Mifepristone Drug Information

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 mifepristone 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 1,200 mg per day for patients>60 kg.

The most frequently reported adverse reactions (reported in ≥20% of patients, regardless of relationship to mifepristone) 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 mifepristone, regardless of relationship to mifepristone, are shown in Table 2. Table 2. Treatment Emergent Adverse Events Occurring in ≥10% of Cushing’s Syndrome Patients Receiving Mifepristone B ody System/Adverse Reaction P ercent (%) of Patients Reporting E vent (n = 50) 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 N ervous system disorders Headache 44 Dizziness 22 Somnolence 10 M u sculoskeletal 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 M etabolism and nutrition disorders Decreased appetite 20 Anorexia 10 V ascular disorders Hypertension 24 R eproductive system and breast disorders Endometrial hypertrophy 38* R espiratory, thoracic, and mediastinal disorders Dyspnea 16 P sychiatric disorders Anxiety 10 *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 mifepristone.

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 mifepristone.

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 mifepristone . Elevations of thyroid-stimulating hormone (TSH) were seen in subjects treated with mifepristone. 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 mifepristone 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 mifepristone’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 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 mifepristone interruption and/or dexamethasone administration. Rash Generalized, maculopapular rash was reported in 2 subjects (4%) in Study 400. Two additional subjects developed pruritus (4%). None resulted in discontinuation of mifepristone, and all the events resolved by the end of the study.

Postmarketing Experience

The following adverse reaction has been identified during post approval use of mifepristone. 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

Drugs Metabolized by

CYP3A Because mifepristone is an inhibitor of CYP3A, concurrent use of mifepristone 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 mifepristone coadministration. Mifepristone 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 . 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 mifepristone. Therefore, the concomitant use of such CYP3A substrates with mifepristone is contraindicated . Other drugs with similar high first pass metabolism in which CYP3A is the primary route of metabolism should be used with extreme caution if coadministered with mifepristone. 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 mifepristone. If drugs that undergo low first pass metabolism by CYP3A or drugs in which CYP3A is not the major metabolic route are coadministered with mifepristone, use the lowest dose of concomitant medication necessary, with appropriate monitoring and follow-up .

CYP3A Inhibitors Medications that inhibit

CYP3A could increase plasma mifepristone concentrations and dose reduction of mifepristone 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 mifepristone.

The benefit of concomitant use of these agents should be carefully weighed against the potential risks. The dose of mifepristone should be limited to 900 mg, and strong inhibitors of CYP3A should be used only when necessary .

CYP3A Inducers No medications that induce

CYP3A have been studied when coadministered with mifepristone. Avoid coadministration of mifepristone and CYP3A inducers such as rifampin, rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, and St. John’s wort.

Drugs Metabolized by

CYP2C8/2C9 Because mifepristone is an inhibitor of CYP2C8/2C9, concurrent use of mifepristone with a drug whose metabolism is largely or solely mediated by CYP2C8/2C9 is likely to result in increased plasma concentrations of the drug. Mifepristone significantly increased exposure of fluvastatin, a typical CYP2C8/2C9 substrate, in healthy subjects. When given concomitantly with mifepristone, 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 .

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 .

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 .

Pregnancy Risk Summary Mifepristone is contraindicated in pregnancy because the use of mifepristone results in pregnancy loss. There are no data that assess the risk of birth defects in women exposed to mifepristone 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 mifepristone 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. The estimated risk of fetal loss is elevated in patients with active Cushing’s syndrome (24% to 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% to 4% and 15% to 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 area). 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 mifepristone did not cause any adverse developmental effects in rats or mice during organogenesis. These deformities were most likely due to the mechanical effects of uterine contractions resulting from antagonism of the progesterone receptor.

Pediatric Use Safety and effectiveness of mifepristone in pediatric patients have not been established.

Mifepristone is contraindicated in: Pregnancy 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. Patients receiving systemic corticosteroids for lifesaving purposes (e.g., immunosuppression after organ transplantation) because mifepristone 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. Patients taking drugs metabolized by CYP3A such as simvastatin, lovastatin, and CYP3A substrates with narrow therapeutic ranges.

Patients receiving systemic corticosteroids for lifesaving purposes. Women with a history of unexplained vaginal bleeding or endometrial hyperplasia with atypia or endometrial carcinoma . Patients with known hypersensitivity to mifepristone or to any of the product components.

There is no experience with overdosage of mifepristone.