`• 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).
`
` 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.
`
`Revised: 05/2017
`
`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.
`
`1
`
`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)
`Warnings and Precautions (5.6)
`
`
`
`
` INDICATIONS AND USAGE
`
`05/2017
`05/2017
`
`
`
`
`
`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).
`
`
`Tablets: 300 mg (3)
`
` DOSAGE FORMS AND STRENGTHS
`
` CONTRAINDICATIONS
`
`• Pregnancy (4.1, 8.1)
`• Use of simvastatin or lovastatin and CYP3A substrates with narrow therapeutic range (4.2)
`
`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
`
`1
`
`TEVA1036
`
`
`
`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.
`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
`Current dose of KORLYM
`Adjustment to dose of KORLYM if adding a strong CYP3A inhibitor
`300 mg
`No change
`600 mg
`Reduce dose to 300 mg. If clinically indicated, titrate to a maximum of 600 mg
`900 mg
`Reduce dose to 600 mg
`1200 mg
`Reduce dose to 600 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 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.
`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 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 600 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.
`
`2
`
`2
`
`
`
`Percent (%) of Patients Reporting Event (n = 50)
`
`48
`26
`18
`12
`10
`
`48
`26
`14
`
`44
`22
`10
`
`30
`16
`14
`12
`
`34
`18
`
`14
`12
`
`20
`10
`
`24
`
`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.
`Table 2. Treatment Emergent Adverse Events Occurring in ≥10% of Cushing’s
`Syndrome Patients Receiving KORLYM
`Body System/Adverse Reaction
`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
`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
`
` 38*
`
`16
`
`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 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)]
`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 600
`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.
`
`3
`
`3
`
`
`
`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)]
`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.
`11 DESCRIPTION
`KORLYM (mifepristone) is a cortisol receptor blocker for oral administration. The chemical name of
`mifepristone is 11ß-(4-dimethylaminophenyl)-17ß-hydroxy-17-(1-propynyl)-estra-4,9-dien-3-one.
`The chemical formula is C29H35NO2; the molecular weight is 429.60, and the structural formula is:
`CH3
`N
`
`3’
`
`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% (mifepristone), 61% (metabolite 1), 48% (metabolite 2), and 45% (metabolite 3)] 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 KORLYM in healthy volunteers. Mean plasma concentrations of three
`active metabolites of mifepristone peak between 2 and 8 hours after multiple doses of
`600 mg/day, and the combined concentrations of the metabolites exceed that of the parent
`mifepristone. Exposure to mifepristone is substantially less than dose proportional. Time to
`steady state is within 2 weeks, and the mean (SD) half-life of the parent mifepristone was
`85 (61) hours following multiple doses of 600 mg/day of KORLYM.
`Studies evaluating the effects of food on the pharmacokinetics of KORLYM demonstrate
`a significant increase in plasma levels of mifepristone when dosed with food. To achieve
`consistent plasma drug concentrations, patients should be instructed to always take their
`medication with meals.
`Distribution
`Mifepristone is highly bound to alpha-1-acid glycoprotein (AAG) and approaches saturation at
`doses of 100 mg (2.5 µM) or more. Mifepristone and its metabolites also bind to albumin and are
`distributed to other tissues, including the centr