The antiprogestational effects of mifepristone will result in the termination of pregnancy (fetal death). Mifepristone promotes unopposed endometrial proliferation that may result in endometrium thickening, cystic dilatation of endometrial glands, and vaginal bleeding. Refer individuals who experience vaginal bleeding during chronic mifepristone treatment to a gynecologist for further evaluation.[48697] The pregnancy termination procedure that uses mifepristone (e.g., Mifeprex) is designed to induce the vaginal bleeding and uterine contractions necessary to produce termination of pregnancy (fetal death). If prolonged heavy bleeding is present following mifepristone administration for termination of pregnancy, the patient should be immediately assessed as this could be a sign of serious complications including, but not limited to, incomplete abortion; prompt medical or surgical intervention may be needed.[28003] According to data from clinical trials, women should expect to experience vaginal bleeding or spotting for an average of 9 to 16 days, while up to 8% may experience some type of bleeding for 30 days or more; bleeding was reported to last for 69 days in one patient in the French trials. In general, the duration of bleeding increase as the duration of the pregnancy to be terminated increases. Of note, 80% to 90% of women report that the bleeding is more heavy than that seen during a normal menstrual period, and uterine hemorrhage occurs in roughly 5% of patients. Excessive uterine bleeding may require treatment by vasoconstrictor drugs, curettage, administration of saline infusions, and/or blood transfusions; decreased hemoglobin concentration, hematocrit, and red blood cell (RBC) count may be seen. In U.S. trials, 4.8% of patients received administration of uterotonic medications, 1% received intravenous fluids, and a blood transfusion was given to 1 of 859 patients. In French trials, vasoconstrictor drugs were used in 4.3%, hemoglobin decreases of more than 2 grams/dL occurred in 5.5%, and blood transfusions were administered in two of 1,800 patients. Heavy bleeding required curettage in 1% of patients. Uterine cramping was common when used for pregnancy termination (83% to 96%). Anemia, leukorrhea, uterine rupture, excessive vaginal bleeding or uterine hemorrhage, ruptured ectopic pregnancy, and hematometra were reported during the postmarketing period when used for pregnancy termination.[28003]

Following pregnancy termination with a mifepristone-containing regimen (e.g., Mifeprex), a high index of suspicion is needed to rule out serious infection or sepsis in any patient presenting with general malaise (including weakness) potential GI infectious symptoms (e.g., emesis, etc.), abdominal discomfort, pelvic pain or tenderness, fever, leukocytosis, sinus tachycardia, or hemoconcentration. Termination of pregnancy poses a risk of serious bacterial infection including fatal septic shock (rare). In the U.S., 0.2% of total women studied (n = 629) experienced sepsis. In the days after a medical abortion, indicators of infection include abdominal or pelvic pain or tenderness, or a sustained fever 100.4 degrees F or greater. Any patient reporting abdominal or pelvic discomfort or general malaise (including weakness), emesis, etc. more than 24 hours after receiving misoprostol, must be carefully evaluated to rule out sepsis (from, for example, Clostridium sordellii). Patients with serious bacterial infections (e.g., Clostridium sordellii) and sepsis can also present without bacteremia, significant findings on pelvic exam, or fever. Deaths have been reported in patients who presented without fever, with or without abdominal/pelvic pain, but with leukocytosis with a marked left shift, sinus tachycardia, hemoconcentration, and general malaise.[28003] As of April 2011, 14 deaths were reported in the U.S. following the use of mifepristone and misoprostol, with 8 of these deaths due to sepsis (7 were Clostridium sordellii positive, 1 was Clostridium perfringens positive) and 1 of the deaths due to a delayed onset of toxic shock-like syndrome (uterine cultures were positive for Peptostreptococcus and fibroid cultures were positive for Prevotella). Of the fatal sepsis cases, 7 reported vaginal misoprostol use and 1 reported buccal misoprostol use. There were also reports of 5 deaths in women from foreign countries with 1 of these deaths being associated with septic shock (Clostridium sordellii was identified in tissue samples). Additionally, during clinical trials with mifepristone for abortion, there were reports of fever and/or chills (48%) and postmarketing reports of post-termination infection including endometritis, endomyometritis, parametritis, pelvic inflammatory disease, salpingitis, and pelvic infection.[28003] With the use of mifepristone for Cushing's disease (e.g., Korlym), serious infections are not common; during clinical trials, sinusitis (14%) and naso-pharyngitis (12%) were reported. Dyspnea was reported in 16% of patients. Patients with endogenous Cushing's syndrome are at risk for opportunistic infections such as Pneumocystis jiroveci pneumonia during Korlym treatment. Patients may present with respiratory distress or dyspnea shortly after initiation of mifepristone. Appropriate diagnostic tests should be undertaken and treatment for Pneumocystis jiroveci should be considered.[48697]

Gastrointestinal (GI) side effects have been reported with mifepristone use, both for pregnancy termination and for the treatment of Cushing's syndrome. Abdominal pain was reported more frequently when mifepristone was used for pregnancy termination (83% to 96%) than when used for Cushing's disease (5% to 10%). Additionally, GI side effects have included nausea (48% in Cushing's syndrome trials; 51% to 75% for pregnancy termination), vomiting (26% in Cushing's syndrome trials; 37% to 48% for pregnancy termination), and diarrhea (12% in Cushing's syndrome trials; 18% to 43% for pregnancy termination). Gastroesophageal reflux (5 to 10%), xerostomia (18%), polydipsia or thirst (5 to 10%), constipation (10%), anorexia (10%), and decreased appetite (20%) were also reported during use for Cushing's syndrome. Dyspepsia has been reported during the postmarketing period.[28003] [48697]

During clinical trials for Cushing's syndrome, two patients reported a generalized, maculopapular rash (4%) and two others developed pruritus (4%). Rare but significant adverse reactions reported in the literature include 1 case of toxic epidermal necrolysis (TEN) which included stomatitis. Angioedema has also been reported during postmarketing experience with mifepristone use for Cushing's syndrome.[48697] When used for termination of pregnancy, there have been postmarketing reports of allergic reaction including anaphylactoid reactions, angioedema, rash (unspecified), hives (urticaria), and pruritus.[28003]

Female patients may complain of menstrual irregularity when mifepristone is used for chronic endocrine conditions. In clinical trials for the treatment of Cushing's syndrome, endometrial hyperplasia, menstrual irregularity, and unusual vaginal bleeding were reported. 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%); 2 of the 5 had normal endometrial thickness. Endometrial biopsies were performed in 6 patients; 5 of these patients had endometrial thickening. No endometrial carcinoma was detected in the sampled cases.[48697] When used off-label for endometriosis and uterine leiomyomas, amenorrhea and anovulation occur, and are typically considered desired effects. Hot flashes or emotional lability have been reported. When used for post-coital contraception, a delay in ovulation, with a longer menstrual cycle and later return of menses, occurs in approximately 10% of patients; women who continue to have unprotected intercourse have a 22% higher pregnancy rate compared to women who use a contraceptive based post-coital method (i.e., the Yuzpe method or levonorgestrel regimen).[26313] [32606] [37679] [37680]

Laboratory abnormalities have been reported with mifepristone use for Cushing's syndrome. Hypoglycemia was reported in 5% to 10% of patients receiving the drug during the various clinical trials. Decreased blood potassium concentrations were common and occurred in 34% of patients during clinical trials. In another study of patients with Cushing's syndrome, hypokalemia was observed in 44% of subjects during treatment. In these cases, hypokalemia responded to treatment with potassium supplementation and/or mineralocorticoid antagonist therapy (e.g., spironolactone or eplerenone). Elevations of thyroid-stimulating hormone (TSH) were seen in subjects treated with mifepristone for Cushing's syndrome. 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 the drug was discontinued at the end of the study. Increased blood triglyceride concentrations were reported in 5% to 10% of patients during the various clinical trials for Cushing's syndrome. Decreased high density lipoprotein-cholesterol (HDL-C) concentrations were observed during treatment and returned to baseline after drug discontinuation.[48697]

Adrenocortical insufficiency was reported in two patients (4%) in the controlled clinical trial for Cushing's syndrome. The most typical symptoms were nausea and decreased appetite, and no hypotension or hypoglycemia was reported during the events. Adrenal insufficiency resolved in both cases with mifepristone interruption and/or dexamethasone administration.[48697]

Adverse vascular and cardiovascular related reactions have been reported with mifepristone use. During trials for Cushing's syndrome, hypertension was reported in 24% of mifepristone-treated patients, edema and pitting edema were reported in 5% to 10%, and peripheral edema was reported in 26% of treated patients.[48697] When used for pregnancy termination (e.g., Mifeprex), there have been postmarketing reports of syncope, fainting, loss of consciousness, hypotension (including orthostatic hypotension), lightheadedness, and sinus tachycardia (including racing pulse, heart palpitations, heart pounding).[28003]

Adverse nervous system reactions have been reported with mifepristone use. More common side effects included headache (44% in Cushing's syndrome trials; 2% to 44% when used for termination of pregnancy); dizziness (22% in Cushing's syndrome trials; 9% to 41% for termination of pregnancy); and anxiety (10% in Cushing's syndrome trials; reported postmarketing for termination of pregnancy). Fatigue (48%), pain (unspecified, 14%), somnolence (10%), insomnia (5% to 10%), asthenia (5% to 10%) and malaise (5% to 10%) were reported during trials for Cushing's syndrome.[28003] [48697]

Musculoskeletal system side effects have been reported with mifepristone use. Arthralgia (30%), back pain (16%), myalgia (14%), pain in an extremity (12%), muscular weakness (myasthenia, 5% to 10%), flank pain (5% to 10%), and musculoskeletal pain in the chest (5% to 10%) were reported during trials for Cushing's syndrome.[48697] Back pain and leg pain were reported during postmarketing experience when mifepristone is used for termination of pregnancy.[28003]

Mifepristone has two distinct FDA-approved uses: pregnancy termination and the treatment of Cushing's syndrome. The possibility for teratogenesis may exist, particularly when mifepristone is followed by misoprostol administration, or in the case of inadvertent pregnancy when mifepristone is used for chronic treatment indications.[28003] [48697] The approved labeling for the Korlym product (used in Cushing's syndrome) describes a report of 13 live births following single dose exposure of mifepristone resulting in infants with no abnormalities.[48697] The approved labeling for mifepristone used for pregnancy termination (e.g., Mifeprex) describes only 1 known abnormality detected following administration of mifepristone alone, in a case where mifepristone failed to induce abortion and surgical abortion was then performed. Of 82 cases where mifepristone failed to induce abortion, there were 26 infants born with no detected abnormalities, 9 surgical abortions performed with no detected fetal abnormalities, and 46 cases where the outcome of the infant or fetus is unknown.[28003]

Mifepristone use for Cushing's disease (e.g., Korlym) is contraindicated for use in individuals with a history of abnormal uterine bleeding, endometrial cancer, or atypical endometrial hyperplasia, due to the potential for mifepristone-induced hormonal and endometrial changes. Mifepristone promotes unopposed endometrial proliferation that may result in endometrium thickening, cystic dilatation of endometrial glands, and vaginal bleeding.[48697]

Mifepristone, when used for medical abortion (e.g., Mifeprex), has been associated with cases of serious bacterial infection, including, although rare, fatal sepsis and septic shock. Patients should promptly report heavy vaginal bleeding, fever, or abdominal pain following treatment. A sustained fever 100.4 degrees F or above for more than 4 hours, severe abdominal pain, pelvic tenderness, syncope, or prolonged heavy vaginal bleeding, more than 24 hours after a medical abortion may be an indication of infection and warrant intervention; however, practitioners should also be alert to atypical presentations including leukocytosis, tachycardia, hemoconcentration, and general malaise (including weakness, nausea, vomiting, or diarrhea). Ensure the patient knows who to call and what to do if she experiences any of these symptoms. Uterine bleeding is expected during medical abortion; however, prolonged heavy bleeding (soaking through 2 thick full-size sanitary pads per hour for 2 consecutive hours) may be a sign of incomplete medical abortion or other complications. Heavy vaginal bleeding after a medical abortion should prompt the patient to seek immediate medical attention. Serious bacterial infections and sepsis, including fatalities, have occurred following the use of mifepristone and vaginal misoprostol and have been reported in the U.S. Clostridium sordellii has been identified as the causative organism in some cases; none of these patients presented with a fever, but they did present with sinus tachycardia, low blood pressure, leukocytosis, and very high red blood cell counts. The patients also had other atypical symptoms including weakness, nausea/vomiting, or diarrhea with or without abdominal pain. No causal relationship has been established between these events and the mifepristone-misoprostol regimen for termination of pregnancy.[28003] Patients with endogenous Cushing's syndrome are at risk for opportunistic infection such as Pneumocystis jiroveci pneumonia (PCP) during mifepristone treatment. Patients may present with respiratory distress shortly after initiation of the drug. Appropriate diagnostic tests should be undertaken and treatment for Pneumocystis jiroveci should be considered.[48697]

Mifepristone has potent antiprogestational effects that will result in the termination of pregnancy. Mifepristone for treatment of Cushing's syndrome (e.g., Korlym) is contraindicated in women who are pregnant. Exclude pregnancy before the initiation of treatment and advise the female patient of the reproductive risk. Pregnancy testing should occur, and female patients of childbearing potential should have a negative pregnancy test before starting the chronic use of mifepristone and such women also must have a repeat negative pregnancy test if the drug is discontinued for more than 14 days. There are contraception requirements for female patients of reproductive potential during chronic treatment with mifepristone; all female patients of childbearing potential should use non-hormonal contraceptives during treatment and for 1 month after stopping treatment, unless the patient has had a surgical sterilization, in which case no additional contraception is needed. Should a woman become pregnant while taking mifepristone chronically, the woman should be apprised of the potential fetal risk. There are no data that assess the risk of birth defects in women exposed to mifepristone during pregnancy. Available data limited to exposure following a single dose of mifepristone during pregnancy showed a higher rate of major birth defects compared to the general population comparator. Animal studies also indicate a potential for fetal harm.[48697] Medical abortion with mifepristone (e.g., Mifeprex) is indicated when the objective is termination of the pregnancy at 70 days gestation or less, but should not be used for termination of later pregnancy. Mifepristone disrupts pregnancy, leading to the expulsion of the products of conception; mifepristone also has the pharmacologic effect of inducing uterine contractions and labor. Should the medication regimen fail to terminate a pregnancy as intended, the woman should be apprised of the potential fetal risks. The risk of adverse developmental outcomes with a continued pregnancy after a failed pregnancy termination with Mifepristone in a regimen with misoprostol is unknown; however, the process of a failed pregnancy termination could disrupt normal embryo-fetal development and result in adverse developmental effects. Cases of failed terminations and continued pregnancy should be reported to the manufacturer at: 1-855-MIFEINFO (1-855-643-3463). Conception can occur following termination and before resumption of normal menses, so appropriate contraception can be initiated as soon as the pregnancy termination has been confirmed, or before the woman resumes sexual intercourse.[28003]

Mifepristone (e.g., Mifeprex) is contraindicated for use if ectopic pregnancy is present.[28003] Do not use the mifepristone-misoprostol combination regimen in patients with confirmed or suspected ectopic pregnancy or undiagnosed adnexal mass; the drug treatment procedure will not be effective to terminate an ectopic pregnancy. Any abdominal pain should be evaluated prior to use and throughout the treatment period, as this may indicate ectopic pregnancy or may indicate an infectious process, which may be serious. The antiprogestin mifepristone has no direct effect on the cytotrophoblast. An undetected ectopic pregnancy may then rupture and cause serious morbidity. Because ectopic pregnancy may be present despite a practitioner's efforts to rule it out prior to use of the drug, the practitioner should consider the possibility of ectopic pregnancy throughout the treatment period and have a plan for its management.[28003]

When used for pregnancy termination, mifepristone is contraindicated in patients with an intrauterine device (IUD) in place. Mifepristone can be used if the IUD is removed.[28003]

Because it is important to have access to appropriate medical care if an emergency develops, mifepristone (e.g., Mifeprex) should not be administered if a patient does not have adequate access to medical facilities equipped to provide emergency treatment of incomplete abortion, blood transfusions, surgery, and emergency resuscitation during the treatment period. Mifepristone should not be used by any patient who may be unable to understand the effects of the termination treatment procedure or to comply with its regimen or the required office visits. Patients should review the required Medication Guide and Patient Agreement Form and should be given a copy of the mifepristone label for review. Patients should discuss their understanding of these materials with their health care providers, and retain the Medication Guide for later reference. Patients should return for a follow-up visit at approximately 7 to 14 days after administration of mifepristone to confirm that the pregnancy is completely terminated. If complete expulsion has not occurred, and the pregnancy is not ongoing, another dose of misoprostol can be administered; however, there have been rare reports of uterine rupture in women receiving mifepristone and misoprostol, including women who received multiple doses of misoprostol within 24 hours. Women who choose a repeat dose of misoprostol should have a follow-up visit approximately 7 days later. The existence of debris in the uterus, if seen on ultrasonography, does not necessarily require surgical removal. Surgical evacuation is recommended in cases of ongoing pregnancies after failed medical abortion.[28003]

Mifepristone (e.g., Korlym), when used in the treatment of Cushing's syndrome, should be used with caution in patients with renal impairment or renal failure, and in patients with mild to moderate hepatic impairment; maximum doses should not exceed 600 mg per day. The chronic use of mifepristone in patients with severe hepatic disease is not recommended. Due to an increased risk of adverse events due to reduced hepatic metabolism, mifepristone should be used with extreme caution in patients taking ketoconazole and other strong CYP3A inhibitors, 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. If use of a strong CYP3A inhibitor is medically necessary, the daily adult mifepristone dose should be limited to 300 mg/day.[48697]

Mifepristone (e.g., Mifeprex) for pregnancy termination is contraindicated in patients with inherited porphyria due to the risk of worsening or precipitating attacks.[28003]

Mifepristone (e.g., Korlym) is for the treatment of hyperglycemia related to Cushing's syndrome. The drug should not be used in the treatment of patients with type 2 diabetes mellitus unless it is secondary to Cushing's syndrome. In patients with Cushing's syndrome, changes in glucose control, antidiabetic medication requirements or insulin levels may provide an early assessment of response (within 6 weeks) and may help guide early dose titration.[48697]

Mifepristone (e.g., Mifeprex) is contraindicated for pregnancy termination in individuals receiving anticoagulant therapy and those with bleeding disorder, due to the risk for heavy bleeding. Use with caution in individuals with pre-existing anemia. The use of mifepristone is assumed to require the same preventive measures as those taken prior to and during surgical abortion to prevent rhesus [Rho] immunization in Rho[D]-negative individuals exposed to Rho[D]-positive fetal blood. All individuals should be scheduled for and return for a follow-up visit at approximately 7 to 14 days after administration of mifepristone to confirm that the pregnancy is completely terminated and evaluate the degree of bleeding. Termination can be confirmed by medical history, clinical examination, human Chorionic Gonadotropin (hCG) testing, or ultrasonographic scan. Lack of bleeding after treatment usually indicates medication failure; however, prolonged or heavy bleeding is not proof of a complete abortion. Prolonged, heavy vaginal bleeding (soaking through 2 thick full-size sanitary pads per hour for 2 consecutive hours) may be a sign of incomplete abortion or other complications; prompt medical and/or surgical intervention may be necessary. Individuals should be instructed to seek immediate medical attention if they experience prolonged, heavy vaginal bleeding. Report hospitalization, blood transfusion, failed terminations, or other serious adverse events to the manufacturer 1-855-643-3463.[28003] When used chronically, mifepristone (e.g., Korlym) should be used with caution in women who have hemorrhagic disorders or are receiving concurrent anticoagulant therapy. 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 during chronic use. Individuals who experience unexplained vaginal bleeding during treatment should be referred to a gynecologist for further evaluation.[48697]

The use of mifepristone in individuals on long-term corticosteroid therapy, such as patients with organ transplant, is considered contraindicated due to the potential risk of adrenal insufficiency.[28003] [48697] Mifepristone (e.g., Mifeprex) is contraindicated in patients with chronic adrenal failure due to a risk of acute renal insufficiency.[28003] During chronic use (e.g., Korlym therapy), monitor closely for signs and symptoms of adrenal insufficiency, including weakness, nausea, increased fatigue, hypotension, and hypoglycemia with chronic use. Discontinue mifepristone if adrenal insufficiency is suspected and administer glucocorticoids immediately; high doses and prolonged treatment may be necessary taking into account the long half-life of mifepristone (85 hours). After symptom resolution, re-instate mifepristone therapy at a lower dose with close monitoring.[48697]

During clinical trials for Cushing's syndrome, hypokalemia was observed during mifepristone (e.g., Korlym) therapy and can occur at any time during treatment. Hypokalemia should therefore be corrected before mifepristone treatment begins. In addition, monitor serum potassium 1 to 2 weeks following dose initiation or increase and periodically thereafter. Correct mifepristone-induced hypokalemia with intravenous or oral potassium supplementation based on clinical need. If hypokalemia persists in spite of potassium supplementation, consider adding mineralocorticoid antagonists. Hypokalemia may increase the risk of a prolonged QT interval due to the drug.[48697]

Caution is warranted when mifepristone (e.g., Korlym) is used chronically in patients with underlying cardiac disease including heart failure and coronary artery disease. Mifepristone does not reduce serum cortisol levels; elevated cortisol levels may activate mineralocorticoid receptors which are also expressed in cardiac tissues. Mifepristone produces QT prolongation in a dose-related manner. Use mifepristone with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, people 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation. No research has been conducted to determine the effect of high dose exposure, concomitant dosing with other QT-prolonging drugs, or potassium channel variants resulting in a long QT interval. Therefore, administer mifepristone at the lowest effective dose and monitor for adverse cardiac events. There are no data on the safety and efficacy of mifepristone in women with chronic medical conditions such as cardiac disease or hypertension, as these patients were generally excluded from clinical trials for pregnancy termination.[28003] [28432] [28457] [48697] [56592] [65180]

Single-dose regimens of mifepristone may be used with caution during breastfeeding. Limited data show undetectable to negligible levels in human milk after single doses with a relative infant dose range of 0.04 to 0.5%.[70364] [70365] The effects in a nursing infant or on milk production are unknown.[28003] [48697] To minimize exposure to a breastfed infant, women who discontinue or interrupt chronic mifepristone treatment may consider pumping and discarding breast milk during treatment and for 18 to 21 days (5 to 6 half-lives) after the last dose, before breast-feeding.[48697]

Clinical studies with mifepristone (e.g., Korlym) for the treatment of Cushing's syndrome did not include sufficient numbers of geriatric patients aged 65 years of age and older to determine whether they respond differently than younger people. In general, dose selection and escalation for an elderly patient should be cautious, due to the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Geriatric patients may be at increased risk for QT prolongation when using mifepristone. Due to the indication for use, mifepristone (e.g., Mifeprex) is not indicated for use in geriatric females.[28003] [28432] [28457] [48697] [56592] [65180]