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Mifepristone

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Mifepristone uses


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.

1 INDICATIONS AND USAGE

Mifepristone (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 (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.

2 DOSAGE AND ADMINISTRATION


Based on clinical response and tolerability, the dose may be increased in 300 mg increments to a maximum of 1200 mg once daily. Do not exceed 20 mg/kg per day (2).

2.1 Adult Dosage

The recommended starting dose is 300 mg orally once daily. Mifepristone must be given as a single daily dose. Mifepristone 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 Mifepristone may be increased in 300 mg increments. The dose of Mifepristone 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 Mifepristone 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 Mifepristone 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.

2.2 Dosing in Renal Impairment

No change in initial dose of Mifepristone is required in renal impairment. The maximum dose should be limited to 600 mg.

2.3 Dosing in Hepatic Impairment

No change in the initial dose of Mifepristone is required in mild to moderate hepatic impairment. The maximum dose should be limited to 600 mg. Mifepristone should not be used in severe hepatic impairment.

3 DOSAGE FORMS AND STRENGTHS

Tablets: 300 mg

Oval shaped, light yellow to yellow tablets debossed with “Corcept” on one side and “300” on the other side. The tablets are not scored.

Tablets: 300 mg (3)

4 CONTRAINDICATIONS

4.1 Pregnancy

Mifepristone is contraindicated in women who are pregnant. Pregnancy must be excluded before the initiation of treatment with Mifepristone or if treatment is interrupted for more than 14 days in females of reproductive potential. Non-hormonal contraceptives should be used during and one month after stopping treatment in all women of reproductive potential.

4.2 Drugs Metabolized by CYP3A

Mifepristone is contraindicated in patients taking 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.

4.3 Corticosteroid Therapy Required for Lifesaving Purposes

Mifepristone is contraindicated in patients who require concomitant treatment with systemic corticosteroids for serious medical conditions or illnesses (e.g., immunosuppression after organ transplantation) because Mifepristone antagonizes the effect of glucocorticoids.

4.4 Women with Risk of Vaginal Bleeding or Endometrial Changes

Mifepristone is contraindicated in the following:

4.5 Known Hypersensitivity to Mifepristone

Mifepristone is contraindicated in patients with prior hypersensitivity reactions to Mifepristone or to any of the product components.

5 WARNINGS AND PRECAUTIONS

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. 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.

5.6 Use of Strong CYP3A Inhibitors

Mifepristone should be used with extreme caution in patients taking ketoconazole and other strong inhibitors of CYP3A, such as itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir, amprenavir, fosamprenavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, telithromycin, or voriconazole, as these could substantially 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 300 mg per day.

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.

6 ADVERSE REACTIONS

Most common adverse reactions in Cushing's syndrome : 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, or 1200 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 1.

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.

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 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

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, maculo-papular 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.

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.

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.

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 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.

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, boceprevir, clarithromycin, conivaptan, lopinavir, mibefradil, posaconazole, saquinavir, telaprevir, telithromycin, or voriconazole may increase exposure to Mifepristone significantly. The clinical impact of this interaction has not been studied. Therefore, extreme caution should be used when these drugs 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 300 mg and used only when necessary.

Moderate inhibitors of CYP3A, such as amprenavir, aprepitant, atazanavir, ciprofloxacin, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, imatinib, or verapamil, should be used with caution when administered in combination with Mifepristone.

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 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 should be used at the smallest recommended doses, and patients should be closely monitored for adverse effects.

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.

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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Category X

Mifepristone is contraindicated in pregnancy. Mifepristone can cause fetal harm when administered to a pregnant woman because the use of Mifepristone results in pregnancy loss. 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.

Human Data

In a report of thirteen live births after single dose Mifepristone exposure, no fetal abnormalities were noted.

Animal Data

Teratology studies 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) were carried out. 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 no teratogenic effects of Mifepristone have been observed to date in rats or mice. These deformities were most likely due to the mechanical effects of uterine contractions resulting from antagonism of the progesterone receptor.

8.3 Nursing Mothers

Mifepristone is present in human milk of women taking the drug. Because of the potential for serious adverse reactions in nursing infants from Mifepristone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness of Mifepristone in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies with Mifepristone 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.

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 Mifepristone should not be used in these patients.

8.8 Females of Reproductive Potential

Due to its anti-progestational activity, Mifepristone causes pregnancy loss. Exclude pregnancy before the initiation of treatment with Mifepristone or if treatment is interrupted for more than 14 days in females of reproductive potential. Recommend contraception for the duration of treatment and for one month after stopping treatment using a non-hormonal medically acceptable method of contraception. If the patient has had surgical sterilization, no additional contraception is needed.

10 OVERDOSAGE

There is no experience with overdosage of Mifepristone.

11 DESCRIPTION

Mifepristone (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 C29H35NO2; 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.

Figure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Mifepristone is a selective antagonist of the progesterone receptor at low doses and blocks the glucocorticoid receptor 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.

12.2 Pharmacodynamics

Because Mifepristone acts at the receptor level to block the effects of cortisol, its antagonistic actions affect the hypothalamic-pituitary-adrenal (HPA) axis in such a way as to further increase circulating cortisol levels while, at the same time, blocking their effects.

Mifepristone and the three active metabolites have greater affinity for the glucocorticoid receptor (100%, 61%, 48%, and 45%, respectively) than either dexamethasone (23%) or cortisol (9%).

12.3 Pharmacokinetics

Absorption

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 Mifepristone 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 Mifepristone.

Studies evaluating the effects of food on the pharmacokinetics of Mifepristone 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 Mifepristone 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 Mifepristone 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. Mifepristone 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

*No effect = 90% CI within range 0.80 – 1.25
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.
5Result 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 Mifepristone on Coadministered Drug
Contraindicated with Mifepristone
1200 mg once daily for 10 days simvastatin1 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 alprazolam2 1 mg single dose alprazolam

4-hydroxy-alprazolam

 1.80

0.76

 0.81

0.39
1200 mg once daily for 7 days fluvastatin3 40 mg single dose fluvastatin 3.57 1.76
1200 mg once daily for 10 days digoxin4 0.125 mg once daily digoxin 1.40 1.64
Effect of Coadministered Drug on Mifepristone
No dosing adjustment required
300 mg once daily for 14 days cimetidine5 800 mg once daily Mifepristone 0.85* 0.75

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Mifepristone was evaluated for carcinogenicity potential in rats and mice. Rats were dosed for up to two years at doses of 5, 25, and 125 mg/kg of Mifepristone. The high dose was the maximum tolerated dose, but exposure at all doses was below exposure at the maximum clinical dose based on AUC comparison. Female rats had a statistically significant increase in follicular cell adenomas/carcinomas and liver adenomas. It is plausible that these tumors are due to drug-induced enzyme metabolism, a mechanism not considered clinically relevant, but studies confirming this mechanism were not conducted with Mifepristone. Mice were also tested for up to 2 years at Mifepristone doses up to the maximum tolerated dose of 125 mg/kg, which provided exposure below the maximum clinical dose based on AUC. No drug-related tumors were seen in mice.

Mifepristone was not genotoxic in a battery of bacterial, yeast, and mammalian 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.

14 CLINICAL STUDIES

14.1 Cushing's Syndrome

An uncontrolled, open-label, 24-week, multicenter clinical study was conducted to evaluate the safety and efficacy of Mifepristone in the treatment of endogenous Cushing's syndrome. The study enrolled 50 subjects with clinical and biochemical evidence of hypercortisolemia despite prior surgical treatment and radiotherapy. The reasons for medical treatment were failed surgery, recurrence of disease, and poor medical candidate for surgery. Forty-three patients (86%) had Cushing's disease, four patients (8%) had ectopic ACTH secretion, and three (6%) had adrenal carcinoma. Baseline characteristics included: mean age of 45 years (range 26 to 71), mean BMI of 36 kg/m2 (range 24 to 66), mean weight 100 kg (range 61 to 199), and mean waist circumference was 119 cm (range 89 to 178); 70% were female; 84% were white and 16% were black or African American. Baseline mean urinary free cortisol level was 365 μg per 24 hr.

Patients belonged to one of two cohorts: 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. Mifepristone 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 Mifepristone. 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 Mifepristone.

16 HOW SUPPLIED/STORAGE AND HANDLING

Mifepristone is supplied as a light yellow to yellow, film-coated, oval-shaped tablet debossed with “Corcept” on one side and “300” on the other. Each tablet contains 300 mg of Mifepristone. Mifepristone tablets are available in bottles of 28 tablets (NDC 76346-073-01) and bottles of 280 tablets (NDC 76346-073-02).

Store at controlled room temperature, 25 °C (77 °F); excursions permitted to 15 to 30 ° C (59 – 86 °F).

17 PATIENT COUNSELING INFORMATION

As a part of patient counseling, doctors must review the Mifepristone Medication Guide with every patient.

17.1 Importance of Preventing Pregnancy

17.3 FDA-Approved Medication Guide

Medication Guide

Mifepristone ® (KOR-lim)

(mifepristone) tablets

Read this Medication Guide before you start taking Mifepristone and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment.

What is the most important information I should know about Mifepristone?

Mifepristone can cause serious side effects, including:


What is Mifepristone?

Mifepristone is a prescription medicine used to treat high blood sugar (hyperglycemia) caused by high cortisol levels in the blood (hypercortisolism) in adults with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or cannot have surgery.

Mifepristone is not for people who have type 2 diabetes mellitus not caused by Cushing's syndrome.

It is not known if Mifepristone is safe and effective in children.

Who should not take Mifepristone?

Do not take Mifepristone if you:


Talk to your doctor before taking Mifepristone if you have any of these conditions.

What should I tell my doctor before taking Mifepristone?

Before taking Mifepristone, tell your doctor if you:


Tell your doctor about all of the medicines you take, including prescription and nonprescription medicines, vitamins and herbal supplements.

Using Mifepristone with certain other medicines can affect each other. Using Mifepristone with other medicines can cause serious side effects.

Especially tell your doctor if you take:


Ask your doctor or pharmacist for a list of these medicines if you are not sure.

Know the medicines you take. Keep a list of them to show to your doctor and pharmacist.

How should I take Mifepristone?


What should I avoid while taking Mifepristone?

You should not drink grapefruit juice while you take Mifepristone. Grapefruit juice may increase the amount of Mifepristone in your blood and increase your chance of having side effects.

What are the possible side effects of Mifepristone?

Mifepristone can cause serious side effects including:


The most common side effects of Mifepristone include:


Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Mifepristone. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Mifepristone?

Store Mifepristone at room temperature, between 68°F to 77°F (20°C to 25°C).

Keep Mifepristone and all medicines out of the reach of children.

General information about the safe and effective use of Mifepristone

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.

Do not use Mifepristone for a condition for which it was not prescribed. Do not give Mifepristone to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about Mifepristone. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Mifepristone that is written for healthcare professionals.

For more information, call 1-855-4KORLYM (1-855-456-7596) or visit www.korlym.com or www.corcept.com.

What are the ingredients in Mifepristone?

Active ingredient: Mifepristone

Inactive ingredients: 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.

This Medication Guide has been approved by the US Food and Drug Administration.

Manufactured for:

Corcept Therapeutics Incorporated

Menlo Park, CA 94025

Mifepristone ® is a registered trademark of Corcept Therapeutics Incorporated.

©2016 Corcept Therapeutics Incorporated. All rights reserved.

K-00004 OCT 2016

PRINCIPAL DISPLAY PANEL - for 28 Tablets Bottle Label

NDC 76346-073-01

28 Tablets Rx only

Mifepristone ®

Mifepristone


Take tablets whole. Do not split, crush or chew.

ATTENTION PHARMACIST: Dispense attached Medication Guide to each patient.

================================================================

PRINCIPAL DISPLAY PANEL - for 280 Tablets Bottle Label

NDC 76346-073-02

280 Tablets Rx only

Mifepristone

Mifepristone


Take tablets whole. Do not split, crush or chew.

ATTENTION PHARMACIST: Dispense attached Medication Guide to each patient

Mifepristone pharmaceutical active ingredients containing related brand and generic drugs:


Mifepristone available forms, composition, doses:

Price
Mifeprex 200 mg tablet90.0 USD
Tablets; Oral; Mifepristone 200 mg
Tablets; Oral; Mifepristone 50 mg

Mifepristone destination | category:


Mifepristone Anatomical Therapeutic Chemical codes:


Mifepristone pharmaceutical companies:


References

  1. Dailymed."KORLYM (MIFEPRISTONE) TABLET [CORCEPT THERAPEUTICS INC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."MIFEPRISTONE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "mifepristone". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Mifepristone?

Depending on the reaction of the Mifepristone after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Mifepristone not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Mifepristone addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Mifepristone, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Mifepristone consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

Visitor reported useful

No survey data has been collected yet

Visitor reported side effects

No survey data has been collected yet

One visitor reported price estimates

What is your opinion about drug cost? Did you feel the cost is apt, or did you feel it is expensive?
The report given by the sdrugs.com website users shows the following figures about several people who felt the medicine Mifepristone is expensive, and the medicine is not expensive. The results are mixed. The perception of the cost of the medicine to be expensive or not depends on the brand name of the medicine, country, and place where it is sold, and the affordability of the patient. You can choose a generic drug in the place of the branded drug to save the cost. The efficiency of the medicine will not vary if it is generic or a branded one.
Visitors%
Expensive1
100.0%

Visitor reported frequency of use

No survey data has been collected yet

Two visitors reported doses

What is the dose of Mifepristone drug you are taking?
According to the survey conducted among sdrugs.com website users, the maximum number of people are using the following dose 501mg-1g. Few medications come in only one or two doses. Few are specific for adult dose and child dose. The dose of the medicine given to the patient depends on the severity of the symptom/disease. There can be dose adjustments made by the doctor, based on the progression of the disease. Follow-up is important.
Visitors%
501mg-1g1
50.0%
101-200mg1
50.0%

Visitor reported time for results

No survey data has been collected yet

Visitor reported administration

No survey data has been collected yet

Visitor reported age

No survey data has been collected yet

Visitor reviews


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The information was verified by Dr. Rachana Salvi, MD Pharmacology


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