Mifepristone: uses, dosing, side effects & brands

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,…

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 )

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 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 )]