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

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
• Women who became pregnant with an IUD in place should be assessed for ectopic pregnancy
• Use with caution in women <35 years who smoke 10 or more cigarettes daily
• Any termination of pregnancy, including those resulting from mifepristone use, may result in serious, potentially fatal infections and bleeding (see Black Box Warnings)
• 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

Korlym

• Do not use for treatment of hyperglycemia unrelated to Cushing syndrome
• Adrenal insufficiency may occur; discontinue therapy if signs or symptoms occur and administer glucocorticoids
• Hypokalemia should be corrected prior to treatment and monitored for during treatment
• Women may experience endometrial thickening or unexpected vaginal bleeding; use with caution if patient also has a hemorrhagic disorder or is on anticoagulant therapy
• Avoid use with QT interval-prolonging drugs or in patients with potassium channel variants resulting in a long QT interval
• 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)

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)