MIFEPRISTONE

Dosage and Administration ( 2.5 ) 11/2019

1 INDICATIONS AND USAGE Mifepristone is a cortisol receptor blocker indicated to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery. LIMITATIONS OF USE: Mifepristone should not be used in the treatment of patients with type 2 diabetes unless it is secondary to Cushing's syndrome. Mifepristone is a cortisol receptor blocker indicated to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery ( 1 ). Important Limitations of Use: Do not use for the treatment of type 2 diabetes mellitus unrelated to endogenous Cushing's syndrome.

2 DOSAGE AND ADMINISTRATION 200 mg mifepristone tablet on Day 1, followed 24 to 48 hours after mifepristone tablet dosing by 800 mcg buccal misoprostol. ( 2.1 ) Instruct the patient what to do if significant adverse reactions occur. ( 2.2 ) Follow-up is needed to confirm complete termination of pregnancy. ( 2.3 ) 2.1 Dosing Regimen For purposes of this treatment, pregnancy is dated from the first day of the last menstrual period. The duration of pregnancy may be determined from menstrual history and clinical examination. Assess the pregnancy by ultrasonographic scan if the duration of pregnancy is uncertain or if ectopic pregnancy is suspected. Remove any intrauterine device (“IUD”) before treatment with Mifepristone Tablets, 200 mg begins [see Contraindications (4)] . The dosing regimen for Mifepristone Tablets, 200 mg and misoprostol is: Mifepristone Tablets, 200 mg orally + misoprostol 800 mcg buccally • Day One : Mifepristone Tablets, 200 mg Administration One 200 mg tablets of Mifepristone is taken in a single oral dose. • Day Two or Three : Misoprostol Administration (minimum 24-hour interval between, Mifepristone Tablet, 200 mg and misoprostol) Four 200 mcg tablets (total dose 800 mcg) of misoprostol are taken by the buccal route. Tell the patient to place two 200 mcg misoprostol tablets in each cheek pouch (the area between the cheek and gums) for 30 minutes and then swallow any remnants with water or another liquid (see Figure 1 ). Patients taking Mifepristone Tablets, 200 mg must take misoprostol within 24 to 48 hours after taking Mifepristone Tablets. The effectiveness of the regimen may be lower if misoprostol is administered less than 24 hours or more than 48 hours after mifepristone administration. Because most women will expel the pregnancy within 2 to 24 hours of taking misoprostol [see Clinical Studies ( 14 )], discuss with the patient an appropriate location for them to be when taking the misoprostol, taking into account that expulsion could begin within 2 hours of administration. figure-1 2.2 Patient Management Following Misoprostol Administration During the period immediately following the administration of misoprostol, the patient may need medication for cramps or gastrointestinal symptoms [see Adverse Reactions ( 6 )] . Give the patient: Instructions on what to do if significant discomfort, excessive vaginal bleeding or other adverse reactions occur A phone number to call if the patient has questions following the administration of the misoprostol The name and phone number of the healthcare provider who will be handling emergencies. 2.3 Post-treatment Assessment: Day 7 to 14 Patients should follow-up with their healthcare provider approximately 7 to 14 days after the administration of Mifepristone Tablets, 200 mg. This assessment is very important to confirm that complete termination of pregnancy has occurred and to evaluate the degree of bleeding. Termination can be confirmed by medical history, clinical examination, human Chorionic Gonadotropin (hCG) testing, or ultrasonographic scan. Lack of bleeding following treatment usually indicates failure; however, prolonged or heavy bleeding is not proof of a complete abortion. The existence of debris in the uterus (e.g., if seen on ultrasonography) following the treatment procedure will not necessarily require surgery for its removal. Patients should expect to experience vaginal bleeding or spotting for an average of 9 to 16 days. Women report experiencing heavy bleeding for a median duration of 2 days. Up to 8% of women may experience some type of bleeding for more than 30 days. Persistence of heavy or moderate vaginal bleeding at the time of follow-up, however, could indicate an incomplete abortion. If complete expulsion has not occurred, but the pregnancy is not ongoing, patients may be treated with another dose of misoprostol 800 mcg buccally. There have been rare reports of uterine rupture in women who took Mifepristone Tablets, 200 mg and misoprostol, in …

3 DOSAGE FORMS AND STRENGTHS Tablets containing 200 mg of mifepristone each, supplied as 1 tablet on one blister card. Mifepristone tablets are light yellow coloured, round, biconvex tablets debossed with “CC12” on one side and plain on other side and free from physical defects. Tablets containing 200 mg of mifepristone each, supplied as 1 tablet on one blister card

4 CONTRAINDICATIONS Administration of Mifepristone Tablets, 200 mg and misoprostol for the termination of pregnancy (the “treatment procedure”) is contraindicated in patients with any of the following conditions: Confirmed or suspected ectopic pregnancy or undiagnosed adnexal mass (the treatment procedure will not be effective to terminate an ectopic pregnancy) [ see Warnings and Precautions ( 5.4 )] Chronic adrenal failure (risk of acute adrenal insufficiency) Concurrent long-term corticosteroid therapy (risk of acute adrenal insufficiency) History of allergy to mifepristone, misoprostol, or other prostaglandins (allergic reactions including anaphylaxis, angioedema, rash, hives, and itching have been reported [ see Adverse Reactions ( 6.2 )]) Hemorrhagic disorders or concurrent anticoagulant therapy (risk of heavy bleeding) Inherited porphyrias (risk of worsening or of precipitation of attacks) Use of Mifepristone Tablets, 200 mg and misoprostol for termination of intrauterine pregnancy is contraindicated in patients with an intrauterine device (“IUD”) in place (the IUD might interfere with pregnancy termination). If the IUD is removed, Mifepristone Tablets, 200 mg may be used. Confirmed/suspected ectopic pregnancy or undiagnosed adnexal mass ( 4 ) Chronic adrenal failure ( 4 ) Concurrent long-term corticosteroid therapy ( 4 ) History of allergy to mifepristone, misoprostol, or other prostaglandins ( 4 ) Hemorrhagic disorders or concurrent anticoagulant therapy ( 4 ) Inherited porphyria ( 4 ) Intrauterine device (IUD) in place ( 4 )

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 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 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. 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 Body System/Adverse Reaction Percent (%) of Patients Reporting Event (n = 50) *The denominator was 26 females who had baseline and end-of-trial transvaginal ultrasound 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 Nervous system disorders Headache 44 Dizziness 22 Somnolence 10 Musculoskeletal 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 Metabolism and nutrition disorders Decreased appetite 20 Anorexia 10 Vascular disorders Hypertension 24 Reproductive system and breast disorders Endometrial hypertrophy 38* Respiratory, thoracic, and mediastinal disorders Dyspnea 16 Psychiatric disorders Anxiety 10 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 w …

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 ). 7.1 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 co-administration. 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 co-administered 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 co-administered with mifepristone, 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 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 )] 7.3 CYP3A Inducers No medications that induce CYP3A have been studied when co-administered with mifepristone. Avoid co-administration of mifepristone and CYP3A inducers such as rifampin, rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, and St. John's wort. 7.4 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 med …

8 USE IN SPECIFIC POPULATIONS 8.1 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. [See Contraindications ( 4 )] The estimated risk of fetal loss is elevated in patients with active Cushing's syndrome (24-30%), 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 2-4% and 15-20%, 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. 8.2 Lactation Risk Summary Mifepristone is present in human milk, however, there are no data on the amount of mifepristone in human milk, the effects on the breastfed infant, or the effects on milk production during long term use of mifepristone (see Data) . The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for mifepristone and any potential adverse effects on the breastfed child from mifepristone or from the underlying maternal condition. Clinical Considerations To minimize exposure to a breastfed infant, women who discontinue or interrupt mifepristone treatment may consider pumping and discarding milk during treatment and for 18-21 days (5-6 half-lives) after the last dose, before breastfeeding. Data Available published data based on intake of a single dose of 600 mg of mifepristone in 10 breastfeeding women who were 6-12 months postpartum showed a small amount in breast milk (the estimated relative infant dose was 0.5%). The half-life of mifepristone is longer with repeat dosing compared to a single dose; therefore, there may be greater exposure with long term use. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Due to its anti-progestational activity, mifepristone causes pregnancy loss. Perform pregnancy testing before the initiation of treatment with mifepristone or if treatment is interrupted for more than 14 days in females of reproductive potential. Contraception Recommend non-hormon …

12.1 Mechanism of Action Mifepristone is a selective antagonist of the progesterone receptor at low doses and blocks the glucocorticoid receptor (GR-II) at higher doses. Mifepristone has high affinity for the GR-II receptor but little affinity for the GR-I (MR, mineralocorticoid) receptor. In addition, mifepristone appears to have little or no affinity for estrogen, muscarinic, histaminic, or monoamine receptors.

11 DESCRIPTION Mifepristone is a cortisol receptor blocker for oral administration. The chemical name of mifepristone is 11β-(4-dimethylaminophenyl)-17β-hydroxy-17α-(1-propynyl)-estra-4, 9-dien-3-one. The chemical formula is C 29 H 35 NO 2 ; the molecular weight is 429.60, and the structural formula is: Mifepristone demonstrates a pH-related solubility profile. The greatest solubility is achieved in acidic media (~ 25 mg/mL at pH 1.5) and solubility declines rapidly as the pH is increased. At pH values above 2.5 the solubility of mifepristone is less than 1 mg/mL. Each mifepristone tablet for oral use contains 300 mg of mifepristone. The inactive ingredients of mifepristone tablets are silicified microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose, sodium lauryl sulfate, magnesium stearate, hypromellose, titanium dioxide, triacetin, D&C yellow 10 aluminum lake, polysorbate 80, and FD&C yellow 6 aluminum lake. Structural Formula

10 OVERDOSAGE No serious adverse reactions were reported in tolerance studies in healthy non-pregnant female and healthy male subjects where mifepristone was administered in single doses greater than 1,800 mg (ninefold the recommended dose for medical abortion). If a patient ingests a massive overdose, the patient should be observed closely for signs of adrenal failure.

16 HOW SUPPLIED/STORAGE AND HANDLING Mifepristone Tablets, 200 mg is only available through a restricted program called the Mifepristone REMS Program [see Warnings and Precautions ( 5.3 )]. Mifepristone Tablets, 200 mg is supplied as light yellow coloured, round, biconvex tablets debossed with “CC12” on one side and plain on other side and free from physical defects. Each tablet contains 200 mg of mifepristone. One tablet is individually blistered on one blister card that is packaged in an individual package (National Drug Code 84670-014-01). Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature].