Mifepristone

Mifepristone is a cortisol receptor blocker indicated to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery. LIMITATIONS OF USE: Mifepristone should not be used in the treatment of patients with type 2 diabetes unless it is secondary to Cushing's syndrome. Important Limitations of Use: Do not use for the treatment of type 2 diabetes mellitus unrelated to endogenous Cushing's syndrome.

Mifepristone is a selective antagonist of the progesterone receptor at low doses and blocks the glucocorticoid receptor (GR-II) at higher doses. Mifepristone has high affinity for the GR-II receptor but little affinity for the GR-I (MR, mineralocorticoid) receptor. In addition, mifepristone appears to have little or no affinity for estrogen, muscarinic, histaminic, or monoamine receptors.

Obtain a negative pregnancy test in females of reproductive potential prior to initiating treatment with mifepristone or if treatment is interrupted for more than 14 days. Administer once daily orally with a meal. The recommended starting dose is 300 mg once daily. Based on clinical response and tolerability, the dose may be increased in 300 mg increments to a maximum of 1200 mg once daily. Do not exceed 20 mg/kg per day. Renal impairment: do not exceed 600 mg once daily. Mild-to-moderate hepatic impairment: do not exceed 600 mg once daily. Do not use in severe hepatic impairment. Concomitant administration with strong CYP3A inhibitors: Do not exceed 900 mg once daily.

Mifepristone is contraindicated in: Pregnancy Patients taking drugs metabolized by CYP3A such as simvastatin, lovastatin, and CYP3A substrates with narrow therapeutic ranges, such as cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus, due to an increased risk of adverse events. Patients receiving systemic corticosteroids for lifesaving purposes (e.g., immunosuppression after organ transplantation) because mifepristone antagonizes the effect of glucocorticoids. Women with a history of unexplained vaginal bleeding or with endometrial hyperplasia with atypia or endometrial carcinoma.

Boxed warning (termination of pregnancy): Mifepristone is a potent antagonist of progesterone and cortisol via the progesterone and glucocorticoid (GR-II) receptors, respectively. The antiprogestational effects will result in the termination of pregnancy. Adrenal insufficiency: Patients should be closely monitored for signs and symptoms of adrenal insufficiency. Hypokalemia: Hypokalemia should be corrected prior to treatment and monitored for during treatment. Vaginal bleeding and endometrial changes: Women may experience endometrial thickening or unexpected vaginal bleeding. Use with caution if patient also has a hemorrhagic disorder or is on anti-coagulant therapy. QT interval prolongation: Avoid use with QT interval-prolonging drugs, or in patients with potassium channel variants resulting in a long QT interval.

Most common adverse reactions in Cushing's syndrome (≥ 20%): nausea, fatigue, headache, decreased blood potassium, arthralgia, vomiting, peripheral edema, hypertension, dizziness, decreased appetite, endometrial hypertrophy.

Based on the long terminal half-life of mifepristone after reaching steady state, at least 2 weeks should elapse after cessation of mifepristone before initiating or increasing the dose of any interacting concomitant medication. Drugs metabolized by CYP3A: Administer drugs that are metabolized by CYP3A at the lowest dose when used with mifepristone. CYP3A inhibitors: Caution should be used when mifepristone is used with strong CYP3A inhibitors. Limit mifepristone dose to 900 mg per day when used with strong CYP3A inhibitors. CYP3A inducers: Do not use mifepristone with CYP3A inducers. Drugs metabolized by CYP2C8/2C9: Use the lowest dose of CYP2C8/2C9 substrates when used with mifepristone. Drugs metabolized by CYP2B6: Use of mifepristone should be done with caution with bupropion and efavirenz. Hormonal contraceptives: Do not use with mifepristone.

Store at controlled room temperature, 25 °C (77 °F), excursions permitted to 15 to 30 °C (59 – 86 °F).