• Women with history of unexplained vaginal bleeding (4.4)
`
`
`
`
`• Women with endometrial hyperplasia with atypia or endometrial carcinoma
`
`
`
`
`(4.4)
`
`
`----------------------WARNINGS AND PRECAUTIONS------------------------­
`
`• Adrenal insufficiency: Patients should be closely monitored for signs and
`
`
`
`symptoms of adrenal insufficiency (5.1).
`
`
`• Hypokalemia: Hypokalemia should be corrected prior to treatment and
`
`
`
`
`monitored for during treatment (5.2).
`
`
`
`• Vaginal bleeding and endometrial changes: Women may experience
`
`
`endometrial thickening or unexpected vaginal bleeding. Use with caution if
`
`
`
`
`patient also has a hemorrhagic disorder or is on anti-coagulant therapy (5.3).
`
`
`
`
`
`• QT interval prolongation: Avoid use with QT interval-prolonging drugs, or
`
`
`
`
`
`
`in patients with potassium channel variants resulting in a long QT interval
`
`
`
`
`
`(5.4).
`
`• Use of Strong CYP3A Inhibitors: Concomitant use can increase
`
`
`
`
`mifepristone plasma levels. Use only when necessary and limit
`
`
`
`mifepristone dose to 600 mg (5.6).
`
`
`
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
`
`
`
` These highlights do not include all the information needed to use
`KORLYM® safely and effectively. See full prescribing information
`
`
`
`for KORLYM® .
`
`
`KORLYM® (mifepristone) 300 mg Tablets
`
`
`
`
`
`
`Initial U.S. Approval 2000
`
`
`WARNING: TERMINATION OF PREGNANCY
`
`
`
`
`
`
`See full prescribing information for complete boxed warning.
`
`
`
`
`
`Mifepristone has potent antiprogestational effects and will result in the
`
`
`
`
`
`
`termination of pregnancy. Pregnancy must therefore be excluded before
`
`
`the initiation of treatment with KORLYM, or if treatment is interrupted
`
`
`
`
`for more than 14 days in females of reproductive potential.
`
`
`
`
`
`
`
`
`
`
`--------------------------RECENT MAJOR CHANGES---------------------------­
`
`Dosage and Administration (2.4)
`05/2017
`
`
`
`Warnings and Precautions (5.6)
`05/2017
`
`
`
`
`
`--------------------------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 (1).
`
`
`
`
`
`•
`
`
`Important Limitations of Use: Do not use for the treatment of
`
`
`
`type 2 diabetes mellitus unrelated to endogenous Cushing’s
`
`
`
`
`syndrome.
`
`
`
`--------------------DOSAGE AND ADMINISTRATION-------------------------­
`Administer once daily orally with a meal (2.1).
`
`
`
`•
`
`The recommended starting dose is 300 mg once daily (2.1).
`
`
`
`
`
`
`•
`
`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 (2.1).
`
`
`
`
`
`Renal impairment: do not exceed 600 mg once daily (2.2).
`
`
`
`
`
`•
`
`• Mild-to-moderate hepatic impairment: do not exceed 600 mg once
`
`
`
`daily. Do not use in severe hepatic impairment (2.3).
`
`
`Concomitant administration with strong CYP3A inhibitors: Do not
`
`
`
`exceed 600 mg once daily (2.4).
`
`
`
`
`
`
`
`•
`
`
`
`
`
`-----------------------------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
`
`
`
`(6).
`
`
`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.
`
`
`
`
`------------------------------DRUG INTERACTIONS------------------------------­
`
`
`• Drugs metabolized by CYP3A: Administer drugs that are metabolized by
`
`
`
`
`CYP3A at the lowest dose when used with KORLYM (7.1).
`
`
`
`
`
`• CYP3A inhibitors: Caution should be used when KORLYM is used with
`
`
`
`
`
`
`
`strong CYP3A inhibitors. Limit mifepristone dose to 600 mg per day when
`
`
`used with strong CYP3A inhibitors (7.2).
`
`
`
`• CYP3A inducers: Do not use KORLYM with CYP3A inducers (7.3).
`
`
`
`
`
`
`• Drugs metabolized by CYP2C8/2C9: Use the lowest dose of CYP2C8/2C9
`
`
`
`
`
`substrates when used with KORLYM (7.4).
`
`
`
`• Drugs metabolized by CYP2B6: Use of KORLYM should be done with
`
`
`
`
`
`
`
`caution with bupropion and efavirenz (7.5).
`
`
`
`• Hormonal contraceptives: Do not use with KORLYM (7.6).
`
`
`
`
`
`
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------­
`
`• Nursing mothers: Discontinue drug or discontinue nursing (8.3).
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`
`Guide.
`
`
`
`
`-----------------------DOSAGE FORMS AND STRENGTHS-------------------­
`
`
`Tablets: 300 mg (3)
`
`
`
`-------------------------------CONTRAINDICATIONS-----------------------------­
`• Pregnancy (4.1, 8.1)
`
`
`
`
`• Use of simvastatin or lovastatin and CYP3A substrates with narrow
`
`
`
`
`
`therapeutic range (4.2)
`
`• Concurrent long-term corticosteroid use (4.3)
`
`
`
`
`_____________________________________________________________________________
`
`
`
`
`
`
`
`
`
`
`Revised: 05/2017
`
`
`
`
`
`
` 1
`
`Reference ID: 4099012
`
`

`

`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
`WARNING: TERMINATION OF
`
`
`PREGNANCY
`
`1 INDICATIONS AND USAGE
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Adult Dosage
`
`
`
`2.2 Dosing in Renal Impairment
`
`
`
`2.3 Dosing in Hepatic Impairment
`
`
`
`2.4 Concomitant Administration with
`
`
`CYP3A Inhibitors
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`4.1 Pregnancy
`
`
`4.2 Drugs Metabolized by CYP3A
`
`
`
`
`4.3 Corticosteroid Therapy Required for
`
`
`
`Lifesaving Purposes
`
`
`4.4 Women with Risk of Vaginal Bleeding or
`
`
`
`Endometrial Changes
`
`
`4.5 Known Hypersensitivity to Mifepristone
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Adrenal Insufficiency
`
`
`
`5.2 Hypokalemia
`
`
`5.3 Vaginal Bleeding and Endometrial
`
`
`
`
`Changes
`
`
`5.4 QT Interval Prolongation
`
`
`
`5.5 Exacerbation/Deterioration of Conditions
`
`
`
`Treated with Corticosteroids
`
`
`5.6 Use of Strong CYP3A Inhibitors
`
`
`
`5.7 Pneumocystis jiroveci Infection
`
`
`
`5.8 Potential Effects of Hypercortisolemia
`
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`6.2 Postmarketing Experience
`
`
`
`
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 Drugs Metabolized by CYP3A
`
`
`
`
`7.2 CYP3A Inhibitors
`
`
`
`7.3 CYP3A Inducers
`
`
`
`7.4 Drugs Metabolized by CYP2C8/2C9
`
`
`
`7.5 Drugs Metabolized by CYP2B6
`
`
`
`
`7.6 Use of Hormonal Contraceptives
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`
`8.6 Renal Impairment
`
`
`
`8.7 Hepatic Impairment
`
`
`8.8 Females of Reproductive Potential
`
`
`
`10 OVERDOSAGE
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`
`
`12.3 Pharmacokinetics
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis,
`
`Impairment of Fertility
`
`
`14 CLINICAL STUDIES
`
`
`14.1 Cushing’s Syndrome
`
`
`16 HOW SUPPLIED/STORAGE AND
`HANDLING
`
`17 PATIENT COUNSELING
`
`
`INFORMATION
`
`17.1 Importance of Preventing Pregnancy
`
`
`
`
` * Sections or subsections omitted from the full
`
`
`prescribing information are not listed.
`
`
`
`
`__________________________________________________________________
`
`
`
`
`
` 2
`
`Reference ID: 4099012
`
`

`

`
` FULL PRESCRIBING INFORMATION
`
`
`
`
` WARNING: TERMINATION OF PREGNANCY
`
`
`
`
`
`
`Mifepristone is a potent antagonist of progesterone and cortisol via the progesterone and
`
`
`
`
`
`glucocorticoid (GR-II) receptors, respectively. The antiprogestational effects will result in the
`
`
`
`
`
`termination of pregnancy. Pregnancy must therefore be excluded before the initiation of treatment
`with KORLYM and prevented during treatment and for one month after stopping treatment by the
`
`
`
`
`
`use of a non-hormonal medically acceptable method of contraception unless the patient has had a
`
`
`
`
`
`surgical sterilization, in which case no additional contraception is needed. Pregnancy must also be
`
`
`
`
`
`
`
`excluded if treatment is interrupted for more than 14 days in females of reproductive potential.
`
`
`
`
`
`
`
`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
`
`
`mellitus or glucose intolerance and have failed surgery or are not candidates for surgery.
`
`
`LIMITATIONS OF USE:
`
`• KORLYM should not be used in the treatment of patients with type 2 diabetes unless it is
`
`
`
`
`secondary to Cushing’s syndrome.
`
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1 Adult Dosage
`
`
`The recommended starting dose is 300 mg orally once daily. KORLYM must be given as a single daily
`
`
`
`
`
`
`dose. KORLYM should always be taken with a meal. Patients should swallow the tablet whole. Do not
`
`
`
`
`
`split, crush, or chew tablets.
`
`Dosing and titration
`
`The daily dose of KORLYM may be increased in 300 mg increments. The dose of KORLYM may be
`
`
`
`
`
`
`
`
`increased to a maximum of 1200 mg once daily but should not exceed 20 mg/kg per day. Increases in
`
`
`
`
`
`dose should not occur more frequently than once every 2-4 weeks. Decisions about dose increases should
`
`
`
`be based on a clinical assessment of tolerability and degree of improvement in Cushing’s syndrome
`
`
`
`
`manifestations. Changes in glucose control, anti-diabetic medication requirements, insulin levels, and
`
`psychiatric symptoms may provide an early assessment of response (within 6 weeks) and may help guide
`
`
`
`
`
`early dose titration. Improvements in cushingoid appearance, acne, hirsutism, striae, and body weight
`
`
`
`
`
`occur over a longer period of time and, along with measures of glucose control, may be used to determine
`
`dose changes beyond the first 2 months of therapy. Careful and gradual titration of KORLYM
`
`
`
`
`
`accompanied by monitoring for recognized adverse reactions (See Warnings and Precautions 5.1 and 5.2)
`
`may reduce the risk of severe adverse reactions. Dose reduction or even dose discontinuation may be
`
`
`
`
`
`
`needed in some clinical situations. If KORLYM treatment is interrupted, it should be reinitiated at the
`
`
`
`
`
`
`
`lowest dose (300 mg). If treatment was interrupted because of adverse reactions, the titration should aim
`
`
`
`
`for a dose lower than the one that resulted in treatment interruption.
`
`
`
`
`
`
`
` 3
`
`Reference ID: 4099012
`
`

`

`
`
`2.2 Dosing in Renal Impairment
`
`
`
`
`
`No change in initial dose of KORLYM is required in renal impairment. The maximum dose should be
`
`limited to 600 mg. [See Renal Impairment (8.6) and Clinical Pharmacology (12.3)]
`
`
`
`
`
`
`2.3 Dosing in Hepatic Impairment
`
`
`
`
`
`
`No change in the initial dose of KORLYM is required in mild to moderate hepatic impairment. The
`
`
`
`
`maximum dose should be limited to 600 mg. KORLYM should not be used in severe hepatic impairment.
`
`
`[See Hepatic Impairment (8.7) and Clinical Pharmacology (12.3)]
`
`
`
`
`
`2.4 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. [See Warnings and Precautions (5.6), Drug Interactions (7.2)]
`
`
`
`
`
`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
`
`
`
`
`
`
`
`
`
`
`
` Formatted: Border: Left: (Single solid line,
` Auto, 1 pt Line width)
`
`
`
`
`
`
`
`
`
`
`
` Formatted: Border: Left: (Single solid line,
` Auto, 1 pt Line width)
`
`
`
`
`
`
` Formatted: Border: Left: (Single solid line,
` Auto, 1 pt Line width)
`
`
`
`
`
`
` Formatted: Border: Left: (Single solid line,
` Auto, 1 pt Line width)
`
`
`
`
`
`
` Formatted: Border: Left: (Single solid line,
` Auto, 1 pt Line width)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Current dose of
` KORLYM
`
`
` 300 mg
`
` 600 mg
`
` Adjustment to dose of KORLYM
`
`
`
` if adding a strong CYP3A inhibitor
`
`
` No change
`
` Reduce dose to 300 mg. If clinically indicated,
`
` titrate to a maximum of 600 mg
`
`
` Reduce dose to 600 mg
`
`
` Reduce dose to 600 mg
`
`
`
`
`
` 900 mg
`
`
` 1200 mg
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`Tablets: 300 mg
`
`Oval shaped, light yellow to yellow tablets debossed with “Corcept” on one side and “300” on the other
`
`
`
`side. The tablets are not scored.
`
`
`
`4 CONTRAINDICATIONS
`
`
`
`4.1 Pregnancy
`
`
`KORLYM is contraindicated in women who are pregnant. Pregnancy must be excluded before the
`
`
`
`initiation of treatment with KORLYM or if treatment is interrupted for more than 14 days in females of
`
`
`
`
`
`
`
`
`
`
`4
`
`Reference ID: 4099012
`
`

`

`
`
`
`
`reproductive potential. Non-hormonal contraceptives should be used during and one month after stopping
`
`treatment in all women of reproductive potential. [See Use in Specific Populations 8.8]
`
`
`
`
`
`
`
`
`
`
`4.2 Drugs Metabolized by CYP3A
`
`
`
`
`
`
`KORLYM is contraindicated in patients taking simvastatin, lovastatin, and CYP3A substrates with
`
`
`
`narrow therapeutic ranges, such as cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide,
`
`
`quinidine, sirolimus, and tacrolimus, due to an increased risk of adverse events. [See Drug Interactions
`
`
`
`
`
`
`
`(7.1) and Clinical Pharmacology (12.3)]
`
`
`
`
`
`4.3 Corticosteroid Therapy Required for Lifesaving Purposes
`
`
`
`KORLYM is contraindicated in patients who require concomitant treatment with systemic corticosteroids
`
`
`
`for serious medical conditions or illnesses (e.g., immunosuppression after organ transplantation) because
`
`
`
`KORLYM antagonizes the effect of glucocorticoids.
`
`
`
`
`
`
`4.4 Women with Risk of Vaginal Bleeding or Endometrial Changes
`
`
`KORLYM is contraindicated in the following:
`
`
`• Women with a history of unexplained vaginal bleeding
`
`
`• Women with endometrial hyperplasia with atypia or endometrial carcinoma
`
`
`
`
`4.5 Known Hypersensitivity to Mifepristone
`
`
`
`KORLYM is contraindicated in patients with prior hypersensitivity reactions to mifepristone or to any of
`
`the product components.
`
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Adrenal Insufficiency
`
`
`
`
`Patients receiving mifepristone may experience adrenal insufficiency. Because serum cortisol levels
`
`
`
`
`
`remain elevated and may even increase during treatment with KORLYM, serum cortisol levels do not
`
`
`
`
`provide an accurate assessment of hypoadrenalism in patients receiving KORLYM. Patients should be
`
`
`
`closely monitored for signs and symptoms of adrenal insufficiency, including weakness, nausea,
`
`
`
`
`
`
`increased fatigue, hypotension, and hypoglycemia. If adrenal insufficiency is suspected, discontinue
`
`
`
`
`
`treatment with KORLYM immediately and administer glucocorticoids without delay. High doses of
`
`
`supplemental glucocorticoids may be needed to overcome the glucocorticoid receptor blockade produced
`
`
`
`
`by mifepristone. Factors considered in deciding on the duration of glucocorticoid treatment should
`
`
`include the long half-life of mifepristone (85 hours).
`
`
`
`
`
`Treatment with KORLYM at a lower dose can be resumed after resolution of adrenal insufficiency.
`
`Patients should also be evaluated for precipitating causes of hypoadrenalism (infection, trauma, etc.).
`
`
`
`5.2 Hypokalemia
`
`
`
`
`In a study of patients with Cushing’s syndrome, hypokalemia was observed in 44% of subjects during
`
`
`
`
`
`
`treatment with KORLYM. Hypokalemia should be corrected prior to initiating KORLYM. During
`
`
`
`
`
`KORLYM administration, serum potassium should be measured 1 to 2 weeks after starting or increasing
`
`
`
`
`
`
`
`the dose of KORLYM and periodically thereafter. Hypokalemia can occur at any time during KORLYM
`
`
`
`
`
` 5
`
`Reference ID: 4099012
`
`

`

`
`
`
`
`treatment. Mifepristone-induced hypokalemia should be treated with intravenous or oral potassium
`
`
`
`
`
`
`supplementation based on event severity. If hypokalemia persists in spite of potassium supplementation,
`
`consider adding mineralocorticoid antagonists.
`
`
`
`
`
`5.3 Vaginal Bleeding and Endometrial Changes
`
`
`
`
`Being an antagonist of the progesterone receptor, mifepristone promotes unopposed endometrial
`
`
`
`
`proliferation that may result in endometrium thickening, cystic dilatation of endometrial glands, and
`
`
`
`
`vaginal bleeding. KORLYM should be used with caution in women who have hemorrhagic disorders or
`
`are receiving concurrent anticoagulant therapy. Women who experience vaginal bleeding during
`
`
`
`KORLYM treatment should be referred to a gynecologist for further evaluation.
`
`
`
`
`
`5.4 QT Interval Prolongation
`
`
`
`Mifepristone and its metabolites block IKr. KORLYM prolongs the QTc interval in a dose-related
`
`
`
`manner. There is little or no experience with high exposure, concomitant dosing with other QT-
`
`prolonging drugs, or potassium channel variants resulting in a long QT interval. [See Warnings &
`
`
`
`
`Precautions (5.6)] To minimize risk, the lowest effective dose should always be used.
`
`
`
`
`
`
`
`
`
`5.5 Exacerbation/Deterioration of Conditions Treated with Corticosteroids
`
`
`
`
`Use of KORLYM in patients who receive corticosteroids for other conditions (e.g., autoimmune
`
`
`
`
`
`
`disorders) may lead to exacerbation or deterioration of such conditions, as KORLYM antagonizes the
`
`
`desired effects of glucocorticoid in these clinical settings. For medical conditions in which chronic
`
`
`corticosteroid therapy is lifesaving (e.g., immunosuppression in organ transplantation), KORLYM is
`
`contraindicated. [See Contraindications (4.3)]
`
`
`
`
`
`
`5.6 Use of Strong CYP3A Inhibitors
`
`
`KORLYM should be used with caution in patients taking ketoconazole and other strong inhibitors of
`
`
`
`CYP3A, such as itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir, amprenavir,
`
`
`fosamprenavir, clarithromycin, conivaptan, lopinavir/ritonavir, posaconazole, saquinavir, telithromycin,
`
`
`
`
`or voriconazole, as these could increase the concentration of mifepristone in the blood. The benefit of
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`concomitant use of these agents should be carefully weighed against the potential risks. KORLYM should
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`be used in combination with strong CYP3A inhibitors only when necessary, and in such cases the dose
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`should be limited to 600 mg per day. [See Warnings & Precautions (5.4), Drug Interactions (7.2), and
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`Clinical Pharmacology (12.3)]
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`5.7 Pneumocystis jiroveci Infection
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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
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`Reference ID: 4099012
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`6 ADVERSE REACTIONS
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`6.1 Clinical Trials Experience
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`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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`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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`regardless of relationship to KORLYM, are shown in Table 2.
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` 7
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`Reference ID: 4099012
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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
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` Pain in extremity
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` Investigations
` 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
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` 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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`Table 2. 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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` 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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` 8
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`Reference ID: 4099012
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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
`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
`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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` 9
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`Reference ID: 4099012
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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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` 10
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`Reference ID: 4099012
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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, clarithromycin, conivaptan,
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`lopinavir/ritonavir, posaconazole, saquinavir, telithromycin, or voriconazole may increase exposure to
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`mifepristone. Caution should be used when strong CYP3A inhibitors 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 600 mg, and strong inhibitors of CYP3A
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`should be used only when necessary. [See Dosage and Administration (2.4), Warnings & Precautions
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`(5.6), and Clinical Pharmacology (12.3)]
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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
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`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
`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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`8 USE IN SPECIFIC POPULATIONS
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`8.1 Pregnancy
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`Category X
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` 11
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`Reference ID: 4099012
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