mifepristone

Mifepristone is a synthetic steroid that is categorized into two drug classes, antiprogestins and cortisol receptor blockers.

The Mifeprex brand of mifepristone is an antiprogestin, used to terminate intrauterine pregnancy in its early phase, up to 70 days of gestation. Mifepristone causes pregnancy termination by:

• Blocking the activity of progesterone, a natural hormone that prepares the endometrium, the inner lining of the uterus, for implantation and continuation of pregnancy.
• Increasing the concentration of prostaglandin, a natural compound in the body that promotes contraction of the uterine muscle wall (myometrium), which results in menstrual bleeding and termination of pregnancy.

The Korlym brand of mifepristone is a cortisol receptor blocker, used to manage and treat high blood glucose levels (hyperglycemia) in people with Cushing’s syndrome, a disorder that leads to excessive levels of cortisol, a natural steroid hormone. Mifepristone helps lower blood sugar levels by:

• Blocking cortisol from binding to its glucocorticoid receptors, mitigating hyperglycemia caused by excess cortisol levels. Mifepristone, however, does not reduce cortisol levels.

Mifepristone is approved by the FDA for the following uses:

• Pregnancy termination: Termination of pregnancy up to 10 weeks of gestation, in combination with misoprostol, a drug that induces uterus contraction. Mifepristone is typically administered as a single dose followed by misoprostol 24-48 hours later.
• Cushing’s syndrome: Management and treatment 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 cannot have surgery.
• Ovarian cancer: Orphan designation

Mifeprex

• Serious and sometimes fatal infections and bleeding occur very rarely following spontaneous, surgical, and medical abortions
• Atypical presentation of infection reported; patients with serious bacterial infections (eg, Clostridium sordellii) and sepsis can present without fever, bacteremia or significant findings on pelvic examination following an abortion; 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
• Prolonged heavy bleeding may be a sign of incomplete abortion or other complications that requires prompt medical attention
• Should be used only with strict adherence to recommended dosages by medically trained personnel who can provide immediate intensive care in acute surgical facilities

Korlym

• Potent antiprogestational effects and will result in the termination of pregnancy
• Pregnancy must therefore be excluded before the initiation of treatment with Korlym, or if treatment is interrupted for more than 14 days in females of reproductive potential
• Pregnancy must be prevented during treatment and for 1 month after stopping treatment by the use of a nonhormonal medically acceptable method of contraception unless the patient has had a surgical sterilization

Contraindications for mifepristone include:

• Hypersensitivity to mifepristone, misoprostol, other prostaglandins, or components of mifepristone

Mifeprex contraindications

• Confirmed or suspected ectopic pregnancy, undiagnosed adnexal mass, or intrauterine device (IUD) currently in place
• Chronic adrenal failure or concurrent long-term corticosteroid therapy
• Hemorrhagic disorders inherited porphyrias or concurrent anticoagulant therapy

Korlym contraindications

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

Common side effects of mifepristone include:

• Abdominal pain, cramping
• Uterine cramping
• Nausea
• Fatigue
• Headache
• Vomiting
• Diarrhea
• Dizziness
• Endometrial hypertrophy
• Low blood potassium (hypokalemia)
• Joint pain (arthralgia)
• Swelling of extremities (peripheral edema)
• High blood pressure (hypertension)
• Decreased appetite
• Abnormal thyroid function test
• Dry mouth (xerostomia)
• Back pain
• Shortness of breath (dyspnea)
• Muscle pain (myalgia)
• Pain
• Sinus inflammation (sinusitis)
• Nose and throat inflammation (nasopharyngitis)
• Extremity pain
• Constipation
• Drowsiness (somnolence)
• Loss of appetite (anorexia)
• Anxiety
• Gastroesophageal reflux
• Increase in triglycerides
• Low blood sugar (hypoglycemia)
• Decrease in hemoglobin
• Sleeplessness (insomnia)
• Vaginal hemorrhage
• Uterine hemorrhage
• Abnormal uterine bleeding between periods (metrorrhagia)
• Viral infection
• Indigestion (dyspepsia)
• Chills/shivering (rigors)
• Inflammation of the vagina (vaginitis)
• Anemia
• Fainting
• Leg pain
• Whitish discharge from the vagina (leukorrhea)
• Pelvic pain
• Weakness
• Lack of energy (asthenia)
• Feeling unwell (malaise)
• Swelling (edema, pitting edema)
• Swelling of face, tongue and lips (angioedema)
• Thirst
• Muscular weakness
• Flank pain
• Musculoskeletal chest pain
• Potential for heart conduction abnormalities
• Adrenal insufficiency
• Rash
• Itching (pruritus)

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Tablet

• 200mg (Mifeprex)
• 300mg (Korlym)

Pregnancy Termination

Mifeprex is indicated for the medical termination of intrauterine pregnancy through 70 days gestation in combination with misoprostol

• Day 1: 200 mg of mifepristone orally as a single dose under physician supervision
• Days 2-3: 800 mcg of misoprostol in the cheek (buccally) once as a single dose; must be administered a minimum of 24 hours and a maximum of 48 hours following mifepristone dose on day 1
• Days 7-14:
  • Must return for a follow-up visit to confirm complete termination has occurred by medical history, clinical examination, hCG testing, or ultrasonographic scan
  • If complete expulsion has not occurred, but the pregnancy is not ongoing, women may be treated with another dose of misoprostol 800 mcg in the cheek (buccally) with follow-up in approximately 7 days
  • Lack of bleeding following treatment usually indicates failure; however, prolonged or heavy bleeding is not proof of a complete abortion
  • Surgical evacuation is recommended to manage ongoing pregnancies after medical abortion

Cushing Syndrome

Korlym is indicated to control hyperglycemia secondary to hypercortisolism in adults with endogenous Cushing syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery

• 300 mg orally once/day initially; may dose to a maximum of 1200 mg/day, but should not exceed 20 mg/kg/day
• An increase in dose should not occur more frequently than every 2-4 weeks and should be based on an assessment of glucose control, anti-diabetic medication requirements, insulin levels, and psychiatric symptoms

Dosage Modifications (Korlym)
Coadministration with strong CYP3A inhibitors

• Not to exceed 300 mg/day

Renal impairment

• No change in initial dose; limit maximum dose to 600 mg orally once/day

Hepatic impairment

• Mild-to-moderate: No change in initial dose; limit maximum dose to 600 mg orally once/day
• Severe: Do not use

Pediatric

Safety and efficacy of Mifeprex brand of mifepristone in pregnant females below 17 years of age are similar to that observed in adult females.

Safety and efficacy of Korlym brand of mifepristone in pediatric patients have not been established.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

Mifepristone has severe interactions with at least 44 different drugs.

Serious interactions of mifepristone include:

• atorvastatin
• eluxadoline
• fluvastatin
• histrelin
• idelalisib
• mefloquine
• panobinostat
• pimavanserin
• pomalidomide
• rosuvastatin

Mifepristone has moderate interactions with at least 177 different drugs.

Mild interactions of mifepristone include:

• ruxolitinib

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

Mifeprex

The risk of adverse developmental outcomes with a continued pregnancy after a failed pregnancy termination with Mifeprex 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. Birth defects have been reported with a continued pregnancy after a failed pregnancy termination with Mifeprex in a regimen with misoprostol.

Mifeprex is present in breast milk, however, there is no information on the effects of Mifeprex in a regimen with misoprostol on mild production or in a breastfed infant.

Korlym

Korlym is contraindicated for use in pregnancy because it can result in loss of pregnancy. Pregnancy should be ruled out before initiating treatment. Nonhormonal contraceptives should be used during and one month after stopping treatment in all women of reproductive potential.

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

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 the formation of anti-Rho(D) antibodies (e.g., 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 under 35 years of age 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 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 the treatment of hyperglycemia unrelated to Cushing syndrome
• Adrenal insufficiency may occur; discontinue therapy if signs or symptoms occur and administer glucocorticoids
• Low blood potassium (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 (e.g., 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 (e.g., 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)