Dosing and uses of Mifeprex, Korlym (mifepristone)
Adult dosage forms and strengths
tablet
- 200mg (Mifeprex)
- 300mg (Korlym)
Pregnancy Termination
Mifeprex: Indicated for the medical termination of intrauterine pregnancy through 70 days gestation in combination with misoprostoL
Day 1: 200 mg of mifepristone PO as a single dose under physician supervision
Days 2-3: 800 mcg of misoprostol buccally once as a single dose; must be administered a minimum of 24-hr and a maximum of 48-hr following mifeprostone dose on day 1 (see Administration)
Days 7-14
- Must return for 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 buccally with follow-up in ~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
Dosing considerations
- Pregnancy is dated from the first day of the last menstrual period
- Duration of pregnancy may be determined from menstrual history and clinical examination
- Assess the pregnancy by ultrasonographic scan if the duration of pregnancy is uncertain or if ectopic pregnancy is suspected
- Remove any intrauterine device (IUD) before treatment
- 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
Cushing Syndrome
Korlym: 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 PO qDay initially; may dose to a maximum of 1200 mg/day, but should not exceed 20 mg/kg/day
Increase in dose should not occur more frequently than every 2-4 weeks and should be based on assessment of glucose control, antidiabetic 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 PO qDay
Hepatic impairment
- Mild-to-moderate: No change in initial dose; limit maximum dose to 600 mg PO qDay
- Severe: Do not use
Ovarian Cancer (Orphan)
Korlym: Orphan designation for treatment of ovarian cancer
Sponsor
- Corcept Therapeutics, Inc; 149 Commonwealth Drive; Menlo Park, California 94025
Pediatric dosage forms and strengths
Safety and efficacy not established
Mifeprex, Korlym (mifepristone) adverse (side) effects
>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%)
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%)
Warnings
Black box warnings
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
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 and lactation
Pregnancy
Mifeprex: No FDA category rating; indicated for use in the termination of pregnancy
Korlym: X; Due to its antiprogestational activity, causes pregnancy loss
Lactation
Distributed in human milk; because of the potential for serious adverse reactions in nursing infants from mifepristone, 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
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.
Pharmacology of Mifeprex, Korlym (mifepristone)
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
Administration
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)
