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

Concomitant Administration with CYP3A Inhibitors

Ketoconazole and other strong inhibitors of CYP3A, such as itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir, amprenavir and fosamprenavir, clarithromycin, conivaptan, lopinavir/ritonavir, posaconazole, saquinavir, telithromycin, or voriconazole may increase exposure to mifepristone. KORLYM should be used in combination with strong CYP3A inhibitors only when necessary.

Administration of KORLYM to patients already being treated with strong CYP3A inhibitors:

  • Start at a dose of 300 mg. If clinically indicated, titrate to a maximum of 600 mg.

Administration of strong CYP3A inhibitors to patients already being treated with KORLYM:

  • Adjust the dose of KORLYM according to Table 1.

Table 1. Dose adjustment of KORLYM when strong CYP3A inhibitor is added

Current dose of KORLYM Adjustment to dose of KORLYM
if adding a strong CYP3A inhibitor
300 mgNo change
600 mgReduce dose to 300 mg. If clinically indicated, titrate to a maximum of 600 mg
900 mgReduce dose to 600 mg
1200 mgReduce dose to 600 mg

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 simvastatin1 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 alprazolam2 1 mg single dose alprazolam 4-hydroxy-alprazolam 1.80
0.76
0.81
0.39
1200 mg once daily for 7 days fluvastatin3 40 mg single dose fluvastatin 3.57 1.76
1200 mg once daily for 10 days digoxin4 0.125 mg once daily digoxin 1.40 1.64
Effect of Coadministered Drug on KORLYM
Dose adjustment required
600 mg once daily for 17 days ketoconazole 200 mg bid on days 13-17 mifepristone
Metabolite 1†
Metabolite 2†
Metabolite 3†
1.38
1.02
1.67
0.95
1.28
1.06
1.69
0.96
Effect of Coadministered Drug on Korlym
No dosing adjustment required
300 mg once daily for 14 days cimetidine5 800 mg once daily mifepristone 0.85* 0.75
* No effect = 90% CI within range 0.80 – 1.25
Because mifepristone acts at the receptor level to block the effects of cortisol, its antagonistic actions affect the hypothalamic-pituitary-adrenal (HPA) axis in such a way as to further increase circulating cortisol levels while, at the same time, blocking their effects.

Mifepristone and the three active metabolites have greater affinity for the glucocorticoid receptor [100% (mifepristone), 61% (metabolite 1), 48% (metabolite 2), and 45% (metabolite 3)]) than either dexamethasone (23%) or cortisol (9%).

1 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
2 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
3 Result could be representative of other oral drugs with CYP2C8/C9 metabolism
4 Plasma digoxin concentration should be measured after 1 to 2 weeks of concomitant use and following usual clinical practice at appropriate intervals thereafter
5 Result could be representative of other mild inhibitors of CYP3A

Effects of other drugs1

CYP3A Inhibitors

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

Ketoconazole and other strong inhibitors of CYP3A, such as itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir, amprenavir and fosamprenavir, clarithromycin, conivaptan, lopinavir/ritonavir, posaconazole, saquinavir, telithromycin, or voriconazole may increase exposure to mifepristone. Caution should be used when strong CYP3A inhibitors are prescribed in combination with KORLYM. The benefit of concomitant use of these agents should be carefully weighed against the potential risks. The dose of KORLYM should be limited to 600 mg, and strong inhibitors of CYP3A should be used only when necessary.

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; May 2017.

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

Do not use for the treatment of type 2 diabetes mellitus unrelated to endogenous 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 nonhormonal 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.

DOSAGE AND ADMINISTRATION

Administer once daily orally with a meal. The recommended starting dose is 300 mg once daily. Renal impairment: Do not exceed 600 mg once daily. Mild-to-moderate hepatic impairment: Do not exceed 600 mg once daily. Do not use in severe hepatic impairment. Based on clinical response and tolerability, the dose may be increased in 300-mg increments to a maximum of 1200 mg once daily. Do not exceed 20 mg/kg per day.

Concomitant use of Korlym with a strong CYP3A inhibitor resulted in a 38% increase in mean plasma concentration of mifepristone. For patients already being treated with a strong CYP3A inhibitor, start with a Korlym dose of 300 mg per day and titrate to a maximum of 600 mg per day if clinically indicated. When a strong CYP3A inhibitor is administered to patients already receiving Korlym, adjust the dose as follows: For patients receiving a daily dose of 600 mg, reduce the daily dose to 300 mg. Titrate to a maximum of 600 mg per day if clinically indicated. For patients receiving a daily dose of either 900 mg or 1200 mg, reduce the daily dose to 600 mg.

CONTRAINDICATIONS

Pregnancy; use of simvastatin or lovastatin and CYP3A substrates with narrow therapeutic range; concurrent long-term corticosteroid use; women with history of unexplained vaginal bleeding; women with endometrial hyperplasia with atypia or endometrial carcinoma.

WARNINGS AND PRECAUTIONS

Adrenal insufficiency: Patients should be closely monitored for signs and symptoms of adrenal insufficiency.

Hypokalemia: Hypokalemia should be corrected prior to treatment and monitored for during treatment.

Vaginal bleeding and endometrial changes: Women may experience endometrial thickening or unexpected vaginal bleeding. Use with caution if the patient also has a hemorrhagic disorder or is on anticoagulant therapy.

QT interval prolongation: Avoid use with QT interval-prolonging drugs, or in patients with potassium channel variants resulting in a long QT interval.

Use of Strong CYP3A Inhibitors: Concomitant use increases mifepristone plasma levels. Adjust Korlym dose as described in Dosage and Administration. Use only when necessary and do not exceed a Korlym dose of 600 mg.

ADVERSE REACTIONS

Most common adverse reactions in Cushing's syndrome (≥20%): nausea, fatigue, headache, decreased blood potassium, arthralgia, vomiting, peripheral edema, hypertension, dizziness, decreased appetite, endometrial hypertrophy.

DRUG INTERACTIONS

Drugs metabolized by CYP3A: Administer drugs that are metabolized by CYP3A at the lowest dose when used with Korlym.

CYP3A inhibitors: Caution should be used when Korlym is used with strong CYP3A inhibitors. Adjust Korlym dose as described in Dosage and Administration. Use only when necessary, and do not exceed a Korlym dose of 600 mg.

CYP3A inducers: Do not use Korlym with CYP3A inducers.

Drugs metabolized by CYP2C8/2C9: Use the lowest dose of CYP2C8/2C9 substrates when used with Korlym.

Drugs metabolized by CYP2B6: Use of Korlym should be done with caution with bupropion and efavirenz.

Hormonal contraceptives: Do not use with Korlym.

USE IN SPECIFIC POPULATIONS

Nursing mothers: Discontinue drug or discontinue nursing.

Please see accompanying full Prescribing Information and Medication Guide.