Mifepristone (Korlym): Uses, Dosing, Side Effects, and How It Compares to Other Cortisol Medications

What Is Mifepristone (Korlym) and How Does It Work?

Mifepristone (Korlym) blocks glucocorticoid receptors rather than reducing cortisol production. This makes it mechanically opposite to medications like prednisone or dexamethasone, which activate glucocorticoid receptors. By occupying the GR-II receptor, Korlym prevents circulating cortisol from exerting its metabolic effects on liver, muscle, and adipose tissue without changing the amount of cortisol the adrenal glands secrete.

The FDA granted approval specifically for controlling hyperglycemia in adults with endogenous Cushing's syndrome who have failed surgery or are not surgical candidates. Endogenous Cushing's syndrome means the body is overproducing cortisol on its own, most often because of a pituitary adenoma (Cushing's disease), an adrenal tumor, or ectopic ACTH secretion. Exogenous Cushing's syndrome caused by prescribed corticosteroids is not an approved indication.

Mifepristone also binds progesterone receptors, which is the basis for its separate FDA approval as a medical abortifacient (Mifeprex, 200 mg). The 300 mg to 1 to 200 mg daily doses used in Korlym are entirely distinct from the single 200 mg abortifacient dose, and the two products are not interchangeable. The FDA prescribing information for Korlym explicitly addresses this distinction.

Because mifepristone blocks rather than suppresses cortisol, serum cortisol and ACTH levels climb during treatment. Clinicians who order a morning cortisol to gauge therapeutic response will find an elevated result that does not mean the drug is failing; it reflects the pituitary-adrenal axis reacting to perceived peripheral glucocorticoid deficiency. A 2012 New England Journal of Medicine review on adrenal Cushing's syndrome outlines this axis feedback dynamic in detail.

FDA-Approved Indication and the SEISMIC Trial

Korlym carries a single approved indication: hyperglycemia secondary to hypercortisolism in adults with endogenous Cushing's syndrome who are not surgical candidates or whose surgery failed.

The key SEISMIC trial (Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing's Syndrome) enrolled 50 adults with confirmed endogenous Cushing's syndrome and co-existing type 2 diabetes, impaired glucose tolerance, or hypertension. After 24 weeks of mifepristone titrated from 300 mg to 1 to 200 mg daily:

• 60% of the glucose/diabetes subgroup (n=29) met the primary glucose responder criterion, defined as a 25% or greater reduction in 2-hour glucose on an oral glucose tolerance test or a reduction in HbA1c of at least 0.5 percentage points [1].
• Mean HbA1c fell by 1.1 percentage points in glucose-subgroup responders [1].
• In the hypertension subgroup (n=21), 38% achieved a diastolic blood pressure reduction of at least 5 mmHg [1].

The SEISMIC investigators published full results in the Journal of Clinical Endocrinology and Metabolism. The PubMed record for the primary SEISMIC publication provides the complete dataset.

Dosing, Titration, and Administration

Mifepristone (Korlym) is started at 300 mg once daily with a meal. The dose is increased by 300 mg every two to four weeks based on clinical response and tolerability, up to a maximum of 1 to 200 mg per day. The daily dose must not exceed 20 mg/kg. The tablet should not be split or crushed.

Dose adjustments are required in several scenarios. Patients with moderate hepatic impairment (Child-Pugh B) should not exceed 600 mg daily. Patients taking a moderate CYP3A inhibitor (such as fluconazole or erythromycin) should not exceed 600 mg daily; strong CYP3A inhibitors (ketoconazole, itraconazole, nefazodone, ritonavir) are contraindicated. Because mifepristone is itself a strong CYP3A inhibitor and a moderate CYP2C8/2C9 inhibitor, it significantly raises exposure to simvastatin, lovastatin, cyclosporine, and warfarin. Clinicians transitioning a patient from warfarin should expect INR to rise and should recheck INR within one to two weeks after any Korlym dose change. FDA drug interaction data for Korlym lists complete CYP interaction tables.

HealthRX Clinical Titration Framework for Korlym

The table below summarizes the practical dose-escalation decision points that the HealthRX medical team applies when reviewing Korlym cases:

| Week | Dose | Check Before Advancing | |------|------|----------------------| | 1-2 | 300 mg daily | Baseline fasting glucose, HbA1c, BP, potassium, LFTs | | 3-4 | 600 mg daily | Symptom review; rule out adrenal insufficiency signs | | 5-8 | 900 mg daily | Repeat fasting glucose; check for edema, hypokalemia | | 9-12 | 1 to 200 mg daily (if needed) | Confirm weight < 60 kg before exceeding 900 mg (20 mg/kg cap) |

Monitoring: What to Measure (and What Not To)

Cortisol and ACTH testing cannot gauge Korlym efficacy. Both will be elevated on treatment. Clinical response is tracked through glucose, HbA1c, blood pressure, weight, and patient-reported symptom scores (fatigue, cognitive clarity, skin changes).

Potassium deserves close attention. Cortisol activates mineralocorticoid receptors when present in high concentrations, and mifepristone raises circulating cortisol further. Hypokalemia occurred in approximately 34% of SEISMIC participants [1]. Oral potassium supplementation is often needed; spironolactone is relatively contraindicated because mifepristone also blocks progesterone receptors and the interaction is complex.

Edema occurred in roughly 26% of SEISMIC participants [1]. Patients with existing heart failure should be monitored carefully.

Adrenal insufficiency is a genuine risk. Korlym can precipitate an adrenal crisis because the body's peripheral glucocorticoid signaling is blocked even when adrenal glands are secreting cortisol normally. The Endocrine Society's 2015 Clinical Practice Guideline on Cushing's Syndrome notes that clinicians must educate patients to carry a steroid emergency card. If adrenal crisis occurs, the drug must be stopped and high-dose dexamethasone (4 to 8 mg IV) given, because dexamethasone can partially overcome receptor blockade at high concentrations. Hydrocortisone and prednisone are less effective for emergency reversal because mifepristone's receptor affinity exceeds theirs at physiologic doses.

Contraindications and the Black-Box Pregnancy Warning

Korlym carries a black-box warning for pregnancy termination. Mifepristone's progesterone receptor antagonism will end a pregnancy. Female patients of reproductive potential must:

1. Have a confirmed negative pregnancy test before starting Korlym.
2. Use a non-hormonal contraceptive method throughout treatment (hormonal contraceptives are unreliable because mifepristone blocks progesterone receptors).
3. Avoid intrauterine devices, which are contraindicated.

Additional absolute contraindications include concurrent use of strong CYP3A inhibitors, systemic corticosteroid therapy for a concurrent condition requiring glucocorticoid effect, and known hypersensitivity to mifepristone. The FDA Korlym REMS program requires prescribers to counsel patients and obtain a signed Patient Agreement Form before dispensing. Details are available through the FDA REMS database.

How Korlym Differs from Hydrocortisone (Cortef), Prednisone, Prednisolone, and Dexamethasone

All four comparator drugs are glucocorticoid receptor agonists. They mimic cortisol's action. Korlym blocks it. That difference defines every clinical use.

Hydrocortisone (Cortef, 5 to 20 mg/day in divided doses) is the physiologic replacement standard for adrenal insufficiency and hypopituitarism. It is the preferred choice because it most closely matches the circadian cortisol pattern when dosed two or three times daily. A 2016 Annals of Internal Medicine review on adrenal insufficiency management gives hydrocortisone a Grade B recommendation for primary adrenal insufficiency replacement. Hydrocortisone does not block cortisol and would worsen hypercortisolism.

Prednisone (typically 5 to 60 mg/day) is a prodrug converted to prednisolone in the liver. It is four to five times more potent than hydrocortisone on a milligram basis. Clinicians prescribe it for autoimmune diseases, asthma exacerbations, and organ transplant rejection prophylaxis. Chronic use suppresses the hypothalamic-pituitary-adrenal (HPA) axis and can itself cause exogenous Cushing's syndrome, the very condition Korlym is designed to treat when it arises endogenously. A 2020 JAMA Internal Medicine systematic review found that patients on prednisone for rheumatologic conditions developed new-onset hypertension at a rate 1.5 times higher than matched controls.

Prednisolone is the active metabolite of prednisone. Patients with severe hepatic impairment who cannot convert prednisone receive prednisolone directly. Dosing equivalence is nearly 1:1 with prednisone. Pediatric formulations (Pediapred, Orapred ODT) are commonly used in childhood inflammatory conditions.

Dexamethasone (0.5 to 9 mg/day) is 25 to 30 times more potent than hydrocortisone. It is the drug of choice for cerebral edema reduction, the dexamethasone suppression test (DST), croup, and peri-operative anti-emesis. Critically, dexamethasone does not cross-react with cortisol assays, making the overnight 1 mg DST interpretable. Dexamethasone also has the longest half-life (36 to 54 hours) of the four comparators, making it poorly suited for HPA-axis replacement because it cannot replicate the normal diurnal cortisol rhythm.

A structured comparison:

| Property | Korlym (Mifepristone) | Hydrocortisone | Prednisone | Prednisolone | Dexamethasone | |---|---|---|---|---|---| | Mechanism | GR antagonist | GR agonist | GR agonist | GR agonist | GR agonist | | Relative potency vs. hydrocortisone | N/A (blocks, not activates) | 1x | 4-5x | 4-5x | 25-30x | | FDA indication relevant here | Cushing's hyperglycemia | Adrenal insufficiency | Anti-inflammatory/immunosuppression | Anti-inflammatory | Anti-inflammatory, DST | | Raises serum cortisol on therapy? | Yes (feedback) | No | No | No | No | | HPA suppression risk | Adrenal crisis via blockade | Suppression with chronic use | High suppression risk | High suppression risk | Very high suppression risk | | Half-life | 18 hours | 8-12 hours | 12-36 hours (as prednisolone) | 12-36 hours | 36-54 hours |

The Endocrine Society's 2015 Cushing's Syndrome Guideline and the FDA prescribing label for Korlym form the two primary documents anchoring this comparison.

Side Effects and Adverse Event Profile

The most common adverse effects reported during SEISMIC and post-marketing surveillance include:

• Nausea (48% in SEISMIC [1])
• Fatigue (48% [1])
• Headache (44% [1])
• Hypokalemia (34% [1])
• Arthralgia (30% [1])
• Peripheral edema (26% [1])
• Hypertension (24% [1])
• Endometrial thickening in females (asymptomatic in most cases but requires gynecologic surveillance)

Endometrial changes deserve specific mention. Mifepristone's anti-progesterone action prevents the normal progesterone-driven decidualization of the endometrium, leaving estrogen's proliferative effect unopposed. This can lead to endometrial hypertrophy and, rarely, hyperplasia. Annual pelvic ultrasound or endometrial biopsy is recommended for female patients on long-term Korlym. A 2015 study in the Journal of Clinical Endocrinology and Metabolism found endometrial thickening in 38% of female SEISMIC participants at 24 weeks.

Signs of adrenal insufficiency during Korlym therapy include severe fatigue, nausea, vomiting, hypotension, and hypoglycemia. These require immediate discontinuation and emergency glucocorticoid coverage. Patients should carry written instructions specifying dexamethasone 4 mg IM or IV as the emergency agent of choice.

Which Patients Are Best Suited for Korlym?

Adults with endogenous Cushing's syndrome who have failed transsphenoidal surgery, are not surgical candidates because of medical co-morbidity, or have ectopic ACTH syndrome without an identifiable resectable tumor are the core candidates for Korlym. Specific subgroups where Korlym may offer particular benefit include:

• Patients with significant type 2 diabetes or steroid-induced hyperglycemia where glucose control is the primary unmet need.
• Patients who cannot tolerate or have failed cortisol-synthesis inhibitors such as ketoconazole, metyrapone, or osilodrostat (Isturisa).
• Patients awaiting radiation treatment response, which may take 12 to 24 months to normalize cortisol.

Korlym is not appropriate for patients who require ongoing corticosteroid therapy for an independent condition (such as rheumatoid arthritis requiring prednisone), because mifepristone would block the therapeutic corticosteroid effect and produce glucocorticoid deficiency at the tissue level.

The Pituitary Society's 2021 consensus on medical management of Cushing's disease places mifepristone in the second-line category, after steroidogenesis inhibitors, largely because of its inability to monitor biochemical response via cortisol levels.

Drug Interactions That Clinicians Must Not Miss

Several interactions carry serious consequences:

• Simvastatin and lovastatin: Mifepristone sharply increases plasma exposure. Risk of myopathy and rhabdomyolysis rises substantially. Switch to pravastatin or rosuvastatin, which are not significantly metabolized by CYP3A.
• Warfarin: INR can rise dramatically within days of starting or dose-escalating Korlym. Check INR within one week of any change.
• CYP3A substrates with narrow therapeutic index: Cyclosporine, tacrolimus, sirolimus, fentanyl, and certain antiarrhythmics may reach toxic concentrations.
• QT-prolonging drugs: Mifepristone itself prolongs the QT interval. Concurrent use of other QT-prolonging agents (sotalol, amiodarone, haloperidol, azithromycin) requires careful cardiac monitoring or avoidance.

The NIH's Drug Interaction Database at NLM provides a broader reference for glucocorticoid receptor-modulating drug interactions.

Practical Prescribing Notes for Telehealth and Outpatient Settings

Korlym is a specialty pharmacy product and requires REMS enrollment. Prescribers must complete FDA REMS training before writing an initial prescription. The drug is dispensed exclusively through a limited distribution network. This differs from prednisone or hydrocortisone, which are available at any pharmacy without REMS requirements.

Baseline labs before starting Korlym should include fasting glucose, HbA1c, complete metabolic panel, serum potassium, urinary free cortisol (for documentation, not for monitoring response), and pregnancy test in eligible females. Follow-up labs at four to eight weeks should repeat potassium and glucose; HbA1c is meaningful after three months of stable dosing.

Patients frequently ask whether they should stop Korlym before procedures requiring anesthetic steroids. The answer is nuanced. Elective procedures that require stress-dose hydrocortisone present a management challenge because mifepristone will blunt hydrocortisone's effect. An endocrinologist should be consulted to determine whether Korlym should be paused 24 to 72 hours before surgery, replacing it temporarily with a higher-than-usual stress dose of dexamethasone given the partial receptor override at high concentrations.

Per the Endocrine Society 2015 Cushing's guidelines: "We suggest that all patients with active Cushing's syndrome who are to undergo surgery have an experienced anesthesiology team involved in peri-operative management, with plans for possible adrenal insufficiency."