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 mifepristone 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 mifepristone, or if treatment is interrupted for more than 14 days in females of reproductive potential.
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warnings and cautions
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 ). 5.1 Adrenal 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.). 5.2 Hypokalemia 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. 5.3 Vaginal 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. 5.4 QT 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. 5.5 Exacerbation/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 Contraindications ( 4.3 )] . 5.6 Use of Strong CYP3A Inhibitors Mifepristone should be used with caution in patients taking ketoconazole and other strong inhibitors of CYP3A, such as itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir, amprenavir, fosamprenavir, clarithromycin, conivaptan, lopinavir/ritonavir, posaconazole, saquinavir, telithromycin, or voriconazole, as these could increase the concentration of mifepristone in the blood. The benefit of concomitant use of these agents should be carefully weighed against the potential risks. Mifepristone should be used in combination with strong CYP3A inhibitors only when necessary, and in such cases the dose should be limited to 900 mg per day [see Warnings & Precautions ( 5.4 ), Drug Interactions (7.2), and Clinical Pharmacology ( 12.3 )] . 5.7 Pneumocystis jiroveci Infection Patients with endogenous Cushing’s syndrome are at risk for opportunistic infections such as Pneumocystis jiroveci pneumonia during mifepristone treatment. Patients may present with respiratory distress shortly after initiation of mifepristone. Appropriate diagnostic tests should be undertaken and treatment for Pneumocystis jiroveci should be considered. 5.8 Potential Effects of Hypercortisolemia Mifepristone does not reduce serum cortisol levels. Elevated cortisol levels may activate mineralocorticoid receptors which are also expressed in cardiac tissues. Caution should be used in patients with underlying heart conditions including heart failure and coronary vascular disease. 5.9 Risk of Allergic Reactions due to Tartrazine This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.
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 . 6.1 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 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 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 [See Warnings and Precautions ( 5.3 )] 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. 6.2 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