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Aetna Aetna
Clinical Policy Bulletin:
Mifepristone (RU 486)
Number: 0465


Policy

  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): 
  • Alcohol and cocaine dependence
  • Alzheimer's disease
  • Anxiety disorders
  • Breast cancer
  • Cancer metastatic chemoprevention
  • Ectopic ACTH syndrome
  • Endometrial cancer
  • Endometriosis
  • Fallopian tube cancer
  • Gastric cancer
  • Gliomas
  • Metastatic adrenal cortical carcinoma
  • Meningioma
  • Ovarian cancer
  • Peritoneal cancer
  • Post-traumatic stress disorder
  • Prostate cancer
  • Psychotic major depression
  • Schizophrenia
  • Uterine leiomyomas.


Background

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.

An UpToDate review on “Treatment protocols for breast cancer” (Brenner et al, 2013) as well as the National Comprehensive Cancer Network’s clinical practice guideline on breast cancer (2013) do not mention mifepristone as a therapeutic option.

Guo and colleagues (2011) noted that China was the first country that approved mifepristone for abortion.  A total of 6 years after the report published in the Western world indicated that mifepristone may also be effective in treating endometriosis, the first paper on the same topic was published in China in 1997.  Since then, over 160 studies on this topic have been published in China.  These investigators retrieved 104 papers on clinical trials and trial-like studies conducted in China evaluating the use of mifepristone to treat endometriosis that were published in the last 11 years.  They found that the quality of these studies is well below an acceptable level, making it difficult to judge whether mifepristone is truly effective.  There are intriguing signs that these studies, as a whole, have serious anomalies.  The areas that are glaringly deficient are informed consent, choice of outcome measures, the evaluation of outcome measures, data analysis and randomization.  The uniformly low quality is disquieting, given the large quantity of studies, the enormous amount of resource and energy put into these studies and, above all, the weighty issue of treatment efficacy that concerns each and every patient with endometriosis.  Equally disquieting are the low-quality repetition, the absence of a critical, systematic review on the subject, the lack of suggestions for multi-center clinical trials and the seemingly unnecessary duplication of clinical trials without due informed consent. 

Bouchard et al (2011) discussed the mechanism of action of selective progesterone receptor modulators (SPRMs) and summarized the pre-clinical and clinical safety and effectiveness data supporting the potential use of these compounds for gynecologic indications.  Relevant publications from 2005 onward were identified using a PubMed search.  Additional relevant articles were identified from citations within these publications.  Mifepristone was first developed as a progesterone receptor antagonist and licensed for pregnancy termination because of the unique property of this compound to terminate pregnancy when associated with prostaglandins.  Then SPRMs were developed, and among those ulipristal acetate, an efficient emergency contraceptive.  Because SPRMs effectively inhibit endometrial proliferation and reduce endometriotic lesions in animal models, this suggests a possible role in the treatment of endometriosis in humans.  Finally, a number of double-blind, randomized, placebo-controlled trials have demonstrated the effectiveness of asoprisnil, mifepristone, telapristone acetate, and ulipristal acetate in reducing leiomyoma and uterine volume, and suppressing bleeding in women with uterine fibroids.  The authors concluded that mifepristone in combination with prostaglandins has been licensed for pregnancy termination because of its unique ability is this area.  Ulipristal acetate is available for emergency contraception.  Several SPRMs hold further promise as an effective medical therapy for patients suffering from endometriosis and leiomyoma.

An UpToDate review on “Overview of the treatment of endometriosis” (Schenken, 2013) does not mention the use of mifepristone as a therapeutic option.

Grunberg et al (2006) stated that mifepristone is an oral anti-progestational and, to a lesser extent, anti-glucocorticoid agent commonly used for short-term (single-day) therapy.  However, treatment of neoplasms or chronic conditions will require long-term administration.  Meningioma is a benign central nervous system tumor that is often progesterone-but not estrogen-receptor positive, making long-term anti-progestational therapy a logical treatment strategy.  These researchers examined the effects of long-term administration of mifepristone for the treatment of meningioma.  Patients with unresectable meningioma were treated with oral mifepristone 200 mg/day.  This dose was selected to provide significant anti-progestational but not anti-glucocorticoid activity.  Patients also received oral dexamethasone 1 mg/day for the first 14 days.  Serial follow-up allowed evaluation for tolerability and side effects of long-term therapy as well as observation for efficacy (tumor shrinkage or improvement in visual fields).  A total of 28 patients received daily oral mifepristone for a total of 1,626 patient-months of treatment.  The median duration of therapy was 35 months (range of 2 to 157 months).  Repeated oral administration was well-tolerated with mild fatigue (22 patients), hot flashes (13 patients), and gynecomastia/breast tenderness (6 patients) being the most common side effects.  However, endometrial hyperplasia or polyps were documented in 3 patients and 1 patient developed peritoneal adenocarcinoma after 9 years of therapy.  Minor responses (improved automated visual field examination or improved CT or MRI scan) were noted in 8 patients, 7 of whom were male or pre-menopausal female.  The authors concluded that long-term administration of mifepristone is feasible and clinically well-tolerated, with generally mild toxicity.  However, endometrial hyperplasia was noted in several patients.  In view of the association between long-term treatment with tamoxifen and endometrial cancer, this observation will require further investigation and screening.  Minor regression of meningioma that can result in significant clinical benefit is suggested in the male and pre-menopausal female subgroups of patients.

An UpToDate review on “Systemic treatment of recurrent meningioma” (Wen, 2013) states that “Small studies with the progesterone receptor inhibitor mifepristone suggested that this agent resulted in objective improvement in 25 to 30 percent of patients with unresectable meningioma.  However, a multicenter cooperative group phase III trial failed to demonstrate any benefit from treatment with mifepristone.  In this trial, 180 patients were randomly assigned to either mifepristone or placebo.  There was no improvement in median progression-free survival (10 versus 12 months).  The lack of activity in this trial may have been due to loss of expression of progesterone receptor in patients with advanced disease”.  Furthermore, an UpToDate review on “Treatment of benign (WHO grade I) meningioma” (Park et al, 2013) does not mention the use of mifepristone as a therapeutic option.

deBattista et al (2006) stated that abnormalities in the hypothalamic pituitary adrenal axis have been implicated in the pathophysiology of psychotic major depression (PMD).  Recent studies have suggested that mifepristone might have a role in the treatment of PMD.  These investigators from Corcept Therapeutics (Menlo Park, CA) examined the effectiveness of mifepristone treatment of the psychotic symptoms of PMD.  A total of 221 patients, aged 19 to 75 years, who met DSM-IV and SCID criteria for PMD and were not receiving antidepressants or antipsychotics, participated in a double blind, randomized, placebo controlled study.  Patients were randomly assigned to either 7 days of mifepristone (n = 105) or placebo (n = 116) followed by 21 days of usual treatment.  Patients treated with mifepristone were significantly more likely to achieve response, defined as a 30 % reduction in the Brief Psychiatric Rating Scale (BPRS).  In addition, mifepristone-treated patients were significantly more likely to achieve a 50 % reduction in the BPRS Positive Symptom Scale (PSS).  No significant differences were observed on measures of depression.  The authors concluded that a seven 7-day course of mifepristone followed by usual treatment appears to be effective and well-tolerated in the treatment of psychosis in PMD.  This study suggested that mifepristone might represent an alternative to traditional treatments of psychosis in psychotic depression.

Nihalani and Schwartz (2007) noted that Corcept Therapeutics is developing mifepristone for the potential treatment of the psychotic features of PMD and for Alzheimer's disease (AD).  In August 2004, a pivotal phase III trial was initiated in the United States for psychotic features of PMD, a second trial began in October 2004 and these were followed by a European phase III trial in May 2005.  However, in August 2006, September 2006 and March 2007, respectively, these phase III trials failed to meet their endpoints.  A further phase III trial was to commence later in 2007.

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 soft-ware.  Relative risks (RR) with 95 % CI were calculated for dichotomous outcomes.  For continuous data, weighted mean differences (WMD) were calculated.  A total of 9 studies met criteria for inclusion.  A number of drugs were examined, including mifepristone [RU-486], ketoconazole, metyrapone and DHEA.  Three trials were in patients with PMD, 5 trials in non-PMD 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 patients with PMD, there was no evidence of an overall antidepressant 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.

Blasey et al (2011) evaluated the safety and effectiveness of mifepristone for the treatment of psychotic depression and examined if response was significantly greater among patients with mifepristone plasma concentrations above an a priori hypothesized threshold.  A total of 433 patients who met criteria for psychotic depression were randomly assigned to receive 7 days of either mifepristone (300, 600, or 1,200 mg) or placebo.  Response was defined as a 50 % reduction in psychotic symptoms on both days 7 and 56.  Cochran-Mantel-Haenszel tests compared (i) the proportion of responders among patients assigned mifepristone versus placebo, and (ii) the proportion of responders among the subset of patients with plasma concentrations greater than 1,660 ng/ml versus placebo.  Mifepristone was well-tolerated at all 3 doses.  The proportion of responders randomized to mifepristone did not statistically differ from placebo.  Patients with trough mifepristone plasma concentrations greater than 1,660 ng/ml were significantly more likely to have a rapid and sustained reduction in psychotic symptoms than those who received placebo.  The study failed to demonstrate efficacy on its primary end point.  However, the replication of a statistically significant linear association between mifepristone plasma concentration and clinical response indicates that mifepristone at sufficient plasma levels may potentially be effective in rapidly and durably reducing the psychotic symptoms of patients with psychotic depression.

Howland (2013) stated that the hypothalamic-pituitary-adrenal (HPA) axis is the body's main stress-response system, and cortisol is the major adrenal glucocorticoid hormone secreted in human beings.  Hypothalamic-pituitary-adrenal axis activity and cortisol secretion is regulated by a negative feedback system involving glucocorticoid receptors.  Dysregulation of the HPA axis and increased cortisol levels have been implicated in mood, psychotic, and other psychiatric disorders.  Mifepristone, as a potent antagonist of glucocorticoid receptors, has been studied or is currently being investigated as a potential therapeutic agent for alcohol and cocaine dependence, psychotic depression, post-traumatic stress disorder, as well as for mitigating the weight gain associated with the use of anti-psychotic drugs and for improving cognitive dysfunction in schizophrenia and bipolar disorder.

Lenze et al (2014) noted that in older adults with anxiety disorders, chronically elevated cortisol may contribute to cognitive impairment and elevated anxiety.  These researchers conducted a pilot study with mifepristone as a potential treatment for late-life anxiety disorders and co-occurring cognitive dysfunction.  A total of 15 individuals 60 years and older with an anxiety disorder plus cognitive dysfunction participated in the 12-week study.  In the first week, participants were randomly assigned to mifepristone 300 mg daily or placebo.  In the subsequent 3 weeks, all participants received mifepristone 300 mg.  Mifepristone was then discontinued, and the participants were reassessed 8 weeks later.  These researchers examined the following: (i) cognitive changes; (ii) worry symptom severity; (iii) safety and tolerability; and (iv) salivary cortisol before, during, and after mifepristone exposure.  Overall safety, tolerability, and high retention supported the feasibility of this research.  Participants with higher baseline cortisol levels (peak cortisol greater than 6.0 ng/ml, n = 5) showed improvements in memory, executive function, and worry severity after 3 to 4 weeks of mifepristone with persistent memory and worry improvements 8 weeks after mifepristone discontinuation.  Individuals with low-to-normal baseline cortisol (n = 8) showed little to no improvement.  As expected, cortisol levels rose during mifepristone exposure and returned to pre-treatment levels 8 weeks after mifepristone discontinuation.  In the 1st week of treatment, there were no differences between placebo-treated and mifepristone-treated participants.  The authors concluded that the findings of this pilot study warrant further testing of anti-glucocorticoid agents in late-life anxiety disorders with co-occurring cognitive dysfunction.  Moreover, they stated that mifepristone is hypothesized to have benefits in patients with evidence of glucocorticoid excess; directions for further study were discussed.

Chen et al (2014) stated that mifepristone is a born-for-woman molecule discovered 3 decades ago.  Unlike those anti-hypertensive and anti-psychotic pharmaceutical blockbusters, this abortifacient offers relatively low profit potential.  Current understanding of mechanism of action of mifepristone and its on-going clinical trials are changing the views on the drug beyond its abortifacient scope.  These investigators reviewed its metabolism and pharmacokinetic properties including its unique entero-hepatic circulation, its mechanisms of actions involving anti-progesterone and anti-glucocorticoid, growth inhibition of various cancer cell lines, suppression of invasive and metastatic cancer potential, down-regulation of Cdk2, Bcl-2, and NF-kappa B, interference of heterotypic cell adhesion to basement membrane, and cell migration.  They comprehensively analyze recent results from pre-clinical and clinical studies using mifepristone as an anti-cancer drug for breast, meningioma, and gliomas tumors in the central nervous system, prostate cancer, ovarian and endometrial cancer, and gastric adenocarcinoma.  The authors concluded that although mifepristone has more benefits for global public health than originally thought, its effect as a post-metastatic chemotherapeutic agent is limited.  Nonetheless, owing to its unique safe, metabolism and other pharmacological properties, metapristone (the primary metabolite of mifepristone) may have potential for cancer metastatic chemoprevention.

 
CPT Codes / HCPCS Codes / ICD-9 Codes
Other CPT codes related to the CPB:
76801 - 76817
84702 - 84703
HCPCS codes covered if selection criteria are met:
S0190 Mifepristone, oral, 200 mg
S0199 Medically induce abortion by oral ingestion of medication including all associated services and supplies (e.g., patient counseling, office visits, confirmation of pregnancy by HCG, ultrasound to confirm duration of pregnancy, ultrasound to confirm completion of abortion) except drugs
Other HCPCS codes related to the CPB:
S0191 Misoprostol, oral, 200 mcg
ICD-9 codes covered if selection criteria are met:
236.1 Neoplasm of uncertain behavior of placenta [hydatidiform mole]
255.0 Cushing syndrome [who have type 2 diabetes or glucose intolerance and are not candidates for surgery or who have not responded to prior surgery]
630 Hydatidiform mole
635.00 - 635.92 Legally induced abortion
V25.03 Encounter for emergency contraceptive counseling and prescription
V61.7 Other unwanted pregnancy
ICD-9 codes not covered for indications listed in the CPB (not all inclusive):
140.0 - 236.0, 236.2 - 239.9 Malignant neoplasm
293.84 Anxiety disorder in conditions classified elsewhere
295.00 - 295.95 Schizophrenic disorders
296.20 - 296.26 Major depressive disorder, single episode
296.30 - 296.36 Major depressive disorder, recurrent episode
300.00 - 300.09 Anxiety states
303.00 - 303.93 Alcohol dependence syndrome
304.20 - 304.23 Cocaine dependence
309.81 Posttraumatic stress disorder
331.0 Alzheimer's disease
617.0 - 617.9 Endometriosis
644.03 Threatened premature labor, antepartum condition or complication
644.21 Early onset of delivery, delivered, with or without mention of antepartum condition
658.13 Premature rupture of membranes, antepartum condition or complication
Other ICD-9 codes related to the CPB:
V22.0 - V22.2 Normal pregnancy
V23.0 - V23.9 Supervision of high-risk pregnancy


The above policy is based on the following references:
  1. U.S. Department of Health and Human Services, Food and Drug Administration (FDA). FDA approves mifepristone for the termination of early pregnancy. HHS News. Rockville, MD: FDA; September 28, 2000. Available at: http://www.fda.gov/bbs/topics/news/NEW00737.html. Accessed October 3, 2000.
  2. U.S. Department of Health and Human Services, Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER). Mifepristone questions and answers. CDER Drug Information. Rockville, MD: FDA; September 28, 2000. Available at: http://www.fda.gov/cder/drug/infopage/mifepristone/mifepristone-qa.htm. Accessed October 3, 2000.
  3. U.S. Department of Health and Human Services, Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER). Mifepristone medication guide. CDER Drug Information. Rockville, MD: FDA; September 28, 2000. Available at: http://www.fda.gov/cder/drug/infopage/mifepristone/medguide.htm. Accessed October 3, 2000.
  4. U.S. Department of Health and Human Services, Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER). Mifeprex™ (mifepristone) tablets, 200 mg for oral administration only. Product Labeling.. Rockville, MD: FDA; September 28, 2000. Available at: http://www.fda.gov/cder/foi/label/2000/20687lbl.htm. Accessed July 29, 2005.
  5. Winikoff B, Ellertson C, Elul B, et al. Acceptability and feasibility of early pregnancy termination by mifepristone-misoprostol. Results of a large multicenter trial in the United States. Mifepristone Clinical Trials Group. Arch Fam Med. 1998;7(4):360-366.
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  13. American College of Obstetricians and Gynecologists Committee on Practice Bulletins--Gynecology. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists. Medical management of abortion. Obstet Gynecol. 2001;97(4) Suppl:1-13.
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  16. Ho PC, Yu Ng EH, Tang OS. Mifepristone: Contraceptive and non-contraceptive uses. Curr Opin Obstet Gynecol. 2002;14(3):325-330.
  17. Schaff EA, Eisinger SH, Stadalius LS, et al. Low-dose mifepristone 200 mg and vaginal misoprostol for abortion. Contraception. 1999;59(1):1-6.
  18. Schaff EA, Fielding SL, Eisinger SH, et al. Low-dose mifepristone followed by vaginal misoprostol at 48 hours for abortion up to 63 days. Contraception. 2000;61(1):41-46.
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  23. Liao AH, Han XJ, Wu SY, et al. Randomized, double-blind, controlled trial of mifepristone in capsule versus tablet form followed by misoprostol for early medical abortion. Eur J Obstet Gynecol Reprod Biol. 2004;116(2):211-216.
  24. Kulier R, Gulmezoglu AM, Hofmeyr GJ, et al. Medical methods for first trimester abortion. Cochrane Database Syst Rev. 2004;(2):CD002855.
  25. Cheng L, Gülmezoglu AM, Piaggio G, et al. Interventions for emergency contraception. Cochrane Database Syst Rev. 2008;(2):CD001324.
  26. Fiala C, Swahn ML, Stephansson O, Gemzell-Danielsson K. The effect of non-steroidal anti-inflammatory drugs on medical abortion with mifepristone and misoprostol at 13-22 weeks gestation. Hum Reprod. 2005;20(11):3072-3077.
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  28. Berkane N, Verstraete L, Uzan S, et al. Use of mifepristone to ripen the cervix and induce labor in term pregnancies. Am J Obstet Gynecol. 2005;192(1):114-120.
  29. Wing DA, Guberman C, Fassett M. A randomized comparison of oral mifepristone to intravenous oxytocin for labor induction in women with prelabor rupture of membranes beyond 36 weeks' gestation. Am J Obstet Gynecol. 2005;192(2):445-451.
  30. Gallagher P, Watson S, Smith MS, et al. Effects of adjunctive mifepristone (RU-486) administration on neurocognitive function and symptoms in schizophrenia. Biol Psychiatry. 2005;57(2):155-161.
  31. Danish Centre for Evaluation and Health Technology Assessment (DACEHTA). Medical versus surgical first trimester abortion - a health technology assessment. Danish Health Technology Assessment - grant funded projects 5(6). Copenhagen, Denmark: DACEHTA; 2005.
  32. DeBattista C, Belanoff J. C-1073 (mifepristone) in the adjunctive treatment of Alzheimer's disease. Curr Alzheimer Res. 2005;2(2):125-129.
  33. DeBattista C, Belanoff J. The use of mifepristone in the treatment of neuropsychiatric disorders. Trends Endocrinol Metab. 2006;17(3):117-121.
  34. Tang OS, Ho PC. Clinical applications of mifepristone. Gynecol Endocrinol. 2006;22(12):655-659.
  35. Neilson JP, Hickey M, Vazquez J. Medical treatment for early fetal death (less than 24 weeks). Cochrane Database Syst Rev. 2006;(3):CD002253.
  36. Johanssen S, Allolio B. Mifepristone (RU 486) in Cushing's syndrome. Eur J Endocrinol. 2007;157(5):561-569.
  37. Abdel-Aleem H, d'Arcangues C, Vogelsong KM, Gülmezoglu AM. Treatment of vaginal bleeding irregularities induced by progestin only contraceptives. Cochrane Database Syst Rev. 2007;(4):CD003449.
  38. Gallagher P, Malik N, Newham J, et al. Antiglucocorticoid treatments for mood disorders. Cochrane Database Syst Rev. 2008;(1):CD005168.
  39. Lohr PA, Hayes JL, Gemzell-Danielsson K. Surgical versus medical methods for second trimester induced abortion. Cochrane Database Syst Rev. 2008;(1):CD006174.
  40. Carbonell Esteve JL, Acosta R, Heredia B, et al. Mifepristone for the treatment of uterine leiomyomas: A randomized controlled trial. Obstet Gynecol. 2008;112(5):1029-1036.
  41. Malartic C, Morel O, Akerman G, et al. Role of mifepristone for the treatment of uterine fibroid. Gynecol Obstet Fertil. 2008;36(6):668-674.
  42. Sankaran S, Manyonda IT. Medical management of fibroids. Best Pract Res Clin Obstet Gynaecol. 2008;22(4):655-676.
  43. Lethaby AE, Vollenhoven BJ. An evidence-based approach to hormonal therapies for premenopausal women with fibroids. Best Pract Res Clin Obstet Gynaecol. 2008;22(2):307-331.
  44. Kapp N, Lohr PA, Ngo TD, Hayes JL. Cervical preparation for first trimester surgical abortion. Cochrane Database Syst Rev. 2010;(2):CD007207.
  45. Schteingart DE. Drugs in the medical treatment of Cushing's syndrome. Expert Opin Emerg Drugs. 2009;14(4):661-671.
  46. Ramondetta LM, Johnson AJ, Sun CC, et al. Phase 2 trial of mifepristone (RU-486) in advanced or recurrent endometrioid adenocarcinoma or low-grade endometrial stromal sarcoma. Cancer. 2009;115(9):1867-1874.
  47. Rocereto TF, Brady WE, Shahin MS, et al. A phase II evaluation of mifepristone in the treatment of recurrent or persistent epithelial ovarian, fallopian or primary peritoneal cancer: A gynecologic oncology group study. Gynecol Oncol. 2010;116(3):332-334.
  48. Castinetti F, Conte-Devolx B, Brue T. Medical treatment of Cushing's syndrome: Glucocorticoid receptor antagonists and mifepristone. Neuroendocrinology. 2010;92 Suppl 1:125-130.
  49. U.S. Food and Drug Administration (FDA). FDA approves Korlym for patients with endogenous Cushing’s syndrome. FDA News. Silver Spring, MD: FDA; February 17, 2012. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm292462.htm?source=govdelivery. Accessed February 24, 2012.
  50. Grunberg SM, Weiss MH, Russell CA, et al. Long-term administration of mifepristone(RU486): Clinical tolerance during extended treatment of meningioma. Cancer Invest 2006;24(8):727-733.
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  52. Nihalani ND, Schwartz TL. Mifepristone, a glucocorticoid antagonist for the potential treatment of psychotic major depression. Curr Opin Investig Drugs. 2007;8(7):563-569.
  53. Gallagher P, Malik N, Newham J, et al. Antiglucocorticoid treatments for mood disorders. Cochrane Database Syst Rev. 2008;(1):CD005168.
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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.
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