Mifepristone 300 mg Tablet, Film Coated, 28-count

5 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 900 mg ( 5.6 ).

5.1Adrenal Insufficiency Patients receiving mifepristone may experience adrenal insufficiency. Because serum cortisol levels remain elevated and may even increase during treatment with mifepristone, serum cortisol levels do not provide an accurate assessment of hypoadrenalism in patients receiving mifepristone. 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 mifepristone 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 mifepristone 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.).

5.2Hypokalemia In a study of patients with Cushing’s syndrome, hypokalemia was observed in 44% of subjects during treatment with mifepristone. Hypokalemia should be corrected prior to initiating mifepristone. During mifepristone administration, serum potassium should be measured 1 to 2 weeks after starting or increasing the dose of mifepristone and periodically thereafter.

Hypokalemia can occur at any time during mifepristone 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.

5.3Vaginal 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. Mifepristone should be used with caution in women who have hemorrhagic disorders or are receiving concurrent anticoagulant therapy. Women who experience vaginal bleeding during mifepristone treatment should be referred to a gynecologist for further evaluation.

5.4QT Interval Prolongation Mifepristone and its metabolites block IKr. Mifepristone 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.

5.5Exacerbation/Deterioration of Conditions Treated with Corticosteroids Use of mifepristone in patients who receive corticosteroids for other conditions (e.g., autoimmune disorders) may lead to exacerbation or deterioration of such conditions, as mifepristone 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), mifepristone is contraindicated [see…

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 Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical 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 [see Warnings and Precautions ( 5.2 )] . 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…

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 mifepristone 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 mifepristone ( 7.1 ). CYP3A inhibitors: Caution should be used when mifepristone 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 mifepristone with CYP3A inducers ( 7.3 ). Drugs metabolized by CYP2C8/2C9: Use the lowest dose of CYP2C8/2C9 substrates when used with mifepristone ( 7.4 ).

Drugs metabolized by CYP2B6: Use of mifepristone should be done with caution with bupropion and efavirenz ( 7.5 ). Hormonal contraceptives: Do not use with mifepristone ( 7.6 ).

7.1Drugs 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 [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 mifepristone. Therefore, the concomitant use of such CYP3A substrates with mifepristone 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 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 [see Clinical Pharmacology ( 12.3 )] .

7.2CYP3A 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 [see Dosage and Administration ( 2.4 ), Warnings & Precautions ( 5.6 ), and Clinical Pharmacology ( 12.3 )] .

7.3CYP3A 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.

7.4Drugs 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 m…