Continuing Education Activity

Mifepristone is a synthetic steroid. It is a medication most commonly used for medically induced abortions. Mifepristone can also be used in the management and treatment of Cushing's syndrome and uterine leiomyomas. At low doses, mifepristone blocks progesterone by competitively binding its intracellular receptor. At high doses, mifepristone blocks cortisol at the glucocorticoid receptor, thus simultaneously increasing the amount of circulating cortisol, which controls hyperglycemia in patients with Cushing syndrome. The significant adverse reactions to mifepristone include bacterial infections and prolonged, heavy menstrual bleeding. Mifepristone is contraindicated in patients with: an ectopic pregnancy, hypersensitivity to prostaglandins, undiagnosed renal masses, concurrent IUD use, hemorrhagic disorders, and severe anemia. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., dosing, pharmacodynamics, pharmacokinetics, monitoring, and relevant interactions of mifepristone) that pertain to the healthcare team when treating patients with mifepristone.

Objectives:

• Identify the mechanism of action of mifepristone.
• Describe the potential adverse effects of mifepristone.
• Review the appropriate monitoring for patients taking mifepristone.
• Summarize some interprofessional team strategies for improving care coordination and communication to advance Mifepristone and improve outcomes.

Indications

Mifepristone has two main FDA-approved indications. These are pregnancy termination combined with misoprostol through ten weeks gestation and the management and treatment of hyperglycemia in patients exhibiting signs of Cushing syndrome.[1][2][3] In addition to the above indications, mifepristone has shown efficacy with off-label uses when it comes to postcoital emergency contraception, cervical maturation, and adjunct therapy for uterine leiomyomas.[2][4][5][6]

Mechanism of Action

Mifepristone works by being an antagonist of glucocorticoid and progesterone receptors. At low doses, mifepristone works by being a selective antagonist of progesterone. It 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 it does for the glucocorticoid I receptor. 

In the instance of pregnancy termination, mifepristone works by interrupting progesterone. Progesterone is the primary hormone in preparing the endometrium for implantation as well as sensitizing the body to the effects of prostaglandins by increasing their synthesis and decreasing their metabolism. The increase in prostaglandins results in menstrual bleeding, disruption of the endometrium, and then termination.[1][7][8]

Administration

In general, mifepristone is available as an oral tablet in 200 mg and 300 mg preparations. 

For all the indications listed above, the administration of mifepristone is via oral out. For pregnancy termination, mifepristone dosing should be a single dose of 200 mg. For the management and treatment of 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 two-four weeks up to a maximum dose of 1200 mg per day. For emergent postcoital contraception, 600 mg should be given orally in a single dose within seventy-two hours of intercourse. In the treatment of uterine leiomyomas, 25 to 50 mg once daily orally can help reduce the size of the fibroids.[1][3]

In patients with hepatic impairment, additional administration instructions are necessary for managing hyperglycemia with mifepristone. For these patients, the dosing should not exceed 600 mg orally per day. In patients with renal impairment with creatinine clearance of under ninety milliliters per minute, the dose should not exceed 600 mg orally per day. 

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.[9][4]

Mild reactions that may occur 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.[10][3][11][12]

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 had a hypersensitivity reaction to mifepristone in the past or to prostaglandin therapy should not have mifepristone therapy. Hypersensitivity reactions include symptoms of anaphylaxis, angioedema, rash, hives, and pruritis.  

The use of mifepristone in Cushing syndrome patients is contraindicated in patients taking simvastatin, lovastatin, and CYP3A substrates (i.e., cyclosporine, dihydroergotamine, ergotamine, fentanyl, sirolimus, and tacrolimus). Additionally, mifepristone is contraindicated in pregnant patients 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 this medication. If these symptoms develop, the clinician should stop mifepristone immediately.[4][5]

Monitoring

After administering mifepristone, several adverse reactions require monitoring, one of which being 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 in the event they need to seek 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 Clostridium sordellii, which can present atypically.[12]

Prolonged, heavy bleeding after taking mifepristone is a possibility based on the mechanism of action of the drug. Mifepristone promotes endometrial proliferation, leading to endometrial thickening and heavier vaginal bleeding. Bleeding is expected on average for 9-16 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.[10]

When using mifepristone in the management of Cushing syndrome patients, it is crucial to consider the effects on the HPA axis. This treatment can lead to adrenal insufficiency as a result of persistently elevated cortisol levels. Due to this, the 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 started back at a lower dose. Hypokalemia needs to be monitored in these patients as well. Of note, patients receiving treatment for Cushing syndrome are at higher risk for developing opportunistic infections such as Pneumocystis jirovecii pneumonia.[4][5][13]

In general, mifepristone can prolong the QTc interval, and its use merits caution in combination with other drugs that also prolong the QT interval.[14]

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. Also, for patients taking multiple doses of mifepristone, for instance, in managing hyperglycemia in Cushing syndrome, the half-life of the medication is reported to be 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] To avoid problems with mifepristone toxicity and side effects, the suggestion is to titrate the dosages gradually. It is essential to have follow-up and monitoring of the patient during the dosage escalation process.  

Enhancing Healthcare Team Outcomes

The patient will receive the best care if the interprofessional healthcare team works together in an integrated fashion. Collaboration and shared decision-making are the keys to a good outcome. Patients depending on their indication to use mifepristone, will be treated in a variety of locations. Health care providers need to be aware of red flag symptoms if the patient experiences an adverse reaction. For instances of heavy bleeding, the clinician, RN, lab technician, and the pharmacist all need to work together to determine the patient's hemodynamic stability status and find a solution. If the patient develops a bacterial infection, the medical team in recovery needs to start the workup and continue to follow up. The entire team must work together to give the patient support from all angles; this can be especially important for females after losing a pregnancy. Social work support can be important in this case. Patients may require both pre and post-elective abortion counseling. Through interdisciplinary collaborations, health care professionals can ensure the optimum use of mifepristone in their patients. [Level 5]