PATIENT SITE

Important Prescribing Considerations

Cortisol levels1

  • Korlym does not reduce cortisol or ACTH levels. In fact, 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
  • Cortisol levels cannot be used to guide dosing decisions

Pregnancy1

  • Because Korlym is a potent antagonist of progesterone, treatment with Korlym will result in termination of pregnancy
  • Pregnancy must be prevented during treatment with Korlym and for up to 1 month after stopping treatment
  • Serum pregnancy tests should be ordered and reviewed with female patients who are of reproductive potential
    • Before starting Korlym
    • If Korlym is to be restarted after an interruption of more than 14 days

CYP3A41

  • Drug metabolism via the cytochrome P450 system is an important determinant of many drug interactions, which can result in drug toxicities, reduced pharmacologic effects, and adverse drug reactions
  • The CYP3A4 enzyme metabolizes mifepristone, as well as several other commonly used drugs
  • Concurrent use of a drug metabolized by CYP3A4 with mifepristone may cause increased plasma concentrations of that drug
    • Discontinuation or dose reduction may be necessary with Korlym coadministration

Clinical assessment of drug interactions

Summary Table of Korlym Drug-Drug Interaction Effects

Dosing of Mifepristone Coadministered Drug Dosing of Coadministered Drug Geometric Mean Ratio (analyte ratio with/without drug coadministration)
Analyte AUC Cmax
Effect of Korlym on Coadministered Drug
Contraindicated with mifepristone
1200 mg once daily for 10 days simvastatin 80 mg single dose simvastatin acid simvastatin 15.70

10.40
18.20

7.02
Use lowest dose of coadministered drug, based on clinical experience and/or use of therapeutic drug monitoring
1200 mg once daily for 10 days alprazolam 1 mg single dose alprazolam 4-hydroxy-alprazolam 1.80
0.76
0.81
0.39
1200 mg once daily for 7 days fluvastatin§ 40 mg single dose fluvastatin 3.57 1.76
1200 mg once daily for 10 days digoxin 0.125 mg once daily digoxin 1.40 1.64
Effect of Coadministered Drug on Korlym
No dosing adjustment required
300 mg once daily for 14 days cimetidine 800 mg once daily mifepristone 0.85# 0.75
Simvastatin 40 mg dose used as reference for the comparison. Result could be representative of other oral drugs with CYP3A metabolism and high first pass effect: cyclosporine, midazolam, triazolam, pimozide, sildenafil, sirolimus, and tacrolimus
Result could be representative of other oral drugs with CYP3A metabolism and low first pass effect. Clinical significance of any interaction will depend on the therapeutic margin of the drug
§ Result could be representative of other oral drugs with CYP2C8/C9 metabolism
Plasma digoxin concentration should be measured after 1 to 2 weeks of concomitant use and following usual clinical practice at appropriate intervals thereafter
Result could be representative of other mild inhibitors of CYP3A
# No effect = 90% CI within range 0.80 1.25

Effects of other drugs1

Medications that inhibit CYP3A could increase plasma mifepristone concentrations, and dose reduction of Korlym may be required.

  • 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 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.

Monitoring for adrenal insufficiency in patients taking Korlym1

  • Because serum cortisol levels are not decreased during treatment with Korlym, serum cortisol levels do not provide an accurate assessment of adrenal insufficiency
  • Patients on Korlym should be monitored for signs and symptoms of adrenal insufficiency, including:
    • Weakness, nausea, increased fatigue, hypotension, hypoglycemia

Treatment of adrenal insufficiency in patients taking Korlym1,2

  • If adrenal insufficiency is suspected, discontinue Korlym treatment1
  • Administer glucocorticoids without delay1
  • High doses of glucocorticoids may be needed to overcome glucocorticoid receptor blockade1
    • Factors considered in deciding on the duration of glucocorticoid treatment should include the long half-life of Korlym (85 hours)2

Hypokalemia1

  • Low potassium levels are common in Cushing's syndrome and should be normalized before Korlym treatment begins
  • Serum potassium levels should be measured 1 to 2 weeks after starting Korlym treatment and periodically thereafter
  • If hypokalemia occurs during Korlym treatment, it should be treated with oral or IV potassium supplementation. If hypokalemia persists, consider adding mineralocorticoid antagonist therapy

Endometrial effects1

  • Korlym is a progesterone receptor antagonist that may cause endometrium hypertrophy and unexplained vaginal bleeding
  • Korlym is contraindicated in women with unexplained vaginal bleeding and women with endometrial hyperplasia with atypia or endometrial carcinoma
  • Use with caution in women with hemorrhagic disorders or who are receiving concurrent anticoagulant therapy
  • Women who experience unexpected vaginal bleeding during treatment with Korlym should see a gynecologist

Concomitant corticosteroid therapy1

  • Korlym is contraindicated in patients who require concomitant corticosteroid therapy

Please see full Prescribing Information, including Boxed Warning.

To report suspected adverse reactions, contact Corcept Therapeutics at 1-855-844-3270 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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

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

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.