CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
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`APPLICATION NUMBER:
`202107Orig1s000
`
`LABELING
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`TEVA1049
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`• 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 significantly. Use only
`when necessary and limit mifepristone dose to 300 mg (5.6).
`
`
`----------------------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
`
`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
`300 mg per day when used with strong CYP3A inhibitors (5.6,
`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 Section 17 for PATIENT COUNSELING
`INFORMATION and FDA-approved Medication Guide
`
`
`
`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.
`
`
`--------------------INDICATIONS AND USAGE-------------------
`Korlym (mifepristone) is a cortisol receptor blocker indicated to
`control hyperglycemia secondary to hypercortisolism in adult
`patients with endogenous Cushing's syndrome who have type 2
`diabetes mellitus or glucose intolerance and have failed surgery
`or are not candidates for surgery.
`
`Important Limitations of Use (1.1)
`
`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).
`
`The recommended starting dose is 300 mg once daily
`(2).
`
`Renal impairment: do not exceed 600 mg once daily.
` Mild-to-moderate hepatic impairment: do not exceed
`600 mg once daily. Do not use in severe hepatic
`impairment.
`
`
`Based on clinical response and tolerability, the dose may be
`increased in 300 mg increments to a maximum of 1200 mg once
`daily. Do not exceed 20 mg/kg per day (2).
`
`---------------DOSAGE FORMS AND STRENGTHS------------
`• 300 mg tablet
`
`------------------------CONTRAINDICATIONS---------------------
`• Pregnancy (4.1, 8.1)
`• Use of simvastatin or lovastatin and CYP 3A substrates with
`narrow therapeutic range (4.2)
`• Concurrent long-term corticosteroid use (4.3)
`
`
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`Reference ID: 3089791
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`FULL PRESCRIBING INFORMATION: Contents*
`
` 1
`
` INDICATIONS AND USAGE 
`LIMITATIONS OF USE: 
`2 DOSAGE AND ADMINISTRATION 
`2.1 Adult Dosage 
`2.2 Dosing in Renal Impairment 
`2.3 Dosing in Hepatic Impairment 
`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 Laboratory Tests 
`6.3 Vaginal Bleeding and Endometrial
`Changes 
`6.4 Additional Data from Clinical Trials 
`
`6.4.1 Adrenal Insufficiency 
`6.4.2 Rash 
`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
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`Korlym™ (mifepristone) 300 mg tablets for oral use
`
`
`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
`
` 2
`
` 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.
`
` 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
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`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.
`
`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)]
`
`3 DOSAGE FORMS AND STRENGTHS
`Korlym is supplied as a light yellow to yellow oval-shaped tablet debossed with “Corcept” on one side
`and “300” on the other. Each tablet contains 300 mg of mifepristone. 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 reproductive
`potential. Nonhormonal 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.
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`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.
`
`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
`life-saving (e.g., immunosuppression in organ transplantation), Korlym is contraindicated. [See
`Contraindications (4.3)]
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`5.6 Use of Strong CYP3A Inhibitors
`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, nefazodone, posaconazole, ritonavir,
`saquinavir, telaprevir, telithromycin, or voriconazole, as these could substantially increase the
`concentration of 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 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)]
`
`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 mineralcorticoid
`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.
`
`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 1.
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`Table 1. 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
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`44
`22
`10
`
`30
`16
`14
`12
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`34
`18
`
`14
`12
`
`20
`10
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`24
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`38*
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`16
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`6.2 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.
`
`6.3 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.
`
`6.4 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)]
`
`6.4.1 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.
`
`6.4.2 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.
`
`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)]
`
`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, boceprevir, clarithromycin, conivaptan,
`lopinavir, mibefradil, nefazodone, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, or
`voriconazole may increase exposure to mifepristone significantly. The clinical impact of this interaction
`has not been studied. Therefore, extreme caution should be used when these drugs are prescribed in
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`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 300 mg and used only when
`necessary. [See Warnings & Precautions (5.6)]
`
`Moderate inhibitors of CYP3A, such as amprenavir, aprepitant, atazanavir, ciprofloxacin,
`darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, imatinib, or
`verapamil, should be used with caution when administered in combination with Korlym.
`
`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.
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`Category X
`Korlym is contraindicated in pregnancy. Korlym can cause fetal harm when administered to a pregnant
`woman because the use of Korlym results in pregnancy loss. 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 (4.1)]
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`Human Data
`In a report of thirteen live births after single dose mifepristone exposure, no fetal abnormalities were
`noted.
`
`Animal Data
`Teratology studies 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) were carried out. 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 no teratogenic effects of mifepristone
`have been observed to date in rats or mice. These deformities were most likely due to the mechanical
`effects of uterine contractions resulting from antagonism of the progesterone receptor.
`
`8.3 Nursing Mothers
`Mifepristone is present in human milk of women taking the drug. Because of the potential for serious
`adverse reactions in nursing infants from Korlym, a decision should be made whether to discontinue
`nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
`
`8.4 Pediatric Use
`Safety and effectiveness of Korlym in pediatric patients have not been established.
`
`8.5 Geriatric Use
`Clinical studies with Korlym did not include sufficient numbers of patients aged 65 and over to determine
`whether they respond differently than younger people.
`
`8.6 Renal Impairment
`The maximum dose should not exceed 600 mg per day in renally impaired patients. [See Clinical
`Pharmacology (12.3)]
`
`8.7 Hepatic Impairment
`In patients with mild to moderate hepatic impairment, the maximum dose should not exceed 600 mg per
`day. The pharmacokinetics of mifepristone in patients with severe hepatic impairment has not been
`studied, and Korlym should not be used in these patients. [See Clinical Pharmacology (12.3)]
`
`8.8 Females of Reproductive Potential
`Due to its anti-progestational activity, Korlym causes pregnancy loss. Exclude pregnancy before the
`initiation of treatment with Korlym or if treatment is interrupted for more than 14 days in females of
`reproductive potential. Recommend contraception for the duration of treatment and for one month after
`stopping treatment using a non-hormonal medically acceptable method of contraception. If the patient has
`had surgical sterilization, no additional contraception is needed.
`
`10 OVERDOSAGE
`There is no experience with overdosage of Korlym.
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`11 DESCRIPTION
`Korlym (mifepristone) is a cortisol receptor blocker for oral administration. The chemical name of
`mifepristone is 11β-(4-dimethylaminophenyl)-17β-hydroxy-17α-(1-propynyl)-estra-4, 9-dien-3-one. The
`chemical formula is C29H35NO2; the molecular weight is 429.60; and the structural formula is:
`
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`Mifepristone demonstrates a pH-related solubility profile. The greatest solubility is achieved in acidic
`media (~ 25 mg/mL at pH 1.5) and solubility declines rapidly as the pH is increased. At pH values above
`2.5 the solubility of mifepristone is less than 1 mg/mL.
`
`Each Korlym tablet for oral use contains 300 mg of mifepristone. The inactive ingredients of Korlym
`tablets are silicified microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose, sodium
`lauryl sulfate, magnesium stearate, hypromellose, titanium dioxide, triacetin, D&C yellow 10 aluminum
`lake, polysorbate 80, and FD&C yellow 6 aluminum lake.
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`Mifepristone is a selective antagonist of the progesterone receptor at low doses and blocks the
`glucocorticoid receptor (GR-II) at higher doses. Mifepristone has high affinity for the GR-II receptor but
`little affinity for the GR-I (MR, mineralocorticoid) receptor. In addition, mifepristone appears to have
`little or no affinity for estrogen, muscarinic, histaminic, or monoamine receptors.
`
`12.2 Pharmacodynamics
`Because mifepristone acts at the receptor level to block the effects of cortisol, its antagonistic actions
`affect the hypothalamic-pituitary-adrenal (HPA) axis in such a way as to further increase circulating
`cortisol levels while, at the same time, blocking their effects.
`
`Mifepristone and the three active metabolites have greater affinity for the glucocorticoid receptor (100%,
`61%, 48%, and 45%, respectively) than either dexamethasone (23%) or cortisol (9%).
`
`12.3 Pharmacokinetics
`Absorption
`Following oral administration, time to peak plasma concentrations of mifepristone occurred between 1
`and 2 hours following single dose, and between 1 and 4 hours following multiple doses of 600 mg of
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`Korlym in healthy voluntee