Mifepristone

Usage

Mifepristone is prescribed for the following medical conditions:

• Medical termination of intrauterine pregnancy: Used up to 70 days (10 weeks) after the first day of the last menstrual period. It is used in a regimen with misoprostol.
• Control of hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing’s syndrome: Prescribed for patients who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery. Not indicated for type 2 diabetes unrelated to Cushing’s syndrome.

Pharmacological Classification:

• Antiprogestogen (primarily)
• Antiglucocorticoid
• Antiandrogen (weak)

Mechanism of Action: Mifepristone primarily acts as a progesterone receptor antagonist, binding to progesterone receptors and blocking the effects of progesterone, a hormone crucial for maintaining pregnancy. This action leads to decidual necrosis, cervical softening, and increased uterine contractility, resulting in the termination of pregnancy when used with misoprostol. In Cushing’s syndrome, its antiglucocorticoid properties help control hyperglycemia.

Alternate Names

• RU 486

Brand Names:

• Mifeprex (for pregnancy termination)
• Korlym (for Cushing’s syndrome)
• Mifegymiso (mifepristone and misoprostol kit)

How It Works

Pharmacodynamics:

Mifepristone binds to progesterone receptors with higher affinity than progesterone itself, effectively blocking progesterone’s actions. This leads to endometrial breakdown, cervical ripening, and increased uterine sensitivity to prostaglandins (like misoprostol), causing uterine contractions and expulsion of the pregnancy. It also exhibits antiglucocorticoid activity by antagonizing cortisol at the glucocorticoid receptor.

Pharmacokinetics:

• Absorption: Rapidly absorbed orally, reaching peak plasma concentrations within 1.3 hours (when taken with a high-fat meal).
• Metabolism: Primarily metabolized in the liver by the CYP3A4 enzyme system.
• Elimination: Mifepristone has a long elimination half-life, around 18-21 days. Elimination is mainly through hepatic routes, with a small amount excreted in breast milk.

Mode of Action: Mifepristone acts at a cellular and molecular level by binding to the intracellular progesterone and glucocorticoid receptors. This binding prevents progesterone and cortisol from binding and exerting their physiological effects.

Receptor Binding: Mifepristone competitively binds to progesterone and glucocorticoid receptors.

Enzyme Inhibition/Neurotransmitter Modulation: Mifepristone’s primary mechanism is receptor antagonism, not enzyme inhibition or neurotransmitter modulation.

Dosage

Standard Dosage

Adults:

• Medical Abortion: 200 mg of mifepristone orally on Day 1, followed by 800 mcg of misoprostol (buccally or vaginally) 24 to 48 hours later.
• Cushing’s Syndrome: Initial dose of 300 mg orally once daily with a meal. The dose may be increased in 300 mg increments every 2-4 weeks up to a maximum of 1200 mg daily (not to exceed 20 mg/kg daily).

Children: Use and dose must be determined by a doctor. Safety and efficacy in children for abortion have not been established. For Cushing’s Syndrome, pediatric dosing is determined by the doctor.

Special Cases:

• Elderly Patients: No specific dosage adjustments are recommended.
• Patients with Renal Impairment: For Cushing’s syndrome, the maximum dose is limited to 600 mg/day. Caution advised for medical abortion.
• Patients with Hepatic Dysfunction: For Cushing’s syndrome, the maximum dose is limited to 600 mg/day for mild to moderate impairment. Avoid use in severe hepatic impairment. Caution advised for medical abortion.
• Patients with Comorbid Conditions: Individualized assessment is required.

Clinical Use Cases

Mifepristone is not indicated for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.

Side Effects

Common Side Effects:

• Medical Abortion: Cramping, vaginal bleeding, nausea, vomiting, diarrhea, headache, dizziness, fever/chills, fatigue/weakness.
• Cushing’s Syndrome: Nausea, vomiting, fatigue, headache, hypokalemia, arthralgia, peripheral edema, hypertension, dizziness, decreased appetite, endometrial hypertrophy.

Rare but Serious Side Effects:

• Medical Abortion: Heavy or prolonged bleeding, incomplete abortion, infection, allergic reactions (rash, itching/swelling, severe dizziness, trouble breathing), fever ≥100.4°F (38°C), fainting, fast heartbeat, severe abdominal pain.
• Cushing’s Syndrome: Adrenal insufficiency, QT prolongation, worsening of conditions controlled by corticosteroids, pregnancy loss.

Long-Term Effects:

Chronic complications from prolonged use for medical abortion are rare. For Cushing’s syndrome, long-term use can lead to adrenal insufficiency.

Adverse Drug Reactions (ADR):

Clinically significant ADRs include severe bleeding, serious infections, and allergic reactions.

Contraindications

• Absolute Contraindications: Confirmed or suspected ectopic pregnancy, adrenal insufficiency, allergy to mifepristone or misoprostol, chronic systemic glucocorticoid use, hemorrhagic disorder or concurrent anticoagulant use (excluding aspirin), inherited porphyrias, IUD in place, septic abortion.
• Relative Contraindications: Hemoglobin < 10 g/dL, severe hepatic, renal, respiratory, or cardiovascular disease.

Drug Interactions

• CYP3A4 Inhibitors: (e.g., ketoconazole, itraconazole, ritonavir) increase mifepristone levels. Dosage adjustments may be needed.
• CYP3A4 Inducers: (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort, glucocorticoids) decrease mifepristone levels and may reduce efficacy.
• Anticoagulants/Antiplatelets: (e.g., warfarin, clopidogrel, NSAIDs) increase the risk of bleeding.
• Corticosteroids: Concurrent use may reduce mifepristone’s effectiveness.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: X (for pregnancy termination). Contraindicated in pregnancy for other indications (e.g., Cushing’s syndrome). Mifepristone causes fetal death when administered during pregnancy.
• Breastfeeding: Limited data suggest negligible mifepristone levels in breast milk after a single dose. Breastfeeding can generally continue after a single dose for medical abortion, though monitoring for nausea, vomiting, diarrhea, and poor feeding in the infant is recommended. For long-term use (Cushing’s syndrome), breastfeeding should be avoided, and milk should be pumped and discarded during treatment and for 18-21 days after the last dose due to the long half-life.

Drug Profile Summary

• Mechanism of Action: Progesterone receptor antagonist, antiglucocorticoid.
• Side Effects: Medical abortion: cramping, bleeding, nausea, vomiting. Cushing’s syndrome: nausea, vomiting, fatigue, headache, hypokalemia.
• Contraindications: Ectopic pregnancy, adrenal insufficiency, allergy, bleeding disorders, IUD in place.
• Drug Interactions: CYP3A4 inhibitors and inducers, anticoagulants/antiplatelets, corticosteroids.
• Pregnancy & Breastfeeding: Contraindicated in pregnancy (except for termination). Limited data suggest minimal excretion in breast milk after a single dose.
• Dosage: Medical abortion: 200 mg single dose. Cushing’s syndrome: 300 mg daily, titrated up to 1200 mg daily.
• Monitoring Parameters: For medical abortion: bleeding, signs of infection. For Cushing’s syndrome: blood glucose, potassium levels, signs of adrenal insufficiency.

Popular Combinations

• Mifepristone + Misoprostol: Used for medical abortion and early pregnancy loss.

Precautions

• General Precautions: Verify pregnancy status and gestational age before use. Rule out ectopic pregnancy. Remove IUD if present. Monitor for bleeding and signs of infection.

• Pregnant Women: Contraindicated except for termination of pregnancy.

• Breastfeeding Mothers: Limited data suggests single dose use compatible with breastfeeding. Avoid long-term use.

• Children & Elderly: Individualized assessment necessary for Cushing’s syndrome. Medical abortion safety and efficacy not established in children.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Mifepristone?

A: For medical abortion: 200 mg single oral dose followed by misoprostol. For Cushing’s syndrome: initial 300 mg daily, titrated up to 1200 mg daily.

Q2: Can Mifepristone be used for ectopic pregnancies?

A: No, mifepristone is contraindicated in ectopic pregnancies.

Q3: What are the common side effects of Mifepristone used for medical abortion?

A: Common side effects include cramping, bleeding, nausea, vomiting, diarrhea, headache, fever.

Q4: What are the serious side effects of mifepristone?

A: Serious side effects include heavy bleeding, infection, and allergic reactions.

Q5: How does Mifepristone work in Cushing’s syndrome?

A: It acts as a glucocorticoid receptor antagonist, blocking the effects of excess cortisol and helping control hyperglycemia.

Q6: What are the contraindications for Mifepristone use in Cushing’s syndrome?

A: Contraindications include adrenal insufficiency, allergy to mifepristone, and pregnancy.

Q7: Does Mifepristone interact with other medications?

A: Yes, it interacts with CYP3A4 inhibitors and inducers, anticoagulants/antiplatelets, and corticosteroids.

Q8: Can Mifepristone be used while breastfeeding?

A: Limited data suggest a single dose is generally safe while breastfeeding. Long-term use is contraindicated.

Q9: What is the role of misoprostol in medical abortion?

A: Misoprostol is administered after mifepristone to cause uterine contractions and expulsion of the pregnancy.

Q10: How long does bleeding last after taking Mifepristone for medical abortion?

A: Bleeding typically lasts for 9-16 days but can vary.