mifepristone (Rx)

>10% (Mifeprex)

Abdominal pain, cramping (96%)

Uterine cramping (83%)

Nausea (43-61%)

Headache (2-31%)

Vomiting (1-26%)

Diarrhea (12-20%)

Dizziness (1-12%)

>10% (Korlym)

Fatigue (48%)

Nausea (48%)

Headache (44%)

Endometrial hypertrophy (38%)

Hypokalemia (34%)

Arthralgia (30%)

Vomiting (26%)

Peripheral edema (26%)

Hypertension (24%)

Dizziness (22%)

Decreased appetite (20%)

Abnormal thyroid function test (18%)

Xerostomia (18%)

Back pain (16%)

Dyspnea (16%)

Myalgia (14%)

Pain (14%)

Sinusitis (14%)

Nasopharyngitis (12%)

Extremity pain (12%)

Diarrhea (12%)

Postmarketing reports

• Angioedema

1-10% (Mifeprex)

Fatigue (10%)

Back pain (9%)

Decreased hemoglobin >2 g/dL (6%)

Uterine hemorrhage (5%)

Viral infection (4%)

Dyspepsia (3%)

Insomnia (3%)

Rigors (3%)

Vaginitis (3%)

Anemia (2%)

Anxiety (2%)

Fainting (2%)

Leg pain (2%)

Leukorrhea (2%)

Pelvic pain (2%)

Sinusitis (2%)

Weakness (2%)

1-10% (Korlym)

Constipation (10%)

Somnolence (10%)

Anorexia (10%)

Anxiety (10%)

Gastroesophageal reflux (5-10%)

Abdominal pain (5-10%)

Increased triglycerides (5-10%)

Hypoglycemia (5-10%)

Insomnia (5-10%)

Vaginal hemorrhage, metrorrhagia (5-10%)

General disorders: asthenia, malaise, edema, pitting edema, thirst (5-10%)

Musculoskeletal and connective tissue disorders: muscular weakness, flank pain, musculoskeletal chest pain (5-10%)

Adrenal insufficiency (4%)

Rash (4%)

Pruritus (4%)

Contraindications

Known hypersensitivity to mifepristone, misoprostol, or other prostaglandins

Mifeprex

• Confirmed or suspected ectopic pregnancy, undiagnosed adnexal mass, or IUD currently in place
• Chronic adrenal failure or concurrent long-term corticosteroid therapy
• Hemorrhagic disorders, inherited porphyrias, or concurrent anticoagulant therapy
• Concurrent long-term corticosteroid therapy
• Hypersensitivity to drug or components
• Inherited porphyrias
• Patients with intrauterine device (IUD) in place if terminating intrauterine pregnancy

Korlym

• Pregnancy
• Coadministration with simvastatin or lovastatin and CYP3A substrates with narrow therapeutic range (eg, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus)
• Patients requiring systemic corticosteroids for serious medical conditions
• Women with history of unexplained vaginal bleeding
• Women with endometrial hyperplasia with atypia or endometrial carcinoma

Cautions

Mifeprex

• A clinical examination or ultrasonographic scan should be performed approximately 14 days after mifepristone administration to confirm termination of pregnancy
• Preventive measures to suppress formation of anti-Rho(D) antibodies (eg, administration of Rho(D) immune globulin) should be considered in Rho (D)-negative women
• Use with caution in women <35 years who smoke 10 or more cigarettes daily
• Available only through a restricted program under a REMS called the Mifeprex REMS Program, because of the risks of serious complications; prescribers must be certified and patients must sign a patient agreement form
• Must be dispensed to patients only in certain healthcare settings, specifically clinics, medical offices, and hospitals by or under the supervision of a certified prescriber

• Infection and sepsis

  • Any termination of pregnancy, including those resulting from mifepristone use, may result in serious, potentially fatal infections and bleeding (see Black Box Warnings)
  • As with other types of abortion, cases of serious bacterial infection, including very rare cases of fatal septic shock, reported following the therapy
  • Healthcare providers evaluating a patient who is undergoing a medical abortion should be alert to possibility of this rare event; a sustained (> 4 hours) fever of 100.4°F or higher, severe abdominal pain, or pelvic tenderness in the days after a medical abortion may be indication of infection
  • A high index of suspicion is needed to rule out sepsis (eg, from Clostridium sordellii) if patient reports abdominal pain or discomfort or general malaise (including weakness, nausea, vomiting, or diarrhea) more than 24 hours after taking misoprostol
  • Very rarely, deaths have been reported in patients who presented without fever, with or without abdominal pain, but with leukocytosis with a marked left shift, tachycardia, hemoconcentration, and general malaise
  • No causal relationship between drug and misoprostol use and an increased risk of infection or death established
  • Clostridium sordellii infections have also been reported very rarely following childbirth (vaginal delivery and caesarian section), and in other gynecologic and non-gynecologic conditions

• Uterine bleeding

  • Uterine bleeding occurs in almost all patients during medical abortion; prolonged heavy bleeding (soaking through two thick full-size sanitary pads per hour for two consecutive hours) may be a sign of incomplete abortion or other complications, and prompt medical or surgical intervention may be needed to prevent development of hypovolemic shock
  • Counsel patients to seek immediate medical attention if they experience prolonged heavy vaginal bleeding following a medical abortion
  • Women should expect to experience vaginal bleeding or spotting for an average of 9 to 16 days; women report experiencing heavy bleeding for a median duration of 2 days
  • Up to 8% of all subjects may experience some type of bleeding for 30 days or more. In general, the duration of bleeding and spotting increased as duration of pregnancy increased
  • Decreases in hemoglobin concentration, hematocrit, and red blood cell count may occur in women who bleed heavily
  • Excessive uterine bleeding usually requires treatment by uterotonics, vasoconstrictor drugs, surgical uterine evacuation, administration of saline infusions, and/or blood transfusions
  • Based on data from several large clinical trials, vasoconstrictor drugs were used in 4.3% of all subjects, there was a decrease in hemoglobin of more than 2 g/dL in 5.5% of subjects, and blood transfusions were administered to < 0.1% of subjects
  • Because heavy bleeding requiring surgical uterine evacuation occurs in about 1% of patients, special care should be given to patients with hemostatic disorders, hypocoagulability, or severe anemia

• Ectopic pregnancy

  • Contraindicated in patients with a confirmed or suspected ectopic pregnancy; drug is not effective for terminating ectopic pregnancies
  • Healthcare providers should remain alert to possibility that a patient who is undergoing a medical abortion could have an undiagnosed ectopic pregnancy because some of the expected symptoms experienced with a medical abortion (abdominal pain, uterine bleeding) may be similar to those of a ruptured ectopic pregnancy.
  • The presence of an ectopic pregnancy may have been missed even if the patient underwent ultrasonography prior to being prescribed drug
  • Women who became pregnant with an IUD in place should be assessed for ectopic pregnancy

• REMS program

  • Prescribers must be certified with the program by completing the Prescriber Agreement Form.
  • Patients must sign a Patient Agreement Form.
  • Drug must be dispensed to patients only in certain healthcare settings, specifically clinics, medical offices and hospitals by or under the supervision of a certified prescriber
  • Further information is available at 1-877-4 Early Option (1-877-432-7596)

Korlym

• Do not use for treatment of hyperglycemia unrelated to Cushing syndrome; patients with endogenous Cushing’s syndrome are at risk for opportunistic infections such as Pneumocystis jiroveci pneumonia during treatment; patients may present with respiratory distress shortly after initiation of therapy; appropriate diagnostic tests should be undertaken and treatment for Pneumocystis jiroveci should be considered
• Drug prolongs 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
• Drug 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
• Use of Korlym in patients who receive corticosteroids for other conditions (eg, autoimmune disorders) may lead to exacerbation or deterioration because of Korlym’s glucocorticoid antagonistic effects; for medical conditions in which chronic corticosteroid therapy is life-saving (eg, immunosuppression in organ transplantation), Korlym is contraindicated
• Coadministration with strong CYP3A inhibitors can increase mifepristone plasma levels significantly; use only when necessary and limit mifepristone dose to 300 mg (see Dosage Modification)

• 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
  • Drug should be used with caution in women who have hemorrhagic disorders or are receiving concurrent anticoagulant therapy
  • Women who experience vaginal bleeding during treatment should be referred to a gynecologist for further evaluation

• Adrenal insufficiency

  • Patients receiving mifepristone may experience adrenal insufficiency
  • Because serum cortisol levels remain elevated and may even increase during treatment, serum cortisol levels do not provide an accurate assessment of hypoadrenalism in patients receiving drug
  • 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 drug immediately and administer glucocorticoids without delay
  • High doses of supplemental glucocorticoids may be needed to overcome glucocorticoid receptor blockade produced by mifepristone
  • Factors considered in deciding on duration of glucocorticoid treatment should include the long half-life of mifepristone (85 hr).
  • Treatment 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)

• Hypokalemia

  • In a study of patients with Cushing’s syndrome, hypokalemia observed
  • Hypokalemia should be corrected prior to initiating therapy; during administration, serum potassium should be measured 1-2 weeks after starting or increasing dose and periodically thereafter
  • Hypokalemia can occur at any time during 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

Pregnancy

Drug contraindicated in pregnancy because use results in pregnancy loss; there are no data that assess risk of birth defects in women exposed to drug 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

Pregnancy testing

• Due to its anti-presentational activity, drug causes pregnancy loss; perform pregnancy testing before initiation of treatment or if treatment interrupted for more than 14 days in females of reproductive potential

Contraception

• Recommend non-hormonal contraception for duration of treatment and for one month after stopping treatment; drug interferes with effectiveness of hormonal contraceptives

Animal data

• Administered to pregnant mice, rats, and rabbits during organogenesis caused pregnancy loss in all species at clinically relevant doses based on body surface area comparisons; inhibition of both endogenous and exogenous progesterone by mifepristone at progesterone receptor results in pregnancy loss; if used during pregnancy or if patient becomes pregnant while taking drug, patient should be apprised of potential hazard to a fetus
• Estimated risk of fetal loss is elevated in patients with active Cushing’s syndrome (24-30%), and risk of major birth defects is unknown; in the U.S. general population, estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively

Lactation

Drug is present in human milk, however, there are no data on amount of mifepristone in human milk, effects on breastfed infant, or on milk production during long term use of mifepristone; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for Korlym and any potential adverse effects on breastfed child from drug or from the underlying maternal condition

To minimize exposure to a breastfed infant, women who discontinue or interrupt treatment may consider pumping and discarding milk during treatment and for 18-21 days (5-6 half-lives) after last dose, before breastfeeding

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Stimulate uterine contractility: antiprogestin; also increases prostaglandins by inhibiting prostaglandin dehydrogenase

Blocks cortisol receptor binding, and thereby reduces excess cortisol effects (eg, hyperglycemia) associated with endogenous Cushing syndrome

Absorption

Peak Plasma Time: 1-2 hr (single dose); 1-4 hr (multiple doses)

Peak Plasma Concentration: 2-8 hr

Distribution

Protein Bound: >99% to alpha-1-acid glycoprotein; 96-99% (active metabolites)

Distributed to other tissues including CNS

Metabolism

Extensively metabolized by CYP3A4

Metabolized to 3 active metabolites, of which 2 are the product of demethylation, while a third active metabolite results from hydroxylation

In addition to being a CYP3A4 substrate, it also inhibits and induces CYP3A4

Elimination

Half-life: 20 hr (single dose); 85 hr (parent drug following multiple doses)

Excretion: 90% feces

Oral Administration (Mifeprex)

200 mg PO once given by a healthcare provider in a clinic, medical office, or hospital followed 24-48 hr later by misoprostol buccal administration

Buccal administration (misoprostol)

• Because most women will expel the pregnancy within 2-24 hr of taking misoprostol, discuss with the patient an appropriate location for her to be when she takes the misoprostol, taking into account that expulsion could begin within 2 hr of administration
• Administer misoprostol 800 mcg buccally within 24-48 hr after taking Mifeprex
• The effectiveness of the regimen may be lower if misoprostol is administered <24 hr or >48 hr after mifepristone administration
• Tell the patient to place two 200 mcg misoprostol tablets in each cheek pouch (the area between the cheek and gums) for 30 minutes and then swallow any remnants with water or another liquid
• During the period immediately following the administration of misoprostol, the patient may need medication for cramps or GI symptoms

Oral Administration (Korlym)

Always take with a meal

Must be taken as a single daily dose

Swallow tablet whole, do not split, crush, or chew

Dose reduction or discontinuation may be needed in some clinical situations; if dosage is interrupted, reinitiate at the lowest dose (ie, 300 mg/day)