Mifepristone

FDA Drug Information • Also known as: Korlym, Mifepristone

Brand Names: Korlym, Mifepristone
Drug Class: Progestin Antagonist [EPC]
Route: ORAL
Dosage Form: TABLET, FILM COATED
Product Type: HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

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. 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.

Description

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 C 29 H 35 NO 2 ; the molecular weight is 429.60, and the structural formula is: 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. Structural Formula

What Is Mifepristone Used For?

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. 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

2 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 ). 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 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...

Side Effects (Adverse Reactions)

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. 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 Percent (%) of Patients Reporting Event (n = 50) *The denominator was 26 females who had baseline and end-of-trial transvaginal ultrasound Gastrointestinal disorders Nausea 48 Vomiting 26 Dry mouth 18 Diarrhea 12 Constipation 10 General disorders and administration/site conditions Fatigue 48 Edema peripheral 26 Pain 14 Nervous system disorders Headache 44 Dizziness 22 Somnolence 10 Musculoskeletal and connective tissue disorders Arthralgia 30 Back pain 16 Myalgia 14 Pain in extremity 12 Investigations Blood potassium decreased 34 Thyroid function test abnormal 18 Infections and infestations Sinusitis 14 Nasopharyngitis 12 Metabolism and nutrition disorders Decreased appetite 20 Anorexia 10 Vascular disorders Hypertension 24 Reproductive system and breast disorders Endometrial hypertrophy 38* Respiratory, thoracic, and mediastinal disorders Dyspnea 16 Psychiatric disorders Anxiety 10 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...

Drug Interactions

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. 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 ). 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...

Contraindications

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. Pregnancy ( 4 , 8.1 ) 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 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary 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 misoprostol, 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...

Overdosage

10 OVERDOSAGE There is no experience with overdosage of KORLYM.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING KORLYM is supplied as a light yellow to yellow, film-coated, oval-shaped tablet debossed with “Corcept” on one side and “300” on the other. Each tablet contains 300 mg of mifepristone. KORLYM tablets are available in bottles of 28 tablets (NDC 76346-073-01) and bottles of 280 tablets (NDC 76346-073-02). Store at controlled room temperature, 25 °C (77 °F); excursions permitted to 15 to 30 °C (59 – 86 °F). [See USP Controlled Room Temperature]

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.