Mifepristone

Today's med: Mifepristone (mi FE pris tone)  

(brand names: Korlym, Mifeprex, Index Terms: RU-38486, RU-486)

Drug Class: Progestin Antagonist

Pharmacologic Category: Abortifacient, Antineoplastic Agent, Hormone Antagonist, Antiprogestin, Cortisol Receptor Blocker

Indications: Korlym™: To control hyperglycemia occurring secondary to hypercortisolism in patients with endogenous Cushing’s syndrome who have type 2 diabetes mellitus or glucose intolerance and who failed surgery or who are not surgical candidates

Mifeprex®: Medical termination of intrauterine pregnancy, through day 49 of pregnancy. Patients may need treatment with misoprostol and possibly surgery to complete therapy.

Use: Unlabeled

Treatment of unresectable meningioma; has been studied in the treatment of breast cancer and ovarian cancer; termination of pregnancy ≤63 days of pregnancy

Contraindications: Hypersensitivity to mifepristone or any component of the formulation.  Korlym™ (additional contraindications): Concomitant use of lovastatin, simvastatin, or CYP3A substrates with a narrow therapeutic range (eg, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinine, sirolimus, tacrolimus); concomitant use of systemic corticosteroids for serious medical conditions (eg, immunosuppression following organ transplant); women with a history of unexplained vaginal bleeding, or endometrial hyperplasia with atypia or endometrial carcinoma; pregnancy.  Mifeprex® (additional contraindications): Hypersensitivity to misoprostol; chronic adrenal failure; porphyrias; hemorrhagic disorder or concurrent anticoagulant therapy; pregnancy termination >49 days; intrauterine device (IUD) in place; ectopic pregnancy or undiagnosed adnexal mass; concurrent long-term corticosteroid therapy; inadequate or lack of access to emergency medical services; inability to understand effects and/or comply with treatment

Actions: Mifepristone is a synthetic steroid. At low doses, it competitively binds to the intracellular progesterone receptor, blocking the effects of progesterone. When used for the termination of pregnancy, this leads to contraction-inducing activity in the myometrium. In the absence of progesterone, mifepristone acts as a partial progesterone agonist. At high doses used for the treatment of hyperglycemia in patients with Cushing’s syndrome, mifepristone blocks the effect of cortisol at the glucocorticoid receptor (antagonizes the effects of cortisol on glucose metabolism) while at the same time increasing circulating cortisol concentrations.

Absorption

Oral: Rapid

Metabolism

Hepatic via CYP3A4 to three metabolites (active)

Adverse Effects: 

Adverse events associated with treatment of hyperglycemia in patients with Cushing’s syndrome: >10%: Cardiovascular: Peripheral edema (26%), hypertension (24%)

Central nervous system: Fatigue (48%), headache (44%), dizziness (22%), pain (14%)

Endocrine & metabolic: Hypokalemia (34% to 44%), endometrial hypertrophy (38%), thyroid function tests abnormal (18%)

Gastrointestinal: Nausea (48%), vomiting (26%), appetite decreased (20%), xerostomia (18%), diarrhea (12%)

Genitourinary: Vaginal bleeding (14%)

Neuromuscular & skeletal: Arthralgia (30%), back pain (16%), myalgia (14%), extremity pain (12%)

Respiratory: Dyspnea (16%), sinusitis (14%), nasopharyngitis (12%)

5% to 10%:

Cardiovascular: Edema, pitting edema

Central nervous system: Anxiety (10%), somnolence (10%), insomnia, malaise

Endocrine & metabolic: Hypoglycemia, triglycerides increased

Gastrointestinal: Anorexia (10%), constipation (10%), abdominal pain, GI reflux

Genitourinary: Vaginal hemorrhage, metrorrhagia

Neuromuscular & skeletal: Flank pain, malaise, musculoskeletal chest pain, weakness

Miscellaneous: Thirst

<5% or frequency not defined: Adrenal insufficiency (4%), pruritus (4%), rash (4%), HDL cholesterol decreased

Adverse events associated with treatment for termination of pregnancy: Note: Vaginal bleeding and uterine cramping are expected to occur when this medication is used to terminate a pregnancy; ~90% of women using this medication for this purpose also report adverse reactions on day 3 after the procedure. Bleeding or spotting occurs in most women for a period of 9-16 days. Up to 8% of women will experience some degree of bleeding or spotting for 30 days or more. In some cases, bleeding may be prolonged and heavy, potentially leading to hypovolemic shock.

Central nervous system: Headache (2% to 31%), dizziness (1% to 12%)

Gastrointestinal: Abdominal pain (cramping) (96%), nausea (43% to 61%), vomiting (18% to 26%), diarrhea (12% to 20%)

Genitourinary: Uterine cramping (83%)

1% to 10%:

Cardiovascular: Syncope (1%)

Central nervous system: Fatigue (10%), fever (4%), insomnia (3%), anxiety (2%), fainting (2%)

Gastrointestinal: Dyspepsia (3%)

Genitourinary: Uterine hemorrhage (5%), vaginitis (3%), pelvic pain (2%), endometriosis/salpingitis/pelvic inflammatory disease (1%)

Hematologic: Decreased hemoglobin >2 g/dL (6%), anemia (2%), leukorrhea (2%)

Neuromuscular & skeletal: Back pain (9%), rigors (3%), leg pain (2%), weakness (2%)

Respiratory: Sinusitis (2%)

Miscellaneous: Viral infection (4%)

<1% (Limited to important or life-threatening): Adult respiratory distress syndrome (ADRS), allergic reaction including urticaria and hives, bacterial infection (including an ectopic bacteria such as Clostridium sordellii), Crohn's disease (exacerbation), disseminated intravascular coagulopathy (DIC), dyspnea, hematometra, hypotension, lightheadedness, loss of consciousness, MI, pancreatitis (acute), pelvic infection, postabortal infection, QT prolongation, ruptured ectopic pregnancy, sepsis, septic shock, sickle cell crisis (exacerbation), tachycardia, toxic shock syndrome

Unresectable meningioma trials: Most common adverse effects included breast tenderness or gynecomastia, fatigue, hair thinning, hot flashes, and rash. In premenopausal women, vaginal bleeding may be seen shortly after beginning therapy and cessation of menses is common. Thyroiditis and effects related to antiglucocorticoid activity have also been noted.

Warnings/Precautions: Concerns related to adverse effects:

• Adrenal insufficiency: When used for the treatment of hyperglycemia in patients with Cushing’s syndrome, adrenal insufficiency may occur. Serum cortisol concentrations remain elevated and may increase, and cannot be used for monitoring. If signs and symptoms of adrenal insufficiency occur (eg, fatigue, hypoglycemia, hypotension, nausea, weakness), discontinue mifepristone and administer glucocorticoids (high doses may be needed). Following resolution, treatment may be resumed at a lower dose; evaluate patient for precipitating causes (eg, infection, trauma).

• Bacterial infections: [U.S. Boxed Warning]: When used for the termination of pregnancy, bacterial infections have been reported following use of this product and may have an atypical presentation. In rare cases, these infections may be serious and/or fatal, with septic shock as a potential complication. A causal relationship has not been established. Sustained fever, abdominal pain, or pelvic tenderness should prompt evaluation; however, healthcare professionals are warned that atypical presentations of serious infection without these symptoms have also been noted. Patients presenting with nausea, vomiting, diarrhea, or weakness, with or without abdominal pain or fever, should be evaluated for serious bacterial infection when symptoms occur >24 hours after taking misoprostol. Treatment with antibiotics, including coverage for anaerobic bacteria (eg,Clostridium sordellii) should be initiated. Patients with Cushing’s syndrome may be at risk for opportunistic infections such as Pneumocystis jiroveci pneumonia.

• Bleeding: Regardless of indication, endometrial proliferation is promoted by mifepristone, resulting in endometrial thickening, cystic dilation of endometrial glands, and vaginal bleeding. [U.S. Boxed Warning]: When used for the termination of pregnancy, patients should be counseled to seek medical attention in cases of excessive bleeding. Bleeding occurs and should be expected (average 9-16 days, may be ≥30 days). In some cases, bleeding may be prolonged and heavy and may be a sign of incomplete abortion or other complications, potentially leading to hypovolemic shock; the manufacturer cites soaking through 2 thick sanitary pads per hour for 2 consecutive hours as an example of excessive bleeding. Bleeding may require blood transfusion (rare), curettage, saline infusions, and/or vasoconstrictors. Patients should be instructed to seek medical attention if prolonged heavy vaginal bleeding occurs. When used for termination of pregnancy, use is contraindicated in women with hemorrhagic disorders or those using anticoagulants; use caution in women with severe anemia, hypocoagulability or hemostatic disorders. When used for the treatment of hyperglycemia in patients with Cushing’s syndrome, use caution in women with hemorrhagic disorders or women using anticoagulants and evaluate unexplained vaginal bleeding; use is contraindicated with a history of unexplained vaginal bleeding.

• Hypokalemia: May occur at any time during therapy when used to control hyperglycemia in patients with Cushing’s syndrome. Correct hypokalemia prior to initiation of treatment; monitor potassium levels closely with therapy.

• QT prolongation: May prolong the QT_c interval (dose related); use caution with other QT-prolonging agents.

• Pregnancy: [U.S. Boxed Warning]: Use of mifepristone will result in termination of pregnancy. When used to control hyperglycemia in women with Cushing’s syndrome, pregnancy must be excluded prior to initiation of therapy. Nonhormonal contraception must be used during treatment and for 1 month after discontinuation of therapy unless the patient has had surgical sterilization. Pregnancy must be excluded if treatment is interrupted for ≥14 days.

• Smokers: Use with caution in patients who are heavy smoker (>10 cigarettes/day); these patients were excluded from clinical trials when used as a single dose for the termination of pregnancy.

• Women >35 years: Use with caution in women >35 years of age; these patients were excluded from clinical trials when used as a single dose for the termination of pregnancy.

Standard Dosing:  Oral: Adults:

Hyperglycemia in patients with Cushing’s syndrome (Korlym™): Initial dose: 300 mg once daily. Dose may be increased in 300 mg increments at intervals of ≥2-4 weeks based on tolerability and symptom control. Maximum dose: 1200 mg once daily, not to exceed 20 mg/kg/day. If treatment is interrupted, reinitiate at 300 mg/day or a dose lower than the dose that caused the treatment to be stopped if interruption due to adverse reactions

Dosage adjustment with concurrent use of strong CYP450 inhibitor therapy (eg ketoconazole): Maximum dose 300 mg/day

Termination of pregnancy (Mifeprex®): Treatment consists of 3 office visits by the patient; the patient must read medication guide and sign patient agreement prior to treatment:

Day 1 (mifepristone administration): 600 mg (three 200 mg tablets) taken as a single dose under physician supervision

Day 3 (misoprostol administration): Patient must return to the healthcare provider 2 days following administration of mifepristone; unless abortion has occurred (confirmed using ultrasound or clinical examination): Misoprostol 400 mcg (two 200 mcg tablets); Note: Patient may need treatment for cramps or gastrointestinal symptoms at this time

Day 14 (post-treatment exam): Patient must return to the healthcare provider ~14 days after administration of mifepristone; confirm complete termination of pregnancy by ultrasound or clinical exam. Surgical termination is recommended to manage treatment failures.

Termination of pregnancy (unlabeled dosing): Mifepristone 200 mg orally, followed by misoprostol 800 mcg vaginally 24-48 hours later (ACOG, 2005; FIGO, 2011)

Meningioma, unresectable (unlabeled use; refer to individual protocols): Mifepristone 200 mg/day, continue based on toxicity and response (Grunberg, 1991)

Elderly: Hyperglycemia in patients with Cushing’s syndrome: Refer to adult dosing.

Administration: Hyperglycemia in patients with Cushing’s syndrome: Administer as a single daily dose with a meal. Tablets should be swallowed whole, not crushed, split, or chewed.

Termination of pregnancy: To be taken as a single dose under physician supervision.

Drug interactions: LINK: http://www.drugs.com/drug-interactions/mifepristone.html

A total of 571 drugs (2501 brand and generic names) are known to interact with mifepristone.

• 239 major drug interactions (868 brand and generic names)
• 319 moderate drug interactions (1586 brand and generic names)
• 13 minor drug interactions (47 brand and generic names)

Show all medications in the database that may interact with mifepristone.

Food: increases the blood levels of this medication. If you are only receiving one or two doses, you may take it without regard to meals. However, if you are receiving the medication for long-term treatment, you should take it with food at the same time everyday to maintain consistent blood levels and effects. 

Mifepristone may diminish the therapeutic effect of Contraceptives (Progestins and Estrogens)

CYP3A4 Inducers (Strong): May decrease the serum concentration of Mifepristone. Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP2C9 Substrates: Mifepristone may increase the serum concentration of CYP2C9 Substrates.

CYP2C8 Substrates: Mifepristone may increase the serum concentration of CYP2C8 Substrates.

St Johns Wort: May decrease the serum concentration of Mifepristone. Avoid combination

Mifepristone blocks progesterone (and cortisol and glucocorticoid receptors too)...