e 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 (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 korlym. therefore, the concomitant use of such cyp3a substrates with korlym 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 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 ( 12.3 )] 7.2 cyp3a inhibitors 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, 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 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 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 korlym. avoid co-administration of korlym and cyp3a inducers such as rifampin, rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, and st. john's wort. 7.4 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 ( 12.3 )] 7.5 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 ( 12.3 )] 7.6 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. [see use in specific populations ( 8.3 )]

ol levels do not provide an accurate assessment of hypoadrenalism in patients receiving korlym. 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 korlym 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 korlym 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 korlym. hypokalemia should be corrected prior to initiating korlym. during korlym administration, serum potassium should be measured 1 to 2 weeks after starting or increasing the dose of korlym and periodically thereafter. hypokalemia can occur at any time during korlym 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. korlym should be used with caution in women who have hemorrhagic disorders or are receiving concurrent anticoagulant therapy. women who experience vaginal bleeding during korlym treatment should be referred to a gynecologist for further evaluation. 5.4 qt interval prolongation mifepristone and its metabolites block ikr. korlym 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 korlym in patients who receive corticosteroids for other conditions (e.g., autoimmune disorders) may lead to exacerbation or deterioration of such conditions, as korlym 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), korlym is contraindicated. [see contraindications (4.3)] 5.6 use of strong cyp3a inhibitors korlym 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. korlym 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 korlym treatment. patients may present with respiratory distress shortly after initiation of korlym. appropriate diagnostic tests should be undertaken and treatment for pneumocystis jiroveci should be considered. 5.8 potential effects of hypercortisolemia korlym 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.

4 ), warnings and precautions ( 5.2 ), use in specific populations ( 8.1 , 8.3 )]. 2.2 adult dosage the recommended starting dose is 300 mg orally once daily. korlym must be given as a single daily dose. korlym should always be taken with a meal. patients should swallow the tablet whole. do not split, crush, or chew tablets. dosing and titration the daily dose of korlym may be increased in 300 mg increments. the dose of korlym may be increased to a maximum of 1200 mg once daily but should not exceed 20 mg/kg per day. increases in dose should not occur more frequently than once every 2-4 weeks. decisions about dose increases should be based on a clinical assessment of tolerability and degree of improvement in cushing's syndrome manifestations. changes in glucose control, anti-diabetic medication requirements, insulin levels, and psychiatric symptoms may provide an early assessment of response (within 6 weeks) and may help guide early dose titration. improvements in cushingoid appearance, acne, hirsutism, striae, and body weight occur over a longer period of time and, along with measures of glucose control, may be used to determine dose changes beyond the first 2 months of therapy. careful and gradual titration of korlym accompanied by monitoring for recognized adverse reactions [ see warnings and precautions ( 5.1 ) and ( 5.2 ) ] may reduce the risk of severe adverse reactions. dose reduction or even dose discontinuation may be needed in some clinical situations. if korlym treatment is interrupted, it should be reinitiated at the lowest dose (300 mg). if treatment was interrupted because of adverse reactions, the titration should aim for a dose lower than the one that resulted in treatment interruption. 2.3 dosing in renal impairment no change in initial dose of korlym is required in renal impairment. the maximum dose should be limited to 600 mg. [see renal impairment ( 8.6 ) and clinical pharmacology ( 12.3 )] 2.4 dosing in hepatic impairment no change in the initial dose of korlym is required in mild to moderate hepatic impairment. the maximum dose should be limited to 600 mg. korlym should not be used in severe hepatic impairment. [see hepatic impairment ( 8.7 ) and clinical pharmacology ( 12.3 )] 2.5 concomitant administration with cyp3a inhibitors 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. korlym should be used in combination with strong cyp3a inhibitors only when necessary. [see warnings and precautions ( 5.6 ), drug interactions ( 7.2 )] administration of korlym to patients already being treated with strong cyp3a inhibitors: start at a dose of 300 mg. if clinically indicated, titrate to a maximum of 900 mg. administration of strong cyp3a inhibitors to patients already being treated with korlym: adjust the dose of korlym according to table 1 . table 1. dose adjustment of korlym when strong cyp3a inhibitor is added current dose of korlym adjustment to dose of korlym if adding a strong cyp3a inhibitor 300 mg no change 600 mg reduce dose to 300 mg. if clinically indicated, titrate to a maximum of 600 mg 900 mg reduce dose to 600 mg. if clinically indicated, titrate to a maximum of 900 mg 1200 mg reduce dose to 900 mg

nts 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 2 . table 2. 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) *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 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 ( 5.2 )] 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 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 korlym interruption and /or dexamethasone administration. rash 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. 6.2 postmarketing experience the following adverse reaction has been identified during post approval use of korlym. 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

e 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 (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 korlym. therefore, the concomitant use of such cyp3a substrates with korlym 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 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 ( 12.3 )] 7.2 cyp3a inhibitors 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, 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 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 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 korlym. avoid co-administration of korlym and cyp3a inducers such as rifampin, rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, and st. john's wort. 7.4 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 ( 12.3 )] 7.5 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 ( 12.3 )] 7.6 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. [see use in specific populations ( 8.3 )]

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 korlym and any potential adverse effects on the breastfed child from korlym or from the underlying maternal condition. clinical considerations to minimize exposure to a breastfed infant, women who discontinue or interrupt korlym 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, korlym causes pregnancy loss. perform pregnancy testing before the initiation of treatment with korlym or if treatment is interrupted for more than 14 days in females of reproductive potential. contraception recommend non-hormonal contraception for the duration of treatment and for one month after stopping treatment . korlym interferes with the effectiveness of hormonal contraceptives. [see drug interactions ( 7.6 )] 8.4 pediatric use safety and effectiveness of korlym in pediatric patients have not been established. 8.5 geriatric use clinical studies with korlym did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger people. 8.6 renal impairment the maximum dose should not exceed 600 mg per day in renally impaired patients. [see clinical pharmacology ( 12.3 )] 8.7 hepatic impairment in patients with mild to moderate hepatic impairment, the maximum dose should not exceed 600 mg per day. the pharmacokinetics of mifepristone in patients with severe hepatic impairment has not been studied, and korlym should not be used in these patients . [see clinical pharmacology ( 12.3 )]

ith 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.

rption following oral administration, time to peak plasma concentrations of mifepristone occurred between 1 and 2 hours following single dose, and between 1 and 4 hours following multiple doses of 600 mg of korlym in healthy volunteers. mean plasma concentrations of three active metabolites of mifepristone peak between 2 and 8 hours after multiple doses of 600 mg/day, and the combined concentrations of the metabolites exceed that of the parent mifepristone. exposure to mifepristone is substantially less than dose proportional. time to steady state is within 2 weeks, and the mean (sd) half-life of the parent mifepristone was 85 (61) hours following multiple doses of 600 mg/day of korlym. studies evaluating the effects of food on the pharmacokinetics of korlym demonstrate a significant increase in plasma levels of mifepristone when dosed with food. to achieve consistent plasma drug concentrations, patients should be instructed to always take their medication with meals. distribution mifepristone is highly bound to alpha-1-acid glycoprotein (aag) and approaches saturation at doses of 100 mg (2.5 μm) or more. mifepristone and its metabolites also bind to albumin and are distributed to other tissues, including the central nervous system (cns). as determined in vitro by equilibrium dialysis, binding of mifepristone and its three active metabolites to human plasma proteins was concentration-dependent. binding was approximately 99.2% for mifepristone, and ranged from 96.1 to 98.9% for the three active metabolites at clinically relevant concentrations. metabolism cytochrome p450 3a4 (cyp3a4) has been shown to be involved in mifepristone metabolism in human liver microsomes. two of the known active metabolites are the product of demethylation (one monodemethylated and one di-demethylated), while a third active metabolite results from hydroxylation (monohydroxylated). elimination and excretion excretion is primarily (approximately 90%) via the fecal route. specific populations renal impairment the pharmacokinetics of mifepristone in subjects with severe renal impairment (creatinine clearance [crcl] < 30 ml/min, but not on dialysis) was evaluated following multiple doses of 1200 mg korlym for 7 days. mean exposure to mifepristone increased 31%, with similar or smaller increases in metabolite exposure as compared to subjects with normal renal function (crcl ≥ 90 ml/min). there was large variability in the exposure of mifepristone and its metabolites in subjects with severe renal impairment as compared to subjects with normal renal function (geometric least square mean ratio [ci] for auc of mifepristone: 1.21 [0.71-2.06]; metabolite 1: 1.43 [0.84-2.44]; metabolite 2: 1.18 [0.64-2.17] and metabolite 3: 1.19 [0.71-1.99]). no change in the initial dose of korlym is needed for renal impairment; the maximum dose should not exceed 600 mg per day. hepatic impairment the pharmacokinetics of mifepristone in subjects with moderate hepatic impairment (child-pugh class b) was evaluated in a single- and multiple-dose study (600 mg for 7 days). the pharmacokinetics in subjects with moderate hepatic impairment was similar to those with normal hepatic function. there was large variability in the exposure of mifepristone and its metabolites in subjects with moderate hepatic impairment as compared to subjects with normal hepatic function (geometric least square mean ratio [ci] for auc of mifepristone: 1.02 [0.59-1.76]; metabolite 1: 0.95 [0.52-1.71]; metabolite 2: 1.37 [0.71-2.62] and metabolite 3: 0.62 [0.33-1.16]). due to limited information on safety in patients with mild-to-moderate hepatic impairment, the maximum dose should not exceed 600 mg per day. the pharmacokinetics of mifepristone in patients with severe hepatic disease has not been studied. korlym is not recommended in patients with severe hepatic disease. drug-drug interactions in vitro assessment of drug interactions in vitro studies indicate a potential for cyp-mediated drug interactions by mifepristone and/or its metabolites with substrates of cyp2a6, cyp2c8/2c9, cyp2c19, cyp3a4, cyp1a2, cyp2b6, cyp2d6, and cyp2e1. in vitro studies also indicated an interaction potential for drug transport mediated by p-glycoprotein (p-gp) and breast cancer resistance protein (bcrp). in vitro studies indicate mifepristone metabolism is mediated by cyp3a, and that mifepristone also inhibits and induces cyp3a. in vivo assessment of drug interactions (see table 3 ) table 3. summary table of korlym drug-drug interaction effects *no effect = 90% ci within range 0.80 – 1.25 †see section 12.2 for the relative potencies of the three metabolites 1 simvastatin 40 mg dose used as reference for the comparison. result could be representative of other oral drugs with cyp3a metabolism and high first pass effect: cyclosporine, midazolam, triazolam, pimozide, sildenafil, sirolimus, and tacrolimus 2 result could be representative of other oral drugs with cyp3a metabolism and low first pass effect. clinical significance of any interaction will depend on the therapeutic margin of the drug. 3 result could be representative of other oral drugs with cyp2c8/c9 metabolism 4 plasma digoxin concentration should be measured after 1 to 2 weeks of concomitant use and following usual clinical practice at appropriate intervals thereafter. 5 result could be representative of other mild inhibitors of cyp3a dosing of mifepristone coadministered drug dosing of coadministered drug geometric mean ratio (analyte ratio with/without drug coadministration) analyte auc cmax effect of korlym on coadministered drug contraindicated with mifepristone [see contraindications ( 4 )] 1200 mg once daily for 10 days simvastatin 1 80 mg single dose simvastatin acid simvastatin 15.70 10.40 18.20 7.02 use lowest dose of coadministered drug, based on clinical experience and/or use of therapeutic drug monitoring 1200 mg once daily for 10 days alprazolam 2 1 mg single dose alprazolam 4-hydroxy-alprazolam 1.80 0.76 0.81 0.39 1200 mg once daily for 7 days fluvastatin 3 40 mg single dose fluvastatin 3.57 1.76 1200 mg once daily for 10 days digoxin 4 0.125 mg once daily digoxin 1.40 1.64 effect of coadministered drug on korlym dose adjustment required 600 mg once daily for 17 days ketoconazole 200 mg bid on days 13-17 mifepristone metabolite 1† metabolite 2† metabolite 3† 1.38 1.02 1.67 0.95 1.28 1.06 1.69 0.96 900 mg once daily for 14 days itraconazole 200 mg daily for 14 days mifepristone metabolite 1† metabolite 2† metabolite 3† 1.10 1.04 1.23 0.97 1.20 1.00 1.19 0.94 effect of coadministered drug on korlym no dosing adjustment required 300 mg once daily for 14 days cimetidine 5 800 mg once daily mifepristone 0.85* 0.75

h meals. distribution mifepristone is highly bound to alpha-1-acid glycoprotein (aag) and approaches saturation at doses of 100 mg (2.5 μm) or more. mifepristone and its metabolites also bind to albumin and are distributed to other tissues, including the central nervous system (cns). as determined in vitro by equilibrium dialysis, binding of mifepristone and its three active metabolites to human plasma proteins was concentration-dependent. binding was approximately 99.2% for mifepristone, and ranged from 96.1 to 98.9% for the three active metabolites at clinically relevant concentrations. metabolism cytochrome p450 3a4 (cyp3a4) has been shown to be involved in mifepristone metabolism in human liver microsomes. two of the known active metabolites are the product of demethylation (one monodemethylated and one di-demethylated), while a third active metabolite results from hydroxylation (monohydroxylated). elimination and excretion excretion is primarily (approximately 90%) via the fecal route. specific populations renal impairment the pharmacokinetics of mifepristone in subjects with severe renal impairment (creatinine clearance [crcl] < 30 ml/min, but not on dialysis) was evaluated following multiple doses of 1200 mg korlym for 7 days. mean exposure to mifepristone increased 31%, with similar or smaller increases in metabolite exposure as compared to subjects with normal renal function (crcl ≥ 90 ml/min). there was large variability in the exposure of mifepristone and its metabolites in subjects with severe renal impairment as compared to subjects with normal renal function (geometric least square mean ratio [ci] for auc of mifepristone: 1.21 [0.71-2.06]; metabolite 1: 1.43 [0.84-2.44]; metabolite 2: 1.18 [0.64-2.17] and metabolite 3: 1.19 [0.71-1.99]). no change in the initial dose of korlym is needed for renal impairment; the maximum dose should not exceed 600 mg per day. hepatic impairment the pharmacokinetics of mifepristone in subjects with moderate hepatic impairment (child-pugh class b) was evaluated in a single- and multiple-dose study (600 mg for 7 days). the pharmacokinetics in subjects with moderate hepatic impairment was similar to those with normal hepatic function. there was large variability in the exposure of mifepristone and its metabolites in subjects with moderate hepatic impairment as compared to subjects with normal hepatic function (geometric least square mean ratio [ci] for auc of mifepristone: 1.02 [0.59-1.76]; metabolite 1: 0.95 [0.52-1.71]; metabolite 2: 1.37 [0.71-2.62] and metabolite 3: 0.62 [0.33-1.16]). due to limited information on safety in patients with mild-to-moderate hepatic impairment, the maximum dose should not exceed 600 mg per day. the pharmacokinetics of mifepristone in patients with severe hepatic disease has not been studied. korlym is not recommended in patients with severe hepatic disease. drug-drug interactions in vitro assessment of drug interactions in vitro studies indicate a potential for cyp-mediated drug interactions by mifepristone and/or its metabolites with substrates of cyp2a6, cyp2c8/2c9, cyp2c19, cyp3a4, cyp1a2, cyp2b6, cyp2d6, and cyp2e1. in vitro studies also indicated an interaction potential for drug transport mediated by p-glycoprotein (p-gp) and breast cancer resistance protein (bcrp). in vitro studies indicate mifepristone metabolism is mediated by cyp3a, and that mifepristone also inhibits and induces cyp3a. in vivo assessment of drug interactions (see table 3 ) table 3. summary table of korlym drug-drug interaction effects *no effect = 90% ci within range 0.80 – 1.25 †see section 12.2 for the relative potencies of the three metabolites 1 simvastatin 40 mg dose used as reference for the comparison. result could be representative of other oral drugs with cyp3a metabolism and high first pass effect: cyclosporine, midazolam, triazolam, pimozide, sildenafil, sirolimus, and tacrolimus 2 result could be representative of other oral drugs with cyp3a metabolism and low first pass effect. clinical significance of any interaction will depend on the therapeutic margin of the drug. 3 result could be representative of other oral drugs with cyp2c8/c9 metabolism 4 plasma digoxin concentration should be measured after 1 to 2 weeks of concomitant use and following usual clinical practice at appropriate intervals thereafter. 5 result could be representative of other mild inhibitors of cyp3a dosing of mifepristone coadministered drug dosing of coadministered drug geometric mean ratio (analyte ratio with/without drug coadministration) analyte auc cmax effect of korlym on coadministered drug contraindicated with mifepristone [see contraindications ( 4 )] 1200 mg once daily for 10 days simvastatin 1 80 mg single dose simvastatin acid simvastatin 15.70 10.40 18.20 7.02 use lowest dose of coadministered drug, based on clinical experience and/or use of therapeutic drug monitoring 1200 mg once daily for 10 days alprazolam 2 1 mg single dose alprazolam 4-hydroxy-alprazolam 1.80 0.76 0.81 0.39 1200 mg once daily for 7 days fluvastatin 3 40 mg single dose fluvastatin 3.57 1.76 1200 mg once daily for 10 days digoxin 4 0.125 mg once daily digoxin 1.40 1.64 effect of coadministered drug on korlym dose adjustment required 600 mg once daily for 17 days ketoconazole 200 mg bid on days 13-17 mifepristone metabolite 1† metabolite 2† metabolite 3† 1.38 1.02 1.67 0.95 1.28 1.06 1.69 0.96 900 mg once daily for 14 days itraconazole 200 mg daily for 14 days mifepristone metabolite 1† metabolite 2† metabolite 3† 1.10 1.04 1.23 0.97 1.20 1.00 1.19 0.94 effect of coadministered drug on korlym no dosing adjustment required 300 mg once daily for 14 days cimetidine 5 800 mg once daily mifepristone 0.85* 0.75

an in vitro assays, and an in vivo micronucleus study in mice. the pharmacological activity of mifepristone disrupts the estrus cycle of adult rats at a dose of 0.3 mg/kg (less than human exposure at the maximum clinical dose, based on body surface area). however, following withdrawal of treatment and subsequent resumption of the estrus cycle, there was no effect on reproductive function when mated. a single subcutaneous dose of mifepristone (up to 100 mg/kg) to rats on the first day after birth did not adversely affect future reproductive function in males or females, although the onset of puberty was slightly premature in dosed females. repeated doses of mifepristone (1 mg every other day) to neonatal rats resulted in potentially adverse fertility effects, including oviduct and ovary malformations in females, delayed male puberty, deficient male sexual behavior, reduced testicular size, and lowered ejaculation frequency.

in vivo micronucleus study in mice. the pharmacological activity of mifepristone disrupts the estrus cycle of adult rats at a dose of 0.3 mg/kg (less than human exposure at the maximum clinical dose, based on body surface area). however, following withdrawal of treatment and subsequent resumption of the estrus cycle, there was no effect on reproductive function when mated. a single subcutaneous dose of mifepristone (up to 100 mg/kg) to rats on the first day after birth did not adversely affect future reproductive function in males or females, although the onset of puberty was slightly premature in dosed females. repeated doses of mifepristone (1 mg every other day) to neonatal rats resulted in potentially adverse fertility effects, including oviduct and ovary malformations in females, delayed male puberty, deficient male sexual behavior, reduced testicular size, and lowered ejaculation frequency.

orts: a “diabetes” cohort (29 patients, 26 with type 2 diabetes and 3 with glucose intolerance), and a “hypertension” cohort (21 patients). efficacy was evaluated separately in the two cohorts. korlym treatment was started in all patients at a dose of 300 mg once a day. the study protocol allowed an increase in dose to 600 mg after 2 weeks, and then by additional 300 mg increments every 4 weeks to a maximum of 900 mg per day for patients <60 kg, or 1200 mg per day for patients >60 kg, based on clinical tolerance and clinical response. results in the diabetes cohort patients in the diabetes cohort underwent standard oral glucose tolerance tests at baseline and periodically during the clinical study. anti-diabetic medications were allowed but had to be kept stable during the trial and patients had to be on stable anti-diabetic regimens prior to enrollment. the primary efficacy analysis for the diabetes cohort was an analysis of responders. a responder was defined as a patient who had a ≥ 25% reduction from baseline in glucose auc. the primary efficacy analysis was conducted in the modified intent-to-treat population (n=25) defined as all patients who received a minimum of 30 days on korlym. fifteen of 25 patients (60%) were treatment responders (95% ci: 39%,78%). mean hba1c was 7.4% in the 24 patients with hba1c values at baseline and week 24. for these 24 patients mean reduction in hba1c was 1.1% (95% ci -1.6, -0.7) from baseline to the end of the trial. fourteen of 24 patients had above normal hba1c levels at baseline, ranging between 6.7% and 10.4%; all of these patients had reductions in hba1c by the end of the study (range -0.4 to -4.4%) and eight of 14 patients (57%) normalized hba1c levels at trial end. antidiabetic medications were reduced in 7 of the 15 dm subjects taking antidiabetic medication and remained constant in the others. results in the hypertension cohort there were no changes in mean systolic and diastolic blood pressures at the end of the trial relative to baseline in the modified intent-to-treat population (n=21). signs and symptoms of cushing's syndrome in both cohorts individual patients showed varying degrees of improvement in cushing's syndrome manifestations such as cushingoid appearance, acne, hirsutism, striae, psychiatric symptoms, and excess total body weight. because of the variability in clinical presentation and variability of response in this open label trial, it is uncertain whether these changes could be ascribed to the effects of korlym.