Important Prescribing Considerations

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Important safety considerations when prescribing Korlym®

Korlym is contraindicated in the following circumstances1:

  • Pregnancy
  • Drugs metabolized by CYP3A
  • Corticosteroid therapy required for lifesaving purposes
  • Women with a risk of vaginal bleeding or endometrial changes
  • Known hypersensitivity to mifepristone

Pregnancy1

  • Because Korlym is a potent antagonist of progesterone, treatment with Korlym will result in termination of pregnancy
  • Serum pregnancy tests should be ordered, found to be negative, 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
  • Pregnancy must be prevented during treatment with Korlym and for up to 1 month after stopping treatment
  • Recommend non-hormonal contraception for the duration of treatment and for one month after stopping treatment
    • Korlym interferes with the effectiveness of hormonal contraceptives

Concomitant administration with CYP3A inhibitors1

  • 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 900 mg, and strong inhibitors of CYP3A should be used 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 900 mg
  • Administration of strong CYP3A inhibitors to patients already being treated with Korlym:
    • Adjust the dose of Korlym according to the table below
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 mg No change
600 mg Reduce dose to 300 mg. If clinically indicated, titrate to a maximum of 600 mg
900 mg Reduce dose to 600 mg. If clinically indicated, titrate to a maximum of 900 mg
1200 mg Reduce dose to 900 mg

Drug-drug interactions1

  • 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 the Dosage and Administration section of the Prescribing Information. Use only when necessary, and do not exceed a Korlym dose of 900 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
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
900 mg
once daily for
14 days		 itraconazole 200 mg daily for 14 days mifepristone
Metabolite 1†
Metabolite 2†
Metabolite 3†		 1.10
1.04
1.23
0.97		 1.20
1.00
1.19
0.94
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 3 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.

Concomitant corticosteroid therapy1

  • Korlym is contraindicated in patients who require concomitant corticosteroid therapy for lifesaving purposes

Vaginal bleeding and endometrial hypertrophy1

  • May occur as a result of Korlym antagonism at the progesterone receptor
  • 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

Adrenal insufficiency

Monitoring1
  • 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 closely monitored for signs and symptoms of adrenal insufficiency, including:
    • Weakness, nausea, increased fatigue, hypotension, hypoglycemia
Treatment1,2
  • 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)1,2

Hypokalemia1

Monitoring
  • Low potassium levels are common in Cushing syndrome and should be normalized before Korlym treatment begins
    • Hypokalemia was observed in 44% of patients in the Korlym phase 3 pivotal trial
  • Serum potassium levels should be measured 1 to 2 weeks after starting treatment with Korlym and periodically thereafter
Treatment
  • If hypokalemia occurs during Korlym treatment, it should be treated with oral or IV potassium supplementation. If hypokalemia persists, consider adding mineralocorticoid antagonist therapy (eg, spironolactone)

QT interval prolongation1

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

Nursing mothers1

  • Mifepristone is present in human milk, however, there are no data on the amount of mifepristone in human milk, the effects on the breastfed infant, or the effects on milk production during long term use of mifepristone. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Korlym and any potential adverse effects on the breastfed child from Korlym or from the underlying maternal condition

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

Symptoms of cortisol withdrawal1,3,4

  • Most commonly reported are nausea, fatigue, and headache
  • Typically occur early in the course of treatment (the first 2 weeks)
  • Reflect a Korlym-induced decrease in GR activation
  • Often subside over time as dose is escalated

Please see full Prescribing Information, including Boxed Warning.

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

CYP, cytochrome P450; IV, intravenous.

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References:

  1. Korlym [package insert]. Menlo Park, CA: Corcept Therapeutics Incorporated; November 2019.
  2. Data on file. Corcept Therapeutics Incorporated. Menlo Park, CA.
  3. Yuen KCJ, Williams G, Kushner H, Nguyen D. Association between mifepristone dose, efficacy, and tolerability in patients with Cushing syndrome. Endocr Pract. 2015;21(10):1087-1092.
  4. Fleseriu M, Biller BMK, Findling JW, Molitch ME, Schteingart DE, Gross C; for SEISMIC Study Investigators. Mifepristone, a glucocorticoid antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome. J Clin Endocrinol Metab. 2012;97(6):2039-2049.

Important Safety Information IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNING ON TERMINATION OF PREGNANCY.

BOXED 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

Obtain a negative pregnancy test prior to initiating treatment with Korlym in females of
reproductive potential, or if treatment is interrupted for more than 14 days.
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 900 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 dose to 300 mg. For patients receiving a daily dose of 900 mg, reduce dose to 600 mg.
For patients receiving a daily dose of 1200 mg, reduce dose to 900 mg. Titrate if clinically
indicated and do not exceed a Korlym dose of 900 mg in combination with a strong CYP3A
inhibitor.

CONTRAINDICATIONS

Pregnancy; patients taking simvastatin or lovastatin and CYP3A substrates with narrow
therapeutic ranges; patients receiving systemic corticosteroids for lifesaving purposes; women
with a history of unexplained vaginal bleeding or endometrial hyperplasia with atypia or
endometrial carcinoma; patients with known hypersensitivity to mifepristone or to any of the
product components.

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 900 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 900 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

Lactation: Mifepristone is present in human milk, however, there are no data on the amount of
mifepristone in human milk, the effects on the breastfed infant, or the effects on milk production
during long term use of mifepristone.

Please see accompanying full Prescribing Information and Medication Guide.

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.