What are the indications and safety considerations for using mifepristone in men?

Mifepristone Use in Men

Mifepristone is indicated in men exclusively for the treatment of hyperglycemia secondary to Cushing's disease when they have failed surgery or are not surgical candidates, but it should only be prescribed by clinicians with extensive experience due to significant monitoring challenges and drug interaction risks. 1, 2

Primary Indication in Men

• Cushing's Disease Management: Mifepristone is FDA-approved specifically 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. 2

• Key advantage in men: Unlike ketoconazole, mifepristone does not cause hypogonadism in men, making it a potentially preferable option from an endocrine standpoint. 1

• Clinical benefits: Mifepristone improves key clinical features associated with hypercortisolism, specifically hyperglycemia and weight gain. 1

Critical Safety Considerations Specific to Men

Monitoring Challenges

• No reliable biochemical markers exist for monitoring cortisol levels during mifepristone treatment, which eliminates the ability to use standard cortisol measurements for dosing adjustments or detecting adrenal insufficiency. 1

• Increased risk of adrenal insufficiency due to inability to monitor cortisol levels reliably, requiring heightened clinical vigilance for symptoms rather than laboratory values. 1

• Long half-life complications: If adrenal insufficiency develops, mifepristone's long half-life requires several days of stress-dose glucocorticoid replacement, preferably dexamethasone. 1

Common Adverse Effects

• Hypokalemia worsening is a frequent complication that requires monitoring and management. 1

• Antiglucocorticoid effects may manifest as Addisonian-like syndrome despite elevated blood ACTH and cortisol levels. 3

Drug Interaction Risks

• CYP3A inhibitors (ketoconazole, itraconazole, ritonavir, clarithromycin, etc.) may significantly increase mifepristone exposure and should be avoided or require dose limitation to 600 mg maximum. 2

• Drug-drug interactions must be carefully evaluated before prescribing, as mifepristone has complex metabolic interactions. 4

Dosing Algorithm for Men

Initial Dosing

• Start at 300 mg orally once daily with food; tablets must be swallowed whole, not split, crushed, or chewed. 2

Titration Protocol

• Increase by 300 mg increments no more frequently than every 2-4 weeks based on clinical assessment of tolerability and improvement in Cushing's manifestations. 2

• Maximum dose is 1200 mg once daily but should not exceed 20 mg/kg per day. 2

• Early response indicators (within 6 weeks): Changes in glucose control, anti-diabetic medication requirements, insulin levels, and psychiatric symptoms. 2

• Later response indicators: Improvements in cushingoid appearance, acne, hirsutism, striae, and body weight occur over longer periods. 2

Dose Modifications

• Renal impairment: No change in initial dose, but maximum dose limited to 600 mg. 2

• Hepatic impairment: No change in initial dose for mild-to-moderate impairment, but maximum dose limited to 600 mg; contraindicated in severe hepatic impairment. 2

When to Choose Alternative Agents

• First-line alternatives should be considered: Osilodrostat, metyrapone, or ketoconazole are generally preferred over mifepristone due to more straightforward monitoring and fewer interaction concerns. 1

• Osilodrostat and metyrapone advantages: Rapid cortisol control (within hours), no liver function test limitations, and no hypogonadism in men. 1

• Ketoconazole considerations: Ease of dose titration but requires liver function monitoring; may cause hypogonadism in men, making it less ideal than other options. 1

Clinical Pitfalls to Avoid

• Do not prescribe without specialist expertise: Guidelines explicitly state mifepristone should only be used by clinicians with extensive experience in Cushing's disease management. 1

• Do not rely on cortisol measurements: Standard biochemical monitoring is unreliable; clinical assessment of symptoms is paramount. 1

• Do not ignore drug interactions: Always review the patient's medication list for CYP3A inhibitors and other potential interactions before prescribing. 4, 2

• Do not use for type 2 diabetes unless secondary to Cushing's syndrome: This is an explicit FDA limitation. 2

• Do not assume standard monitoring protocols apply: The inability to use cortisol levels for safety monitoring requires a fundamentally different approach to patient management. 1

Non-Applicable Indications in Men

• Pregnancy termination and contraception: These are the most common uses of mifepristone globally but are obviously not applicable to male patients. 1, 5, 6, 7, 8

• Other investigational uses: While mifepristone has been studied for meningioma, breast cancer, and psychiatric disorders, these remain investigational and are not standard indications in men. 3, 9, 10