1. Aetna considers mifepristone (Mifeprex; also known as RU 486) medically necessary for the medical termination of early pregnancy.

   Notes: Mifepristone is covered only in plans that cover elective abortion.  If the plan has limitations on abortion, the limitations would apply to this drug.  Office visits, ultrasounds and other medications associated with the use of mifepristone are also considered medically necessary in accordance with the terms and conditions of the plan.

   In plans that cover elective abortion, mifepristone is considered part of the medical benefit and is not a pharmacy benefit.

2. Aetna considers oral mifepristone experimental and investigational for labor induction in women in term pregnancy, or women with pre-labor rupture of membranes near term (36 weeks or greater gestational age) because it does not improve labor stimulation, and is associated with more adverse fetal outcomes in near term women.

3. Aetna considers mifepristone medically necessary for the treatment of adults with endogenous Cushing’s syndrome who have type 2 diabetes or glucose intolerance and are not candidates for surgery or who have not responded to prior surgery.

4. Aetna considers mifepristone experimental and investigational for the treatment of the following indications because its effectiveness for these indications has not been established (not an all inclusive list): 

Mifepristone (trade name Mifeprex (Danco Laboratories, New York, NY); also known as RU 486) is used for the medical termination of early pregnancy, defined as 49 days (7 weeks) or less, counting from the beginning of the last menstrual period.  Mifepristone works by blocking the effect of progesterone, a hormone that is needed for pregnancy to continue.

In accordance with the Food and Drug Administration (FDA) approval, mifepristone may be administered only in a clinic, medical office, or hospital, by or under the supervision of a physician.  Medical abortion with mifepristone usually requires 3 office visits by the patient.  The patient is first appropriately counseled.  Some states mandate a waiting period between the counseling and the initiation of the abortion; therefore, there may be a state-mandated extra office visit.  The patient then takes the prescribed dose of mifepristone.  Two days after ingesting mifepristone, the patient returns to her physician.  Unless abortion has occurred and has been confirmed by clinical examination or ultrasound, she takes the prescribed dose of misoprostol, a prostaglandin.  Women return for a follow-up visit approximately 7 to 14 days after taking mifepristone to determine by clinical examination or ultrasound whether the pregnancy has been terminated.

The protocol that received FDA approval was 600 mg mifepristone, followed in 48 hours by 400 ug misoprostol.  This resulted in a 92 to 97 % success rate if taken within 49 days of last menstrual period (LMP).

Subsequent research has supported an effective alternative regimen using a lower dose of 200 mg mifepristone, followed within 24 to 72 hours by 800 ug misoprostol administered vaginally within 69 days of LMP.  This regimen is as least as effective (97 %), with fewer side effects, and results in more rapid expulsion.  About 80 % of users still use the original regimen.  In 2003, the World Health Organization recommends the following protocol for safe abortion -- up to 9 completed weeks (63 days) since LMP: 200 mg mifepristone followed after 36 to 48 hours by 0.8 mg (800 ug) vaginal misoprostol, or 0.4 mg (400 ug) oral misoprostol up to 7 completed weeks (49 days).

Under the terms of the FDA approval, mifepristone will be distributed to physicians who can accurately determine the duration of a patient's pregnancy and detect an ectopic (or tubal) pregnancy.  Physicians who prescribe mifepristone must also be able to provide surgical intervention in cases of incomplete abortion or severe bleeding, or they must make plans in advance to provide such care through others.  The drug is not available in pharmacies.

In a randomized controlled study, Berkane and associates (2005) examined the effectiveness of mifepristone for ripening the cervix and inducing labor in term pregnancies.  A total of 346 women received 50, 100, 200, 400, or 600 mg of mifepristone or placebo.  The principal outcome measure was the number of patients in whom labor occurred between 12 and 45 and 54 hours after treatment or who had a Bishop score 6 or greater.  Maternal and fetal tolerability was also studied.  No significant effectiveness was observed whatever the dose of mifepristone.  Mifepristone was well-tolerated by the mother and fetus.  These researchers concluded that mifepristone, at doses up to 600 mg, does not induce labor within 54 hours in patients with unfavorable cervical status.

In a randomized controlled study (n = 65), Wing and colleagues (2005) compared the use of oral mifepristone with intravenous oxytocin (OT) for labor induction in women with pre-labor rupture of membranes (PROM) at 36 weeks or greater gestational age.  Women with spontaneous PROM were randomly assigned to receive 200 mg mifepristone (n = 33) or OT infusion (n = 32); and subjects were observed for 18 hours.  The average interval from the commencement of induction to delivery was 1,194.1 +/- 568.7 mins for mifepristone-treated subjects and 770.8 +/- 519.9 mins for OT-treated subjects (p = 0.001).  Of the 33 mifepristone-treated subjects and 32 OT-treated subjects, 25 (78.1 %) and 17 (51.5 %), respectively, achieved successful induction (defined as vaginal delivery within 24 hours) (p = 0.01).  Furthermore, there was more fetal distress in the mifepristone-treated group (9 versus 2, p = 0.02), and a trend toward more cesarean births (7 versus 3, p = 0.19) compared to the OT-treated group.  Eleven infants of mifepristone-treated women (33.3 %) and 3 infants of OT-treated women (9.4 %) were admitted to the neonatal intensive care unit (p = 0.02).  These investigators concluded that oral mifepristone administration 18 hours before OT infusion did not improve labor stimulation in women with PROM near term, and was associated with more adverse fetal outcomes.

Gallagher and colleagues (2005) noted that hyper-cortisolemia may cause or exacerbate both neurocognitive impairment and symptoms in patients with schizophrenia.  These investigators examined if anti-glucocorticoid treatments, particularly glucocorticoid receptor (GR) antagonists, would improve neurocognitive functioning and clinical symptoms in this disorder.  In a randomized, double-blind, cross-over, controlled study, a total of 20 patients with schizophrenia were treated with 600 mg/day of the GR-antagonist mifepristone or placebo for 1 week.  Neurocognitive function was evaluated at baseline and 2 weeks after each treatment.  Neuroendocrine profiling was performed at these times and also immediately after each treatment.  Symptoms were evaluated weekly.  Mifepristone administration resulted in a temporary 2- to 3-fold increase in plasma cortisol levels (p < 0.0001).  No significant effects were observed on any measure of neurocognitive function, including the primary outcome measures of spatial working memory and declarative memory.  Minor changes in symptoms occurred in both arms of the study and were indicative of a general improvement over time, irrespective of treatment.  The authors concluded that contrary to their earlier report of positive effects in bipolar disorder, these findings suggested that the GR-antagonist mifepristone has no effect on neurocognitive function or symptoms in this group of patients with schizophrenia.  They noted that future studies in schizophrenia should examine patients with demonstrable hypothalamic-pituitary-adrenal (HPA) axis dysfunction.

In a Cochrane review, Gallagher et al (2008) compared the safety and effectiveness of anti-glucocorticoid agents in the treatment of mood episodes (manic, mixed affective or depressive) with placebo or alternative drug treatment in mood disorders.  Randomized controlled trials comparing anti-glucocorticoid drugs in the treatment of mood episodes with placebo or alternative drug treatment in mood disorders were selected.  Data were extracted and the methodological quality of each study was assessed independently by 2 review authors.  Meta-analyses were performed using Review Manager software. Relative risk (RR) with 95 % confidence intervals (CI) were calculated for dichotomous outcomes.  For continuous data, weighted mean differences (WMD) were calculated.  Nine studies met criteria for inclusion.  A number of drugs were examined, including mifepristone, ketoconazole, metyrapone and DHEA.  Three trials were in patients with psychotic major depression (pMDD), 5 trials in non-psychotic major depression and 1 trial in bipolar disorder.  When examining all trials together across all affective episodes, there was no significant difference in the overall proportion of patients responding to anti-glucocorticoid treatment over placebo, although the mean change in HAM-D scores indicated a significant difference in favor of treatment (WMD -4.54, 95 % CI: -6.78 to -2.29).  Of the 5 trials in non-psychotic depression (unipolar or bipolar), there was a significant difference favoring treatment (HAM-D 50 % reduction: RR 0.72, 95 % CI: 0.56 to 0.91).  In pMDD, there was no evidence of an overall anti-depressant effect (HAM-D 50 % reduction: RR 0.98, 95 % CI: 0.79 to 1.22) or an effect on overall psychopathology (BPRS 30 % reduction: RR 0.96, 95 % CI: 0.76 to 1.22).  In these subtypes, the mean change in HAM-D indicated a significant difference in favor of treatment.  The authors concluded that the use of anti-glucocorticoids in the treatment of mood disorders is at the proof-of-concept stage.  Considerable methodological differences exist between studies with respect to the compounds used and the patient cohorts studied.  Results in some diagnostic subtypes are promising and warrant further investigation to establish the clinical utility of these drugs in the treatment of mood disorders.

DeBattista and Belanoff (2005) noted that Alzheimer's disease (AD) is often associated with abnormalities in the HPA axis.  Elevated cortisol levels in AD may in turn be associated with a more rapid progression of the illness.  Furthermore, elevated cortisol levels may directly contribute to cognitive deficits in AD.  Mifepristone is a potent antagonist of the glucocorticoid receptor and blocks the central actions of cortisol.  These researchers noted that given the limited options for the treatemnt of AD, mifepristone represents an innovative and promising therapeutic approach for this disease.  However, there is currently a lack of well-designed studies to support this approach in treating AD.

Mifepristone blocks the action of cortisol by binding to the glucocorticoid receptor and, therefore, is of potential therapeutic value in Cushing's syndrome. Johanssen and Allolio (2007) reviewed the available evidence concerning the therapeutic effects and adverse events of mifepristone in Cushing's syndrome.  A total of 18 patients has been reported; with daily doses of mifepristone ranging from 5 to 30 mg/kg.  Case reports indicated that the mifepristone-induced receptor blockade may result in significant clinical improvement in patients in whom surgery and inhibitors of adrenal steroidogenesis fail to control hyper-cortisolism.  As a consequence of its rapid onset of action, mifepristone may be particularly useful in acute crises (e.g., in cortisol-induced psychosis).  Adverse effects associated with the use of mifepristone include adrenal insufficiency and, as a result of its anti-progestin action, endometrial hyperplasia in chronic treatment.  The authors stated that well-designed larger clinical trials are needed to better ascertain the value of mifepristone in the treatment of Cushing's syndrome.

In a review on drugs in the medical treatment of Cushing's syndrome, Schteingart (2009) stated that mifepristone is being examined in clinical trials in patients with persistent or recurrent Cushing's disease as well as in patients with metastatic adrenal cortical carcinoma or ectopic ACTH syndrome not amenable to surgery.

Castinetti et al (2010) summarized the results of mifepristone reported in the literature as a treatment of Cushing's syndrome.  Most of the patients were treated due to unsuccessful surgery and/or partially effective anti-cortisolic drugs.  The majority of them presented a rapid decrease of clinical signs of hyper-cortisolism during the first month of treatment; about 50 % experienced a reduction in their elevated blood pressure, and 50 % of the diabetic patients presented improved blood glucose levels.  Mifepristone treatment has 2 main drawbacks: (i) the blockade of glucocorticoid receptors leads to increased ACTH and cortisol levels, making it difficult to adapt the treatment and diagnose adrenal deficiency, and (ii) increased cortisol levels can also lead to severe hypokalemia.  Follow-up of efficacy should only be clinical (weight, blood pressure, skin lesions) and biological (regular blood potassium sampling).  Dose adjustment will be performed based on these parameters.  The lack of a large available prospective cohort of patients on mifepristone, and the scarcity of data on its long-term effects, does not allow recommending it as a first-line drug in the treatment of hyper-cortisolism.  However, as mifepristone is a rapidly effective drug, it can play a role in the management of hyper-cortisolism.  The main indication is the partial efficacy or bad tolerance of other well-known anti-cortisolic drugs, either by replacement (bad tolerance, lack of effectiveness) or addition (multi-modal approach) of mifepristone.

In February 2012, the FDA approved mifepristone (Korlym) to control hyperglycemia in adults with endogenous Cushing’s syndrome.  This drug was approved for use in patients with endogenous Cushing’s syndrome who have type 2 diabetes or glucose intolerance and are not candidates for surgery or who have not responded to prior surgery.  Endogenous Cushing’s syndrome is a serious, debilitating and rare multi-system disorder.  It is caused by the over-production of cortisol by the adrenal glands.  This syndrome most commonly affects adults aged 25 to 40 years.  Approximately 5,000 patients will be eligible for mifepristone treatment, which received an orphan drug designation by the FDA in 2007.

The safety and effectiveness of mifepristone in patients with endogenous Cushing’s syndrome was evaluated in a clinical trial with 50 patients.  A separate open-label extension of this trial is ongoing.  Additional evidence supporting the FDA's approval included several safety pharmacology studies, drug-drug interaction studies and published scientific literature.  Patients experienced significant improvement in blood sugar control during mifepristone treatment, including some patients who had marked reductions in their insulin requirements.  Improvements in clinical signs and symptoms were reported by some patients.  The most common side effects experienced by endogenous Cushing’s syndrome patients treated with mifepristone in clinical trials were nausea, fatigue, headache, arthralgia, vomiting, swelling of the extremities, dizziness and decreased appetite.  Other side effects of mifepristone include adrenal insufficiency, low potassium levels, vaginal bleeding and a potential for heart conduction abnormalities.  Certain drugs used in combination with mifepristone may increase its drug level.  Health care professionals must be aware of the potential for drug-drug interactions and adjust dosing or avoid using certain drugs with Korlym.  Mifepristone should never be used (contraindicated) by pregnant women.

In a randomized controlled trial, Carbonell Esteve and colleagues (2008) examined the effectiveness of mifepristone for the treatment of uterine leiomyomas.  A total of 100 women were randomly assigned to receive oral mifepristone 5 mg or 10 mg daily for 3 months (50 per group).  Abdominal ultrasonography was performed before treatment, at 45 days, and at 3 months to evaluate leiomyoma and uterine volumes.  Endometrial biopsy specimens were taken before and after treatment.  Effectiveness was estimated by the reduction percentages of the leiomyoma and uterine volumes.  After 90 days treatment there was a 45 % (95 % CI: 37 to 54, p < 0.001) and a 57 % (95 % CI: 48 to 67, p < 0.001) reduction in the leiomyoma volume in the 10-mg and 5-mg groups, respectively, and one of 40 % (95 % CI: 34 to 46, p = 0.002), and 36 % (95 % CI: 31 to 40, p < 0.001), respectively, in the uterine volume.  Symptomatic improvement was noted, and the prevalence of symptoms diminished significantly.  There were no significant differences in reduction of volume and symptoms in the treatment groups, p > 0.05 in all cases.  After treatment, 44 of 49 (89.8 %) women from the mifepristone 10 mg group and 45 of 50 (90.0 %) from the 5-mg group, respectively, were amenorrheic (p = 0.487).  Endometrial biopsy after treatment showed simple hyperplasia in 1 of 50 (2.0 %) in the mifepristone 10-mg group.  The authors concluded that 5-mg doses of mifepristone produce reductions in leiomyoma and uterine volumes and symptomatic improvement similar to 10-mg doses.  They also noted that future studies should include longer treatment periods and post-treatment participant evolution follow-up.

Malartic and associates (2008) stated that mifepristone can reduce uterine fibroid tumors' growth by several pathways.  Its efficiency has been widely evaluated in symptomatic patients for more than 10 years.  A significant decrease in fibroid tumors and uterine volume concomitant with better quality of life scores can be obtained with the administration of 5-mg daily doses of mifepristone.  Mifepristone can be compared with gonadotropin-releasing hormone agonists in terms of efficiency.  Observed adverse outcomes are hot flushes (38 %), elevated hepatic enzymes (4 %) and benign endometrial hyperplasia (28 %).  Hot flushes and endometrial hyperplasia are not observed with 5-mg daily doses.  Data suggested that many invasive procedures could be avoided with the routine use of mifepristone for fibroid tumors care.  However, the authors noted that published study periods are only 3 to 12 months; long lasting evaluation in larger groups of patients seems necessary before this treatment could be proposed as routine care.

In a review on medical management of fibroids, Sankaran and Manyonda (2008) stated that 2 progesterone antagonists, mifepristone and asoprisnil, have shown significant promise and warrant further research.  This is in agreement with the observations of Lethaby and Vollenhoven (2008) who noted that limited short-term evidence of 2 progestogenic therapies indicates that low-dose mifepristone may improve quality of life and bleeding in the short-term, and asoprisinil may improve bleeding and fibroid-related symptoms.  They stated that more research is needed on the role of hormonal therapies for women with fibroids.

In a phase II clinical trial, Ramondetta and co-workers (2009) examined the effectiveness of mifepristone in women with advanced or recurrent endometrioid adenocarcinoma or low-grade endometrial stromal sarcoma (LGESS). Mifepristone (200 mg orally) was given daily to patients with progesterone receptor-positive advanced or recurrent endometrioid adenocarcinoma or LGESS.  Patients were evaluated every 4 weeks for toxicity and response.  Quality-of-life data were obtained using the Memorial Symptom Assessment Scale and Functional Assessment for Cancer Therapy.  Twelve of 13 enrolled patients were evaluable in the first phase of accrual.  Stable disease was noted in 3 of 12 patients (at 8 weeks, 12 weeks, and greater than or equal to 77 weeks, respectively), and the median time to disease progression was 48 days.  Among the patients who had stable disease, 2 women had endometrioid endometrial cancer, and 1 woman had LGESS.  No partial or complete responses were observed.  The most frequent grade 1 and 2 toxicities were anorexia, fatigue, and mood alterations observed in 50 %, 50 %, and 58 % of patients, respectively.  The most common grade 3 toxicities were fatigue and dyspnea observed in 25 % and 17 % of patients, respectively.  One patient experienced grade 4 dyspnea.  A total of 33 % of patients had asymptomatic elevations of corticotropin.  No serious treatment-related adverse events occurred.  There were no significant changes in quality of life.  The authors concluded that single-agent mifepristone used in the treatment of recurrent endometrioid adenocarcinoma or LGESS resulted in a stable disease rate of 25 %.  One patient who had a biopsy-positive disease recurrence remained stable at 77 weeks.  Although mifepristone was well-tolerated, as a single agent, it provided limited response as a single agent in women with progesterone receptor-positive uterine tumors.  The authors stated that further research into the best mode of application for mifepristone in the treatment of endometrial cancer is needed.

In a phase II clinical trial, Rocereto and colleagues (2010) assessed the effectiveness and toxicity of mifepristone in patients with ovarian, peritoneal and fallopian tube cancers.  Patients with confirmed epithelial ovarian, peritoneal and fallopian tube cancers which were persistent or recurred in less then 1 year after primary chemotherapy were entered into this study.  Patients were given mifepristone 200 mg by mouth daily for a 28-day cycle.  The medication was stopped for unacceptable toxicity or tumor progression.  A total of 24 patients were entered into the study.  Twenty-two patients were evaluable for response.  Only 1 patient had a partial response for a response rate of only 4.5 % (90 % CI: 0.2 % to 19.8 %).  The authors concluded that mifepristone has not proven to be an effective agent in the treatment of patients with recurrent or persistent ovarian, peritoneal and fallopian tube cancers.