Mifepristone

Class: Oxytocics
VA Class: HS200
Chemical Name: (11 - β,17 - β) - 11 - [4 - (Dimethylamino)phenyl] - 17 - hydroxy - 17 - (1 - propynyl) - estra - 4,9 - dien - 3 - one
Molecular Formula: C29H35NO2
CAS Number: 84371-65-3
Brands: Mifeprex

Warning(s)

  • Risk of serious bacterial (e.g., Clostridium sordellii) infection and sepsis, which can present without fever, bacteremia, or significant findings on pelvic examination.1 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.1 33 (See Infection and Sepsis under Cautions and see Advice to Patients.)

  • Prolonged heavy vaginal bleeding may be a sign of incomplete abortion or other complications; may require prompt medical or surgical intervention.1 (See Hemorrhage under Cautions and see Advice to Patients.)

  • Discuss medication guide and patient agreement with patients.1 Ensure that patients know whom to call and what to do in an emergency.1 If patients visit an emergency room or clinician other than the original prescriber, advise patients to present medication guide to alert clinician of recent medical abortion.1 31 32

REMS:

FDA approved a REMS for mifepristone to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of mifepristone and consists of the following: medication guide, elements to assure safe use, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Progesterone-receptor antagonist; a synthetic derivative of norethindrone.1 2 3 4 5 6 7 8 9 19

Uses for Mifepristone

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.1 2 3 4 5 6 7 10 11 19 20 21 22 23 27 Two days after mifepristone, misoprostol must be administered to induce uterine contraction unless complete abortion has been confirmed.1 11 27

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Has been used with vaginal administration of misoprostol for termination of pregnancy;2 10 11 27 however, such use very rarely has resulted in fatal bacterial infection and sepsis.1 33 37 38 39 (See Infection and Sepsis under Cautions.)

Mifepristone Dosage and Administration

General

  • Restricted distribution program; not available through community pharmacies.1 22 28 Contact distributor at 877-432-7596.1 22

  • Clinicians must sign prescriber’s agreement form before ordering from distributor or prescribing; agreement and order forms available on Internet ().22 28

  • Before administration, patient must read manufacturer’s medication guide; both patient and clinician must sign patient agreement form.1 22 23 24

  • Remove any intrauterine contraceptive device (IUD) prior to administration of mifepristone.1

  • Medical facilities equipped to provide blood transfusions, resuscitation, and/or surgical intervention must be available during treatment and follow-up.1 22

  • 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.1 22

  • May require medications for treatment of adverse effects (e.g., cramping, GI symptoms) after misoprostol administration.1

Administration

Oral Administration

Administer orally as a single dose without regard to meals.1

Dosage

Adults

Termination of Pregnancy
Oral

600 mg as a single dose.1 Two days later, administer misoprostol 400 mcg orally unless complete abortion confirmed.1

Cautions for Mifepristone

Contraindications

  • Confirmed or suspected ectopic pregnancy, undiagnosed adnexal mass, or IUD currently in place.1 (See General under Dosage and Administration.)

  • Chronic adrenal failure or long-term corticosteroid therapy.1

  • Known hypersensitivity to mifepristone, misoprostol, or other prostaglandins.1

  • Hemorrhagic disorders, inherited porphyrias, or concurrent anticoagulant therapy.1

  • Inability to understand effects of or to comply with treatment regimen.1

  • Inadequate access to medical facilities equipped to provide emergency treatment of incomplete abortion, blood transfusion, and emergency resuscitation during treatment and follow-up.1

Warnings/Precautions

Warnings

Hemorrhage

Vaginal bleeding heavier than with normal menses occurs in almost all women receiving mifepristone and misoprostol.1 3 11 19 20 21 29 Bleeding or spotting expected for average of 9–16 days;1 19 20 in ≤8% of patients may last ≥30 days.1 10 19 20 29

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.1 Advise patients to seek immediate medical attention if prolonged heavy vaginal bleeding or syncope occurs.1 (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.1

Infection and Sepsis

Serious bacterial infection (including very rare cases of fatal septic shock) reported; causal relationship to mifepristone-misoprostol regimen not established.1 33 37 39

Serious bacterial (e.g., C. sordellii) infection and sepsis can present without fever, bacteremia, or substantial findings on pelvic examination.1 33 39 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.1 33 39 These deaths occurred in women who received misoprostol intravaginally; causal relationship to risk of infection or death not established.1 33 37 38 39 C. sordellii infections also reported very rarely following childbirth (vaginal delivery and cesarean section) and in other gynecologic and nongynecologic conditions.1 33 39

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.1 33 37 38 (See Advice to Patients.) Consider obtaining CBC to identify patients with hidden infection.37 38

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.37 38 Routine anti-infective prophylaxis not recommended at this time because of insufficient data.37 38

Confirmation of Pregnancy Termination

Risk of fetal harm if pregnancy continues.1 23 24 Perform clinical examination or ultrasonographic scan 14 days after administration to confirm pregnancy termination; failure should be managed with surgical termination.1 22 23 24

Ruptured Ectopic Pregnancy

Ruptured ectopic pregnancy, including fatal hemorrhage, reported, although causality not established.29 30 Mifepristone is not effective for termination of ectopic pregnancy.1 22 (See Contraindications under Cautions.) Consider possibility that ectopic pregnancy may be present and establish plan for its management.1 22

Death

At least 2 unexplained deaths reported.36 37 One was determined by FDA to be unrelated to abortion or to use of mifepristone or misoprostol.36 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.36

Pending further investigation, be aware of specific circumstances and directions for use as well as risks (e.g., sepsis) associated with mifepristone.37

Inform patients of early manifestations that may warrant immediate medical evaluation.37 (See Warnings under Cautions and also see Advice to Patients.)

Major Toxicities

MI

MI reported, although causality to mifepristone-misoprostol regimen not established.29 30

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.1 22 Patients must have access to medical facilities equipped to provide blood transfusions and resuscitation.1 22

Suppression of Rh Isoimmunization

Consider administration of Rho(D) immune globulin in Rho(D)-negative women.1 3 10 11 18

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.1

Specific Populations

Pregnancy

Category X.

Used for termination of pregnancy (through 49 days of gestation); no other FDA-approved indication for use in pregnancy.1

Lactation

Not known whether mifepristone is distributed into milk;1 discard milk for several days after administration.1 23

Pediatric Use

Safety and efficacy not established in females <18 years of age.1

Common Adverse Effects

Abdominal pain, nausea, headache, vomiting, diarrhea, dizziness, fatigue, back pain, uterine hemorrhage.1 Note that vaginal bleeding and uterine cramping are expected effects.1 (See Hemorrhage under Cautions.)

Interactions for Mifepristone

Extensively metabolized by CYP3A4.1 3

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased plasma mifepristone concentrations); however, specific drugs and food not studied to date.1

Inducers of CYP3A4: Potential pharmacokinetic interaction (decreased plasma mifepristone concentrations); however, specific drugs and food not studied to date.1

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.1

Specific Drugs and Foods

Drug or Food

Interaction

Carbamazepine

Possible decreased serum mifepristone concentrations1

Dexamethasone

Possible decreased serum mifepristone concentrations1

Erythromycin

Possible increased serum mifepristone concentrations1

Grapefruit juice

Possible increased serum mifepristone concentrations1

Itraconazole

Possible increased serum mifepristone concentrations1

Ketoconazole

Possible increased serum mifepristone concentrations1

Phenobarbital

Possible decreased serum mifepristone concentrations1

Phenytoin

Possible decreased serum mifepristone concentrations1

Rifampin

Possible decreased serum mifepristone concentrations1

St. John’s wort

Possible decreased serum mifepristone concentrations1

Mifepristone Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed from the GI tract following oral administration.1 3 Absolute bioavailability is 69%,1 but is reduced to 40% after first pass effect.a 3 Peak plasma concentrations attained in about 1–2 hours.1 a

Distribution

Extent

Not known whether mifepristone is distributed into milk.1

Plasma Protein Binding

98% (mainly to albumin and α1-acid glycoprotein).1

Elimination

Metabolism

Extensively metabolized in the liver by CYP3A4 to 3 major active metabolites.1 3

Elimination Route

Excreted in feces (83%) and in urine (9%).1 a

Half-life

Initial elimination half-life, 12–72 hours; terminal elimination half-life, 18 hours.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Actions

  • Binds to progesterone receptor, antagonizing endometrial and myometrial effects of progesterone, resulting in down-regulation of progesterone-dependent genes.1 2 3 4 5 6 7 8 27 Inhibition of progesterone in pregnancy results in detachment of conception product and pregnancy termination.1 2 3 5 6 8 9 Also promotes uterine contractions and softening of cervix.1 2 3 4 5 6 7 9 27

  • Sensitizes myometrium to effects of prostaglandins (e.g., misoprostol) that stimulate uterine contraction and expulsion of the products of conception.1 2 3 4 5 6 7 9 27

  • At higher doses, exhibits antiglucocorticoid activity.1 3 5 6 7 8 9

Advice to Patients

  • Importance of carefully reading medication guide and reading and signing the patient agreement form before receiving mifepristone.1 22 23 24 31 If visiting an emergency room or a clinician other than the original prescriber, present medication guide to alert clinician of recent medical abortion.1 31 32

  • Importance of understanding procedures for emergency situations and of obtaining a telephone number for emergency contact with clinicians.1 23 24

  • Possible need for surgical intervention if complete abortion does not occur following mifepristone and misoprostol administration.1 22 23 24 Risk of fetal malformation if the pregnancy continues.1 23 24

  • Importance of adherence to treatment regimen and follow-up appointment schedule.1

  • Risk of severe infection and bleeding.1 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,1 31 32 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.1 34 35

  • 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.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal preparations.1 23

  • Importance of women informing their clinician if they are breast-feeding.1 23

  • Importance of informing patients of other important precautionary information.1 (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.22 28 (See General under Dosage and Administration.)

Mifepristone

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet

200 mg

Mifeprex (with povidone; single-dose packet containing 3 tablets)

Danco

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 27, 2011. 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.

References

1. Danco Laboratories, LLC; Mifeprex (mifepristone) oral tablet prescribing information. New York, NY; 2005 Jul.

2. Christin-Maitre S, Bouchard P, Spitz IM. Medical termination of pregnancy. N Engl J Med. 2000; 342:946-56.

3. Heikinheimo O. Clinical pharmacokinetics of mifepristone. Clin Pharmacokinet. 1997; 33:7-17. [PubMed 9250420]

4. Mahajan DK, London SN. Mifepristone (RU486): a review. Fertil Steril. 1997; 68:967-76. [IDIS 398835] [PubMed 9418681]

5. Avrech OM, Bukovsky I, Golan A et al. Mifepristone (RU486) alone or in combination with a prostaglandin analogue for termination of early pregnancy: a review. Fertil Steril. 1991; 56:385-93. [IDIS 289661] [PubMed 1894013]

6. Spitz IM, Bardin CW. Mifepristone (RU 486)—a modulator of progestin and glucocorticoid action. N Engl J Med. 1993; 329:404-12. [IDIS 318211] [PubMed 8326975]

7. Brogden RN, Goa KL, Faulds D. Mifepristone: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential. Drugs. 1993; 45:384-409. [PubMed 7682909]

8. Baulieu EE. RU-486 as an antiprogesterone steroid: from receptor to contragestion and beyond. JAMA. 1989; 262:1808-14. [IDIS 259553] [PubMed 2674487]

9. Mifegyne (mifepristone), a new antiprogestagen with potential therapeutic use in human fertility control.Drugs. 1988; 35:187-91.

10. Grimes DA. Medical abortion in early pregnancy: a review of the evidence. Obstet Gynecol. 1997; 89:790-6. [IDIS 386385] [PubMed 9166323]

11. Newhall EP, Winikoff B. Abortion with mifepristone and misoprostol: regimens, efficacy, acceptability and future directions.Am J Obstet Gynecol. 2000; 183:S44-53. [IDIS 451553] [PubMed 10944369]

12. Searle. Cytotec (misoprostol) oral tablets prescribing information. Skokie, IL; 2000 Oct 2.

13. Monk JP, Clissold SP. Misoprostol: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of peptic ulcer disease. Drugs. 1987; 33:1-30. [IDIS 228650] [PubMed 3102205]

14. Cullen M, Searle. Dear health care provider: Important drug warning concerning unapproved use of intravaginal or oral misoprostol in pregnant women for induction of labor or abortion. Skokie, IL; 2000 Aug 23. From FDA web site ()

15. American College of Obstetricians and Gynecologists. News release: ACOG issues letter on safety of misoprostol. Washington, DC; 2000 Oct 12.

16. Anon. ACOG committee opinion: induction of labor with misoprostol. Obstet Gynecol. 1999; 94:1-2. (IDIS 440248)

17. American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins. Induction of labor. Practice Bulletin No. 10. Washington, DC: American College of Obstetricians and Gynecologists; 1999 Nov.

18. American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins. Prevention of Rh D alloimmunization. Practice Bulletin No. 4. Washington, DC: American College of Obstetricians and Gynecologists; 1999 May.

19. Spitz IM, Bardin CW, Benton L et al. Early pregnancy termination with mifepristone and misoprostol in the United States. N Engl J Med. 1998; 338:1241-7. [IDIS 403670] [PubMed 9562577]

20. Peyron R, Aubény E, Targosz V et al. Early termination of pregnancy with mifepristone (RU 486) and the orally active prostaglandin misoprostol. N Engl J Med. 1993; 328:1509-13. [IDIS 314636] [PubMed 8479487]

21. Aubény E, Peyron R, Turpin CL et al. Termination of early pregnancy (up to 63 days of amenorrhea) with mifepristone and increasing doses of misoprostol. Int J Fertil Menopausal Stud. 1995; 40:85-91. [Originally published as Termination of early pregnancy (up to and after 63 days of amenorrhea) with mifepristone (RU 486) and increasing doses of misoprostol. Corrected in erratum: Int J Fertil Menopausal Stud. 1996; 41:56.]

22. Danco Laboratories. Mifeprex (mifepristone) tablets, 200 mg: prescriber’s agreement. From FDA website (). (undated)

23. Danco Laboratories. Mifepristone medication guide. From FDA website (). 6 Nov 2000.

24. Danco Laboratories. Patient agreement: Mifeprex (mifepristone) tablets. From FDA website (). 21 Sept 2000.

25. Population Council, New York, NY: Personal communication.

26. Pharmacia & Upjohn, Skokie, IL: Personal communication.

27. Anon. Mifepristone (RU 486). Med Lett Drugs Ther. 2000; 42: 101-102.

28. Anon. Mifepristone questions and answers. From FDA website (). 28 Sept 2000.

29. Danco Laboratories. Dear health care provider letter regarding new safety information for mifepristone. New York, NY; 2002 Apr. From FDA website ()

30. Food and Drug Administration. Mifepristone questions and answers. Rockville, MD; 2002 Apr 17. From FDA website ()

31. Danco Laboratories. Mifepristone medication guide. From FDA website (). 12 Nov 2004.

32. Danco Laboratories. Patient agreement: Mifeprex (mifepristone) tablets. From FDA website (). 12 Nov 2004.

33. Danco Laboratories. Dear health care provider letter regarding new safety information for mifepristone. New York, NY; 2005 Jul. From FDA website ().

34. Danco Laboratories. Mifepristone medication guide. From FDA website (). 19 Jul 2005.

35. Danco Laboratories. Patient agreement: Mifeprex (mifepristone) tablets. From FDA website (). 19 Jul 2005.

36. Food and Drug Administration. Mifeprex (mifepristone) information (April 10, 2006 update). Rockville, MD; 2006 Apr 10. From FDA website ().

37. Food and Drug Administration. FDA Public Health Advisory: Sepsis and Medical Abortion Update (March 17, 2006). Rockville, MD; 2006 Mar 17. From FDA website ().

38. Food and Drug Administration. FDA Public Health Advisory: Sepsis and Medical Abortion (November 4, 2005 update). Rockville, MD; 2005 Nov 4. From FDA website ().

39. Fischer M, Bhatnagar J, Guarner J et al. Fatal toxic shock syndrome associated with Clostridium sordellii after medical abortion. N Engl J Med. 2005; 353:2352-60. [PubMed 16319384]

a. Sarkar NN. Mifepristone: bioavailability, pharmacokinetics and use-effectiveness. Eur J Obstet Gynecol Reprod Biol. 2002; 101:113-20. [PubMed 11858883]

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