Generic Name: mifepristone

Brand Names: Mifeprex

Uses

Termination of Pregnancy

Termination of intrauterine pregnancy through 49 days of gestation, dated from first day of last menstrual period or determined by clinical examination or ultrasonographic scan. Two days after mifepristone, misoprostol must be administered to induce uterine contraction unless complete abortion has been confirmed.

Has been used with vaginal† administration of misoprostol for termination of pregnancy; however, such use very rarely has resulted in fatal bacterial infection and sepsis. (See Infection and Sepsis under Cautions.)

Dosage and Administration

General

• Restricted distribution program; not available through community pharmacies. Contact distributor at 877-432-7596.
• Clinicians must sign prescriber’s agreement form before ordering from distributor or prescribing; agreement and order forms available on Internet (http://www.earlyoptionpill.com).
• Before administration, patient must read manufacturer’s medication guide; both patient and clinician must sign patient agreement form.
• Remove any intrauterine contraceptive device (IUD) prior to administration of mifepristone.
• Medical facilities equipped to provide blood transfusions, resuscitation, and/or surgical intervention must be available during treatment and follow-up.
• Regimen requires 3 visits with clinician: day 1 mifepristone administration; day 3 misoprostol administration (unless complete abortion confirmed); and day 14 follow-up examination to confirm complete pregnancy termination and to assess severity of any continued bleeding.
• May require medications for treatment of adverse effects (e.g., cramping, GI symptoms) after misoprostol administration.

Administration

Oral Administration

Administer orally as a single dose without regard to meals.

Dosage

Adults

Termination of Pregnancy

Oral

600 mg as a single dose. Two days later, administer misoprostol 400 mcg orally unless complete abortion confirmed.

Cautions

Contraindications

• Confirmed or suspected ectopic pregnancy, undiagnosed adnexal mass, or IUD currently in place. (See General under Dosage and Administration.)
• Chronic adrenal failure or long-term corticosteroid therapy.
• Known hypersensitivity to mifepristone, misoprostol, or other prostaglandins.
• Hemorrhagic disorders, inherited porphyrias, or concurrent anticoagulant therapy.
• Inability to understand effects of or to comply with treatment regimen.
• Inadequate access to medical facilities equipped to provide emergency treatment of incomplete abortion, blood transfusion, and emergency resuscitation during treatment and follow-up.

Warnings/Precautions

Warnings

Hemorrhage

Vaginal bleeding heavier than with normal menses occurs in almost all women receiving mifepristone and misoprostol. Bleeding or spotting expected for average of 9–16 days; in ≤8% of patients may last ≥30 days.

Prolonged heavy vaginal bleeding (i.e., soaking through 2 thick full-size sanitary pads per hour for 2 consecutive hours) may indicate incomplete abortion or other complications; may require prompt medical or surgical intervention to prevent hypovolemic shock. Advise patients to seek immediate medical attention if prolonged heavy vaginal bleeding or syncope occurs. (See Advice to Patients.)

Treat excessive bleeding with uterotonics, vasoconstrictors, saline infusions, and/or blood transfusions or curettage; caution in patients with hemostatic disorders, hypocoagulability, or severe anemia.

Infection and Sepsis

Serious bacterial infection (including very rare cases of fatal septic shock) reported; causal relationship to mifepristone-misoprostol regimen not established.

Serious bacterial (e.g., C. sordellii) infection and sepsis can present without fever, bacteremia, or substantial findings on pelvic examination. Deaths reported very rarely in patients who presented without fever, with or without abdominal pain, but with leukocytosis with a marked left shift, tachycardia, hemoconcentration, and general malaise. These deaths occurred in women who received misoprostol intravaginally†; causal relationship to risk of infection or death not established. C. sordellii infections also reported very rarely following childbirth (vaginal delivery and cesarean section) and in other gynecologic and nongynecologic conditions.

Maintain a high index of suspicion to rule out serious infection and sepsis (e.g., from C. sordellii) if sustained fever (temperature ≥38°C persisting for >4 hours), severe abdominal pain, or pelvic tenderness occurs within several days of medical abortion, or if abdominal pain/discomfort or general malaise (including weakness, nausea, vomiting, or diarrhea), with or without fever, occurs >24 hours after administration of misoprostol. (See Advice to Patients.) Consider obtaining CBC to identify patients with hidden infection.

If infection is suspected, FDA recommends initiating appropriate anti-infective therapy that includes coverage against anaerobic bacteria (e.g., C. sordellii) immediately; optimum anti-infective regimen not established. Routine anti-infective prophylaxis not recommended at this time because of insufficient data.

Confirmation of Pregnancy Termination

Risk of fetal harm if pregnancy continues. Perform clinical examination or ultrasonographic scan 14 days after administration to confirm pregnancy termination; failure should be managed with surgical termination.

Ruptured Ectopic Pregnancy

Ruptured ectopic pregnancy, including fatal hemorrhage, reported, although causality not established. Mifepristone is not effective for termination of ectopic pregnancy. (See Contraindications under Cautions.) Consider possibility that ectopic pregnancy may be present and establish plan for its management.

Death

At least 2 unexplained deaths reported. One was determined by FDA to be unrelated to abortion or to use of mifepristone or misoprostol. Cause of the other reported death, which was preceded by manifestations of infection, was still under investigation when the 2006–07 edition of AHFS Drug Information Essentials went to press.

Pending further investigation, be aware of specific circumstances and directions for use as well as risks (e.g., sepsis) associated with mifepristone.

Inform patients of early manifestations that may warrant immediate medical evaluation. (See Warnings under Cautions and also see Advice to Patients.)

Major Toxicities

MI

MI reported, although causality to mifepristone-misoprostol regimen not established.

General Precautions

Medical Personnel and Facilities

Clinicians should be able to assess gestational age of embryo, diagnose ectopic pregnancy, and provide or ensure availability of surgical intervention in cases of incomplete abortion or severe bleeding. Patients must have access to medical facilities equipped to provide blood transfusions and resuscitation.

Suppression of Rh Isoimmunization

Consider administration of Rh_o(D) immune globulin in Rh_o(D)-negative women.

Other Medical Conditions

Safety, efficacy, and pharmacokinetics not studied in patients with chronic medical conditions (e.g., severe anemia; insulin-dependent diabetes mellitus; hypertension; cardiovascular, respiratory, hepatic, or renal disease), history of heavy smoking, or in women >35 years of age who smoke ≥10 cigarettes daily.

Specific Populations

Pregnancy

Category X.

Used for termination of pregnancy (through 49 days of gestation); no other FDA-approved indication for use in pregnancy.

Lactation

Not known whether mifepristone is distributed into milk; discard milk for several days after administration.

Pediatric Use

Safety and efficacy not established in females <18 years of age.

Common Adverse Effects

Abdominal pain, nausea, headache, vomiting, diarrhea, dizziness, fatigue, back pain, uterine hemorrhage. Note that vaginal bleeding and uterine cramping are expected effects. (See Hemorrhage under Cautions.)

Interactions

Extensively metabolized by CYP3A4.

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased plasma mifepristone concentrations); however, specific drugs and food not studied to date.

Inducers of CYP3A4: Potential pharmacokinetic interaction (decreased plasma mifepristone concentrations); however, specific drugs and food not studied to date.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4: Potential pharmacokinetic interaction (increased serum substrate concentrations); caution if administered concurrently with drugs that are CYP3A4 substrates and have a narrow therapeutic range.

Specific Drugs and Foods

Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed from the GI tract following oral administration. Absolute bioavailability is 69%, but is reduced to 40% after first pass effect. Peak plasma concentrations attained in about 1–2 hours.

Distribution

Extent

Not known whether mifepristone is distributed into milk.

Plasma Protein Binding

98% (mainly to albumin and α₁-acid glycoprotein).

Elimination

Metabolism

Extensively metabolized in the liver by CYP3A4 to 3 major active metabolites.

Elimination Route

Excreted in feces (83%) and in urine (9%).

Half-life

Initial elimination half-life, 12–72 hours; terminal elimination half-life, 18 hours.

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).

Actions

• Binds to progesterone receptor, antagonizing endometrial and myometrial effects of progesterone, resulting in down-regulation of progesterone-dependent genes. Inhibition of progesterone in pregnancy results in detachment of conception product and pregnancy termination. Also promotes uterine contractions and softening of cervix.
• Sensitizes myometrium to effects of prostaglandins (e.g., misoprostol) that stimulate uterine contraction and expulsion of the products of conception.
• At higher doses, exhibits antiglucocorticoid activity.

Advice to Patients

• Importance of carefully reading medication guide and reading and signing the patient agreement form before receiving mifepristone. If visiting an emergency room or a clinician other than the original prescriber, present medication guide to alert clinician of recent medical abortion.
• Importance of understanding procedures for emergency situations and of obtaining a telephone number for emergency contact with clinicians.
• Possible need for surgical intervention if complete abortion does not occur following mifepristone and misoprostol administration. Risk of fetal malformation if the pregnancy continues.
• Importance of adherence to treatment regimen and follow-up appointment schedule.
• Risk of severe infection and bleeding. Contact clinician (or visit emergency room if clinician is unavailable) if sustained fever (temperature ≥38°C persisting for >4 hours), severe abdominal pain, prolonged heavy bleeding (soaking through 2 thick full-size sanitary pads per hour for 2 consecutive hours), or syncope occurs within several days of medical abortion, or if abdominal pain/discomfort or general malaise (including weakness, nausea, vomiting, or diarrhea), with or without fever, occurs >24 hours after administration of misoprostol.
• Importance of initiating contraception immediately after confirmation of abortion or before resuming sexual intercourse; risk of pregnancy exists immediately after termination of existing pregnancy and before normal menses begin.
• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal preparations.
• Importance of women informing their clinician if they are breast-feeding.
• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Distribution of mifepristone is restricted. (See General under Dosage and Administration.)

AHFS Drug Information. © Copyright, 1959-2009, Selected Revisions July 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.