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. 7
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)
|General disorders and administration/site conditions|
|Nervous system disorders|
|Musculoskeletal and connective tissue disorders|
|Pain in extremity||12|
|Blood potassium decreased||34|
|Thyroid function test abnormal||18|
|Infections and infestations|
|Metabolism and nutrition disorders|
|Reproductive system and breast disorders|
|Respiratory, thoracic, and mediastinal disorders|
|*The denominator was 26 females who had baseline and end-of-trial transvaginal ultrasound|
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]
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
Investigations: blood triglycerides increased
Metabolism and nutrition disorders: hypoglycemia
Musculoskeletal and connective tissue disorders: muscular weakness, flank pain, musculoskeletal chest pain
Psychiatric disorders: insomnia
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.
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.
Read the Korlym (mifepristone) Side Effects Center for a complete guide to possible side effects
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
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, CLINICAL PHARMACOLOGY]
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]
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]
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 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 AND PRECAUTIONS]
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.
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.
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]
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]
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.
Last reviewed on RxList: 2/23/2012
This monograph has been modified to include the generic and brand name in many instances.
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