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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Medication Safety Issues
Sound-alike/look-alike issues:
Mifeprex® may be confused with Mirapex®
Mifepristone may be confused with misoprostol
High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Pronunciation
(mi FE pris tone)
U.S. Brand Names
Index Terms
Generic Available
No
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Medical termination of intrauterine pregnancy, through day 49 of pregnancy. Patients may need treatment with misoprostol and possibly surgery to complete therapy
Use: Unlabeled/Investigational
Treatment of unresectable meningioma; has been studied in the treatment of breast cancer, ovarian cancer, and adrenal cortical carcinoma
Restrictions
Investigators wishing to obtain the agent for use in oncology patients must apply for a patient-specific IND from the FDA. Mifepristone will be supplied only to licensed physicians who sign and return a “Prescriber's Agreement.” Distribution of mifepristone will be subject to specific requirements imposed by the distributor. Mifepristone will not be available to the public through licensed pharmacies.
Not available in Canada
Pregnancy Risk Factor
X
Pregnancy Considerations
This medication is used to terminate pregnancy; there are no approved treatment indications for its use during pregnancy. Prostaglandins (including mifepristone and misoprostol) may have teratogenic effects when used during pregnancy. If treatment fails, there is a risk of fetal malformation. In sexually active women, pregnancy can occur prior to the first menstrual period following treatment. Appropriate contraception can be started as soon as termination of pregnancy is confirmed or before sexual intercourse is resumed.
Lactation
Excretion in breast milk unknown/contraindicated
Breast-Feeding Considerations
Breast milk should be discarded for a few days following use of this medication.
Contraindications
Hypersensitivity to mifepristone, misoprostol, other prostaglandins, or any component of the formulation; 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
Warnings/Precautions
Boxed warnings:
• Bacterial infections: See “Concerns related to adverse effects” below.
• Bleeding: See “Concerns related to adverse effects” below.
• Medication guide: See “Other warnings/precautions” below.
• Patient instruction: See “Other warnings/precautions” below.
Concerns related to adverse effects:
• Bacterial infections: [U.S. Boxed Warning]: Bacterial infections have been reported following use of this product. 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.
• Bleeding: [U.S. Boxed Warning]: 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, potentially leading to hypovolemic shock; the manufacturer cites soaking through two thick sanitary pads per hour for two consecutive hours as an example of excessive bleeding. Bleeding may require blood transfusion (rare), curettage, saline infusions, and/or vasoconstrictors.
Disease-related concerns:
• Anemia: Safety and efficacy have not been established for use in women with severe anemia.
• Cardiovascular disease: Safety and efficacy have not been established for use in women with chronic cardiovascular disease as well as hypertension.
• Diabetes: Safety and efficacy have not been established for use in women with insulin-dependent diabetes mellitus.
• Hepatic impairment: Safety and efficacy have not been established for use in women with hepatic impairment.
• Renal impairment: Safety and efficacy have not been established for use in women with renal impairment.
• Respiratory disease: Safety and efficacy have not been established for use in women with respiratory disease.
Special populations:
• Pediatrics: Safety and efficacy have not been established in children.
• Smokers: Use with caution in patients who are heavy smoker (>10 cigarettes/day); these patients were excluded from clinical trials.
• Women >35 years: Use with caution in women >35 years; these patients were excluded from clinical trials.
Other warnings/precautions:
• Confirmation of terminated pregnancy: 14 days following treatment confirmation of pregnancy termination by clinical exam or ultrasound must be made. Manufacturer recommends surgical termination of pregnancy when medical termination fails or is not complete. Prescriber should determine in advance whether they will provide such care themselves or through other providers. Preventative measures to prevent rhesus immunization must be taken prior to surgical abortion.
• Ectopic pregnancy: Ultrasound should be used if an ectopic pregnancy is suspected or if duration of pregnancy is uncertain. Ultrasonography may not identify all ectopic pregnancies, and healthcare providers should be alert for signs and symptoms which may be related to undiagnosed ectopic pregnancy in any patient who receives mifepristone.
• Experienced physician: To be administered only by physicians who can date pregnancy, diagnose ectopic pregnancies, provide access to surgical abortion (if needed), and can provide access to emergency care. Medication will be distributed directly to these physicians following signed agreement with the distributor. Must be administered under supervision by the qualified physician.
• Medication guide: [U.S. Boxed Warning]: Patients undergoing treatment with mifepristone should be instructed to bring their Medication Guide with them when an obtaining treatment from an emergency room or healthcare provider that did not prescribe the medication initially in order to identify that they are undergoing a medical abortion.
• Patient instruction: [U.S. Boxed Warning]: Patient must be instructed of the treatment procedure and expected effects. A signed agreement form must be kept in the patient's file. Physicians may obtain patient agreement forms, physician enrollment forms, and medical consultation directly from Danco Laboratories at 1-877-432-7596. Prescriber should also give the patient clear instructions on whom to call and what to do in the event of an emergency following administration of therapy.
• Pregnancy dating: Pregnancy is dated from day 1 of last menstrual period (presuming a 28-day cycle, ovulation occurring midcycle). Pregnancy duration can be determined using menstrual history and clinical examination. Ultrasound should be used if duration of pregnancy is uncertain.
• Reporting of adverse effects: Adverse effects (including blood transfusions, hospitalization, ongoing pregnancy, and other major complications) must be reported in writing to the medication distributor.
Adverse Reactions
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. 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.
>10%:
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%: Significant ALT/AST, alkaline phosphatase, and GT changes have been reported rarely
Postmarketing and/or case reports: 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
In trials for unresectable meningioma, the most common adverse effects included fatigue, hot flashes, gynecomastia or breast tenderness, hair thinning, 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.
Metabolism/Transport Effects
Substrate of CYP3A4 (minor); Inhibits CYP2D6 (weak), 3A4 (weak)
Drug Interactions
There are no known significant interactions.
Ethanol/Nutrition/Herb Interactions
Food: Do not take with grapefruit juice; grapefruit juice may inhibit mifepristone metabolism leading to increased levels.
Herb/Nutraceutical: Avoid St John's wort (may induce mifepristone metabolism, leading to decreased levels).
Storage
Store at room temperature of 25°C (77°F).
Mechanism of Action
Mifepristone, a synthetic steroid, 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. Mifepristone also has weak antiglucocorticoid and antiandrogenic properties; it blocks the feedback effect of cortisol on corticotropin secretion.
Pharmacodynamics/Kinetics
Absorption: Oral: rapid
Protein binding: 98% to albumin and ?1-acid glycoprotein
Metabolism: Hepatic via CYP3A4 to three metabolites (may possess some antiprogestin and antiglucocorticoid activity)
Bioavailability: Oral: 69%
Half-life elimination: Terminal: 18 hours following a slower phase where 50% eliminated between 12-72 hours
Time to peak: Oral: 90 minutes
Excretion: Feces (83%); urine (9%)
Dosage
Oral:
Adults:
Termination of pregnancy: Treatment consists of three office visits by the patient; the patient must read medication guide and sign patient agreement prior to treatment:
Day 1: 600 mg (three 200 mg tablets) taken as a single dose under physician supervision
Day 3: Patient must return to the healthcare provider 2 days following administration of mifepristone; unless abortion has occurred (confirmed using ultrasound or clinical examination): 400 mcg (two 200 mcg tablets) of misoprostol; patient may need treatment for cramps or gastrointestinal symptoms at this time
Day 14: 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.
Meningioma (unlabeled use): Refer to individual protocols. The dose used in meningioma is usually 200 mg/day, continued based on toxicity and response.
Elderly: Safety and efficacy have not been established
Dosage adjustment in renal impairment: Safety and efficacy have not been established
Dosage adjustment in hepatic impairment: Safety and efficacy have not been established; use with caution due to CYP3A4 metabolism
Monitoring Parameters
Clinical exam and/or ultrasound to confirm complete termination of pregnancy; hemoglobin, hematocrit, and red blood cell count in cases of heavy bleeding. Consider CBC in any patient who reports nausea, vomiting, or diarrhea and weakness with or without abdominal pain, and without fever or other signs of infection more than 24 hours after administration of misoprostol.
Test Interactions
hCG levels will not be useful to confirm pregnancy termination until at least 10 days following mifepristone treatment
Patient Education
This medication is used to terminate pregnancy under 7 weeks. It must be administered under direction of a qualified physician. You will need follow-up visits as directed by your prescriber (approximately 3 days and 14 days after treatment). Surgical termination of pregnancy may be required if medication fails; there is a risk of fetal malformation if treatment fails. You may experience vaginal bleeding and cramping that is heavier than a normal menstrual period; report immediately if severe or persistent. You may experience nausea, vomiting, and diarrhea. It is possible to get pregnant before your next period. Once the pregnancy has proved to be ended, contraception should be started before having sexual intercourse. Read carefully all information about this medication provided by your prescriber. Pregnancy/breast-feeding precautions: Your physician will give you a phone number to call for problems, questions, or emergencies; you should not use this medication if you do not have access to emergency care. You will be given a medication guide to help you understand this medication and its effects. It is important to review this carefully. Ask any questions you may have. You will also be required to sign a form saying that you understand the effects of this treatment and are able to return to the physician for follow-up appointments. Do not breast-feed. Discard breast milk for a few days following use of this medication.
Additional Information
Medication will be distributed directly to qualified physicians following signed agreement with the distributor, Danco Laboratories. It will not be available through pharmacies. Major adverse reactions (hospitalization, blood transfusion, ongoing pregnancy, etc) should be reported to Danco Laboratories.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause dizziness, fatigue, insomnia, or anxiety
Mental Health: Effects on Psychiatric Treatment
Gastrointestinal side effects are common; use caution with lithium, valproic acid, and SSRIs. Fluoxetine, fluvoxamine, and nefazodone may increase mifepristone serum levels and/or toxicity; monitor. Carbamazepine, phenobarbital, and St John's wort may increase the metabolism of mifepristone, resulting in decreased mifepristone levels and/or effect; monitor.
Nursing: Physical Assessment/Monitoring
May only be administered under supervision of a qualified physician. Patient must be instructed in procedure and sign patient agreement forms. Assess results of laboratory tests and adverse reactions. Monitor for excessive bleeding. Monitor vital signs. Assess knowledge/teach patient interventions to reduce side effects, and adverse reactions to report. Pregnancy risk factor X: This medication is used to terminate pregnancy.
Oncology: Emetic Potential
Mild
Oncology: Vesicant
No
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet: 200 mg
References
ACOG, ACOG Practice Bulletin, Clinical Management Guidelines of Obstetrician-Gynecologists, Number 67, October 2005, "Medical Management of Abortion," Obstet Gynecol, 2005, 106(4):871-82.
Fischer M, Bhatnagar J, Guarner J, et al, "Fatal Toxic Shock Syndrome Associated With Clostridium sordellii After Medical Abortion," N Engl J Med, 2005, 353(22):2352-60.
Gary M and Harrison D, "Analysis of Severe Adverse Events Related to the Use of Mifepristone as an Abortifacient," Ann Pharmacother, 2005, 40(2):191-7.
Grumberg SM, Weiss MH, Spitz IM, et al, “Treatment of Unresectable Meningiomas With the Antiprogesterone Agent Mifepristone,” J Neurosurg, 1991, 74(6):861-6.
Perrault D, Eisenhauer EA, Pritchard KI, et al, “Phase II Study of the Progesterone Antagonist Mifepristone in Patients With Untreated Metastatic Breast Carcinoma: A National Cancer Institute of Canada Clinical Trials Group Study,” J Clin Oncol, 1996, 14(10):2709-12.
Rocereto TF, Saul HM, Aikins JA, et al, “Phase II Study of Mifepristone (RU486) in Refractory Ovarian Cancer,” Gynecol Oncol, 2000, 77(3):429-32.
Spitz IM and Bardin CW, “Mifepristone (RU486) - A Modulator of Progestin and Glucocorticoid Action,” N Engl J Med, 1993, 329(6):404-12.
International Brand Names
Lexi-Comp.com
Last full review/revision June 2009
Content last modified June 2009
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