PATIENT SITE

Determining the Effective Dose of Korlym for Your Patient

The recommended starting dose for Korlym is 300 mg once daily. Cortisol levels cannot be used to determine the dose of Korlym. Decisions about dose increases should be based on a clinical assessment of tolerability and degree of improvement in Cushing's syndrome manifestations, including changes in:

  • Glucose control
  • Antidiabetic medication requirements
  • Insulin levels
  • Psychiatric symptoms
  • Cushingoid appearance
  • Acne
  • Hirsutism
  • Striae
  • Body weight

The pivotal trial assessed a broad range of these symptoms. Individual patients showed varying degrees of improvement in these Cushing's syndrome manifestations.1 Because of the variability in clinical presentation and variability of response in this open-label trial, it is uncertain whether these changes could be ascribed to the effects of Korlym.2

Change in mean AUCinsulin in all patients not taking insulin

Chart Image

The data in the above chart includes patients in both the diabetes and hypertension cohorts.1

AUC = area under the concentration-time curve. ET = early termination.

Source: Fleseriu M, et al.1

Changes in weight and body composition1

By Week 24/ET in the modified intent-to-treat population (n=46), the median change in body weight was 5.7±7.4%

  • 24 patients lost ≥5% of their baseline weight (12 patients lost ≥10%)
  • Mean percent total body fat declined from 42.3% overall at baseline to 38.7% (a reduction of 3.6%)
  • Waist circumference decreased by 6.8±5.8 cm in women and by 8.4±5.9 cm in men

Changes in Cushingoid appearance1,2

Individual patients showed varying degrees of improvement in Cushingoid appearance assessments, including:

  • Moon facies
  • Plethora
  • Fat distribution
  • Acne
  • Hirsutism
  • Striae

Changes in mood and cognition

In patients with Cushing's syndrome and at least mild depression, depression was measured using the Beck Depression Inventory-II (BDI-II) scale. Median BDI-II scores improved in the modified intent-to-treat population (baseline 14.5, range 0-49; Week 24/ET 9.5, range 0-36).1

The BDI-II is a 21-question scale that measures the severity of depressive symptoms. Questions are answered on a scale of 0 (I don't feel sad) to 3 (I am so sad that I can't stand it).3,4

Cognition scores were measured by the Trail-Making Test (TMT) at Week 24/ET. There were improvements in both Trail A (a median decrease of 4 seconds) and Trail B (a median decrease of 12 seconds).1

The TMT comprises 2 parts that measure cognitive ability. Parts A and B are completed in succession. Part A requires the patient to draw a line connecting 25 numbers in numerical order. Part B requires the connection of 25 numbers and letters in sequential order.

1. Fleseriu M, Biller BM, Findling JW, Molitch ME, Schteingart DE, Gross C; on behalf of the SEISMIC Study Investigators. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing's syndrome. J Clin Endocrinol Metab. 2012;97(6):2039-2049.

2. Korlym full Prescribing Information. Corcept Therapeutics Incorporated; 2013.

3. Data on file, Corcept Therapeutics Incorporated. March 31, 2013.

4. Beck AT, Steer RA, Ball R, Ranieri W. Comparison of Beck Depression Inventories-IA and-II in psychiatric outpatients. J Pers Assess. 1996;67(3):588-597.

INDICATIONS AND USAGE

Korlym (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.

Important Limitations of Use

Korlym should not be used in the treatment of patients with type 2 diabetes unless it is secondary to Cushing's syndrome.

IMPORTANT SAFETY INFORMATION

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. Pregnancy must therefore be excluded before the initiation of treatment with Korlym and prevented during treatment and for one month after stopping treatment by the use of a non-hormonal medically acceptable method of contraception unless the patient has had a surgical sterilization, in which case no additional contraception is needed. Pregnancy must also be excluded if treatment is interrupted for more than 14 days in females of reproductive potential.

Contraindications

Korlym is contraindicated in women who are pregnant. Pregnancy must be excluded before the initiation of treatment with Korlym or if treatment is interrupted for more than 14 days in females of reproductive potential. Nonhormonal contraceptives should be used during and one month after stopping treatment in all women of reproductive potential.

Korlym is contraindicated in patients taking 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.

Korlym is contraindicated in patients who require concomitant treatment with systemic corticosteroids for serious medical conditions or illnesses (e.g., immunosuppression after organ transplantation) because Korlym antagonizes the effect of glucocorticoids.

Korlym is contraindicated in women with a history of unexplained vaginal bleeding and women with endometrial hyperplasia with atypia or endometrial carcinoma.

Korlym is contraindicated in patients with prior hypersensitivity reactions to mifepristone or to any of the product components.

Warnings and Precautions

Patients receiving mifepristone may experience adrenal insufficiency. Because serum cortisol levels remain elevated and may even increase during treatment with Korlym, serum cortisol levels do not provide an accurate assessment of hypoadrenalism in patients receiving Korlym. Patients should be closely monitored for signs and symptoms of adrenal insufficiency, including weakness, nausea, increased fatigue, hypotension, and hypoglycemia. If adrenal insufficiency is suspected, discontinue treatment with Korlym immediately and administer glucocorticoids without delay. High doses of supplemental glucocorticoids may be needed to overcome the glucocorticoid receptor blockade produced by mifepristone. Factors considered in deciding on the duration of glucocorticoid treatment should include the long half-life of mifepristone (85 hours). Treatment with Korlym at a lower dose can be resumed after resolution of adrenal insufficiency. Patients should also be evaluated for precipitating causes of hypoadrenalism (infection, trauma, etc.).

In a study of patients with Cushing's syndrome, hypokalemia was observed in 44% of subjects during treatment with Korlym. Hypokalemia should be corrected prior to initiating Korlym. During Korlym administration, serum potassium should be measured 1 to 2 weeks after starting or increasing the dose of Korlym and periodically thereafter. Hypokalemia can occur at any time during Korlym treatment. Mifepristone-induced hypokalemia should be treated with intravenous or oral potassium supplementation based on event severity. If hypokalemia persists in spite of potassium supplementation, consider adding mineralocorticoid antagonists.

Being an antagonist of the progesterone receptor, mifepristone promotes unopposed endometrial proliferation that may result in endometrium thickening, cystic dilatation of endometrial glands, and vaginal bleeding. Korlym should be used with caution in women who have hemorrhagic disorders or are receiving concurrent anticoagulant therapy. Women who experience vaginal bleeding during Korlym treatment should be referred to a gynecologist for further evaluation.

Mifepristone and its metabolites block IKr. Korlym prolongs the QTc interval in a dose-related manner. There is little or no experience with high exposure, concomitant dosing with other QT-prolonging drugs, or potassium channel variants resulting in a long QT interval. To minimize risk, the lowest effective dose should always be used.

Use of Korlym in patients who receive corticosteroids for other conditions (e.g., autoimmune disorders) may lead to exacerbation or deterioration of such conditions, as Korlym antagonizes the desired effects of glucocorticoid in these clinical settings. For medical conditions in which chronic corticosteroid therapy is life-saving (e.g., immunosuppression in organ transplantation), Korlym is contraindicated.

Korlym should be used with extreme caution in patients taking ketoconazole and other strong inhibitors of CYP3A, such as itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir, amprenavir, fosamprenavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, telithromycin, or voriconazole, as these could substantially increase the concentration of mifepristone in the blood. The benefit of concomitant use of these agents should be carefully weighed against the potential risks. Mifepristone should be used in combination with strong CYP3A inhibitors only when necessary, and in such cases the dose should be limited to 300 mg per day.

Patients with endogenous Cushing's syndrome are at risk for opportunistic infections such as Pneumocystis jiroveci pneumonia during Korlym treatment. Patients may present with respiratory distress shortly after initiation of Korlym. Appropriate diagnostic tests should be undertaken and treatment for Pneumocystis jiroveci should be considered.

Korlym does not reduce serum cortisol levels. Elevated cortisol levels may activate mineralocorticoid receptors which are also expressed in cardiac tissues. Caution should be used in patients with underlying heart conditions including heart failure and coronary vascular disease.

Adverse Reactions

The most frequently reported adverse reactions (reported in ≥20% of patients, regardless of relationship to Korlym) were nausea, fatigue, headache, decreased blood potassium, arthralgia, vomiting, peripheral edema, hypertension, dizziness, decreased appetite, and endometrial hypertrophy. Drug-related adverse events resulted in dose interruption or reduction in study drug in 40% of patients.

Please see full Prescribing Information and Medication Guide.