Mifepristone

Approved Indications:

• Medical Termination of Intrauterine Pregnancy:
  • Used in combination with misoprostol for termination of pregnancy up to 70 days (10 weeks) gestation.
  • FDA approved as a two-drug regimen (Mifepristone + Misoprostol).
• Management of Hyperglycemia in Cushing’s Syndrome:
  • For patients with endogenous Cushing’s syndrome who have type 2 diabetes mellitus or glucose intolerance and for whom surgery is not an option or has failed.

Important Off-label / Clinically Accepted Uses:

• Cervical ripening and labor induction (investigational/off-label use)
• Missed abortion or intrauterine fetal demise (early second trimester)
• Endometriosis and uterine fibroids (under investigation or limited off-label)
• Emergency contraception (higher doses, off-label use)

Route of Administration: Oral only

Medical Termination of Pregnancy (up to 70 days gestation):

• Adults:
  Mifepristone 200 mg orally as a single dose, followed 24–48 hours later by misoprostol 800 mcg buccally or vaginally.

Hyperglycemia in Cushing’s Syndrome:

• Starting Dose: 300 mg orally once daily with food
• Titration: May be increased in 300 mg increments at 2- to 4-week intervals based on clinical response.
• Maximum Dose: 1200 mg/day or 20 mg/kg/day (whichever is lower)

Special Populations:

• Pediatrics: Not recommended for use in children.
• Elderly: Use with caution; no specific dosage adjustment unless renal/hepatic impairment is present.
• Renal Impairment: No adjustment in mild/moderate impairment; caution in severe impairment.
• Hepatic Impairment: Use with caution; avoid in moderate to severe hepatic dysfunction.

Mifepristone is a progesterone receptor antagonist with glucocorticoid receptor antagonistic activity. It binds competitively to intracellular progesterone receptors in the uterus and placenta, blocking the action of endogenous progesterone, a hormone necessary to maintain pregnancy. This leads to decidual breakdown, detachment of the embryo, cervical softening, and increased uterine sensitivity to prostaglandins, thereby inducing abortion. In Cushing’s syndrome, Mifepristone antagonizes glucocorticoid receptors, reducing the effects of elevated cortisol.

• Absorption:
  • Oral bioavailability is ~70%
  • Peak plasma concentration (Tmax): ~1.3 hours (range: 0.5–4 hours)
• Distribution:
  • High protein binding (>98%) to albumin and α1-acid glycoprotein
  • Volume of distribution: ~20 L
• Metabolism:
  • Hepatic, primarily via CYP3A4
  • Metabolized into three major active metabolites
• Elimination:
  • Half-life: ~18–85 hours (mean ~20–30 hours)
  • Excreted mainly via feces (83%) and urine (9%)

• Pregnancy:
  • Category X (Contraindicated) – Known to cause pregnancy loss. Use is restricted to approved indication under medical supervision. Contraindicated in ongoing pregnancy.
• Lactation:
  • Mifepristone is excreted in human milk.
  • Not recommended during breastfeeding. If used, breastfeeding should be avoided for at least several days due to potential risks to the infant.

• Primary Class: Antiprogestin
• Subclass: Progesterone receptor antagonist / Glucocorticoid receptor antagonist

• Confirmed or suspected ectopic pregnancy
• Chronic adrenal failure
• Concurrent corticosteroid therapy (may be antagonized)
• Bleeding disorders or current anticoagulant therapy
• Inherited porphyrias
• Allergy to Mifepristone or excipients
• Women with an IUD in place (must be removed before use for pregnancy termination)

• Serious bleeding: May occur; surgical intervention may be required in rare cases.
• Incomplete abortion: Follow-up is necessary to ensure complete termination.
• Infection/sepsis: Rare but life-threatening bacterial infections have occurred.
• QT prolongation: Caution with other QT-prolonging drugs.
• Loss of cortisol control in Cushing’s syndrome: May lead to adrenal insufficiency or hypokalemia.
• Psychiatric symptoms: Monitor for mood changes or suicidal ideation.

Common Side Effects (Pregnancy Termination Use):

• Vaginal bleeding (nearly universal, may last up to 2 weeks)
• Cramping, abdominal pain
• Nausea, vomiting
• Diarrhea, dizziness
• Headache, fatigue

Serious/Rare Adverse Effects:

• Hemorrhage requiring transfusion
• Sepsis or septic shock (rare but fatal cases reported)
• Uterine rupture (very rare, more likely in late-term or scarred uterus)
• Hypokalemia (in Cushing’s syndrome patients)
• QT prolongation

• CYP3A4 inhibitors (e.g., ketoconazole, itraconazole):
  ↑ Mifepristone plasma levels; caution advised.
• CYP3A4 inducers (e.g., rifampin, phenytoin):
  ↓ Efficacy due to enhanced metabolism.
• Corticosteroids:
  Antagonized by Mifepristone → reduced efficacy of steroid therapy.
• Anticoagulants/NSAIDs:
  ↑ Risk of bleeding.
• Drugs prolonging QT interval (e.g., quinidine, amiodarone):
  Additive risk of QT prolongation.

• FDA REMS Program:
  Mifepristone is distributed under a Risk Evaluation and Mitigation Strategy (REMS), requiring certified prescribers and pharmacies.
• January 2023 (FDA update):
  Allowing certified retail pharmacies to dispense Mifepristone directly, improving access.
• Ongoing legal and regulatory reviews:
  Especially in relation to abortion access and state-level restrictions.
• New recommendations by ACOG and WHO:
  Support use up to 10 weeks gestation with simplified protocols.

• Storage Temperature:
  20°C to 25°C (68°F to 77°F); excursions permitted to 15°C–30°C
• Humidity/Light:
  Store in a dry place, protected from excess moisture and direct light.
• Handling:
  No refrigeration or reconstitution needed. Keep out of reach of children.