Dosing & Monitoring

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Administration of Korlym® requires careful and gradual titration and potassium monitoring1

Finding the right dose

  • The recommended starting dose of Korlym is 300 mg/day1
  • The dose may be increased by 300 mg (to a maximum of 1200 mg daily) every 2 to 4 weeks as needed. Dose should not exceed 20 mg/kg per day1
  • Decisions about dose increases should be based on a clinical assessment of tolerability and the degree of improvement in Cushing syndrome manifestations1

Doses at which FIRST improvements were observed in the Korlym phase 3 pivotal trial2*†:

Administering Korlym dosage

*Clinical response based on improvement in metabolic, physical, neurologic, and social assessments compared with baseline.2

Dosing considerations

  • Obtain a negative pregnancy test in females of reproductive potential prior to initiating treatment with Korlym or if treatment is interrupted for more than 14 days1
  • Administer once daily orally with a meal. Patients should swallow the tablet whole. Do not split, crush, or chew Korlym tablets1
  • Renal impairment: Do not exceed 600 mg once daily1
  • Mild-to-moderate hepatic impairment: Do not exceed 600 mg once daily. Do not use in severe hepatic impairment1
  • Concomitant use of Korlym with a strong CYP3A inhibitor resulted in a 38% increase in mean plasma concentration of mifepristone1
    • For patients already being treated with a strong CYP3A inhibitor, start with a Korlym dose of 300 mg/day and titrate to a maximum of 900 mg/day if clinically indicated1
    • 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 900 mg, reduce the daily dose to 600 mg. Titrate to a maximum of 900 mg per day if clinically indicated. For patients receiving a daily dose of 1200 mg, reduce the daily dose to 900 mg1
  • The number of serious adverse events (AEs) did not increase with dose increases over time2
  • The frequency of the 4 most commonly reported AEs (nausea, fatigue, headache, and hypokalemia) did not increase over time1,2

For additional information see AEs and Important Prescribing Considerations.

Determining the effective dose of Korlym for your patient

Evaluating patient response
  • To evaluate response in patients treated with Korlym, assess improvements in areas such as insulin sensitivity, weight loss, and mental status1
    • Improvements may be observed within the first 6 weeks of therapy
  • Measurement of serum cortisol levels is not an effective measure of response1
  • If adequate improvement is not observed, further dose increases should be considered1
Monitoring to help guide dose changes
Initial dose changes within the first 6 weeks of therapy Dose changes beyond 2 months of therapy
  • Check potassium levels approximately 2 weeks after the first dose and before and after each dose increase
  • Make alterations to antidiabetic medications (including insulin) as needed
  • Monitor blood pressure and adjust medications as needed
  • Monitor for improvement of psychiatric symptoms (depression) and glucose control (fasting plasma glucose)
  • Monitor for improvements in:
    • Glucose control (HbA1c)
    • Body weight/circumference
    • Cushingoid appearance (including acne, hirsutism, and striae)
 Important treatment considerations
MR overstimulation—suspected hypokalemia Excess GR antagonism—suspected adrenal insufficiency
How to manage it:
  • Monitor potassium levels1
  • Potassium supplementation, or the use of an MR antagonist, may be employed to normalize potassium levels1
  • Monitor blood pressure; if the patient is not hypotensive, the patient is unlikely to be suffering from adrenal insufficiency1,2
  • If the patient is found to be hypotensive, discontinue treatment with Korlym1
Background:
  • The enzyme 11β-HSD2, which normally protects the MR from cortisol stimulation, can be overwhelmed in states of cortisol excess1,2
  • Excess GR antagonism, which may be seen with Korlym therapy, is differentiated from adrenal insufficiency by high, rather than low, circulating levels of cortisol and normal functioning of the renin-angiotensin-aldosterone system (RAAS)2
  • Side effects such as fatigue, nausea, and headache may be attributable to the temporary effects of cortisol withdrawal. Effects of cortisol withdrawal typically occur early in treatment and are expected to subside over time as dose is escalated2

CYP, cytochrome P450.

†Study design: SEISMIC (Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing’s Syndrome) was a phase 3, uncontrolled, open-label, 24-week, multicenter clinical study of 50 subjects with endogenous Cushing syndrome. All 50 subjects had clinically significant hypercortisolism. Subjects received 300 mg to 1200 mg of Korlym per day for up to 24 weeks. Forty-three patients had Cushing disease, of which 42 had previously undergone pituitary surgery. Four patients had ectopic adrenocorticotropic hormone (ACTH) secretion, and 3 had adrenal carcinoma. Forty-six subjects received at least 30 days of dosing during the 24-week study period and were included in a modified intent-to-treat analysis.

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.