP3A substrates (ie, cyclosporine, dihydroergotamine, ergotamine, fentanyl, sirolimus, and tacrolimus).[27][28]

Additionally, mifepristone is contraindicated in patients who are pregnant for the control of hyperglycemia. If the patient has a history of unexplained vaginal bleeding, endometrial cancer, or endometrial hyperplasia with signs of atypia, they should not receive mifepristone. Physicians need to be watchful for symptoms of abdominal pain, infection, sepsis, and vaginal bleeding after starting mifepristone. If these symptoms develop, the clinician should stop mifepristone immediately.[4][5]

Boxed Warning: 

Termination of pregnancy (mifepristone for Cushing syndrome-related hyperglycemia)

Clinicians should exclude pregnancy before stating mifepristone or if treatment is interrupted for >14 days in females of reproductive potential. Clinicians should advise patients to use non-hormonal contraceptives; no contraception is required if the patient has surgical sterilization.

Risk of severe infections and bleeding (mifepristone for medical termination of pregnancy)

Infection: After administering mifepristone, several adverse reactions require monitoring, including severe bacterial infections post-medical abortion or post-dilatation and curettage procedure where the use of mifepristone was indicated. There is no causal relationship between the drug and developing an infection, but they can occur. Before prescribing mifepristone, the patient should understand the risks, signs to look for, and a plan of action if they need help. Signs to look out for include sustained fever, severe abdominal pain, heavy bleeding, syncope, or general malaise lasting more than 24 hours after taking the medication. If a bacterial infection occurs, there is a high possibility that the pathogen is Clostridium sordellii, which can present atypically.[29]

Bleeding: Prolonged, heavy bleeding after taking mifepristone is a possibility based on the drug's mechanism of action. Mifepristone promotes endometrial proliferation, leading to endometrial thickening and heavier vaginal bleeding. Bleeding is expected on average for 9 to 16 days post-pregnancy termination. The manufacturer describes excessive bleeding as soaking through 2 thick pads every hour. If excessive bleeding occurs, it could point to an incomplete abortion or other complications. In these instances, monitoring for hypovolemic shock becomes important.[30][26]

Monitoring

When using mifepristone in managing patients with Cushing syndrome, clinicians must consider the effects on the HPA axis. This treatment can lead to adrenal insufficiency due to persistently elevated cortisol levels. Due to this, cortisol levels should not serve as a monitoring parameter. Clinically, watch for signs of fatigue, hypoglycemia, hypotension, nausea, or weakness. If the clinician observes these, discontinue mifepristone and administer high-dose steroids. Once resolved, mifepristone may be restarted at a lower dose.

Hypokalemia needs to be monitored in these patients as well. A pre-treatment potassium level of 4.0 mEq/L is suggested to reduce the risk of hypokalemia. If the potassium is <4.0 mEq/L, consider potassium repletion.[31] Patients receiving Cushing syndrome treatment are at higher risk for developing opportunistic infections such as Pneumocystis jirovecii pneumonia.[4][5][32] Mifepristone can prolong the QTc interval and its use merits caution in combination with other drugs that also prolong the QT interval.[33] 

According to ACOG, clinicians should evaluate patients after the administration of mifepristone for termination of pregnancy. This monitoring is crucial to ensure the complete termination of pregnancy. Termination can be confirmed by medical history, physical examination, human chorionic gonadotropin (hCG), and ultrasonography.[34]

Toxicity

Mifepristone is metabolized in the liver by CYP3A4; thus, medications that are CYP3A4 inhibitors can result in higher concentrations of mifepristone in the patient. For patients taking multiple doses of mifepristone in managing hyperglycemia in Cushing syndrome, the medication's half-life is reportedly around 85 hours. During this time, the significant symptoms to watch for are cardiogenic. Hypokalemia is very common due to the effects of cortisol on unopposed mineralocorticoid receptors.[4] 

Patients should be observed closely for signs and symptoms of adrenal insufficiency.[4] Hypokalemia and hypertension can be due to Cushing syndrome and may not always suggest excess glucocorticoid receptor antagonism due to mifepristone. Persistent and difficult-to-treat hypertension and hypokalemia may indicate excess glucocorticoid receptor antagonism, requiring discontinuation of mifepristone and rescue treatment with steroids.[31] 

To avoid problems with mifepristone toxicity and adverse effects, the suggestion is to titrate the dosage gradually. Following up and monitoring the patient during the dosage escalation process is essential. Mifepristone is included in the US National Institute for Occupational Safety and Health (NIOSH) hazardous drugs list. Healthcare providers should take appropriate precautions, such as wearing gloves and safe dispensing.[35]

Enhancing Healthcare Team Outcomes

Due to ongoing controversies, clinicians should be up-to-date with medicolegal aspects when prescribing mifepristone.[36] Mifepristone is available through the REMS (Risk Evaluation and Mitigation Strategies) program, which incorporates Ensuring Elements To Assure Safe Use (ETASU).[30] The mifepristone REMS Program was revised in January 2023.[37]

• Mifepristone can only be prescribed by a healthcare provider certified under the Mifepristone REMS Program.
• Healthcare providers need to complete a prescriber agreement form to prescribe mifepristone.
• The patient agreement form must be discussed and signed by the health care provider and patient; counseling regarding the risks of the mifepristone regimen is required.
• The patient must be given a copy of the patient agreement form and FDA-approved mifepristone medication guide.
• Mifepristone may only be dispensed by a certified pharmacy that has completed the pharmacy agreement form. 
• Certified pharmacies must be competent in shipping, tracking, and delivering mifepristone to the patient on time.

The patient will receive optimal care if the interprofessional healthcare team works together in an integrated fashion with open communication channels. Collaboration and shared decision-making are the keys to a good outcome. Depending on the indication of mifepristone, patients will be treated in various locations. Healthcare providers must be aware of red flag symptoms if the patient experiences an adverse reaction. For instance, clinicians, nursing staff, lab technicians, and pharmacists should work together to ensure the patient's hemodynamic stability in cases of heavy bleeding. If the patient develops a bacterial infection, an infectious disease specialist should be consulted to provide evidence-based care. Endocrinologists should be consulted for the management of endogenous hypercortisolism-related hyperglycemia. Gynecologists should ensure the termination of pregnancy.

The entire team must work together to support the patient from all angles; this can be especially important for females after losing a pregnancy. Social work support can be crucial in this case. Patients may require both pre and post-elective abortion counseling. An interprofessional team approach and open communication between physicians, advanced practice practitioners, specialists, pharmacists, nurses, and social workers can ensure the optimum use of mifepristone in their patients.