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MIFEPRISTONE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Mifepristone is a substituted 19-nor steroid compound, derived from norethisterone, with potent anti-progestogenic activity, anti-glucocorticoid activity, and weak anti-androgenic activity.

Specific Substances

    1) Mifepristone
    2) Mifegyne
    3) RU-486
    4) RU-38486
    5) CAS 84371-65-3

Available Forms Sources

    A) FORMS
    1) Mifepristone is available as 200 mg and 300 mg tablets (Prod Info Korlym(TM) oral tablets, 2012; Prod Info MIFEPREX(R) oral tablets, Apr).
    B) USES
    1) Mifepristone is indicated for the medical termination of intrauterine pregnancy for pregnancies up to 49 days in duration (Prod Info MIFEPREX(R) oral tablets, Apr).
    2) Mifepristone (Korlym(R)) is also indicated for controlling hyperglycemia secondary to hypercortisolism in adults with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance, and have failed surgery or are ineligible for surgery; it should not be used in patients with type 2 diabetes unless it is associated with Cushing's syndrome (Prod Info Korlym(TM) oral tablets, 2012).
    3) Mifepristone has also been used as an emergency contraceptive agent, in the treatment of inoperable meningiomas, as a cervical ripening and labor induction agent, to decrease the tumor volume in patients with uterine leiomyomas, in the treatment of Cushing's syndrome, as a combination agent with methotrexate in the medical treatment of ectopic pregnancy, as an ovarian function suppression agent used in patients with endometriosis, and for the rapid reversal of psychotic major depression (Schreiber et al, 2006; Brown et al, 2002; Xiao et al, 2002; Belanoff et al, 2001; Ashok et al, 2001; Chu et al, 2001; Wagaarachchi et al, 2001; Kettel et al, 1998; Frydman et al, 1991a; Nieman et al, 1985; Beaufrere et al, 1987; Urquhart & Templeton, 1990; Rocereto et al, 2000; Eisinger et al, 2003).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Mifepristone is used for the medical termination of intrauterine pregnancy through 49 days' pregnancy. It is also indicated for controlling hyperglycemia secondary to hypercortisolism in adults with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance, and have failed surgery or are ineligible for surgery; it should not be used in patients with type 2 diabetes unless it is associated with Cushing's syndrome. Mifepristone has also been used in a variety of conditions, including dilation of cervical canal, emergency contraception, and ovarian cancer.
    B) PHARMACOLOGY: Mifepristone competitively inhibits the actions of progesterone at progesterone-receptor sites, resulting in termination of pregnancy. The combination of mifepristone and misoprostol causes expulsion of the products of conception through decidual necrosis, myometrial contractions, and cervical softening.
    C) TOXICOLOGY: Mifepristone possesses antiglucocorticoid activity, with approximately the same affinity for glucocorticoid receptors as dexamethasone. The drug has also demonstrated the ability to abolish the negative feedback control of cortisol on the pituitary-adrenal axis and to inhibit the ACTH inhibitory activity of dexamethasone, which may result in adrenal failure following administration of massive doses of mifepristone.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: Uterine bleeding (may be severe), abdominal pain and cramping, nausea, vomiting, diarrhea, headache, dizziness, fatigue, back pain. OTHER EFFECTS: Hypotension, tachycardia, dyspnea, rash, dizziness, elevated liver enzymes, fever.
    F) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. In tolerance studies, no serious adverse reactions were observed in healthy non-pregnant women and healthy men in single doses greater than 3-fold the recommended doses for termination of pregnancy.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Fever was reported in patients after receiving mifepristone and misoprostol.
    0.2.20) REPRODUCTIVE
    A) Mifepristone is classified as FDA pregnancy category X. An ultrasound performed at 17 weeks gestation on a 30-year-old woman, who had taken 400 mg of mifepristone at 6 weeks of amenorrhea and then decided against medical termination of pregnancy, showed a complete lack of amniotic sac, and no appearance of fetal stomach, gallbladder, and urinary tract. No congenital defects were found in other reports. Abortion may occur. Mifepristone is excreted in human breast milk. In a case series, progesterone administration was effective in 4 of 6 patients for the reversal of mifepristone-induced abortion. Four viable infants were subsequently delivered between 37 and 40 weeks gestation, without neonatal complications or birth defects.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of mifepristone use in humans.

Laboratory Monitoring

    A) Mifepristone plasma concentrations are not clinically useful or readily available.
    B) Monitor CBC in patients with significant vaginal bleeding.
    C) Monitor vital signs and liver enzyme levels following significant overdose.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    E) Patients with severe or persistent bleeding after mifepristone administration for elective termination of pregnancy should be evaluated for incomplete abortion/retained products of conception by pelvic exam and ultrasound.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Patients may only need observation. Manage mild hypotension with IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Symptomatic and supportive care is the mainstay of treatment. Treat severe hypotension with fluids and vasopressors if necessary. Severe uterine bleeding, necessitating blood transfusions and curettage in some instances, may occur following therapeutic administration of mifepristone as sole therapy or in combination therapy with prostaglandin or misoprostol administration. Consultation should be made with obstetrics and gynecology in cases of uterine hypertonicity or bleeding after ingestion.
    C) DECONTAMINATION
    1) PREHOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    2) HOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Perform early in patients with symptoms of airway compromise, although this is unlikely to be necessary in mifepristone-only ingestions.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) Hemodialysis and hemoperfusion are UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.
    G) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.
    2) ADMISSION CRITERIA: Patients with significant symptoms and/or abnormal vital signs should be admitted. Pregnant patients with symptoms of vaginal bleeding or contractions should be evaluated by an obstetrician/gynecologist.
    3) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear. Obstetrician/gynecologist should be consulted for any case of excessive uterine bleeding or contractions and in the case of inadvertent administration to a pregnant woman who does not desire early pregnancy termination.
    H) PITFALLS
    1) When managing a suspected mifepristone overdose, the possibility of multidrug involvement should be considered. Falsely attributing patient's symptoms to mifepristone when the true underlying cause is due to another etiology. Always consider the possibility of ectopic pregnancy or septic abortion in a patient taking mifepristone for pregnancy termination.
    I) PHARMACOKINETICS
    1) Rapidly absorbed with an absolute bioavailability of 69% following a 20 mg oral dose. Protein binding: 98%, primarily to alpha 1-acid glycoprotein. The mean apparent volume of distribution following oral administration of a single mifepristone dose (4 mg/kg) in 6 women was 1.47 +/- 0.25 L/kg. Metabolism: Primarily in the liver via N-demethylation and terminal hydroxylation of the 17-propynyl chain. Excretion: Approximately 83% of a 600 mg mifepristone dose is detected in the feces 11 days after ingestion. Elimination half-life: 18 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Spontaneous abortion, spontaneous labor.

Range Of Toxicity

    A) TOXICITY: A specific minimum toxic dose of mifepristone has not been established. In tolerance studies, no serious adverse reactions were observed in healthy non-pregnant women and healthy men in single doses greater than 3-fold the recommended doses for termination of pregnancy. THERAPEUTIC DOSE: ADULTS: 600 mg as a single oral dose. CHILDREN: The safety and efficacy of mifepristone has not been established in the pediatric population.

Clinical Effects

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fever was reported in patients after receiving mifepristone and misoprostol.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) MIFEPRISTONE WITH MISOPROSTOL: Fever was reported in 4% of patients, involved in US clinical trials, following administration of mifepristone and misoprostol (Prod Info MIFEPREX(R) oral tablets, Apr).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension (including orthostatic) has been reported during post-marketing experience (Prod Info MIFEPREX(R) oral tablets, Apr).
    b) CASE REPORT: A 31-year-old woman, who was a heavy smoker, developed cardiovascular shock and died during an abortion procedure performed early in pregnancy following administration of mifepristone and sulprostone (Anon, 1991).
    B) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia has been reported during post-marketing experience (Prod Info MIFEPREX(R) oral tablets, Apr).
    C) MYOCARDIAL INFARCTION
    1) WITH THERAPEUTIC USE
    a) The manufacturer has reported the occurrence of a myocardial infarction in a 21-year-old woman following combination therapy with mifepristone and misoprostol. A causal relationship between the use of mifepristone and misoprostol combination therapy and the development of a myocardial infarction has not been established (Anon , 2002).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Dyspnea has been reported during post-marketing experience (Prod Info MIFEPREX(R) oral tablets, Apr).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) FATIGUE
    1) WITH THERAPEUTIC USE
    a) Fatigue is a fairly common occurrence following therapeutic administration of mifepristone and may be related to the amount of blood loss secondary to uterine bleeding (Spitz & Bardin, 1993; Rodger & Baird, 1990; Couzinet et al, 1986; Shoupe et al, 1986).
    b) INCIDENCE: Weakness and tiredness were reported in 25% of patients (n=76) following therapeutic administration of mifepristone, 100 mg/day for 7 days (Mishell et al, 1987).
    c) MIFEPRISTONE WITH MISOPROSTOL: Fatigue was reported in 10% of patients, involved in US clinical trials, following administration of mifepristone and misoprostol (Prod Info MIFEPREX(R) oral tablets, Apr).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headaches have been reported following mifepristone therapy and may be dose-related (Rodger & Baird, 1990; Shoupe et al, 1986; Kovacs et al, 1984).
    b) INCIDENCE: Headaches were reported in 13% of patients (n=30) who received mifepristone therapeutically, 50 mg/day for 7 days, and in 17% of patients (n=76) who received mifepristone therapy, 100 mg/day for 7 days (Mishell et al, 1987).
    c) MIFEPRISTONE WITH MISOPROSTOL: Headache was reported in 31% of patients, involved in US clinical trials, following administration of mifepristone and misoprostol (Prod Info MIFEPREX(R) oral tablets, Apr).
    C) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness has occurred in patients receiving mifepristone therapy (Muhl, 1993; Haspels, 1985) Vervest & Haspels, 1985) and may be related to the amount of blood loss secondary to uterine bleeding in these patients.
    b) MIFEPRISTONE WITH MISOPROSTOL: Dizziness was reported in 12% of patients, involved in US clinical trials, following administration of mifepristone and misoprostol (Prod Info MIFEPREX(R) oral tablets, Apr).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting are frequent occurrences following mifepristone therapy (Gouk et al, 1999; Brogden et al, 1993; Muhl, 1993; Grimes et al, 1988; Couzinet et al, 1986). It is difficult to determine if nausea and vomiting are a direct result of mifepristone therapy or a consequence of early pregnancy.
    b) INCIDENCE: In US clinical trials, 61% and 26% of patients reported nausea and vomiting, respectively, after receiving mifepristone and misoprostol (Prod Info MIFEPREX(R) oral tablets, Apr).
    c) INCIDENCE: In 50 patients who were given 3 oral doses of 200 mg mifepristone, 28% and 20% reported the occurrence of nausea and vomiting, respectively (Rodger & Baird, 1990).
    B) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain has been frequently reported following therapeutic administration of mifepristone by itself or in combination therapy with prostaglandin or misoprostol administration (Grimes et al, 1988; Mishell et al, 1987; Shoupe et al, 1986; Haspels, 1985).
    b) MIFEPRISTONE WITH MISOPROSTOL: Abdominal pain or cramping was reported in 96% of patients, involved in US clinical trials, following administration of mifepristone and misoprostol (Prod Info MIFEPREX(R) oral tablets, Apr).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) MIFEPRISTONE WITH MISOPROSTOL: Diarrhea was reported in 20% of patients, involved in US clinical trials, following administration of mifepristone and misoprostol (Prod Info MIFEPREX(R) oral tablets, Apr).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ABNORMAL LIVER FUNCTION
    1) WITH THERAPEUTIC USE
    a) Transiently elevated liver transaminase levels were reported in one patient who received mifepristone, 5 mg daily for 6 months (Kettel et al, 1998a).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) HEMATOMETRA
    1) WITH THERAPEUTIC USE
    a) Severe uterine bleeding, necessitating blood transfusions and curettage in some instances, may occur following therapeutic administration of mifepristone as sole therapy or in combination therapy with prostaglandin or misoprostol administration (Prod Info MIFEPREX(R) oral tablets, Apr; Gouk et al, 1999; Grimes et al, 1988; Mishell et al, 1987).
    b) CASE REPORT: Uterine rupture, with severe hemorrhage, occurred in a 26-year-old female, during a second trimester abortion, following administration of mifepristone and misoprostol. In order to control the blood loss, a hysterectomy and right salpingo- oophorectomy were performed. Approximately 4000 milliliters was estimated as the overall blood loss (Phillips et al, 1996).
    c) MIFEPRISTONE WITH MISOPROSTOL: Uterine hemorrhage was reported in 5% of patients, involved in US clinical trials, following administration of mifepristone and misoprostol (Prod Info MIFEPREX(R) oral tablets, Apr).
    B) INDUCED TERMINATION OF PREGNANCY COMPLICATED BY SEPSIS
    1) WITH THERAPEUTIC USE
    a) Cases of serious bacterial infections, including rare cases of fatal septic shock, have been reported. The deaths were associated with the intravaginal administration of misoprostol, which is a non-FDA approved route of administration. No causal relationship between these events and the use of mifepristone and misoprostol has been established. Signs of infection include sustained fever of 100.4 degrees Fahrenheit or higher, severe abdominal pain, pelvic tenderness, prolonged heavy bleeding, syncope, and abdominal pain or discomfort or general malaise (including weakness, nausea, vomiting or diarrhea) more than 24 hours after taking mifepristone. Atypical presentations of serious bacterial infection (eg, Clostridium sordellii) and sepsis can occur without fever, with or without abdominal pain, but with a marked left shift, tachycardia, hemoconcentration, and general malaise. A high level of suspicion is needed to rule out sepsis (Prod Info MIFEPREX(R) oral tablets, Apr; FDA, 2005).
    b) Two women (aged 21 and 29 years) died from a clostridial infection after starting oral mifepristone 200 mg and vaginal misoprostol 800 mcg for medical abortions (7 weeks and 5 weeks gestation respectively). Both patients reported severe abdominal cramping, vomiting and diarrhea and were hospitalized on day 5 and day 7 after the treatment, respectively. Symptoms included tachycardia and leukocytosis. One patient also had pleural effusion, ascites, and hypotension and the other patient developed hemoconcentration. One day after hospitalization, the 29-year old woman died of sepsis with acute respiratory distress, and 5 days after hospitalization the 21-year old woman died from sepsis with acute renal failure and disseminated intravascular coagulation. Abortion-related infection with Clostridium sordellii was later confirmed in cervical and uterine cultures. Buccal instead of vaginal administration of misoprostol and routine antibiotic prophylaxis are recommended (Meites et al, 2010).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia, with a significant decrease in hemoglobin level, may be expected to occur as a result of the severe uterine bleeding that is associated with mifepristone administration (Prod Info MIFEPREX(R) oral tablets, Apr; Shoupe et al, 1986) Vervest & Haspels, 1985).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) A generalized maculopapular erythematous eruption occurred in 8 of 11 patients within 9 days of beginning mifepristone therapy, 10 mg/kg/day. The rash spontaneously resolved, in all patients, within 6 days after cessation of mifepristone therapy (Laue et al, 1990).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BACKACHE
    1) WITH THERAPEUTIC USE
    a) MIFEPRISTONE WITH MISOPROSTOL: Back pain was reported in 9% of patients, involved in US clinical trials, following administration of mifepristone and misoprostol (Prod Info MIFEPREX(R) oral tablets, Apr).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) ADRENAL CORTICAL HYPOFUNCTION
    1) WITH THERAPEUTIC USE
    a) Adrenal insufficiency, characterized by nausea, anorexia, extreme weakness and malaise, myalgias and arthralgias, headache, and orthostatic hypotension, occurred in one patient 10 days after beginning mifepristone therapy, 10 mg/kg/day. The patient recovered following discontinuation of mifepristone and administration of dexamethasone (Laue et al, 1990).
    2) WITH POISONING/EXPOSURE
    a) Due to mifepristone's antiglucocorticoid activity, it is speculated that mifepristone overdose ingestions may result in adrenal failure (Prod Info MIFEPREX(R) oral tablets, Apr).

Reproductive

    3.20.1) SUMMARY
    A) Mifepristone is classified as FDA pregnancy category X. An ultrasound performed at 17 weeks gestation on a 30-year-old woman, who had taken 400 mg of mifepristone at 6 weeks of amenorrhea and then decided against medical termination of pregnancy, showed a complete lack of amniotic sac, and no appearance of fetal stomach, gallbladder, and urinary tract. No congenital defects were found in other reports. Abortion may occur. Mifepristone is excreted in human breast milk. In a case series, progesterone administration was effective in 4 of 6 patients for the reversal of mifepristone-induced abortion. Four viable infants were subsequently delivered between 37 and 40 weeks gestation, without neonatal complications or birth defects.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) In a prospective, multicenter, observational study of women exposed to mifepristone alone (n=46) or mifepristone with misoprostol (n=59) during the first 12 weeks of pregnancy, a 4.2% rate of major congenital malformations (95% CI, 1.2% to 10.4%) was reported among the 94 live births, a rate slightly higher than the 2% to 3% rate of major congenital malformations seen among the general population. Most exposures (81%) occurred between gestational weeks 5 and 9. Major malformations included Claude Bernard-Horner syndrome with stridor (mifepristone only with no concomitant drug exposure); hydrocephalus with triventricular dilatation and adductus thumb (mifepristone only with no concomitant drug exposure; spontaneous abortion at 18 weeks' gestation); Mobius syndrome (combination mifepristone and misoprostol with no concomitant drug exposure); and mild hypoplasia of the cerebellar vermis combined with club foot with 4 toes, incomplete genital development, and retrognathism with a slight cleft palate, trismus, and swallowing disorder (combination exposure with no concomitant drug exposure). In 2 of these cases, congenital malformations could be attributed to other causes (ie, Claude Bernard-Horner syndrome in a large-for-gestational age neonate with possible trauma during delivery; confirmation of streptococcus chorioamnionitis in the infant with hydrocephalus) (Bernard et al, 2013).
    2) CASE REPORT: An ultrasound performed at 17 weeks gestation on a 30-year-old woman, who had taken 400 mg of mifepristone at 6 weeks of amenorrhea and then decided against medical termination of pregnancy, showed a complete lack of amniotic sac, and no appearance of fetal stomach, gallbladder, and urinary tract. The pregnancy was terminated at 18 weeks gestation with prostaglandin administration. Examination of the fetus showed typical sirenomelia, with fusion of the lower limbs and a single flexed foot, possibly associated with administration of mifepristone in early pregnancy (Pons et al, 1991).
    B) ANIMAL DATA
    1) RABBITS: Skull deformities occurred in rabbits following administration of mifepristone at doses approximately one-sixth that of human exposure; however, it is speculated that these deformities may have been a result of the mechanical effects of uterine contractions resulting from decreased progesterone levels (Prod Info Mifeprex(TM), mifepristone, 2000).
    C) LACK OF EFFECT
    1) REVERSAL OF MIFEPRISTONE-INDUCED ABORTION: In a case series, progesterone administration was effective in 4 of 6 patients for the reversal of mifepristone-induced abortion. All subjects (age, 19 to 25 years) chose to attempt reversal of pregnancy termination after ingestion of mifepristone, but prior to ingestion of misoprostol. The gestational age at intervention was 7 to 11 weeks in 5 cases and unknown in 1 case. In the 4 successful cases, patients received an initial dose of progesterone in oil 200 mg IM 30 to 72 hours after mifepristone ingestion, with additional doses of progesterone in oil 200 mg IM or oral micronized progesterone administered at various schedules and durations. In one unsuccessful case, the patient received progesterone in oil 200 mg IM for 1 dose (timing of mifepristone unknown) with abortion completed shortly thereafter. In the other unsuccessful case, the patient received progesterone 200 mg oral capsule intravaginally 7 hours following mifepristone administration, plus 2 doses of progesterone in oil 200 mg IM at 18 hours and at day 2, with abortion completed on day 3. In the 4 successful cases, viable infants were subsequently delivered between 37 and 40 weeks gestation, without neonatal complications or birth defects (Delgado & Davenport, 2012).
    2) There were no fetal abnormalities in a report of 13 live births following single-dose mifepristone exposure (Prod Info Korlym(TM) oral tablets, 2012).
    3) There were no congenital defects reported in neonates following maternal administration of mifepristone at approximately 8 weeks gestation and at 37.5 to 42 weeks gestation (Frydman et al, 1991; Lim et al, 1990).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Mifepristone is classified as FDA pregnancy category X (Prod Info Korlym(TM) oral tablets, 2012).
    B) ABORTION
    1) Mifepristone induces abortions in 50% to 94% of pregnant women with less than 55 days of amenorrhea (Grimes et al, 1988; Mishell et al, 1987; Couzinet et al, 1986; Haspels, 1985; Kovacs et al, 1984).
    a) REVERSAL OF MIFEPRISTONE-INDUCED ABORTION: In a case series, progesterone administration was effective in 4 of 6 patients for the reversal of mifepristone-induced abortion. All subjects (age, 19 to 25 years) chose to attempt reversal of pregnancy termination after ingestion of mifepristone, but prior to ingestion of misoprostol. The gestational age at intervention was 7 to 11 weeks in 5 cases and unknown in 1 case. In the 4 successful cases, patients received an initial dose of progesterone in oil 200 mg IM 30 to 72 hours after mifepristone ingestion, with additional doses of progesterone in oil 200 mg IM or oral micronized progesterone administered at various schedules and durations. In one unsuccessful case, the patient received progesterone in oil 200 mg IM for 1 dose (timing of mifepristone unknown) with abortion completed shortly thereafter. In the other unsuccessful case, the patient received progesterone 200 mg oral capsule intravaginally 7 hours following mifepristone administration, plus 2 doses of progesterone in oil 200 mg IM at 18 hours and at day 2, with abortion completed on day 3. In the 4 successful cases, viable infants were subsequently delivered between 37 and 40 weeks gestation, without neonatal complications or birth defects (Delgado & Davenport, 2012).
    C) PLACENTAL BARRIER
    1) Mifepristone and its metabolite, RU 42,633, were detected in the maternal and fetal circulation and in the amniotic fluid, approximately 4 hours after oral administration of 600 mg mifepristone. The maternal:fetal ratios for mifepristone and its metabolite were 9:1 and 17:1, respectively (Hill et al, 1990).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Mifepristone is excreted in human milk (Prod Info Korlym(TM) oral tablets, 2012).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of mifepristone use in humans.
    3.21.4) ANIMAL STUDIES
    A) TUMORS
    1) A statistically significant increase in follicular cell adenomas/carcinomas and liver adenomas were noted in female rats administered mifepristone 5, 25, and 125 mg/kg (exposure less than the maximum clinical dose based on AUC comparison) for 2 years. Causality may have been due to drug-induced enzyme metabolism, but further studies confirming this mechanism were not conducted. No drug-related tumors were seen in mice administered the same dosage regimen (Prod Info Korlym(TM) oral tablets, 2012).

Genotoxicity

    A) No genotoxicity was reported with mifepristone in a battery of bacterial, yeast, and mammalian in vitro assays, and an in vivo micronucleus study in mice (Prod Info Korlym(TM) oral tablets, 2012). Specific studies performed included Ames test with and without metabolic activation; gene conversion test in Saccharomyces cerevisiae D4 cells; forward mutation in Schizosaccharomyces pompe P1 cells; induction of unscheduled DNA synthesis in cultured HeLa cells; induction of chromosome aberrations in CHO cells; in vitro test for gene mutation in V79 Chinese hamster lung cells; and micronucleus test in mice (Prod Info MIFEPREX(R) oral tablets, 2009).

Summary Of Exposure

    A) USES: Mifepristone is used for the medical termination of intrauterine pregnancy through 49 days' pregnancy. It is also indicated for controlling hyperglycemia secondary to hypercortisolism in adults with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance, and have failed surgery or are ineligible for surgery; it should not be used in patients with type 2 diabetes unless it is associated with Cushing's syndrome. Mifepristone has also been used in a variety of conditions, including dilation of cervical canal, emergency contraception, and ovarian cancer.
    B) PHARMACOLOGY: Mifepristone competitively inhibits the actions of progesterone at progesterone-receptor sites, resulting in termination of pregnancy. The combination of mifepristone and misoprostol causes expulsion of the products of conception through decidual necrosis, myometrial contractions, and cervical softening.
    C) TOXICOLOGY: Mifepristone possesses antiglucocorticoid activity, with approximately the same affinity for glucocorticoid receptors as dexamethasone. The drug has also demonstrated the ability to abolish the negative feedback control of cortisol on the pituitary-adrenal axis and to inhibit the ACTH inhibitory activity of dexamethasone, which may result in adrenal failure following administration of massive doses of mifepristone.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: Uterine bleeding (may be severe), abdominal pain and cramping, nausea, vomiting, diarrhea, headache, dizziness, fatigue, back pain. OTHER EFFECTS: Hypotension, tachycardia, dyspnea, rash, dizziness, elevated liver enzymes, fever.
    F) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. In tolerance studies, no serious adverse reactions were observed in healthy non-pregnant women and healthy men in single doses greater than 3-fold the recommended doses for termination of pregnancy.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Mifepristone plasma concentrations are not clinically useful or readily available.
    B) Monitor CBC in patients with significant vaginal bleeding.
    C) Monitor vital signs and liver enzyme levels following significant overdose.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    E) Patients with severe or persistent bleeding after mifepristone administration for elective termination of pregnancy should be evaluated for incomplete abortion/retained products of conception by pelvic exam and ultrasound.

Methods

    A) CHROMATOGRAPHY
    1) Chromosorb(R) column chromatography and high performance liquid chromatography have been described for the determination of mifepristone and its metabolites in human plasma (Heikinheimo et al, 1987; Heikinheimo et al, 1986).
    B) IMMUNOASSAY
    1) Radioimmunoassay was used to detect mifepristone and its metabolites in human plasma (Heikinheimo et al, 1986; Swahn et al, 1986a). The sensitivity of this assay was 0.05 IU/mL (Liu et al, 1988).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with significant symptoms and/or abnormal vital signs should be admitted. Pregnant patients with symptoms of vaginal bleeding or contractions should be evaluated by an obstetrician/gynecologist.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear. Obstetrician/gynecologist should be consulted for any case of excessive uterine bleeding or contractions and in the case of inadvertent administration to a pregnant woman who does not desire early pregnancy termination.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.

Monitoring

    A) Mifepristone plasma concentrations are not clinically useful or readily available.
    B) Monitor CBC in patients with significant vaginal bleeding.
    C) Monitor vital signs and liver enzyme levels following significant overdose.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    E) Patients with severe or persistent bleeding after mifepristone administration for elective termination of pregnancy should be evaluated for incomplete abortion/retained products of conception by pelvic exam and ultrasound.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) Consider activated charcoal in patients with large, recent ingestions who are awake and cooperative.
    2) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Mifepristone plasma concentrations are not clinically useful or readily available.
    2) Monitor CBC in patients with significant vaginal bleeding.
    3) Monitor vital signs and liver enzyme levels following significant overdose.
    4) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    5) Patients with severe or persistent bleeding after mifepristone administration for elective termination of pregnancy should be evaluated for incomplete abortion/retained products of conception by pelvic exam and ultrasound.
    B) PROGESTERONE
    1) PREVENTION OF MIFEPRISTONE INDUCED ABORTION
    a) Progesterone has been used to attempt to prevent abortion in women who initially desired a medical abortion and changed their minds after taking mifepristone but prior to taking misoprostol. In a case series, progesterone administration was effective in 4 of 6 patients for the prevention of mifepristone-induced abortion. All subjects (age, 19 to 25 years) chose to attempt to prevent pregnancy termination after ingestion of mifepristone, but prior to ingestion of misoprostol for medical abortion. The gestational age at intervention was 7 to 11 weeks in 5 cases and unknown in 1 case. In the 4 successful cases, patients received an initial dose of progesterone in oil 200 mg IM 30 to 72 hours after mifepristone ingestion, with additional doses of progesterone in oil 200 mg IM or oral micronized progesterone administered at various schedules and durations. In one unsuccessful case, the patient received progesterone in oil 200 mg IM for 1 dose (timing of mifepristone unknown) with abortion completed shortly thereafter. In the other unsuccessful case, the patient received progesterone 200 mg oral capsule intravaginally 7 hours following mifepristone administration, plus 2 doses of progesterone in oil 200 mg IM at 18 hours and at day 2, with abortion completed on day 3. In the 4 successful cases, viable infants were subsequently delivered between 37 and 40 weeks gestation, without neonatal complications or birth defects (Delgado & Davenport, 2012).
    C) HEMORRHAGE
    1) Severe uterine bleeding, necessitating blood transfusions and curettage in some instances, may occur following therapeutic administration of mifepristone as sole therapy or in combination therapy with prostaglandin or misoprostol administration (Prod Info MIFEPREX(R) oral tablets, Apr; Gouk et al, 1999; Grimes et al, 1988; Mishell et al, 1987).
    D) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

Enhanced Elimination

    A) SUMMARY
    1) Hemodialysis and hemoperfusion are UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.

Range Of Toxicity

Summary

    A) TOXICITY: A specific minimum toxic dose of mifepristone has not been established. In tolerance studies, no serious adverse reactions were observed in healthy non-pregnant women and healthy men in single doses greater than 3-fold the recommended doses for termination of pregnancy. THERAPEUTIC DOSE: ADULTS: 600 mg as a single oral dose. CHILDREN: The safety and efficacy of mifepristone has not been established in the pediatric population.

Therapeutic Dose

    7.2.1) ADULT
    A) KORLYM(TM)
    1) The recommended starting dose is 300 mg orally once daily. Maximum dose, 1200 mg once daily or 20 mg/kg per day (Prod Info Korlym(TM) oral tablets, 2012).
    B) MIFEPREX(R)
    1) The recommended regimen is three 200-mg tablets (600 mg) in a single oral dose (Prod Info MIFEPREX(R) oral tablets, 2009).
    7.2.2) PEDIATRIC
    A) KORLYM(TM)
    1) Safety and efficacy have not been established in pediatric patients (Prod Info Korlym(TM) oral tablets, 2012).
    B) MIFEPREX(R)
    1) The safety and efficacy have not been established in the pediatric population (Prod Info MIFEPREX(R) oral tablets, 2009).

Maximum Tolerated Exposure

    A) In tolerance studies, no serious adverse reactions were observed in healthy non-pregnant women and healthy men in single doses greater than 3-fold the recommended doses for termination of pregnancy (Prod Info Mifeprex(R), 2004).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Mifepristone is the first synthesized antiprogestin agent with progesterone and glucocorticoid antagonist activity at the receptor site. The drug is a synthetic 19-norsteroid with a side chain at C-17 and an extra ring at C-11 (Couzinet & Schaison, 1988). The abortifacient action of mifepristone is thought to be mediated through antiprogesterone effects on endometrial progesterone receptors. When administered during the luteal phase, the antiprogesterone effects induce menses and permit the release of prostaglandins from the endometrium (Schaison et al, 1985; Kelly et al, 1986).
    B) The primary target for mifepristone and antiprogesterone effects in early pregnancy is the decidua where there are a large number of progesterone receptors (Baulieu, 1989). This causes levels of human chorionic gonadotropin to decrease rapidly, once the embryo is detached. Next, the maintenance of ovarian function is withdrawn which leads to an irreversible luteolytic effect. Mifepristone may also be active in aiding the release of endogenous prostaglandins. This leads to increased contractibility of the myometrium, cervical softening and dilation which may facilitate the evacuation of the lining of the uterus and embryo.
    C) Mifepristone also binds to androgen receptors, but has negligible antiandrogen activity since the drug has a much lower affinity for the receptors than testosterone (Couzinet & Schaison, 1988).

Toxicologic Mechanism

    A) Mifepristone possesses antiglucocorticoid activity, with approximately the same affinity for glucocorticoid receptors as dexamethasone (Bertagna et al, 1984). The drug has also demonstrated the ability to abolish the negative feedback control of cortisol on the pituitary-adrenal axis and to inhibit the the ACTH inhibitory activity of dexamethasone (Gaillard et al, 1984), which may result in adrenal failure following administration of massive doses of mifepristone (Prod Info Korlym(TM) oral tablets, 2012).

Physicochemical

Physical Characteristics

    A) Mifepristone is a yellow powder. It is very soluble in methanol, chloroform, and acetone, and is poorly soluble in water, hexane, and isopropyl ether (Prod Info Mifeprex(TM), mifepristone, 2000).

Molecular Weight

    A) 429.6 (Prod Info Mifeprex(TM), mifepristone, 2000)

References

General Bibliography

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    55) Product Information: MIFEPREX(R) oral tablets, mifepristone oral tablets. Danco Laboratories, LLC (per Manufacturer), New York, NY, Apr.
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    59) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
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