` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
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`KORLYM® safely and effectively. See full prescribing information
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`for KORLYM® .
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`KORLYM® (mifepristone) 300 mg Tablets Initial U.S. Approval 2000
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`WARNING: TERMINATION OF PREGNANCY
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`See full prescribing information for complete boxed warning.
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`Mifepristone has potent antiprogestational effects and will result in the
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`termination of pregnancy. Pregnancy must therefore be excluded before
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`the initiation of treatment with KORLYM, or if treatment is interrupted
`for more than 14 days in females of reproductive potential.
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`--------------------------INDICATIONS AND USAGE----------------------------­
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`KORLYM (mifepristone) is a cortisol receptor blocker indicated to control
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`hyperglycemia secondary to hypercortisolism in adult patients with
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`endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose
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`intolerance and have failed surgery or are not candidates for surgery (1).
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`--------------------DOSAGE AND ADMINISTRATION-------------------------­
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`Administer once daily orally with a meal (2).
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`•
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`The recommended starting dose is 300 mg once daily (2).
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`•
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`Renal impairment: do not exceed 600 mg once daily.
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`•
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`• Mild-to-moderate hepatic impairment: do not exceed 600 mg once
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`daily. Do not use in severe hepatic impairment.
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`• Women with endometrial hyperplasia with atypia or endometrial carcinoma
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`(4.4)
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`----------------------WARNINGS AND PRECAUTIONS------------------------­
`• Adrenal insufficiency: Patients should be closely monitored for signs and
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`symptoms of adrenal insufficiency (5.1).
`• Hypokalemia: Hypokalemia should be corrected prior to treatment and
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`monitored for during treatment (5.2).
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`• Vaginal bleeding and endometrial changes: Women may experience
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`endometrial thickening or unexpected vaginal bleeding. Use with caution if
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`patient also has a hemorrhagic disorder or is on anti-coagulant therapy (5.3).
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`• QT interval prolongation: Avoid use with QT interval-prolonging drugs, or
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`in patients with potassium channel variants resulting in a long QT interval
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`(5.4).
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`• Use of Strong CYP3A Inhibitors: Concomitant use can increase
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`mifepristone plasma levels significantly. Use only when necessary and
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`limit mifepristone dose to 300 mg (5.6).
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`•
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`Important Limitations of Use: Do not use for the treatment of
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`type 2 diabetes mellitus unrelated to endogenous Cushing’s
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`syndrome.
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`-----------------------------ADVERSE REACTIONS-------------------------------­
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`Most common adverse reactions in Cushing’s syndrome (≥ 20%): nausea,
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`fatigue, headache, decreased blood potassium, arthralgia, vomiting, peripheral
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`edema, hypertension, dizziness, decreased appetite, endometrial hypertrophy
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`(6).
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`To report suspected adverse reactions, contact Corcept Therapeutics at
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`1-855-844-3270 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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`------------------------------DRUG INTERACTIONS------------------------------­
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`• Drugs metabolized by CYP3A: Administer drugs that are metabolized by
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`CYP3A at the lowest dose when used with KORLYM (7.1).
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`• CYP3A inhibitors: Caution should be used when KORLYM is used with
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`strong CYP3A inhibitors. Limit mifepristone dose to 300 mg per day when
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`used with strong CYP3A inhibitors (5.6, 7.2).
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`• CYP3A inducers: Do not use KORLYM with CYP3A inducers (7.3).
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`Based on clinical response and tolerability, the dose may be increased in
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`• Drugs metabolized by CYP2C8/2C9: Use the lowest dose of CYP2C8/2C9
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`300 mg increments to a maximum of 1200 mg once daily. Do not exceed
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`substrates when used with KORLYM (7.4).
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`20 mg/kg per day (2).
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`• Drugs metabolized by CYP2B6: Use of KORLYM should be done with
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`caution with bupropion and efavirenz (7.5).
`-----------------------DOSAGE FORMS AND STRENGTHS-------------------­
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`• Hormonal contraceptives: Do not use with KORLYM (7.6).
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`Tablets: 300 mg (3)
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`-----------------------USE IN SPECIFIC POPULATIONS-----------------------­
`-------------------------------CONTRAINDICATIONS-----------------------------­
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`• Nursing mothers: Discontinue drug or discontinue nursing (8.3).
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`• Pregnancy (4.1, 8.1)
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`• Use of simvastatin or lovastatin and CYP3A substrates with narrow
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`See 17 for PATIENT COUNSELING INFORMATION and Medication
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`therapeutic range (4.2)
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`Guide.
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`• Concurrent long-term corticosteroid use (4.3)
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`• Women with history of unexplained vaginal bleeding (4.4)
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`Revised: 10/2016
`_____________________________________________________________________________
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`Reference ID: 4003895
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` 1
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`

`

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` FULL PRESCRIBING INFORMATION: CONTENTS*
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` WARNING: TERMINATION OF
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` PREGNANCY
` 7 DRUG INTERACTIONS
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` 1 INDICATIONS AND USAGE
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` 7.1 Drugs Metabolized by CYP3A
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` 2 DOSAGE AND ADMINISTRATION
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` 7.2 CYP3A Inhibitors
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` 2.1 Adult Dosage
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` 7.3 CYP3A Inducers
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` 2.2 Dosing in Renal Impairment
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` 7.4 Drugs Metabolized by CYP2C8/2C9
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` 2.3 Dosing in Hepatic Impairment
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` 7.5 Drugs Metabolized by CYP2B6
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` 3 DOSAGE FORMS AND STRENGTHS
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` 7.6 Use of Hormonal Contraceptives
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` 4 CONTRAINDICATIONS
` 8 USE IN SPECIFIC POPULATIONS
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` 4.1 Pregnancy
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` 8.1 Pregnancy
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` 4.2 Drugs Metabolized by CYP3A
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` 8.3 Nursing Mothers
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` 4.3 Corticosteroid Therapy Required for
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` 8.4 Pediatric Use
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` Lifesaving Purposes
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` 8.5 Geriatric Use
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` 4.4 Women with Risk of Vaginal Bleeding or
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` 8.6 Renal Impairment
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` Endometrial Changes
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` 8.7 Hepatic Impairment
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` 4.5 Known Hypersensitivity to Mifepristone
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` 8.8 Females of Reproductive Potential
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` 5 WARNINGS AND PRECAUTIONS
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` 10 OVERDOSAGE
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` 5.1 Adrenal Insufficiency
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` 11 DESCRIPTION
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` 5.2 Hypokalemia
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` 12 CLINICAL PHARMACOLOGY
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` 5.3 Vaginal Bleeding and Endometrial
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` 12.1 Mechanism of Action
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` Changes
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` 12.2 Pharmacodynamics
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` 5.4 QT Interval Prolongation
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` 12.3 Pharmacokinetics
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` 5.5 Exacerbation/Deterioration of Conditions
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` 13 NONCLINICAL TOXICOLOGY
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` 13.1 Carcinogenesis, Mutagenesis,
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` Treated with Corticosteroids
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` Impairment of Fertility
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` 5.6 Use of Strong CYP3A Inhibitors
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` 5.7 Pneumocystis jiroveci Infection
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` 14 CLINICAL STUDIES
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` 14.1 Cushing’s Syndrome
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` 5.8 Potential Effects of Hypercortisolemia
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` 16 HOW SUPPLIED/STORAGE AND
` 6 ADVERSE REACTIONS
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` HANDLING
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` 6.1 Clinical Trials Experience
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` 17 PATIENT COUNSELING
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` 6.2 Postmarketing Experience
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` INFORMATION
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` 17.1 Importance of Preventing Pregnancy
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` 17.3 FDA-Approved Medication Guide
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` * Sections or subsections omitted from the full
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`prescribing information are not listed.
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`__________________________________________________________________
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`Reference ID: 4003895
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` 2
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`

`

`
` FULL PRESCRIBING INFORMATION
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`
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` WARNING: TERMINATION OF PREGNANCY
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`Mifepristone is a potent antagonist of progesterone and cortisol via the progesterone and
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`glucocorticoid (GR-II) receptors, respectively. The antiprogestational effects will result in the
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` termination of pregnancy. Pregnancy must therefore be excluded before the initiation of treatment
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`with KORLYM and prevented during treatment and for one month after stopping treatment by the
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`use of a non-hormonal medically acceptable method of contraception unless the patient has had a
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`surgical sterilization, in which case no additional contraception is needed. Pregnancy must also be
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`excluded if treatment is interrupted for more than 14 days in females of reproductive potential.
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`1 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
`
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`mellitus or glucose intolerance and have failed surgery or are not candidates for surgery.
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`LIMITATIONS OF USE:
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`• KORLYM should not be used in the treatment of patients with type 2 diabetes unless it is
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`secondary to Cushing’s syndrome.
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`2 DOSAGE AND ADMINISTRATION
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`2.1 Adult Dosage
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`The recommended starting dose is 300 mg orally once daily. KORLYM must be given as a single daily
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`dose. KORLYM should always be taken with a meal. Patients should swallow the tablet whole. Do not
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`split, crush, or chew tablets.
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`Dosing and titration
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`The daily dose of KORLYM may be increased in 300 mg increments. The dose of KORLYM may be
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`increased to a maximum of 1200 mg once daily but should not exceed 20 mg/kg per day. Increases in
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`dose should not occur more frequently than once every 2-4 weeks. Decisions about dose increases should
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`be based on a clinical assessment of tolerability and degree of improvement in Cushing’s syndrome
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`manifestations. Changes in glucose control, anti-diabetic medication requirements, insulin levels, and
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`psychiatric symptoms may provide an early assessment of response (within 6 weeks) and may help guide
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`early dose titration. Improvements in cushingoid appearance, acne, hirsutism, striae, and body weight
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`occur over a longer period of time and, along with measures of glucose control, may be used to determine
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`dose changes beyond the first 2 months of therapy. Careful and gradual titration of KORLYM
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`accompanied by monitoring for recognized adverse reactions (See Warnings and Precautions 5.1 and 5.2)
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`may reduce the risk of severe adverse reactions. Dose reduction or even dose discontinuation may be
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`needed in some clinical situations. If KORLYM treatment is interrupted, it should be reinitiated at the
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`lowest dose (300 mg). If treatment was interrupted because of adverse reactions, the titration should aim
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`for a dose lower than the one that resulted in treatment interruption.
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`Reference ID: 4003895
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` 3
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`

`

`2.2 Dosing in Renal Impairment
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`No change in initial dose of KORLYM is required in renal impairment. The maximum dose should be
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`limited to 600 mg. [See Renal Impairment (8.6) and Clinical Pharmacology (12.3)]
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`2.3 Dosing in Hepatic Impairment
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`No change in the initial dose of KORLYM is required in mild to moderate hepatic impairment. The
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`maximum dose should be limited to 600 mg. KORLYM should not be used in severe hepatic impairment.
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`[See Hepatic Impairment (8.7) and Clinical Pharmacology (12.3)]
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`3 DOSAGE FORMS AND STRENGTHS
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`Tablets: 300 mg
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`Oval shaped, light yellow to yellow tablets debossed with “Corcept” on one side and “300” on the other
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`side. The tablets are not scored.
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`4 CONTRAINDICATIONS
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`4.1 Pregnancy
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`KORLYM is contraindicated in women who are pregnant. Pregnancy must be excluded before the
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`initiation of treatment with KORLYM or if treatment is interrupted for more than 14 days in females of
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`reproductive potential. Non-hormonal contraceptives should be used during and one month after stopping
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`treatment in all women of reproductive potential. [See Use in Specific Populations 8.8]
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`4.2 Drugs Metabolized by CYP3A
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`KORLYM is contraindicated in patients taking simvastatin, lovastatin, and CYP3A substrates with
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`narrow therapeutic ranges, such as cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide,
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`quinidine, sirolimus, and tacrolimus, due to an increased risk of adverse events. [See Drug Interactions
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`(7.1) and Clinical Pharmacology (12.3)]
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`4.3 Corticosteroid Therapy Required for Lifesaving Purposes
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`KORLYM is contraindicated in patients who require concomitant treatment with systemic corticosteroids
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`for serious medical conditions or illnesses (e.g., immunosuppression after organ transplantation) because
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`KORLYM antagonizes the effect of glucocorticoids.
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`4.4 Women with Risk of Vaginal Bleeding or Endometrial Changes
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`KORLYM is contraindicated in the following:
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`• Women with a history of unexplained vaginal bleeding
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`
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`• Women with endometrial hyperplasia with atypia or endometrial carcinoma
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`4.5 Known Hypersensitivity to Mifepristone
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`KORLYM is contraindicated in patients with prior hypersensitivity reactions to mifepristone or to any of
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`the product components.
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` 4
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`Reference ID: 4003895
`
`

`

`
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` 5 WARNINGS AND PRECAUTIONS
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` 5.1 Adrenal Insufficiency
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` Patients receiving mifepristone may experience adrenal insufficiency. Because serum cortisol levels
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` remain elevated and may even increase during treatment with KORLYM, serum cortisol levels do not
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` provide an accurate assessment of hypoadrenalism in patients receiving KORLYM. Patients should be
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` closely monitored for signs and symptoms of adrenal insufficiency, including weakness, nausea,
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` increased fatigue, hypotension, and hypoglycemia. If adrenal insufficiency is suspected, discontinue
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` treatment with KORLYM immediately and administer glucocorticoids without delay. High doses of
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`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
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`include the long half-life of mifepristone (85 hours).
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`Treatment with KORLYM at a lower dose can be resumed after resolution of adrenal insufficiency.
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`Patients should also be evaluated for precipitating causes of hypoadrenalism (infection, trauma, etc.).
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`5.2 Hypokalemia
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`In a study of patients with Cushing’s syndrome, hypokalemia was observed in 44% of subjects during
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`treatment with KORLYM. Hypokalemia should be corrected prior to initiating KORLYM. During
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`KORLYM administration, serum potassium should be measured 1 to 2 weeks after starting or increasing
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`the dose of KORLYM and periodically thereafter. Hypokalemia can occur at any time during KORLYM
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`treatment. Mifepristone-induced hypokalemia should be treated with intravenous or oral potassium
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`supplementation based on event severity. If hypokalemia persists in spite of potassium supplementation,
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`consider adding mineralocorticoid antagonists.
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`5.3 Vaginal Bleeding and Endometrial Changes
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`Being an antagonist of the progesterone receptor, mifepristone promotes unopposed endometrial
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`proliferation that may result in endometrium thickening, cystic dilatation of endometrial glands, and
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`vaginal bleeding. KORLYM should be used with caution in women who have hemorrhagic disorders or
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`are receiving concurrent anticoagulant therapy. Women who experience vaginal bleeding during
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`KORLYM treatment should be referred to a gynecologist for further evaluation.
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`5.4 QT Interval Prolongation
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`Mifepristone and its metabolites block IKr. KORLYM prolongs the QTc interval in a dose-related
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`manner. There is little or no experience with high exposure, concomitant dosing with other QT-
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`prolonging drugs, or potassium channel variants resulting in a long QT interval. [See Warnings &
`
`
`
`Precautions (5.6)] To minimize risk, the lowest effective dose should always be used.
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`5.5 Exacerbation/Deterioration of Conditions Treated with Corticosteroids
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`Use of KORLYM in patients who receive corticosteroids for other conditions (e.g., autoimmune
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`disorders) may lead to exacerbation or deterioration of such conditions, as KORLYM antagonizes the
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`desired effects of glucocorticoid in these clinical settings. For medical conditions in which chronic
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`corticosteroid therapy is lifesaving (e.g., immunosuppression in organ transplantation), KORLYM is
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`contraindicated. [See Contraindications (4.3)]
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`Reference ID: 4003895
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`
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`
`
` 5
`
`

`

` 5.6 Use of Strong CYP3A Inhibitors
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`
`
`
`
`
` 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,
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`telaprevir, telithromycin, or voriconazole, as these could substantially increase the concentration of
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`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
`
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`only when necessary, and in such cases the dose should be limited to 300 mg per day. [See Warnings &
`
`
`
`Precautions (5.4), Drug Interactions (7.2), and Clinical Pharmacology (12.3)]
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`
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`5.7 Pneumocystis jiroveci Infection
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`
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`Patients with endogenous Cushing’s syndrome are at risk for opportunistic infections such as
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`Pneumocystis jiroveci pneumonia during KORLYM treatment. Patients may present with respiratory
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`distress shortly after initiation of KORLYM. Appropriate diagnostic tests should be undertaken and
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`treatment for Pneumocystis jiroveci should be considered.
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`5.8 Potential Effects of Hypercortisolemia
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`KORLYM does not reduce serum cortisol levels. Elevated cortisol levels may activate mineralocorticoid
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`receptors which are also expressed in cardiac tissues. Caution should be used in patients with underlying
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`heart conditions including heart failure and coronary vascular disease.
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`6 ADVERSE REACTIONS
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`6.1 Clinical Trials Experience
`
`
`Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed
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`cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in
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`clinical practice.
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`Safety data on the use of KORLYM are available from 50 patients with Cushing’s syndrome enrolled in
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`an uncontrolled, open-label, multi-center trial (Study 400). Forty-three patients had Cushing’s disease and
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`all except one had previously undergone pituitary surgery. Four patients had ectopic ACTH secretion, and
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`three had adrenal carcinoma. Patients were treated for up to 24 weeks. A dose of 300 mg per day was
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`administered for the initial 14 days; thereafter, the dose could be escalated in increments of 300 mg per
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`day based on assessments of tolerability and clinical response. Doses were escalated up to 900 mg per day
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`for patients <60 kg, or 1200 mg per day for patients >60 kg.
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`The most frequently reported adverse reactions (reported in ≥20% of patients, regardless of relationship to
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`KORLYM) were nausea, fatigue, headache, decreased blood potassium, arthralgia, vomiting, peripheral
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`
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`edema, hypertension, dizziness, decreased appetite, and endometrial hypertrophy. Drug-related adverse
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`events resulted in dose interruption or reduction in study drug in 40% of patients.
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`The adverse reactions that occurred in ≥10% of the Cushing’s syndrome patients receiving KORLYM,
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`
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`regardless of relationship to KORLYM, are shown in Table 1.
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`Reference ID: 4003895
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` 6
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`

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`Table 1. Treatment Emergent Adverse Events Occurring in ≥10% of Cushing’s Syndrome Patients
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`Receiving KORLYM
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` Body System/Adverse Reaction
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` Percent (%) of
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` Patients Reporting
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` Event
` (n = 50)
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`Reference ID: 4003895
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` 7
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` 48
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` 26
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` 18
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` 12
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` 10
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` 48
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` 26
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` 14
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` 44
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` 22
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` 10
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` 30
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` 16
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` 14
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` 12
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` 34
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` 18
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` 14
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` 12
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` 20
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` 10
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` 24
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` 38*
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` 16
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` Gastrointestinal disorders
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` Nausea
` Vomiting
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` Dry mouth
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` Diarrhea
` Constipation
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` General disorders and administration/site conditions
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` Fatigue
` Edema peripheral
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` Pain
` Nervous system disorders
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` Headache
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` Dizziness
` Somnolence
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` Musculoskeletal and connective tissue disorders
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` Arthralgia
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` Back pain
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` Myalgia
` Pain in extremity
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` Investigations
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` Blood potassium decreased
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` Thyroid function test abnormal
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` Infections and infestations
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` Sinusitis
` Nasopharyngitis
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` Metabolism and nutrition disorders
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` Decreased appetite
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` Anorexia
` Vascular disorders
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` Hypertension
` Reproductive system and breast disorders
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` Endometrial hypertrophy
` Respiratory, thoracic, and mediastinal disorders
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` Dyspnea
` Psychiatric disorders
` 10
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` Anxiety
` *The denominator was 26 females who had baseline and end-of-trial transvaginal ultrasound
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`Laboratory Tests
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`Reductions in high density lipoprotein-cholesterol (HDL-C) levels have been observed following
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`treatment with KORLYM. In study subjects that experienced declines in HDL-C, levels returned to
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`baseline following discontinuation of drug. The clinical significance of the treatment-related reduction in
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`HDL-C levels in patients with Cushing’s syndrome is not known.
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`In a study of patients with Cushing’s syndrome, hypokalemia was observed in 44% of subjects during
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`treatment with KORLYM. In these cases, hypokalemia responded to treatment with potassium
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`supplementation and/or mineralocorticoid antagonist therapy (e.g., spironolactone or eplerenone).
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`Hypokalemia should be corrected prior to initiating KORLYM. [See Warnings and Precautions (5.2)]
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`Elevations of thyroid-stimulating hormone (TSH) were seen in subjects treated with KORLYM. Of the
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`42 subjects with detectable TSH at baseline, eight (19%) had increases in TSH above the normal range,
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`while remaining asymptomatic. The TSH levels returned to normal in most patients without intervention
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`when KORLYM was discontinued at the end of the study.
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`Vaginal Bleeding and Endometrial Changes
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`In Study 400, the thickness of the endometrium increased from a mean of 6.14 mm at baseline (n=23) to
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`15.7 mm at end-of-trial (n=18) in premenopausal women; in postmenopausal women the increase was
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`from 2.75 mm (n=6) to 7.35 mm (n=8). Endometrial thickness above the upper limit of normal was
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`reported in 10/26 females who had baseline and end-of-trial transvaginal ultrasound (38%). The
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`endometrial thickness returned to the normal range in 3 out of 10 patients 6 weeks after treatment
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`cessation at the end of the study. Vaginal bleeding occurred in 5 out of 35 females (14%). Two of five
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`subjects with vaginal bleeding had normal endometrial thickness. Endometrial biopsies were performed in
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`six patients; five of these patients had endometrial thickening. No endometrial carcinoma was detected in
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`the sampled cases.
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`Additional Data from Clinical Trials
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`The following are adverse events that were reported in Study 400 at frequencies of ≥ 5% to 10%, and may
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`be related to KORLYM’s mechanism of action:
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`Gastrointestinal disorders: gastroesophageal reflux, abdominal pain
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`General disorders and administration site conditions: asthenia, malaise, edema, pitting edema, thirst
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`Investigations: blood triglycerides increased
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`Metabolism and nutrition disorders: hypoglycemia
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`Musculoskeletal and connective tissue disorders: muscular weakness, flank pain, musculoskeletal chest
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`pain
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`Psychiatric disorders: insomnia
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`Reproductive system and breast disorders: vaginal hemorrhage, metrorrhagia [See Warnings and
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`Precautions (5.3)]
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`Adrenal Insufficiency
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`Adrenal insufficiency was reported in two subjects (4%) in Study 400. The most typical symptoms of
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`adrenal insufficiency were nausea and decreased appetite. No hypotension or hypoglycemia was reported
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`Reference ID: 4003895
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`during the events. Adrenal insufficiency resolved in both cases with KORLYM interruption and /or
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`dexamethasone administration.
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`Rash
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`Generalized, maculo-papular rash was reported in 2 subjects (4%) in Study 400. Two additional subjects
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`developed pruritus (4%). None resulted in discontinuation of KORLYM, and all the events resolved by
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`the end of the study.
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`6.2 Postmarketing Experience
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`The following adverse reaction has been identified during post-approval use of KORLYM. Because these
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`reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably
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`estimate their frequency or establish a causal relationship to drug exposure.
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`- Angioedema
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`7 DRUG INTERACTIONS
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`Based on the long terminal half-life of mifepristone after reaching steady state, at least 2 weeks should
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`elapse after cessation of KORLYM before initiating or increasing the dose of any interacting concomitant
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`medication.
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`7.1 Drugs Metabolized by CYP3A
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`Because KORLYM is an inhibitor of CYP3A, concurrent use of KORLYM with a drug whose
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`metabolism is largely or solely mediated by CYP3A is likely to result in increased plasma concentrations
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`of the drug. Discontinuation or dose reduction of such medications may be necessary with KORLYM co­
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`administration.
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`KORLYM increased the exposure to simvastatin and simvastatin acid significantly in healthy subjects.
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`Concomitant use of simvastatin or lovastatin is contraindicated because of the increased risk of myopathy
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`and rhabdomyolysis. [See Contraindications (4.2), Clinical Pharmacology 12.3]
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`The exposure of other substrates of CYP3A with narrow therapeutic ranges, such as cyclosporine,
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`dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus, may be
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`increased by concomitant administration with KORLYM. Therefore, the concomitant use of such CYP3A
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`substrates with KORLYM is contraindicated. [See Contraindications (4.2)]
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`Other drugs with similar high first pass metabolism in which CYP3A is the primary route of metabolism
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`should be used with extreme caution if co-administered with KORLYM. The lowest possible dose and/or
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`a decreased frequency of dosing must be used with therapeutic drug monitoring when possible. Use of
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`alternative drugs without these metabolic characteristics is advised when possible with concomitant
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`KORLYM.
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`If drugs that undergo low first pass metabolism by CYP3A or drugs in which CYP3A is not the major
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`metabolic route are co-administered with KORLYM, use the lowest dose of concomitant medication
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`necessary, with appropriate monitoring and follow-up. [See Clinical Pharmacology (12.3)]
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`Reference ID: 4003895
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`7.2 CYP3A Inhibitors
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`Medications that inhibit CYP3A could increase plasma mifepristone concentrations and dose reduction of
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`KORLYM may be required.
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`Ketoconazole and other strong inhibitors of CYP3A, such as itraconazole, nefazodone, ritonavir,
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`nelfinavir, indinavir, atazanavir, amprenavir and fosamprenavir, boceprevir, clarithromycin, conivaptan,
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`lopinavir, mibefradil, posaconazole, saquinavir, telaprevir, telithromycin, or voriconazole may increase
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`exposure to mifepristone significantly. The clinical impact of this interaction has not been studied.
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`Therefore, extreme caution should be used when these drugs are prescribed in combination with
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`KORLYM. The benefit of concomitant use of these agents should be carefully weighed against the
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`potential risks. The dose of KORLYM should be limited to 300 mg and used only when necessary. [See
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`Warnings & Precautions (5.6)]
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`Moderate inhibitors of CYP3A, such as amprenavir, aprepitant, atazanavir, ciprofloxacin,
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`darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, imatinib, or
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`verapamil, should be used with caution when administered in combination with KORLYM.
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`7.3 CYP3A Inducers
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`No medications that induce CYP3A have been studied when co-administered with KORLYM. Avoid co­
`administration of KORLYM and CYP3A inducers such as rifampin, rifabutin, rifapentin, phenobarbital,
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`phenytoin, carbamazepine, and St. John’s wort.
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`7.4 Drugs Metabolized by CYP2C8/2C9
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`Because KORLYM is an inhibitor of CYP2C8/2C9, concurrent use of KORLYM with a drug whose
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`metabolism is largely or solely mediated by CYP2C8/2C9 is likely to result in increased plasma
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`concentrations of the drug.
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`KORLYM significantly increased exposure of fluvastatin, a typical CYP2C8/2C9 substrate, in healthy
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`subjects. When given concomitantly with KORLYM, drugs that are substrates of CYP2C8/2C9
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`(including non-steroidal anti-inflammatory drugs, warfarin, and repaglinide) should be used at the
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`smallest recommended doses, and patients should be closely monitored for adverse effects. [See Clinical
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`Pharmacology (12.3)]
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`7.5 Drugs Metabolized by CYP2B6
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`Mifepristone is an inhibitor of CYP2B6 and may cause significant increases in exposure of drugs that are
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`metabolized by CYP2B6 such as bupropion and efavirenz. Since no study has been conducted to evaluate
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`the effect of mifepristone on substrates of CYP2B6, the concomitant use of bupropion and efavirenz
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`should be undertaken with caution. [See Clinical Pharmacology (12.3)]
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`7.6 Use of Hormonal Contraceptives
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`Mifepristone is a progesterone-receptor antagonist and will interfere with the effectiveness of hormonal
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`contraceptives. Therefore, non-hormonal contraceptive methods should be used.
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`Reference ID: 4003895
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` 10
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`8 USE IN SPECIFIC POPULATIONS
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`8.1 Pregnancy
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`Category X
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`KORLYM is contraindicated in pregnancy. KORLYM can cause fetal harm when administered to a
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`pregnant woman because the use of KORLYM results in pregnancy loss. The inhibition of both
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`endogenous and exogenous progesterone by mifepristone at the progesterone receptor results in
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`pregnancy loss. If KORLYM is used during pregnancy or if the patient becomes pregnant while taking
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`this drug, the patient should be apprised of the potential hazard to a fetus. [See Contraindications (4.1)]
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`Human Data
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`In a report of thirteen live births after single dose mifepristone exposure, no fetal abnormalities were
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`noted.
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`Animal Data
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`Teratology studies in mice, rats and rabbits at doses of 0.25 to 4.0 mg/kg (less than human exposure at the
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`maximum clinical dose, based on body surface area) were carried out. Because of the anti-progestational
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`activity of mifepristone, fetal losses were much higher than in control animals. Skull deformities were
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`detected in rabbit studies at less than human exposure, although no teratogenic effects of mifepristone
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`have been observed to date in rats or mice. These deformities were most likely due to the mechanical
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`effects of uterine contractions resulting from antagonism of the progesterone receptor.
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`8.3 Nursing Mothers
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`Mifepristone is present in human milk of women taking the drug. Because of the potential for serious
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`adverse reactions in nursing infants from KORLYM, a decision should be made whether to discontinue
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`nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
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`8.4 Pediatric Use
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`Safety and effectiveness of KORLYM in pediatric patients have not been established.
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`8.5 Geriatric Use
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`Clinical studies with KORLYM did not include sufficient numbers of patients aged 65 and over to
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`determine whether they respond differently than younger people.
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`8.6 Renal Impairment
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`The maximum dose should not exceed 600 mg per day in renally impaired patients. [See Clinical
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`Pharmacology (12.3)]
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`Reference ID: 4003895
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` 11
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` 8.7 Hepatic Impairment
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` In patients with mild to moderate hepatic imp