What is the starting and maintenance dose of Korlym (mifepristone) for a patient with hypercortisolism associated with endogenous Cushing's syndrome?

Korlym (Mifepristone) Dosing for Hypercortisolism

Start Korlym at 300 mg orally once daily with food, and titrate upward in 300 mg increments every 2-4 weeks based on clinical response, up to a maximum of 1200 mg daily (not exceeding 20 mg/kg/day). 1

Starting Dose

• Initiate at 300 mg once daily, taken with a meal 1
• Patients must swallow the tablet whole—do not split, crush, or chew 1
• Obtain a negative pregnancy test in females of reproductive potential before starting treatment 1

Dose Titration Strategy

• Increase by 300 mg increments at intervals of 2-4 weeks, based on clinical assessment of tolerability and degree of improvement in Cushing's syndrome manifestations 1
• Maximum dose is 1200 mg once daily, but should not exceed 20 mg/kg per day 1
• Early response indicators (within 6 weeks) include changes in glucose control, anti-diabetic medication requirements, insulin levels, and psychiatric symptoms 1
• Later indicators (beyond 2 months) include improvements in cushingoid appearance, acne, hirsutism, striae, and body weight 1

Maintenance Dosing

• The maintenance dose is highly variable and determined by clinical response rather than biochemical markers 2, 1
• In the pivotal trial, doses ranged from 300-1200 mg daily, with 60% of patients achieving significant improvement in glycemic control 3
• Careful and gradual titration accompanied by monitoring for adverse reactions may reduce the risk of severe adverse reactions 1

Dose Adjustments for Special Populations

Renal Impairment

• No change in initial dose required 1
• Maximum dose limited to 600 mg in any degree of renal impairment 1

Hepatic Impairment

• No change in initial dose for mild to moderate hepatic impairment 1
• Maximum dose limited to 600 mg in mild to moderate hepatic impairment 1
• Do not use in severe hepatic impairment 1

Concomitant Strong CYP3A Inhibitors

• If starting mifepristone in patients already on strong CYP3A inhibitors (ketoconazole, itraconazole, ritonavir, etc.): start at 300 mg and titrate to maximum of 900 mg 1
• If adding strong CYP3A inhibitors to patients already on mifepristone: reduce dose according to current dose (e.g., if on 1200 mg, reduce to 900 mg; if on 900 mg, reduce to 600 mg; if on 600 mg, reduce to 300 mg) 1

Critical Monitoring Considerations

• No reliable biochemical markers exist for monitoring cortisol levels during mifepristone therapy, as it blocks the glucocorticoid receptor while cortisol levels remain elevated 2
• Monitor clinically for signs of adrenal insufficiency, which occurred in fewer than 5% of patients in trials 4
• Close monitoring for hypokalemia is essential, as this was a common adverse event and can be severe 2, 3, 5
• Monitor for hypertension, as blood pressure may paradoxically increase despite treatment 5
• In women, monitor for endometrial hyperplasia with long-term use 3, 6

Treatment Interruption and Reinitiation

• If treatment is interrupted, reinitiate at the lowest dose (300 mg) 1
• If interrupted due to adverse reactions, titrate to a dose lower than the one that caused treatment interruption 1
• If treatment is interrupted for more than 14 days in females of reproductive potential, obtain a negative pregnancy test before restarting 1

Key Clinical Pitfalls

• Mifepristone should only be used by clinicians with extensive experience in Cushing's disease, as the inability to monitor cortisol levels biochemically increases risk for unrecognized adrenal insufficiency 2
• If adrenal insufficiency develops, it requires stress-dose glucocorticoid replacement, preferably dexamethasone (due to mifepristone's long half-life requiring several days of coverage) 2
• The drug's antiprogestin effects cause vaginal bleeding and endometrial changes that require monitoring 2, 3
• Extensive drug-drug interactions exist due to effects on multiple cytochrome P450 enzymes 2, 1, 4