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Introduction ⬇

VA Class:HS200

ATC Class:G03XB01

AHFS Class:

Generic Name(s):

Chemical Name:

Molecular Formula:

Notification

REMS:

FDA approved a REMS for mifepristone (Mifeprex® and approved generic tablets) to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of mifepristone and consists of the following: elements to assure safe use and implementation system. See the FDA REMS page ([Web]).

Mifepristone, a synthetic derivative of the progestin norethindrone, is a progesterone- and glucocorticoid-receptor antagonist.1,2,3,4,5,6,7,8,9,19,40

Uses ⬆ ⬇

[Section Outline]

Termination of Pregnancy !!navigator!!

Mifepristone (Mifeprex® and generics) is FDA-labeled for use in conjunction with misoprostol for the medical termination of intrauterine pregnancy (i.e., medical abortion) through 70 days of gestation as dated from the first day of the last menstrual period; duration of pregnancy may be determined by menstrual history or clinical examination, or with an ultrasonographic scan if duration of pregnancy is uncertain or ectopic pregnancy is suspected.1,2,3,4,5,6,7,10,11,19,20,21,22,27,45 For termination of pregnancy, a single dose of mifepristone is administered, followed by misoprostol administered 24-48 hours after the mifepristone dose.1 Misoprostol must be administered 24-48 hours following mifepristone administration.1 Misoprostol, a prostaglandin E1 analog, induces uterine contractions and expulsion of the products of conception.2,11,12,13,19,27

In clinical studies in women with pregnancies of up to 70 days of gestation, oral mifepristone followed by oral misoprostol was effective for medical termination of pregnancy (i.e., complete expulsion of pregnancy without the need for surgical intervention) in approximately 96-97% of the women.1,2,19,20,21 The remaining patients later had surgical intervention due to incomplete abortion, excessive bleeding, ongoing pregnancy, medical necessity, or at the patient's request.1 As gestational age increased, efficacy of the mifepristone and misoprostol regimen decreased;2,4,11,19,21 complete medical abortion was reported in 98.1% of pregnancies at less than 49 days of gestation compared with 96.8, 94.7, and 92.7% of pregnancies at 50-56, 57-63, and 64-70 days of gestation, respectively.1 Surgical intervention for ongoing pregnancy was reported for 0.3, 0.8, 2, and 3.1% of pregnancies at less than 49, 50-56, 57-63, and 64-70 days of gestation, respectively.1 In one study that included pregnancies through 70 days of gestation, 23-38% of patients reported expulsion of the products of conception within 3 hours, and over 90% of patients reported expulsion within 24 hours of misoprostol administration.1

Although the manufacturer of misoprostol states that it has not conducted and does not intend to conduct research to support use in pregnancy (e.g., termination of pregnancy),14 mifepristone is labeled by FDA for use with misoprostol for termination of pregnancy,1 and the American College of Obstetricians and Gynecologists (ACOG) states that the medication abortion regimen supported by major medical organizations nationally and internationally includes mifepristone and misoprostol; if mifepristone is unavailable, then a misoprostol-only regimen is an acceptable alternative.44

Mifepristone also has been used for termination of pregnancy during the second or third trimester†,3,4,6,7 induction of labor†,3,4,6,7 postcoital contraception†,3,4,5,6,7 endometriosis†,3,4,6 leiomyoma†,3,4 and meningioma†.3,4,6 Mifepristone also has been used with intravaginal misoprostol (using tablets formulated for oral administration) for termination of pregnancy;2,10,11,27 however, such use very rarely has resulted in fatal bacterial infection and sepsis.37,38,39

Hyperglycemia Secondary to Cushing's Syndrome !!navigator!!

Mifepristone (Korlym®) is used for the management of hyperglycemia secondary to hypercortisolism in adults with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not surgical candidates.40 Mifepristone is designated an orphan drug by FDA for the treatment of clinical manifestations of endogenous Cushing's syndrome.41

Mifepristone is not indicated for treatment of type 2 diabetes mellitus that is not secondary to Cushing's syndrome.40

Efficacy and safety of mifepristone for the management of hyperglycemia secondary to Cushing's syndrome were evaluated in an uncontrolled, open-label, multicenter study of 24 weeks' duration in adults with endogenous Cushing's syndrome and associated type 2 diabetes mellitus, impaired glucose tolerance (defined as blood glucose concentration of 140-199 mg/dL following a 2-hour oral glucose tolerance test [oGTT]), or hypertension.40,43 Patients in this study had failed surgery, experienced disease recurrence, or were not considered surgical candidates.40 Of the 50 patients enrolled in the study, 29 had type 2 diabetes mellitus or impaired glucose tolerance (diabetes cohort), and 21 had hypertension (hypertension cohort).40,43 All patients received an initial mifepristone dosage of 300 mg once daily; dosage could be increased to 600 mg once daily after 2 weeks and then increased, based on tolerability and clinical response, in 300-mg increments every 4 weeks to a maximum of 900 or 1200 mg once daily in patients weighing less than or greater than 60 kg, respectively.40,43 Existing antidiabetic therapy was continued throughout the study, without dosage increases or additions to therapy.40

The primary end point for the diabetes cohort was the proportion of patients who experienced at least a 25% reduction in glucose area under the plasma concentration-time curve (AUC) following oGTT from baseline to week 24.40,43 For the hypertension cohort, the primary end point was change in diastolic blood pressure from baseline to week 24; a response was defined as a decrease of at least 5 mm Hg.43 At week 24, 60% of patients in the diabetes cohort achieved at least 25% reduction in glucose AUC.40,43 Mifepristone treatment also substantially decreased glycosylated hemoglobin (hemoglobin A1c; HbA1c); of the 24 patients with HbA1c measurements, the mean reduction in HbA1c was 1.1%.40,43 In the 15 patients receiving antidiabetic agents at baseline, either dosage of the antidiabetic agent was reduced or antidiabetic therapy remained stable.40 There were no substantial changes in mean systolic and diastolic blood pressures in the hypertension cohort.40,43

Dosage and Administration ⬆ ⬇

[Section Outline]

General !!navigator!!

Mifepristone (Mifeprex® and generics) is used for the medical termination of pregnancy and is intended for use by clinicians who are able to assess the gestational age of an embryo and to diagnose ectopic pregnancy.1,22,30,45 If necessary, clinicians also must be able to provide surgical intervention in cases of incomplete abortion or severe bleeding or ensure that such services are available from others, and patients must have access to medical facilities equipped to provide blood transfusions and resuscitation.1,22 Any intrauterine contraceptive device (IUD) should be removed prior to administration of mifepristone for termination of pregnancy.1

Mifepristone (Korlym®) is used for the management of hyperglycemia secondary to Cushing's syndrome.40 Women of childbearing potential should be evaluated for pregnancy prior to initiation of the drug.40

Because mifepristone may cause hypokalemia in patients with Cushing's syndrome, serum potassium concentrations should be monitored and corrected prior to initiation of mifepristone (Korlym®), 1-2 weeks after initiation of the drug or dosage increases, and periodically during therapy.1

Because of the long half-life of mifepristone at steady state, the manufacturer of mifepristone (Korlym®) states at least 2 weeks must elapse between discontinuance of mifepristone and initiation or dosage increases of any interacting concomitant drugs.40

Mifepristone REMS Program

For termination of pregnancy, mifepristone (Mifeprex® and generics) is only available through the Mifepristone Risk Evaluation and Mitigation Strategy (REMS) Program.1,22 The goal of the Mifepristone REMS Program is to mitigate the risk of serious complications associated with mifepristone when used for medical termination of pregnancy through 10 weeks gestation by requiring that prescribers have the necessary qualifications to assess whether patients are appropriate candidates for the drug and to provide necessary intervention in case of complications, ensuring that mifepristone is only dispensed by certified pharmacies or by or under the supervision of certified prescribers, and requiring that patients be informed of the risks of the treatment regimen.22 Although a causal association has not been determined, serious adverse events have been reported in patients receiving mifepristone, including 2 cases of ectopic pregnancy resulting in death and several fatal cases of severe systemic infection.22

Under the Mifepristone REMS, clinicians must be certified to prescribe the drug; pharmacists must be certified to dispense the drug; and patients must review the patient agreement form and manufacturer's medication guide before they can receive the drug.22 The previous requirement for mifepristone to be dispensed only in certain health care settings (e.g., clinics, medical offices, hospitals) has been removed from the current REMS, and certified pharmacies may now dispense mifepristone directly to patients upon receipt of a prescription from a certified prescriber.22 Additional information about the Mifepristone REMS Program is available at 877-432-7596 or [Web].1,22

Termination of Pregnancy

Mifepristone (Mifeprex® and generics) is administered orally as a single dose, followed by intrabuccal administration of misoprostol 24-48 hours later.1,45 The effectiveness of the regimen may be reduced if misoprostol is administered less than 24 hours or more than 48 hours after the mifepristone dose.1

For intrabuccal administration of misoprostol, patients should be instructed to place 2 misoprostol tablets in each side of the mouth between the cheek and gums for 30 minutes, then swallow any remnants with water or another liquid.1

Misoprostol should be administered in an appropriate setting for the patient, taking into account that expulsion of uterine contents could begin within 2 hours of misoprostol administration.1 Medications for treatment of adverse effects (e.g., cramping, GI symptoms) may be needed in the period immediately following misoprostol administration.1

Patients should be advised regarding appropriate actions to take if severe discomfort, excessive vaginal bleeding, or other adverse reactions occur.1 The name and telephone number of the clinician who will be handling emergencies and a telephone number to call with any questions following administration of misoprostol also should be provided to the patient.1

The manufacturers state that patients must return for a follow-up clinical examination approximately 7-14 days after receiving mifepristone and misoprostol to confirm complete termination of pregnancy and to assess severity of any continued bleeding.1,45 However, some experts state that the type of follow-up visit after medical abortion has evolved over time, and routine in-person follow-up is not necessary after an uncomplicated medication abortion.44 Termination of pregnancy may be confirmed by medical history, clinical examination, human chorionic gonadotropin (hCG) testing, or ultrasonographic scan.1 Persistence of moderate to heavy vaginal bleeding at this follow-up visit could indicate an incomplete abortion.1 Lack of bleeding following the mifepristone and misoprostol regimen usually indicates treatment failure; however, prolonged or heavy bleeding is not proof of a complete abortion.1 Surgical termination is recommended to manage failure of medical abortion after the mifepristone and misoprostol regimen.1 Debris seen in the uterus on ultrasonography following the regimen will not necessarily require surgery for removal.1

Hyperglycemia Secondary to Cushing's Syndrome

Mifepristone (Korlym®) is administered orally once daily with a meal.40 Tablets should be swallowed whole and should not be split, crushed, or chewed.40

Dosage !!navigator!!

Termination of Pregnancy

The recommended dosage of mifepristone (Mifeprex® and generics) for the medical termination of pregnancy is 200 mg orally as a single dose followed by intrabuccal administration of misoprostol (800 mcg as a single dose given 24-48 hours after the mifepristone dose).1,45

If complete expulsion of the products of conception has not occurred at the follow-up examination, and the pregnancy is not ongoing, another intrabuccal dose of misoprostol (800 mcg) may be administered.1 Uterine rupture has been reported rarely in women receiving mifepristone and misoprostol for termination of pregnancy, including women with prior uterine rupture or scarring and those receiving multiple doses of misoprostol within 24 hours.1 Patients should return for a follow-up examination approximately 7 days after administration of the repeated misoprostol dose to assess for complete pregnancy termination.1

Hyperglycemia Secondary to Cushing's Syndrome

The recommended initial dosage of mifepristone (Korlym®) for the management of hyperglycemia secondary to hypercortisolism in adults with endogenous Cushing's syndrome is 300 mg once daily.40 Dosage may be increased in increments of 300 mg at intervals of no less than 2-4 weeks based on clinical response and tolerability up to a maximum dosage of 20 mg/kg daily.40 The maximum recommended dosage of mifepristone is 1200 mg once daily.40

Careful and gradual dosage titration and monitoring for adverse reactions may reduce the risk of severe adverse effects.40 Interruption of therapy and/or dosage reduction may be necessary in some clinical situations.40 If treatment is interrupted, mifepristone should be reinitiated at the lowest dosage (i.e., 300 mg once daily).40 If treatment is interrupted as a result of adverse effects, the drug should be titrated to a lower dosage.40

Changes in glucose control, antidiabetic medication requirements, serum insulin concentration, and psychiatric symptoms may provide an early assessment of response (i.e., within 6 weeks) and may help guide early dosage titration.40 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 dosage adjustments beyond the first 2 months of therapy.40

Dosage Modification for Concomitant Use with Cytochrome P-450 (CYP) 3A Inhibitors

Mifepristone (Korlym®) should be used concomitantly with drugs that are potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A only when necessary.40 If concomitant use is clinically warranted, the manufacturer of mifepristone (Korlym®) recommends that mifepristone dosage should not exceed 600 mg once daily.40

If mifepristone therapy is initiated for management of hyperglycemia secondary to Cushing's syndrome in a patient who is already receiving a potent CYP3A inhibitor, the recommended starting dosage of mifepristone is 300 mg once daily.40 If clinically indicated, the dosage of mifepristone may be titrated to a maximum of 600 mg once daily in such patients.40

If a potent CYP3A inhibitor is initiated in a patient who is already receiving mifepristone therapy for management of hyperglycemia secondary to Cushing's syndrome, dosage adjustment of mifepristone may be necessary.40 In patients already receiving mifepristone 300 mg once daily, no dosage adjustment is required.40 In those already receiving mifepristone 600 mg once daily, dosage should be reduced to 300 mg once daily; dosage may be titrated to a maximum of 600 mg once daily if clinically indicated.40 For patients already receiving mifepristone 900 or 1200 mg once daily, dosage should be reduced to 600 mg once daily.40

Special Populations !!navigator!!

The manufacturer of mifepristone (Mifeprex®) makes no special population dosage recommendations for use of mifepristone for the medical termination of pregnancy.1

If mifepristone (Korlym®) is used for the management of hyperglycemia secondary to Cushing's syndrome in patients with renal impairment or mild to moderate hepatic impairment, the maximum recommended mifepristone dosage is 600 mg once daily; initial dosage adjustment is not necessary.40 Mifepristone for the management of hyperglycemia secondary to Cushing's syndrome in patients with severe hepatic impairment is not recommended; the drug has not been studied in this patient population.40

Cautions ⬆ ⬇

[Section Outline]

Contraindications !!navigator!!

Warnings/Precautions !!navigator!!

Warnings

Fetal/Neonatal Morbidity and Mortality

Mifepristone causes termination of pregnancy1,40 and, when used for management of hyperglycemia secondary to Cushing's syndrome, is contraindicated during pregnancy.40 A boxed warning about this risk has been included in the prescribing information for the mifepristone preparation used in the treatment of Cushing's syndrome (Korlym®).40

Pregnancy must be excluded prior to initiation of mifepristone (Korlym®), and women of childbearing potential should use effective, nonhormonal contraception during therapy and for 1 month after discontinuance of the drug, unless the woman has undergone surgical sterilization.40 In addition, such patients should be reevaluated for pregnancy if therapy is interrupted for more than 14 days.40

If mifepristone (Korlym®) is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.40

Hemorrhage

Serious and sometimes fatal bleeding can occur rarely following spontaneous, surgical, and medical abortions, including use of mifepristone.1 A causal relationship to mifepristone and misoprostol has not been established.1 A boxed warning about this risk has been included in the prescribing information for the mifepristone preparation used for the medical termination of intrauterine pregnancy (Mifeprex® and generics).1,45

Uterine bleeding occurs in almost all women receiving mifepristone in conjunction with misoprostol for termination of pregnancy.1,3,11,19,20,21 Based on clinical studies, bleeding or spotting should be expected for an average of 9-16 days;1,19,20 heavy bleeding has been reported for a median duration of 2 days.1 Although more bleeding occurs after pregnancy termination with the mifepristone and misoprostol regimen than after a surgical abortion,2,10,11 in most patients the total blood loss is not clinically important and is indistinguishable from that associated with a spontaneous miscarriage.6,10,11 However, in about 8% of patients, bleeding continued 30 days or longer, and the duration of bleeding and spotting generally increased as the duration of pregnancy increased.1,10,19,20 Severity of uterine bleeding should be assessed when the patient returns for follow-up examination approximately 7-14 days after the mifepristone and misoprostol regimen.1

Severe uterine bleeding may occur following spontaneous, surgical, or medical abortion (including following mifepristone administration).1 Prolonged heavy vaginal bleeding (i.e., soaking through 2 thick full-size sanitary pads per hour for 2 consecutive hours) may be a sign of incomplete abortion or other complications, and prompt medical or surgical intervention may be required to prevent the development of hypovolemic shock.1 Patients should be advised to seek immediate medical attention if prolonged heavy vaginal bleeding or syncope occurs following mifepristone administration.1 Decreases in hemoglobin concentration, hematocrit, and red blood cell count may occur in women who experience heavy bleeding.1

Excessive uterine bleeding usually requires treatment with uterotonics, vasoconstrictors, saline infusions, and/or blood transfusions or surgical uterine evacuation.1 In approximately 1% of patients, heavy bleeding requiring surgical uterine evacuation occurs, and caution should be exercised in patients with hemostatic disorders, hypocoagulability, or severe anemia.1

Infection and Sepsis

Serious and sometimes fatal bacterial (e.g., Clostridium sordellii ) infections and sepsis, which can present without fever, bacteremia, or significant findings on pelvic examination, can occur rarely following spontaneous, surgical, and medical abortions, including use of mifepristone; a causal relationship to mifepristone and misoprostol has not been established.1,30,37,39 A boxed warning about this risk has been included in the prescribing information for the mifepristone preparation used for the medical termination of intrauterine pregnancy (Mifeprex® and generics).1,45

Serious bacterial (e.g., Clostridium sordellii ) infection and sepsis can present without fever, bacteremia, or substantial findings on pelvic examination.1,39 Deaths have been reported very rarely in patients who presented without fever, with or without abdominal pain, but with leukocytosis with a marked left shift, tachycardia, hemoconcentration, and general malaise.1,39 These deaths occurred in women who received intravaginal misoprostol; however, a causal relationship between use of mifepristone and misoprostol and risk of infection or death has not been established.37,38,39 Furthermore, C. sordellii infections also have been reported very rarely following childbirth (vaginal delivery and cesarean section) and in other gynecologic and nongynecologic conditions.1,39

Clinicians should maintain a high index of suspicion to rule out serious infection and sepsis if sustained fever (temperature of 38°C or higher persisting for more than 4 hours), severe abdominal pain, or pelvic tenderness occurs within several days of medical abortion, or if abdominal pain/discomfort or general malaise (including weakness, nausea, vomiting, or diarrhea), with or without fever, occurs more than 24 hours after administration of misoprostol.1,30,37,38

The American College of Obstetricians and Gynecologists (ACOG) states that the routine use of prophylactic antibiotics is not recommended in patients undergoing medical abortion.44 Following concerns about serious, rare, and deadly infection with clostridial bacteria in patients undergoing medical abortion, ACOG states that there is no evidence of a specific connection between clostridial organisms and medical abortion.44

Other Warnings and Precautions

Ectopic Pregnancy

Mifepristone is not effective for the termination of ectopic pregnancy and is contraindicated for use in patients with confirmed or suspected ectopic pregnancy.1 The manufacturer states that, despite the clinician's best effort to rule out ectopic pregnancy, the possibility that such a condition may be present during the treatment period should be considered; some of the expected symptoms experienced with a medical abortion (e.g., abdominal pain, uterine bleeding) may be similar to those of a ruptured ectopic pregnancy.1

Patients who became pregnant with an IUD in place should be evaluated for ectopic pregnancy.1

Adrenal Insufficiency

Adrenal insufficiency may occur in patients receiving mifepristone for management of hyperglycemia secondary to Cushing's syndrome.40 In patients with Cushing's syndrome, serum cortisol concentrations remain elevated and may increase during treatment with mifepristone resulting from blockade of glucocorticoid receptors; therefore, serum cortisol concentrations are not a reliable parameter for assessment of adrenal insufficiency.40 Patients should be closely monitored for manifestations of adrenal insufficiency, including weakness, nausea, increased fatigue, hypotension, and hypoglycemia.40

If adrenal insufficiency is suspected, mifepristone should be immediately discontinued and glucocorticoid therapy initiated; patients should be evaluated for precipitating causes of adrenal insufficiency (e.g., infection, trauma).40 High dosages of glucocorticoid may be necessary to overcome glucocorticoid-receptor blockade produced by mifepristone.40 Duration of glucocorticoid therapy should take into account the long half-life of mifepristone (85 hours).40 Upon resolution of adrenal insufficiency, mifepristone therapy may be resumed at a lower dosage.40

Hypokalemia

Hypokalemia has been reported in 44% of patients with Cushing's syndrome receiving mifepristone and can occur at any time during mifepristone therapy.40

Serum potassium concentrations should be monitored and corrected prior to initiating mifepristone in patients with Cushing's syndrome, 1-2 weeks after initiation of therapy or dosage increases, and periodically during therapy.40 Hypokalemia may be treated with IV or oral potassium supplementation, based on clinical severity.40 If hypokalemia persists despite potassium supplementation, addition of mineralocorticoid (aldosterone) antagonist therapy should be considered.40

Vaginal Bleeding and Endometrial Changes

Progesterone-receptor blockade by mifepristone promotes unopposed endometrial proliferation and may result in endometrial thickening, cystic dilatation of endometrial glands, and uterine bleeding in women not undergoing medical abortion.40 Women receiving mifepristone for management of clinical manifestations of Cushing's syndrome who experience unexplained vaginal bleeding during therapy with the drug should be referred to a gynecologist for further evaluation.40

Uterine rupture has been reported rarely in women receiving mifepristone and misoprostol for termination of pregnancy, including women with prior uterine rupture or scarring and those receiving multiple doses of misoprostol within 24 hours.1 Women who choose to use a repeat dose of misoprostol should have a follow-up visit with their healthcare provider in approximately 7 days to assess for complete termination.1

Prolongation of QT Interval

Mifepristone and its metabolites block the rapidly activating delayed rectifier potassium current Ikr and produce dose-related prolongation of the QT interval.40 Data on the effects of high mifepristone dosages, concomitant use of other drugs that prolong the QT interval, or use in patients with long QT interval are limited.40

The manufacturer of mifepristone (Korlym®) states that the lowest possible effective dosage of mifepristone should be used to minimize risk of QT-interval prolongation, and the drug should be avoided in patients with potassium channel variants resulting in a long QT interval.40 In addition, concomitant use of mifepristone and drugs that prolong the QT interval should be avoided.40

Exacerbation/Deterioration of Conditions Treated with Corticosteroids

Mifepristone antagonizes the effects of glucocorticoids; therefore, use of mifepristone for management of hyperglycemia secondary to Cushing's syndrome in patients receiving corticosteroid therapy for other conditions (e.g., autoimmune disorders) may lead to exacerbation or deterioration of such conditions.40 Use of mifepristone in patients with Cushing's syndrome is contraindicated in patients with conditions where corticosteroid therapy is considered lifesaving (e.g., immunosuppression in organ transplantation).40

Concomitant Use with Potent CYP3A Inhibitors

Mifepristone (Korlym®) should be used with caution in patients receiving ketoconazole or other potent inhibitors of CYP3A, since concomitant use may increase mifepristone systemic exposure.40 The benefits of such concomitant use should be carefully weighed against the potential risks.40 Mifepristone (Korlym®) should be used concomitantly with potent CYP3A inhibitors only when necessary; if concomitant use is clinically warranted, the dosage of mifepristone should not exceed 600 mg once daily.40

Suppression of Rh Isoimmunization

As with a surgical abortion, preventive measures to suppress formation of anti-Rho(D) antibodies (e.g., administration of Rho[D] immune globulin) should be considered in Rho(D)-negative women who receive the mifepristone and misoprostol regimen for medical abortion.1,3,10,11,18

Death

As of December 31, 2018, 24 deaths have been reported in women receiving mifepristone for the medical termination of pregnancy, including 2 cases of ectopic pregnancy.30 In addition, there were several reported cases of sepsis that also resulted in some fatalities.30 A causal relationship to mifepristone has not been established because of concomitant use of other drugs, other medical or surgical treatments, concurrent medical conditions, and lack of information about the patient's health status and clinical management.30

Pending further investigation, clinicians and patients should be aware of the specific circumstances and directions for use as well as risks (e.g., sepsis) associated with mifepristone therapy.37 In addition, clinicians should inform patients of early potential manifestations that may warrant immediate medical evaluation.37

Pneumocystis jirovecii Pneumonia

Patients with endogenous Cushing's syndrome receiving mifepristone have an increased risk of opportunistic infections such as Pneumocystis jirovecii (formerly known as Pneumocystis carinii ) pneumonia (PCP).40 Patients should be monitored closely for possible PCP, including respiratory distress early in treatment; if PCP is diagnosed, appropriate therapy should be provided.40

Effects of Hypercortisolism

In patients with Cushing's syndrome, serum cortisol concentrations remain elevated and may increase during mifepristone therapy.40 Elevated serum cortisol concentrations may activate mineralocorticoid (aldosterone) receptors that are expressed in cardiac tissues.40 Caution should be used in patients with underlying cardiac conditions, including heart failure and coronary vascular disease.40

Specific Populations

Pregnancy

Mifepristone (Mifeprex® and generics) is used in conjunction with misoprostol for the medical termination of pregnancy (through 70 days of gestation) and is not labeled by FDA for any other indication during pregnancy.1,45 The drug is contraindicated in women with a confirmed or suspected ectopic pregnancy.1,45

Mifepristone (Korlym®) is contraindicated in pregnancy.40 Pregnancy must be excluded prior to initiation of the drug for the management of hyperglycemia secondary to Cushing's syndrome in women of childbearing potential and such women should use nonhormonal contraceptives during and for 1 month after the drug is discontinued.40

Lactation

Mifepristone is distributed into milk at low to undetectable concentrations.1,40 Limited data indicate the weight-adjusted infant dose in milk may be no more than 0.5% of the maternal dose.1

Data are not available on the effects of mifepristone (Mifeprex®) used in conjunction with misoprostol for termination of pregnancy on a breast-fed infant or on milk production.1 The developmental and health benefits of breast-feeding should be considered along with any potential adverse effects on the breast-fed child from mifepristone used in conjunction with misoprostol.1

Because of the potential for serious adverse reactions to mifepristone in nursing infants, the manufacturer of mifepristone (Korlym®) states that a decision should be made whether to discontinue nursing or the drug in women with hyperglycemia secondary to Cushing's syndrome.40

Pediatric Use

Safety and efficacy of mifepristone (Mifeprex®) for termination of pregnancy have been established in pregnant females, including those younger than 17 years of age.1

Safety and efficacy of mifepristone (Korlym®) for management of hyperglycemia secondary to Cushing's syndrome have not been established in pediatric patients.40

Geriatric Use

Clinical studies of mifepristone (Korlym®) did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.40

Hepatic Impairment

Moderate hepatic impairment (Child-Pugh class B) did not appear to substantially affect the pharmacokinetics of mifepristone in single- and multiple-dose pharmacokinetic studies; however, there was high interpatient variability in the exposure of mifepristone and its metabolites.40 Because of limited information on safety in patients with hepatic impairment, dosage of mifepristone for the management of hyperglycemia secondary to Cushing's syndrome should not exceed 600 mg once daily in patients with mild or moderate hepatic impairment.40 Mifepristone has not been evaluated in patients with severe hepatic impairment.40

Renal Impairment

Systemic exposure of mifepristone is increased 31% in patients with severe renal impairment (creatinine clearance less than 30 mL/minute not requiring dialysis) compared with individuals with normal renal function.40 Dosage of mifepristone in patients with hyperglycemia secondary to Cushing's syndrome in patients with renal impairment should not exceed 600 mg once daily.40

Common Adverse Effects !!navigator!!

Mifepristone (Mifeprex®): Vaginal bleeding and abdominal pain/cramping are expected effects when mifepristone is used for termination of pregnancy.1 Adverse effects occurring in over 15% of patients receiving mifepristone in conjunction with misoprostol for termination of pregnancy in clinical studies include nausea, weakness, fever/chills, vomiting, headache, diarrhea, and dizziness.1

Mifepristone (Korlym®): Adverse effects occurring in 20% or more of patients with Cushing's syndrome receiving mifepristone in the open-label study include nausea,40,43 fatigue,40,43 headache,40,43 hypokalemia,40,43 arthralgia,40,43 vomiting,40,43 peripheral edema,40,43 hypertension,40,43 dizziness,40,43 decreased appetite,40,43 and endometrial hypertrophy.40,43

Drug Interactions ⬆ ⬇

[Section Outline]

Mifepristone is metabolized primarily by cytochrome P-450 (CYP) isoenzyme 3A4.1,40 In vitro studies demonstrate that mifepristone inhibits and induces CYP3A.40 The drug also inhibits CYP isoenzymes 2C8, 2C9, and 2B6 in vitro.40 In vitro studies indicate potential drug interactions with substrates of CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4.40

In vitro studies indicate potential interactions between mifepristone and drugs transported by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).40

Because of the long half-life of mifepristone at steady state, the manufacturer states at least 2 weeks should elapse between discontinuance of mifepristone for management of hyperglycemia secondary to Cushing's syndrome and initiation or dosage increases of any interacting concomitant drugs.40

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes !!navigator!!

CYP3A Inhibitors

Concomitant use of mifepristone and potent inhibitors of CYP3A4 may increase plasma concentrations of mifepristone and dosage reduction of mifepristone may be required.1,40

Mifepristone should be used with caution and only when necessary in patients currently or recently receiving therapy with potent CYP3A4 inhibitors.1,40 If concomitant use of a potent CYP3A inhibitor (e.g., atazanavir, clarithromycin, conivaptan, fosamprenavir, indinavir, itraconazole, ketoconazole, the fixed combination of lopinavir and ritonavir [lopinavir/ritonavir], nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, voriconazole) is clinically warranted, the manufacturer of mifepristone (Korlym®) states that the maximum recommended dosage of the drug for the management of hyperglycemia in patients with Cushing's syndrome is 600 mg once daily.40

Grapefruit juice should be avoided in patients receiving mifepristone.40

Cimetidine

Concomitant use of mifepristone (300 mg daily for 14 days) and cimetidine (800 mg daily; a weak CYP3A inhibitor) slightly decreased peak plasma concentrations and systemic exposure of mifepristone; the manufacturer of mifepristone (Korlym®) states dosage adjustment is not required during concomitant use.40

CYP3A Inducers

Concomitant use of mifepristone and inducers of CYP3A4 (e.g., carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, St. John's wort [ Hypericum perforatum ]) may result in increased mifepristone metabolism and decreased serum mifepristone concentrations.1

Clinical effects of such an interaction on termination of pregnancy are unknown.1

Concomitant use of daily mifepristone for management of hyperglycemia secondary to Cushing's syndrome and CYP3A4 inducers should be avoided.40

CYP3A Substrates

Concomitant use of mifepristone with drugs that are metabolized by CYP3A4 may result in increased systemic exposure of the substrate drug.1,40 Concomitant use of daily mifepristone for management of hyperglycemia secondary to Cushing's syndrome and substrates of CYP3A4 that have a narrow therapeutic index (e.g., cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) is contraindicated.40 Because of the increased risk of rhabdomyolysis, concomitant use of daily mifepristone and simvastatin or lovastatin in patients with Cushing's syndrome also is contraindicated.40 Caution should be exercised if single-dose mifepristone for the termination of pregnancy is used concomitantly with substrates of CYP3A4 that have a narrow therapeutic index.1

Drugs that undergo extensive first-pass metabolism that are metabolized by CYP3A (e.g., midazolam, sildenafil, triazolam) should be used with extreme caution in patients with Cushing's syndrome receiving daily mifepristone.40 If concomitant use cannot be avoided, the manufacturer of mifepristone (Korlym®) recommends using the lowest effective dosage of the CYP3A substrate; therapeutic drug monitoring of the CYP3A substrate is recommended when possible.40 An alternative to such CYP3A substrates also is advised for concomitant use with daily mifepristone when possible.40

If daily mifepristone for management of hyperglycemia secondary to Cushing's syndrome is used concomitantly with drugs that undergo minimal first-pass metabolism via CYP3A or are metabolized by CYP3A to a lesser extent, the manufacturer recommends using the lowest effective dose of the concomitant drug and/or decreased dosing frequency of the CYP3A substrate and monitoring for adverse effects; therapeutic drug monitoring of the CYP3A substrate is recommended when possible.40

Alprazolam

Concomitant use of mifepristone (1200 mg daily for 10 days) and alprazolam (single 1-mg dose; a CYP3A substrate with minimal first-pass effect) increased systemic exposure of alprazolam by 80% and decreased 4-hydroxy-alprazolam exposure by 24%.40

Simvastatin

In healthy individuals, concomitant use of mifepristone (1200 mg daily for 10 days) and simvastatin (single 80-mg dose; a CYP3A substrate with extensive first-pass effect) increased systemic exposure to simvastatin and simvastatin acid by approximately 10.4- and 15.7-fold, respectively.40 Concomitant use of mifepristone and simvastatin is contraindicated.40

CYP2B6 Substrates

Concomitant use of mifepristone with drugs that are metabolized by CYP2B6 (e.g., bupropion, efavirenz) may result in increased systemic exposure of such drugs.40 Caution is advised if mifepristone is used concomitantly with substrates of CYP2B6.40

CYP2C8 and/or 2C9 Substrates

Concomitant use of mifepristone with drugs that are metabolized principally by CYP2C8 and/or 2C9 (e.g., nonsteroidal anti-inflammatory agents [NSAIAs], repaglinide, warfarin) may result in increased systemic exposure of such drugs.40 If daily mifepristone for management of hyperglycemia secondary to Cushing's syndrome is used concomitantly with drugs that are substrates of CYP2C8 and/or 2C9, the manufacturer recommends the CYP2C8 and/or 2C9 substrates be given at the lowest effective dosage and the patient closely monitored for adverse effects.40

Fluvastatin

In healthy individuals, concomitant use of mifepristone (1200 mg daily for 7 days) and fluvastatin (single 40-mg dose; a CYP2C8 and 2C9 substrate) increased systemic exposure of fluvastatin by approximately 3.6-fold.40

Drugs that Prolong the QT Interval !!navigator!!

Effects of concomitant use of mifepristone and drugs that prolong the QT interval are not known; concomitant use should be avoided.40

Digoxin !!navigator!!

Concomitant use of mifepristone (1200 mg daily for 10 days) and digoxin (0.125 mg daily) increased systemic exposure and peak plasma concentration of digoxin 1.4- and 1.6-fold, respectively.40 The manufacturer of mifepristone (Korlym®) recommends that plasma digoxin concentrations should be assessed after 1-2 weeks of concomitant use and periodically as clinically appropriate.40

Hormonal Contraceptives !!navigator!!

Mifepristone is a progesterone-receptor antagonist and may reduce the efficacy of hormonal contraceptives.40 Nonhormonal methods of contraception should be used in women of childbearing potential with Cushing's syndrome who are receiving daily mifepristone.40

Other Information ⬆ ⬇

Description

Mifepristone, a synthetic derivative of the progestin norethindrone, is a progesterone- and glucocorticoid-receptor antagonist.1,2,3,4,5,6,7,8,9,19,40 Mifepristone is a selective antagonist of the progesterone receptor at lower dosages and exhibits antiglucocorticoid activity at higher dosages.1,3,5,6,7,8,9,40 At higher dosages, mifepristone acts as a glucocorticoid-receptor antagonist but exhibits little affinity for the mineralocorticoid (aldosterone) receptor.40 At dosages of 1 mg/kg or higher, mifepristone antagonizes the endometrial and myometrial effects of progesterone in women; dosages of 4.5 mg/kg or higher cause compensatory elevation of corticotropin (ACTH) and cortisol in humans.1 The drug also has been shown to have weak antiandrogenic activity.1,5,7,8,9 Mifepristone exhibits little to no affinity for estrogen, muscarinic, histamine, or monoamine receptors.40

Mifepristone binds to the progesterone receptor with greater affinity than progesterone, competitively antagonizing the endometrial and myometrial effects of progesterone and resulting in down-regulation of progesterone-dependent genes.1,2,3,4,5,6,7,8,27 Since the continuance of a viable pregnancy depends on progesterone, detachment of the products of conception and termination of pregnancy result.1,2,3,5,6,8,9 In addition, mifepristone promotes uterine contractions and softening of the cervix and sensitizes the myometrium to effects of prostaglandins (e.g., misoprostol) that stimulate uterine contractions and expulsion of the products of conception.1,2,3,4,5,6,7,9,27 In the absence of progesterone, mifepristone acts as a partial progestin agonist.6,7,9

Mifepristone (Mifeprex®) is rapidly absorbed following oral administration and reaches peak plasma concentrations approximately 45 and 90 minutes following single 200- and 600-mg doses, respectively.1 Time to peak plasma concentration occurs 1-2 and 1-4 hours following single and multiple 600-mg oral doses of mifepristone (Korlym®), respectively; peak plasma concentrations of the active metabolites occur 2-8 hours following multiple 600-mg oral doses.40 Administration with food substantially increases plasma concentrations of mifepristone.40 The absolute oral bioavailability of a single 20-mg dose of mifepristone in women of childbearing age is 69%.1 Mifepristone is 98-99% bound to plasma proteins (mainly albumin and α1-acid glycoprotein);40 binding of the drug and its active metabolites is concentration dependent.40 Mifepristone and its metabolites are distributed into milk and other tissues, including the CNS.1,40 Mifepristone is extensively metabolized, principally via the cytochrome P-450 (CYP) 3A4 isoenzyme1,3,27 into 3 known active metabolites.40 The drug and its metabolites are excreted mainly in feces (83-90%)1,40,46 with smaller amounts excreted in urine (9%).1,3,5,7,8 The initial half-life of the drug is 12-72 hours; the terminal elimination half-life is 18 hours.1 The half-life following multiple doses of 600 mg daily is 85 hours.40

Advice to Patients

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations ⬆ ⬇

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of mifepristone (Mifeprex® and generics) is restricted.1,30,42,45 The drug can be obtained only through the Mifepristone REMS program.1

Mifepristone (Korlym®) is available through a designated specialty pharmacy.42 Information regarding distribution of the drug is available from the manufacturer at 855-456-7596 or [Web].42

Mifepristone

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

200 mg*

Mifeprex®

Danco

Mifepristone Tablets

300 mg

Korlym®

Corcept Therapeutics

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Copyright ⬆ ⬇

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions January 18, 2023. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References ⬆

1. Danco Laboratories, LLC. Mifeprex® (mifepristone) oral tablets prescribing information. New York, NY; 2020 Oct.

2. Christin-Maitre S, Bouchard P, Spitz IM. Medical termination of pregnancy. N Engl J Med . 2000; 342:946-56. [PubMed 10738054]

3. Heikinheimo O. Clinical pharmacokinetics of mifepristone. Clin Pharmacokinet . 1997; 33:7-17. [PubMed 9250420]

4. Mahajan DK, London SN. Mifepristone (RU486): a review. Fertil Steril . 1997; 68:967-76. [PubMed 9418681]

5. Avrech OM, Bukovsky I, Golan A et al. Mifepristone (RU486) alone or in combination with a prostaglandin analogue for termination of early pregnancy: a review. Fertil Steril . 1991; 56:385-93. [PubMed 1894013]

6. Spitz IM, Bardin CW. Mifepristone (RU 486)—a modulator of progestin and glucocorticoid action. N Engl J Med . 1993; 329:404-12. [PubMed 8326975]

7. Brogden RN, Goa KL, Faulds D. Mifepristone: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential. Drugs . 1993; 45:384-409. [PubMed 7682909]

8. Baulieu EE. RU-486 as an antiprogesterone steroid: from receptor to contragestion and beyond. JAMA . 1989; 262:1808-14. [PubMed 2674487]

9. Mifegyne (mifepristone), a new antiprogestagen with potential therapeutic use in human fertility control. Drugs . 1988; 35:187-91.

10. Grimes DA. Medical abortion in early pregnancy: a review of the evidence. Obstet Gynecol . 1997; 89:790-6. [PubMed 9166323]

11. Newhall EP, Winikoff B. Abortion with mifepristone and misoprostol: regimens, efficacy, acceptability and future directions. Am J Obstet Gynecol . 2000; 183:S44-53. [PubMed 10944369]

12. Searle. Cytotec® (misoprostol) oral tablets prescribing information. Skokie, IL; 2000 Oct 2.

13. Monk JP, Clissold SP. Misoprostol: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of peptic ulcer disease. Drugs . 1987; 33:1-30. [PubMed 3102205]

14. Cullen M, Searle. Dear health care provider: Important drug warning concerning unapproved use of intravaginal or oral misoprostol in pregnant women for induction of labor or abortion. Skokie, IL; 2000 Aug 23.

15. American College of Obstetricians and Gynecologists. News release: ACOG issues letter on safety of misoprostol. Washington, DC; 2000 Oct 12.

16. Anon. ACOG committee opinion: induction of labor with misoprostol. Obstet Gynecol . 1999; 94:1-2.

17. American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins. Induction of labor. Practice Bulletin No. 10. Washington, DC: American College of Obstetricians and Gynecologists; 1999 Nov.

18. American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins. Prevention of Rh D alloimmunization. Practice Bulletin No. 4. Washington, DC: American College of Obstetricians and Gynecologists; 1999 May.

19. Spitz IM, Bardin CW, Benton L et al. Early pregnancy termination with mifepristone and misoprostol in the United States. N Engl J Med . 1998; 338:1241-7. [PubMed 9562577]

20. Peyron R, Aubény E, Targosz V et al. Early termination of pregnancy with mifepristone (RU 486) and the orally active prostaglandin misoprostol. N Engl J Med . 1993; 328:1509-13. [PubMed 8479487]

21. Aubény E, Peyron R, Turpin CL et al. Termination of early pregnancy (up to 63 days of amenorrhea) with mifepristone and increasing doses of misoprostol. Int J Fertil Menopausal Stud . 1995; 40:85-91. [PubMed 8574255]

22. Food and Drug Administration. Questions and answers on Mifeprex. Silver Spring, MD; 2023 Jan 4. From FDA website.Questions and answers on mifepristone for medical termination of pregnancy through ten weeks gestation. From the FDA website. [Web]

25. Population Council, New York, NY: Personal communication.

26. Pharmacia & Upjohn, Skokie, IL: Personal communication.

27. Anon. Mifepristone (RU 486). Med Lett Drugs Ther. 2000; 42: 101-102.

30. Food and Drug Administration. Questions and answers on Mifeprex. Silver Spring, MD; 2019 Apr 12. From FDA website. [Web]

36. Food and Drug Administration. Mifeprex (mifepristone) information. Silver Spring, MD; 2018 Feb 5. From FDA website. Accessed 2019 Aug 2. [Web]

37. Food and Drug Administration. FDA Public Health Advisory: Sepsis and Medical Abortion Update (March 17, 2006). Silver Spring, MD; 2006 Mar 17.

38. Food and Drug Administration. FDA Public Health Advisory: Sepsis and Medical Abortion (November 4, 2005 update). Silver Spring, MD; 2005 Nov 4.

39. Fischer M, Bhatnagar J, Guarner J et al. Fatal toxic shock syndrome associated with Clostridium sordellii after medical abortion. N Engl J Med . 2005; 353:2352-60. [PubMed 16319384]

40. Corcept Therapeutics, Inc. Korlym® (mifepristone) tablets prescribing information. Menlo Park, CA; 2017 May.

41. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed 2016 Jul 27. [Web]

42. Corcept Therapeutics, Inc. Support program for access and reimbursement for Korlym® (SPARK). From Korlym® website. Accessed 2019 Aug 2. [Web]

43. Fleseriu M, Biller BM, Findling JW et al. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing's syndrome. J Clin Endocrinol Metab . 2012; 97:2039-49. [PubMed 22466348]

44. American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins. Medical abortion up to 70 days of gestation. Practice Bulletin No. 225. Washington, DC: American College of Obstetricians and Gynecologists; 2014 Mar. [Web]

45. GenBioPro, Inc. Mifepristone oral tablets prescribing information. Las Vegas, NV; 2019 Feb

46. Sarkar NN. Mifepristone: bioavailability, pharmacokinetics and use-effectiveness. Eur J Obstet Gynecol Reprod Biol . 2002; 101:113-20. [PubMed 11858883]