What is mifepristone 300 mg?

Mifepristone 300 mg: Medication Overview

Mifepristone 300 mg is a selective progesterone receptor antagonist and glucocorticoid receptor blocker available as an oral tablet, primarily FDA-approved for treating hyperglycemia in adults with Cushing's syndrome who have failed surgery or are not surgical candidates. 1

Primary FDA-Approved Indication

Mifepristone 300 mg tablets are specifically approved for controlling high blood sugar (hyperglycemia) caused by elevated cortisol levels (hypercortisolism) in adults with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or cannot undergo surgery. 1

Mechanism of Action

• Dual receptor antagonism: Acts as a selective progesterone receptor antagonist at low doses and blocks the glucocorticoid receptor (GR-II) at higher doses 1
• High receptor affinity: Mifepristone and its three active metabolites demonstrate greater affinity for the glucocorticoid receptor (100%, 61%, 48%, and 45% respectively) compared to dexamethasone (23%) or cortisol (9%) 1
• Minimal cross-reactivity: Little to no affinity for estrogen, muscarinic, histaminic, or monoamine receptors 1

Dosing and Administration

Standard Dosing Protocol

• Starting dose: 300 mg once daily with food 1, 2
• Dose escalation: May increase to 600 mg after 2 weeks, then by 300 mg increments every 4 weeks based on clinical tolerance and response 1
• Maximum dose:
  • 900 mg/day for patients <60 kg
  • 1200 mg/day for patients >60 kg
  • Should not exceed 20 mg/kg/day 2

Special Populations

• Renal impairment: Maximum dose should not exceed 600 mg per day 1
• Hepatic impairment: Maximum dose should not exceed 600 mg per day in mild to moderate impairment; contraindicated in severe hepatic impairment 1

Clinical Efficacy in Cushing's Syndrome

In the pivotal trial of 50 adults with endogenous Cushing's syndrome 1, 3:

Diabetes Cohort (n=29)

• 60% response rate (defined as ≥25% reduction in glucose AUC)
• Mean HbA1c decreased from 7.4% to 6.3% (reduction of 1.1%)
• Fasting plasma glucose decreased from 149.0 mg/dL to 104.7 mg/dL
• 57% of patients with elevated baseline HbA1c normalized their levels

Hypertension Cohort (n=21)

• 38% showed diastolic blood pressure response

Additional Benefits

• Mean weight reduction of 5.7% with significant waist circumference decrease
• 87% showed significant improvement in overall clinical status
• Improvements noted in insulin resistance, depression, cognition, and quality of life 3

Off-Label Uses in Obstetrics and Gynecology

While mifepristone is widely known for medication abortion, the 300 mg dose has specific applications:

Medication Abortion (14-27 weeks gestation)

Mifepristone 200 mg is as effective as 600 mg when combined with misoprostol for second-trimester medication abortion, with both doses achieving the same mean abortion time of 6.9 hours. 4 The 300 mg dose falls between these studied doses but is not the standard recommendation—use 200 mg for this indication.

Other Gynecologic Applications

Mifepristone has been investigated for management of early pregnancy loss, intrauterine fetal demise, ectopic pregnancy, labor induction, contraception, and treatment of abnormal uterine bleeding, though these remain off-label uses. 5

Critical Safety Considerations

Absolute Contraindications 1

• Pregnancy (causes pregnancy termination)
• Concurrent use of specific medications: simvastatin, lovastatin, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus
• Requirement for corticosteroid therapy for other serious medical conditions
• Women with intact uterus who have unexplained vaginal bleeding, endometrial hyperplasia, or endometrial cancer

Pregnancy Prevention Requirements

• Mandatory pregnancy testing before initiation and if treatment interrupted >14 days
• Non-hormonal contraception required during treatment and for one month after stopping (mifepristone interferes with hormonal contraceptives) 1

Common Adverse Events 3

• Nausea, fatigue, headache
• Hypokalemia (monitor potassium levels)
• Endometrial thickening in women
• Arthralgia, vomiting, edema
• Adrenal insufficiency (<5% of patients)

Monitoring Challenges

Critical limitation: Because mifepristone acts at the receptor level to block cortisol effects, circulating cortisol levels increase while their effects are blocked. This means cortisol measurements cannot be used to guide dosing or monitor for adrenal insufficiency. 6, 7

• Dose adjustments must be based on clinical parameters only (primarily glucose control and weight reduction)
• Requires experienced clinicians familiar with managing Cushing's syndrome 6
• If adrenal insufficiency suspected, may require 2-8 mg dexamethasone daily 7

Pharmacokinetics 1

• Time to peak: 1-4 hours after multiple doses
• Half-life: 85 hours (mean) following multiple 600 mg doses
• Protein binding: ~99.2% (highly bound to alpha-1-acid glycoprotein)
• Food effect: Significant increase in plasma levels when taken with food—always administer with meals for consistent absorption
• Time to steady state: Within 2 weeks

Key Clinical Pearls

1. The 300 mg tablet is the starting dose for Cushing's syndrome, not a standalone therapeutic dose—most patients require titration to higher doses for optimal effect

2. For medication abortion between 14-27 weeks, use 200 mg mifepristone (not 300 mg), followed by misoprostol 36-48 hours later 4

3. Monitor clinical response, not cortisol levels—this is fundamentally different from other Cushing's treatments

4. Extensive drug interactions exist due to CYP3A4 effects—review all concurrent medications before prescribing

5. Pregnancy prevention is non-negotiable—this medication will terminate pregnancy at any stage