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
`
`
`
`• Patients taking drugs metabolized by CYP3A such as simvastatin,
`lovastatin, and CYP3A substrates with narrow therapeutic ranges (4)
`• Patients receiving systemic corticosteroids for lifesaving purposes (4)
`• Women with a history of unexplained vaginal bleeding or endometrial
`hyperplasia with atypia or endometrial carcinoma (4)
`• Patients with known hypersensitivity to mifepristone or to any of the
`product components (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 900 mg (5.6).
`
`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 (2.5) 10/2019
`
`--------------------------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).
`
`
`
`-----------------------------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 900 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).
`
`
`
`-----------------------DOSAGE FORMS AND STRENGTHS--------------------
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Tablets: 300 mg (3)
`
`Guide.
`-------------------------------CONTRAINDICATIONS------------------------------
`
`
`
`
`• Pregnancy (4, 8.1)
` Revised: 11/2019
`_____________________________________________________________________________
`
`•
`
`Important Limitations of Use: Do not use for the treatment of
`type 2 diabetes mellitus unrelated to endogenous Cushing’s
`syndrome.
`
`
`--------------------DOSAGE AND ADMINISTRATION--------------------------
`Obtain a negative pregnancy test in females of reproductive
`•
`potential prior to initiating treatment with KORLYM or if
`treatment is interrupted for more than 14 days. (2.1)
`Administer once daily orally with a meal (2.2).
`The recommended starting dose is 300 mg once daily (2.2).
`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 (2.2).
`Renal impairment: do not exceed 600 mg once daily (2.3).
`•
`• Mild-to-moderate hepatic impairment: do not exceed 600 mg once
`daily. Do not use in severe hepatic impairment (2.4).
`Concomitant administration with strong CYP3A inhibitors: Do not
`exceed 900 mg once daily (2.5).
`
`•
`•
`•
`
`•
`
`Reference ID: 4516016
`
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`1
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`

`

`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: TERMINATION OF
`PREGNANCY
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Testing Prior to and During KORLYM
`Administration
`2.2 Adult Dosage
`2.3 Dosing in Renal Impairment
`2.4 Dosing in Hepatic Impairment
`2.5 Concomitant Administration with CYP3A
`Inhibitors
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`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
`
`7.2 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
`8.2 Lactation
`8.3 Females and Males of Reproductive
`Potential
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`
`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
` DRUG INTERACTIONS
`
`prescribing information are not listed.
`7.1 Drugs Metabolized by CYP3A
`__________________________________________________________________
`
`
`
`
`
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`Reference ID: 4516016
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`

`
`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 Testing Prior to and During KORLYM Administration
`Obtain a negative pregnancy test in females of reproductive potential prior to initiating treatment with
`KORLYM or if treatment is interrupted for more than 14 days [see Contraindications (4), Warnings and
`Precautions (5.2), Use in Specific Populations (8.1, 8.3)].
`
`2.2 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
`3
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`Reference ID: 4516016
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`

`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.
`
`2.3 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)]
`
`2.4 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)]
`
`2.5 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 900 mg.
`
`
`Administration of strong CYP3A inhibitors to patients already being treated with KORLYM:
`• Adjust the dose of KORLYM according to Table 1.
`
`Table 1. Dose adjustment of KORLYM when strong CYP3A inhibitor is added
`
`
`Current dose of
`KORLYM
`300 mg
`600 mg
`
`900 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. If clinically indicated,
`titrate to a maximum of 900 mg
`Reduce dose to 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.
`
`
`
`Reference ID: 4516016
`
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`

`4
`
` CONTRAINDICATIONS
`
` KORLYM is contraindicated in:
`
`• Pregnancy [See Dosage and Administration (2.1), Use in Specific Populations (8.1,8.3)]
`
`• Patients taking drugs metabolized by CYP3A such as 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)]
`
`• Patients receiving systemic corticosteroids for lifesaving purposes (e.g., immunosuppression after
`organ transplantation) because KORLYM antagonizes the effect of glucocorticoids.
`
`• Women with a history of unexplained vaginal bleeding or with endometrial hyperplasia with
`atypia or endometrial carcinoma.
`
`• Patients with known hypersensitivity 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
`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.
`
`Reference ID: 4516016
`
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`

`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
`concomitant use of these agents should be carefully weighed against the potential risks. KORLYM should
`be used in combination with strong CYP3A inhibitors only when necessary, and in such cases the dose
`should be limited to 900 mg per day. [See Warnings & Precautions (5.4), Drug Interactions (7.2), and
`Clinical Pharmacology (12.3)]
`
`5.7 Pneumocystis jiroveci Infection
`Patients with endogenous Cushing’s syndrome are at risk for opportunistic infections such as
`Pneumocystis jiroveci pneumonia during KORLYM treatment. Patients may present with respiratory
`distress shortly after initiation of KORLYM. Appropriate diagnostic tests should be undertaken and
`treatment for Pneumocystis jiroveci should be considered.
`
`5.8 Potential Effects of Hypercortisolemia
`KORLYM does not reduce serum cortisol levels. Elevated cortisol levels may activate mineralocorticoid
`receptors which are also expressed in cardiac tissues. Caution should be used in patients with underlying
`heart conditions including heart failure and coronary vascular disease.
`
`
`
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`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed
`cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in
`clinical practice.
`
`Safety data on the use of KORLYM are available from 50 patients with Cushing’s syndrome enrolled in
`an uncontrolled, open-label, multi-center trial (Study 400). Forty-three patients had Cushing’s disease and
`all except one had previously undergone pituitary surgery. Four patients had ectopic ACTH secretion, and
`three had adrenal carcinoma. Patients were treated for up to 24 weeks. A dose of 300 mg per day was
`administered for the initial 14 days; thereafter, the dose could be escalated in increments of 300 mg per
`day based on assessments of tolerability and clinical response. Doses were escalated up to 900 mg per day
`for patients <60 kg, or 1200 mg per day for patients >60 kg.
`
`The most frequently reported adverse reactions (reported in ≥20% of patients, regardless of relationship to
`KORLYM) were nausea, fatigue, headache, decreased blood potassium, arthralgia, vomiting, peripheral
`edema, hypertension, dizziness, decreased appetite, and endometrial hypertrophy. Drug-related adverse
`events resulted in dose interruption or reduction in study drug in 40% of patients.
`
`The adverse reactions that occurred in ≥10% of the Cushing’s syndrome patients receiving KORLYM,
`regardless of relationship to KORLYM, are shown in Table 2.
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`Reference ID: 4516016
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`Table 2. Treatment Emergent Adverse Events Occurring in ≥10% of Cushing’s Syndrome Patients
`Receiving KORLYM
`
`
`
`Body System/Adverse Reaction
`
`Percent (%) of
`Patients Reporting
`Event
`(n = 50)
`
`Gastrointestinal disorders
`Nausea
`Vomiting
`Dry mouth
`Diarrhea
`Constipation
`General disorders and administration/site conditions
`Fatigue
`Edema peripheral
`Pain
`Nervous system disorders
`Headache
`Dizziness
`Somnolence
`Musculoskeletal and connective tissue disorders
`Arthralgia
`Back pain
`Myalgia
`Pain in extremity
`Investigations
`Blood potassium decreased
`Thyroid function test abnormal
`Infections and infestations
`Sinusitis
`Nasopharyngitis
`Metabolism and nutrition disorders
`Decreased appetite
`Anorexia
`Vascular disorders
`Hypertension
`Reproductive system and breast disorders
`Endometrial hypertrophy
`Respiratory, thoracic, and mediastinal disorders
`Dyspnea
`Psychiatric disorders
`10
`Anxiety
`*The denominator was 26 females who had baseline and end-of-trial transvaginal ultrasound
`
`48
`26
`18
`12
`10
`
`48
`26
`14
`
`44
`22
`10
`
`30
`16
`14
`12
`
`34
`18
`
`14
`12
`
`20
`10
`
`24
`
`38*
`
`16
`
`
`
`
`
`
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`Reference ID: 4516016
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`

`Laboratory Tests
`Reductions in high density lipoprotein-cholesterol (HDL-C) levels have been observed following
`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
`HDL-C levels in patients with Cushing’s syndrome is not known.
`
`In a study of patients with Cushing’s syndrome, hypokalemia was observed in 44% of subjects during
`treatment with KORLYM. In these cases, hypokalemia responded to treatment with potassium
`supplementation and/or mineralocorticoid antagonist therapy (e.g., spironolactone or eplerenone).
`Hypokalemia should be corrected prior to initiating KORLYM. [See Warnings and Precautions (5.2)]
`
`Elevations of thyroid-stimulating hormone (TSH) were seen in subjects treated with KORLYM. Of the
`42 subjects with detectable TSH at baseline, eight (19%) had increases in TSH above the normal range,
`while remaining asymptomatic. The TSH levels returned to normal in most patients without intervention
`when KORLYM was discontinued at the end of the study.
`
`Vaginal Bleeding and Endometrial Changes
`In Study 400, the thickness of the endometrium increased from a mean of 6.14 mm at baseline (n=23) to
`15.7 mm at end-of-trial (n=18) in premenopausal women; in postmenopausal women the increase was
`from 2.75 mm (n=6) to 7.35 mm (n=8). Endometrial thickness above the upper limit of normal was
`reported in 10/26 females who had baseline and end-of-trial transvaginal ultrasound (38%). The
`endometrial thickness returned to the normal range in 3 out of 10 patients 6 weeks after treatment
`cessation at the end of the study. Vaginal bleeding occurred in 5 out of 35 females (14%). Two of five
`subjects with vaginal bleeding had normal endometrial thickness. Endometrial biopsies were performed in
`six patients; five of these patients had endometrial thickening. No endometrial carcinoma was detected in
`the sampled cases.
`
`Additional Data from Clinical Trials
`The following are adverse events that were reported in Study 400 at frequencies of ≥ 5% to 10%, and may
`be related to KORLYM’s mechanism of action:
`
`Gastrointestinal disorders: gastroesophageal reflux, abdominal pain
`General disorders and administration site conditions: asthenia, malaise, edema, pitting edema, thirst
`Investigations: blood triglycerides increased
`Metabolism and nutrition disorders: hypoglycemia
`Musculoskeletal and connective tissue disorders: muscular weakness, flank pain, musculoskeletal chest
`pain
`Psychiatric disorders: insomnia
`Reproductive system and breast disorders: vaginal hemorrhage, metrorrhagia [See Warnings and
`Precautions (5.3)]
`
`Adrenal Insufficiency
`Adrenal insufficiency was reported in two subjects (4%) in Study 400. The most typical symptoms of
`adrenal insufficiency were nausea and decreased appetite. No hypotension or hypoglycemia was reported
`
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`during the events. Adrenal insufficiency resolved in both cases with KORLYM interruption and /or
`dexamethasone administration.
`
`Rash
`Generalized, maculo-papular rash was reported in 2 subjects (4%) in Study 400. Two additional subjects
`developed pruritus (4%). None resulted in discontinuation of KORLYM, and all the events resolved by
`the end of the study.
`
`6.2 Postmarketing Experience
`
`The following adverse reaction has been identified during post approval use of KORLYM. Because these
`reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably
`estimate their frequency or establish a causal relationship to drug exposure.
`
`
`- Angioedema
`
`
`
` 7
`
` DRUG INTERACTIONS
`Based on the long terminal half-life of mifepristone after reaching steady state, at least 2 weeks should
`elapse after cessation of KORLYM before initiating or increasing the dose of any interacting concomitant
`medication.
`
`7.1 Drugs Metabolized by CYP3A
`Because KORLYM is an inhibitor of CYP3A, concurrent use of KORLYM with a drug whose
`metabolism is largely or solely mediated by CYP3A is likely to result in increased plasma concentrations
`of the drug. Discontinuation or dose reduction of such medications may be necessary with KORLYM co-
`administration.
`
`KORLYM increased the exposure to simvastatin and simvastatin acid significantly in healthy subjects.
`Concomitant use of simvastatin or lovastatin is contraindicated because of the increased risk of myopathy
`and rhabdomyolysis. [See Contraindications (4.2), Clinical Pharmacology 12.3]
`
`The exposure of other substrates of CYP3A with narrow therapeutic ranges, such as cyclosporine,
`dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus, may be
`increased by concomitant administration with KORLYM. Therefore, the concomitant use of such CYP3A
`substrates with KORLYM is contraindicated. [See Contraindications (4.2)]
`
`Other drugs with similar high first pass metabolism in which CYP3A is the primary route of metabolism
`should be used with extreme caution if co-administered with KORLYM. The lowest possible dose and/or
`a decreased frequency of dosing must be used with therapeutic drug monitoring when possible. Use of
`alternative drugs without these metabolic characteristics is advised when possible with concomitant
`KORLYM.
`
`If drugs that undergo low first pass metabolism by CYP3A or drugs in which CYP3A is not the major
`metabolic route are co-administered with KORLYM, use the lowest dose of concomitant medication
`necessary, with appropriate monitoring and follow-up. [See Clinical Pharmacology (12.3)]
`
`
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`

`7.2 CYP3A Inhibitors
`Medications that inhibit CYP3A could increase plasma mifepristone concentrations and dose reduction of
`KORLYM may be required.
`
`Ketoconazole and other strong inhibitors of CYP3A, such as itraconazole, nefazodone, ritonavir,
`nelfinavir, indinavir, atazanavir, amprenavir and fosamprenavir, clarithromycin, conivaptan, lopinavir
`/ritonavir, posaconazole, saquinavir, telithromycin, or voriconazole may increase exposure to
`mifepristone. Caution should be used when strong CYP3A inhibitors are prescribed in combination with
`KORLYM. The benefit of concomitant use of these agents should be carefully weighed against the
`potential risks. The dose of KORLYM should be limited to 900 mg, and strong inhibitors of CYP3A
`should be used only when necessary. [See Dosage and Administration (2.4), Warnings & Precautions
`(5.6), and Clinical Pharmacology (12.3)]
`
`7.3 CYP3A Inducers
`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,
`phenytoin, carbamazepine, and St. John’s wort.
`
`7.4 Drugs Metabolized by CYP2C8/2C9
`Because KORLYM is an inhibitor of CYP2C8/2C9, concurrent use of KORLYM with a drug whose
`metabolism is largely or solely mediated by CYP2C8/2C9 is likely to result in increased plasma
`concentrations of the drug.
`
`KORLYM significantly increased exposure of fluvastatin, a typical CYP2C8/2C9 substrate, in healthy
`subjects. When given concomitantly with KORLYM, drugs that are substrates of CYP2C8/2C9
`(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
`Pharmacology (12.3)]
`
`7.5 Drugs Metabolized by CYP2B6
`Mifepristone is an inhibitor of CYP2B6 and may cause significant increases in exposure of drugs that are
`metabolized by CYP2B6 such as bupropion and efavirenz. Since no study has been conducted to evaluate
`the effect of mifepristone on substrates of CYP2B6, the concomitant use of bupropion and efavirenz
`should be undertaken with caution. [See Clinical Pharmacology (12.3)]
`
`7.6 Use of Hormonal Contraceptives
`Mifepristone is a progesterone-receptor antagonist and will interfere with the effectiveness of hormonal
`contraceptives. Therefore, non-hormonal contraceptive methods should be used. [See Use In Specific
`Populations (8.3)]
`
`
` 8
`
` USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`Risk Summary
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`Reference ID: 4516016
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`KORLYM is contraindicated in pregnancy because the use of KORLYM results in pregnancy loss. There
`are no data that assess the risk of birth defects in women exposed to KORLYM during pregnancy.
`Available data limited to exposure following a single dose of mifepristone during pregnancy showed a
`higher rate of major birth defects compared to the general population comparator (See Data).
`Mifepristone administered to pregnant mice, rats, and rabbits during organogenesis caused pregnancy
`loss in all species at clinically relevant doses based on body surface area comparisons (See Data).The
`inhibition of both endogenous and exogenous progesterone by mifepristone at the progesterone receptor
`results in pregnancy loss. If KORLYM is used during pregnancy or if the patient becomes pregnant while
`taking this drug, the patient should be apprised of the potential hazard to a fetus. [See Contraindications
`(4)]
`
`The estimated risk of fetal loss is elevated in patients with active Cushing’s syndrome (24-30%), and the
`risk of major birth defects is unknown. In the U.S. general population, the estimated background risks of
`major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%,
`respectively.
`
`Data
`
`Human Data
`There are no data on long term exposure to mifepristone in pregnancy. Available data are limited to
`exposure to a single dose of mifepristone for pregnancy termination. In a prospective study in France of
`46 pregnancies exposed to a single dose of mifepristone alone and 59 pregnancies exposed to a single
`dose of mifepristone and misopristol, the overall major birth defect rate (4%) was greater than the general
`population background rate of 2 to 3% (2 birth defects in each group). There was no pattern of birth
`defects identified.
`
`Animal Data
`
`Reproductive studies were performed in mice, rats and rabbits at doses of 0.25 to 4.0 mg/kg (less than
`human exposure at the maximum clinical dose, based on body surface area). Because of the anti-
`progestational activity of mifepristone, fetal losses were much higher than in control animals. Skull
`deformities were detected in rabbit studies at less than human exposure, although mifepristone did not
`cause any adverse developmental effects in rats or mice during organogenesis. These deformities were
`most likely due to the mechanical effects of uterine contractions resulting from antagonism of the
`progesterone receptor.
`
`8.2 Lactation
`
`Risk Summary
`
`Mifepristone is present in human milk, however, there are no data on the amount of mifepristone in
`human milk, the effects on the breastfed infant, or the effects on milk production during long term use of
`mifepristone (see Data). The developmental and health benefits of breastfeeding should be considered
`along with the mother’s clinical need for Korlym and any potential adverse effects on the breastfed child
`from Korlym or from the underlying maternal condition.
`
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`Clinical Considerations
`To minimize exposure to a breastfed infant, women who discontinue or interrupt KORLYM treatment
`may consider pumping and discarding milk during treatment and for 18-21 days (5-6 half-lives) after the
`last dose, before breastfeeding.
`
`Data
`
`Available published data based on intake of a single dose of 600 mg of mifepristone in 10 breastfeeding
`women who were 6-12 months postpartum showed a small amount in breast milk (the estimated relative
`infant dose was 0.5%). The half-life of mifepristone is longer with repeat dosing compared to a single
`dose; therefore, there may be greater exposure with long term use.
`
`8.3 Females and Males of Reproductive Potential
`
`Pregnancy Testing
`
`Due to its anti-progestational activity, KORLYM causes pregnancy loss. Perf