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, and second trimester abortion.

    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. Mifepristone for endogenous Cushings is considered not medically necessary for persons with the following contraindications: pregnancy; concurrent long‐term corticosteroid use; women with a history of unexplained vaginal bleeding; and women with endometrial hyperplasia with atypia or endometrial carcinoma.

  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
    • Chronic multi-symptom illness
    • Ectopic ACTH syndrome
    • Endometrial cancer
    • Endometriosis
    • Fallopian tube cancer
    • Gastric cancer
    • Gliomas
    • Metastatic adrenal cortical carcinoma
    • Meningioma
    • Non-small cell lung cancer
    • Ovarian cancer / ovarian cancer metastasis
    • 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:
  1. the blockade of glucocorticoid receptors leads to increased ACTH and cortisol levels, making it difficult to adapt the treatment and diagnose adrenal deficiency, and
  2. 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 excess cortisol in endogenous Cushing's syndrome is caused by tumors that usually occur in the pituitary or adrenal glands that over‐produce, or prompt the over‐production of cortisol. Although cortisol at normal levels is essential to health, in excess it causes a variety of problems, including hyperglycemia, upper body obesity, a rounded face, stretch marks on the skin, an accumulation of fat on the back, thin and easily bruised skin, muscle weakness, bone weakness, persistent infections, hypertension, fatigue, irritability, anxiety, psychosis and depression. Women may have menstrual irregularities and facial hair growth, while men may have decreased fertility or erectile dysfunction. More than 70 percent of Cushing’ syndrome patients suffer from glucose intolerance or diabetes. The treatment of an endogenous Cushing’ syndrome patient depends on the cause. The first‐line approach is surgery to remove the tumor. If surgery is not successful or is not an option, radiation may be used, but that therapy can take up to ten years to achieve full effect. Surgery and radiation are successful in only approximately one‐half of all cases. If left untreated, Cushing’ syndrome has a five‐year mortality rate of 50 percent. An orphan disease, Cushing’ syndrome occurs in about 20,000 people in the United States, mostly women between the ages of 25 and 40 years.

Korlym (mifepristone) is a cortisol receptor blocker. Excess cortisol, a glucocorticoid, causes a variety of problems including hyperglycemia. Mifepristone is a selective antagonist of the progesterone receptor at low doses and blocks the glucocorticoid receptor (GR‐II) at higher doses. Mifepristone has high affinity for the GR‐II receptor but little affinity for the GR‐I (MR, mineralocorticoid) receptor. In addition, mifepristone appears to have little or no affinity for estrogen, muscarinic, histaminic, or monoamine receptors.

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.

Mifepristone is available as Korlym in 300 mg tablets. The recommended starting dose for Korlym (mifepristone) is 300 mg once daily. Korlym (mifepristone) must be given as a single daily dose. Patients should always take Korlym with a meal. The dose of Korlym may be increased to a maximum of 1200 mg once daily but should not exceed 20 mg/kg. Increases in dose should not occur more frequently than once every 2‐4 weeks.

Dosing Adjustments:

  • Renal Impairment: Do not exceed 600mg/day
  • Mild to moderate hepatic impairment: Do not exceed 600mg/day

Black Box Warning: Termination of Pregnancy

Mifepristone is a potent antagonist of progesterone and cortisol via the progesterone and glucocorticoid (GR‐II) receptors, respectively. The antiprogestational effects will result in the termination of pregnancy. Pregnancy must therefore be excluded before the initiation of treatment with Korlym and prevented during treatment and for one month after stopping treatment by the use of a non‐hormonal medically acceptable method of contraception unless the patient has had a surgical sterilization, in which case no additional contraception is needed. Pregnancy must also be excluded if treatment is interrupted for more than 14 days in females of reproductive potential.

Other Warnings/Precautions:

  • Do not use for the treatment of type 2 diabetes mellitus unrelated to endogenous Cushing’s syndrome
  • Caution with use of simvastatin or lovastatin and CYP 3A substrates with narrowtherapeutic range
  • Vaginal bleeding and endometrial changes: Women may experience endometrial thickening or unexpected vaginal bleeding; use with caution if patient also has a hemorrhagic disorder or is on anti‐coagulant therapy
  • QT interval prolongation: Avoid use with QT interval‐prolonging drugs, or in patients with potassium channel variants resulting in a long QT interval
  • Use of Strong CYP3A Inhibitors: Concomitant use can increase mifepristone plasma levels significantly; use only when necessary and limit mifepristone dose to 300 mg
  • Hormonal contraceptives: Do not use with Korlym

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
  1. the proportion of responders among patients assigned mifepristone versus placebo, and
  2. 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:
  1. cognitive changes;
  2. worry symptom severity;
  3. safety and tolerability; and
  4. 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.

Meningioma:

In a multi-center, prospective, randomized, placebo-controlled phase III clinical trial, Ji and colleagues (2015) examined the role of mifepristone in the treatment of unresectable meningioma. Eligible patients were randomly assigned to receive either mifepristone or placebo for 2 years unless disease progressed.  Patients who were stable or responding to protocol therapy after 2 years had the option to continue with the same blinded therapy.  Serial follow-up allowed assessment of efficacy and toxicity.  Time to treatment failure and overall survival (OS) were ascertained for all randomly assigned patients.  On progression, patients receiving placebo could cross-over and receive active drug.  Among 164 eligible patients, 80 were randomly assigned to mifepristone and 84 to placebo; 24 patients (30 %) were able to complete 2 years of mifepristone without disease progression, adverse effects, or other reasons for discontinuation; 28 patients (33 %) in the placebo-arm completed the 2-year study.  There was no statistical difference between the arms in terms of failure-free or OS.  The authors concluded that long-term administration of mifepristone was well-tolerated but had no impact on patients with unresectable meningioma.

Cossu and co-workers (2015) performed a systematic literature review to analyze the clinical application and the safety of mifepristone in meningioma patients. A systematic search was performed through Medline, Cochrane, and clinicaltrials.gov databases from 1960 to 2014.  Studies were selected through a PICO approach.  Population was meningioma patients, meningioma cells cultures, and animal models.  Intervention was mifepristone administration.  Control was placebo administration or any other drug tested.  Outcomes were clinical and radiological responsiveness, safety profile, and cell growth inhibition.  A total of 7 pre-clinical and 6 clinical studies and 1 abstract were included.  Encouraging results were found in pre-clinical studies.  Concerning clinical studies, the response rate to mifepristone in terms of radiological regression and symptomatic improvement/stability in patients with inoperable meningioma was low.  In meningiomatosis, favorable preliminary results were recorded.  The safety profile was good.  The authors concluded that no clear evidence exists to recommend mifepristone in inoperable meningiomas.  They noted that preliminary encouraging results were found in diffuse meningiomatosis; multicenter placebo-controlled trials are needed.

Chronic Multi-Symptom Illness:

Golier et al (2016) stated that no pharmacological treatments have been demonstrated to effectively treat chronic multi-symptom illness (CMI) in Gulf War veterans (GWV). In a randomized, double-blind, cross-over clinical trial, these researchers evaluated the effect of mifepristone in GWV with CMI.  This study consisted of two 6-week treatment phases separated by a 1-month washout period, and was conducted at a Veterans Affairs (VA) hospital between 2008 and 2011.  Participants were randomized to receive either 200 mg of mifepristone per day or matched placebo first.  The primary clinical outcome measure was change in self-reported physical health.  Neurocognitive functioning and self-reported measures of depression, PTSD, and fatigue were secondary outcomes.  A total of 65 participants enrolled, of whom 36 were randomized and 32 (mean age of 49.1 (7.2) years) completed the study.  Physical and mental health status and neurocognitive functioning were poor at baseline.  Mifepristone treatment was not associated with improvement in self-reported physical health (p = 0.838) or in other self-reported measures of mental health.  Mifepristone treatment was significantly associated with improvements in verbal learning (p = 0.008, d = 0.508), in the absence of improvement in other cognitive measures (working memory (p = 0.914), visual learning (p = 0.643) and a global composite measure (p = 0.937).  Baseline morning cortisol levels and lysozyme IC50-DEX, a measure of peripheral glucocorticoid sensitivity, displayed a significant relationship with end-point verbal learning scores (p = 0.012 and p = 0.007, respectively).  The magnitude of cortisol change during treatment mediated the improvement in verbal learning.  This study was negative for the primary and secondary clinical outcomes.  However, the data suggested a moderate dose of mifepristone may have circumscribed cognitive-enhancing effects in CMI.  The authors concluded that further study is needed to determine whether and through which mechanisms mifepristone treatment can yield clinically meaningful improvement in cognitive function in CMI or other neuropsychiatric conditions associated with HPA axis dysregulation.

Uterine Fibroids:

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.

In a multi-center, randomized controlled trial (RCT), Liu and colleagues (2017) evaluated the safety and effectiveness of 10 mg and 25 mg mifepristone per day compared with 3.75 mg enantone in treating uterine fibroids.  A total of 501 subjects with symptomatic uterine fibroids were enrolled and randomized into the group of 10-mg, 25-mg mifepristone and 3.75-mg enantone (with 307, 102 and 92 subjects respectively), with 458 subjects completed the treatment.  Three months of daily therapy with oral mifepristone (at a dose of either 10 mg or 25 mg) or once-monthly subcutaneous injections of enantone (at a dose of 3.75 mg) were used.  Change in volume of the largest uterine fibroid was the primary efficacy variable, and secondary efficacy variables included changes in anemia and relevant symptom.  Safety evaluation included the analyses of adverse events (AEs), laboratory values, and relevant endometrial changes.  After 3 months of treatment, the mean volume of the largest leiomyoma was significantly reduced by mifepristone 10 mg or 25 mg or enantone 3.75 mg (40.27 %, 42.59 % and 44.49 % respectively) (p < 0.0001).  Percentage change from baseline in largest leiomyoma volume was not statistically significant among the 3 groups (p  = 0.1057).  Most of the patients in all groups experienced amenorrhea after the treatment.  There were also significant elevations in red blood cell count, hemoglobin and hematocrit (p < 0.0001), and significant reductions in prevalence of dysmenorrhea, pelvic pressure, non-menstrual abdominal pain (p < 0.0001) in each group, while no significant difference among the 3 groups.  All study medications were well-tolerated, and no serious AE was reported.  Treatment-related AE rate was significantly lower in mifepristone 10-mg group, compared to Enantone 3.75-mg group (13.59 % versus 32.58 %, p = 0.0002).  In both mifepristone groups, estradiol levels were maintained in the pre-menopausal range, whereas patients in the enantone group had a significant reduction to post-menopausal levels (p < 0.0001).  The authors concluded that 10-mg is as effective as 2-5mg mifepristone and 3.75-mg enantone with minimal drug-related side effects, and may provide an alternative for clinical application, especially for patient who are in peri-menopause with uterine fibroids.

This study had several drawbacks:
  1. it was not specifically designed to assess surgical outcomes, and these researchers had no follow-up data regarding patients’ relapses and/or resumption of their regular menstrual cycles after the treatment,
  2. all subjects were Han Chinese, which may limit generalization of the results to other populations,
  3. the duration of treatment was restricted to 13 weeks.  Thus, more data on the risk and benefits of long-term treatment with mifepristone are needed,
  4. there are methodological limitations such as the lack of support for the sample size selection and blinding, and
  5. potential bias may have been introduced owing to the lack of blinding during the study. 
The authors noted that based on the previous data and this study, 10 mg of mifepristone showed potential for greater clinical use.  Additionally, compared with enantone and 25 mg of mifepristone, it offers a more suitable alternative for patients before surgery because it can be orally administered with a comparable reduction in fibroid size, fewer side effects, and improvement in the hemoglobin level, decreasing the potential risk of a blood transfusion during the surgery.  However, they stated that further studies of the safety of long-term 10-mg mifepristone treatment are needed for clinical application, especially for peri-menopausal patients who may be able to take it to decrease the size of uterine fibroids and relieve related symptoms until menopause.

Non-Small Cell Lung Cancer:

Check and colleagues (2016) showed long-term high-quality survival following single-agent treatment with mifepristone in 2 cases of advanced metastatic cancer.  Because no biopsy was performed (patient refused) the exact type of lung cancer was not determined but the majority of oncologists who evaluated the patient thought that the rapid onset and syndrome of inappropriate anti-diuretic hormone was more consistent with small-cell lung cancer.  The FDA granted a compassionate-use investigational new drug (IND) approval for use of single-agent 200 mg mifepristone orally/day to a moribund woman with never-treated metastatic lung cancer and a male with bilateral renal cell carcinoma who had undergone only a unilateral hemi-nephrectomy.  Both had long-term high-quality survival (5 years for the patient with lung cancer with complete remission of all lung lesions, and 12 years for the male patient with kidney cancer).  Neither patient had any side-effects from mifepristone therapy.  The authors stated that these cases helped influence the FDA in granting an investigator-initiated IND study on advanced non-small cell lung cancer (NSCLC).

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Non-small cell lung cancer” (Version 5.2017) does not mention mifepristone as a therapeutic option.

Endometriosis:

Fu and colleagues (2017) evaluated the safety and the effectiveness of PRMs primarily in terms of pain relief as compared with other treatments or placebo or no treatment in women of reproductive age with endometriosis.  These investigators searched the following electronic databases, trial registers, and websites: the Cochrane Gynaecology and Fertility Group (CGFG) Specialized Register of Controlled Trials, the Central Register of Studies Online (CRSO), MEDLINE, Embase, PsycINFO, clinicaltrials.gov, and the World Health Organization (WHO) platform, from inception to November 28, 2016.  They hand-searched reference lists of articles retrieved by the search.  They included RCTs published in all languages that examined effects of PRMs for treatment of symptomatic endometriosis.  These researchers used standard methodological procedures as expected by the Cochrane Collaboration.  Primary outcomes included measures of pain and side effects.  A total of 10 RCTs with 960 women were included.  Two RCTs compared mifepristone versus placebo or versus a different dose of mifepristone, 1 RCT compared asoprisnil versus placebo, 1 compared ulipristal versus leuprolide acetate, and 4 compared gestrinone versus danazol, gonadotropin-releasing hormone (GnRH) analogs, or a different dose of gestrinone.  The quality of evidence ranged from high to very low.  The main limitations were serious risk of bias (associated with poor reporting of methods and high or unclear rates of attrition in most studies), very serious imprecision (associated with low event rates and wide CIs), and indirectness (outcome assessed in a select subgroup of participants).  Mifepristone versus placebo: 1 study made this comparison and reported rates of painful symptoms among women who reported symptoms at baseline.  At 3 months, the mifepristone group had lower rates of dysmenorrhea (odds ratio (OR) 0.08, 95 % CI: 0.04 to 0.17; 1 RCT, n = 352; moderate-quality evidence), suggesting that if 40 % of women taking placebo experience dysmenorrhea, then between 3 % and 10 % of women taking mifepristone will do so.  The mifepristone group also had lower rates of dyspareunia (OR 0.23, 95 % CI: 0.11 to 0.51; 1 RCT, n = 223; low-quality evidence).  However, the mifepristone group had higher rates of side effects: Nearly 90 % had amenorrhea and 24 % had hot flushes, although the placebo group reported only 1 event of each (1 %) (high-quality evidence).  Evidence was insufficient to show differences in rates of nausea, vomiting, or fatigue, if present.  Mifepristone dose comparisons: 2 studies compared doses of mifepristone and found insufficient evidence to show differences between different doses in terms of effectiveness or safety, if present.  However, subgroup analysis of comparisons between mifepristone and placebo suggest that the 2.5-mg dose may be less effective than the 5-mg or 10-mg doses for treating dysmenorrhea or dyspareunia.  Gestrinone comparisons: 1 study compared gestrinone with danazol, and another study compared gestrinone with leuprolin.  Evidence was insufficient to show differences, if present, between gestrinone and danazol in rate of pain relief (those reporting no or mild pelvic pain) (OR 0.71, 95 % CI: 0.33 to 1.56; 2 RCTs, n = 230; very low-quality evidence), dysmenorrhea (OR 0.72, 95 % CI: 0.39 to 1.33; 2 RCTs, n = 214; very low-quality evidence), or dyspareunia (OR 0.83, 95 % CI: 0.37 to 1.86; 2 RCTs, n = 222; very low-quality evidence).  The gestrinone group had a higher rate of hirsutism (OR 2.63, 95 % CI: 1.60 to 4.32; 2 RCTs, n = 302; very low-quality evidence) and a lower rate of decreased breast size (OR 0.62, 95 % CI: 0.38 to 0.98; 2 RCTs, n = 302; low-quality evidence).  Evidence was insufficient to show differences between groups, if present, in rate of hot flushes (OR 0.79, 95 % CI: 0.50 to 1.26; 2 RCTs, n = 302; very low-quality evidence) or acne (OR 1.45, 95 % CI: 0.90 to 2.33; 2 RCTs, n = 302; low-quality evidence).  When researchers compared gestrinone versus leuprolin through measurements on the 1 to 3 verbal rating scale (lower score denotes benefit), the mean dysmenorrhea score was higher in the gestrinone group (MD 0.35 points, 95 % CI: 0.12 to 0.58; 1 RCT, n = 55; low-quality evidence), but the mean dyspareunia score was lower in this group (MD 0.33 points, 95 % CI: 0.62 to 0.04; low-quality evidence).  The gestrinone group had lower rates of amenorrhea (OR 0.04, 95 % CI: 0.01 to 0.38; 1 RCT, n = 49; low-quality evidence) and hot flushes (OR 0.20, 95 % CI: 0.06 to 0.63; 1 study, n = 55; low quality evidence) but higher rates of spotting or bleeding (OR 22.92, 95 % CI: 2.64 to 198.66; 1 RCT, n = 49; low-quality evidence).  Evidence was insufficient to show differences in effectiveness or safety between different doses of gestrinone, if present.  Asoprisnil versus placebo: 1 study (n = 130) made this comparison but did not report data suitable for analysis.  Ulipristal versus leuprolide acetate: 1 study (n = 38) made this comparison but did not report data suitable for analysis.  The authors concluded that among women with endometriosis, moderate-quality evidence showed that mifepristone relieved dysmenorrhea, and low-quality evidence suggested that this agent relieved dyspareunia, although amenorrhea and hot flushes were common side effects.  Data on dosage were inconclusive, although they suggested that the 2.5-mg dose of mifepristone may be less effective than higher doses.  These investigators found insufficient evidence to permit firm conclusions about the safety and effectiveness of other progesterone receptor modulators.

Second Trimester Abortion:

On behalf of Society of Family Planning, Borgatta (2011) noted that labor induction abortion is effective throughout the 2nd trimester.  Patterns of use and gestational age limits vary by locality.  Earlier gestations (typically 12 to 20 weeks) have shorter abortion times than later gestational ages, but differences in complication rates within the 2nd trimester according to gestational age have not been demonstrated.  The combination of mifepristone and misoprostol is the most effective and fastest regimen.  Typically, mifepristone 200 mg is followed by use of misoprostol 24 to 48 hours later; 95 % of abortions are complete within 24 hours of misoprostol administration.  Compared with misoprostol alone, the combined regimen results in a clinically significant reduction of 40 % to 50 % in time to abortion and can be used at all gestational ages.  However, mifepristone is not widely available.  Accordingly, prostaglandin analogs without mifepristone (most commonly misoprostol or gemeprost) or high-dose oxytocin are used.  Misoprostol is more widely used because it is inexpensive and stable at room temperature.  Misoprostol alone is best used vaginally or sublingually, and doses of 400 mcg are generally superior to 200 mcg or less.  Dosing every 3 hours is superior to less frequent dosing, although intervals of up to 12 hours are effective when using higher doses (600 or 800 mcg) of misoprostol.  Abortion rates at 24 hours are approximately 80 % to 85 %.  Although gemeprost has similar outcomes as compared to misoprostol, it has higher cost, requires refrigeration, and can only be used vaginally.  High-dose oxytocin can be used in circumstances when prostaglandins are not available or are contraindicated.  Osmotic dilators do not shorten induction times when inserted at the same time as misoprostol; however, their use prior to induction using misoprostol has not been studied.  Pre-procedure-induced fetal demise has not been studied systematically for possible effects on time to abortion.  While isolated case reports and retrospective reviews document uterine rupture during 2nd-trimester induction with misoprostol, the magnitude of the risk is not known.  The relationship of individual uterotonic agents to uterine rupture is not clear.  Based on existing evidence, the Society of Family Planning recommended that, when labor induction abortion is performed in the 2nd trimester, combined use of mifepristone and misoprostol is the ideal regimen to effect abortion quickly and completely.  The Society of Family Planning further recommended that alternative regimens, primarily misoprostol alone, should only be used when mifepristone is not available.

Fox and Krajewski (2014) stated that for a dilation and evacuation (D&E) procedure, the cervix must be dilated sufficiently to allow passage of operative instruments and products of conception without injuring the uterus or cervical canal.  Pre-operative preparation of the cervix reduces the risk of cervical laceration and uterine perforation.  The cervix may be prepared with osmotic dilators, pharmacologic agents or both.  Dilapan-S™ and laminaria are the 2 osmotic dilators currently available in the United States.  Laminaria tents, made from dehydrated seaweed, require 12 to 24 hours to achieve maximum dilation.  Dilapan-S™, made of synthetic hydrogel, achieved significant dilation within 4 hours and is thus preferable for same-day procedures.  A single set of 1 to several dilators is usually adequate for D&E before 20 weeks' gestation.  Misoprostol, a prostaglandin E1 analog, is sometimes used instead of osmotic dilators.  It is generally regarded as safe and effective; however, misoprostol achieved less dilation than over-night osmotic tents.  The literature supported same-day cervical preparation with misoprostol or Dilapan-S™ up to 18 weeks' gestation.  As the evidence regarding alternative regimens increases, highly experienced D&E providers may consider same-day regimens at later gestations utilizing serial doses of misoprostol or a combination of osmotic and pharmacologic agents.  Misoprostol use as an adjunct to over-night osmotic dilation is not significantly beneficial before 19 weeks' gestation.  Limited data demonstrated the safety of misoprostol before D&E in patients with a prior cesarean delivery.  Mifepristone, a progesterone receptor antagonist, is also effective for cervical preparation prior to D&E, although data to support its use are limited.  The Society of Family Planning recommended pre-operative cervical preparation to decrease the risk of complications when performing a D&E.  Since no single protocol has been found to be superior in all situations, clinical judgment is warranted when selecting a method of cervical preparation.

Abbas et al (2016) compared outcomes with simultaneous administration of mifepristone and misoprostol with a regimen in which the drugs are administered at a 24-hour interval for 2nd-trimester abortion.  In this placebo-controlled, double-blind trial, participants were randomized to receive mifepristone either 24 hours before or at the same time as misoprostol.  Participants were hospitalized to receive 400 micrograms buccal misoprostol at 3-hour intervals up to 48 hours or until uterine expulsion.  The primary outcome was the proportion of women who experienced uterine expulsion within 24 hours after the first misoprostol dose and this required 504 women to examine the hypothesis that this rate would be 85 % in the 24-hour interval arm compared with 70 % in the simultaneous arm.  Secondary outcomes included total abortion time from mifepristone and misoprostol.  From February 2013 to April 2014, a total 509 women were enrolled.  Women in the 24-hour interval arm were more likely to abort within 24 hours (94.4 % compared with 85.0 %, relative risk 1.11, 95 % confidence interval [CI]: 1.05 to 1.18).  At 48 hours, the rate was similar in the 2 arms (96.8 % [24-hour interval] and 95.7 % [simultaneous], relative risk 1.01, 95 % CI: 0.97 to 1.04).  Median misoprostol dosing time was shorter in the 24-hour interval arm (7.7 compared with 13 hours; p < 0.001) and consistent with the median misoprostol doses required (3 compared with 5; p < 0.001).  Median time from mifepristone to uterine expulsion was longer in the 24-hour interval arm (32.3 compared with 13 hours; p < 0.001).  Both regimens had high acceptability rates and reported similar side effects and pain scores.  The authors concluded that administering mifepristone and misoprostol simultaneously resulted in lower expulsion rates within 24 hours of taking misoprostol, longer median misoprostol treatment times, and required more misoprostol doses.  At 48 hours, both regimens work equally well.  Simultaneous dosing resulted in less total time from the first clinical contact to complete abortion.

Shaw and Lerma (2016) reviewed the recent literature on surgical 2nd-trimester abortion, with specific attention to cervical preparation techniques.  Confirming previous studies, a recent retrospective observational cohort study, including 54,911 abortions, estimated the total abortion-related complication rate to be 0.41 % for 2nd-trimester or later procedures.  Cervical preparation is known to reduce risks associated with 2nd-trimester dilation and evacuation (D&E).  When considering adjuncts to osmotic dilators for cervical preparation prior to D&E after 16 weeks, both misoprostol and mifepristone are effective alone and in combination or as adjuncts to osmotic dilators.  Misoprostol consistently has been shown to cause more pain and cramping than placebo, but is an effective adjunct to osmotic dilators after 16 weeks.  Although mifepristone has fewer side-effects, at its current price, it may not be as cost-effective as misoprostol.  The authors concluded that 2nd-trimester abortion is safe.  The use of mifepristone and misoprostol for 2nd-trimester abortion has improved safety and efficacy of medical and surgical methods when used alone or in combination and as adjuncts to osmotic dilators.  An important aspect of D&E, cervical preparation, is not a one-size-fits-all practice; the approach and methods are contingent on patient, provider and setting and should consider all the evidence-based options.

In a retrospective, observational study, Nissi and associates (2016) evaluated factors affecting clinical effectiveness of the 2nd-trimester medical terminations using mifepristone and misoprostol combination.  A total of 142 consecutive women underwent medical abortion on 12 to 24 weeks of gestation.  Clinical data were collected from Oulu University Hospital patients' records for the period between January 2008 and June 2011.  The associations between patient characteristics and different outcomes were evaluated using the standard statistical test for correlation.  The majority (92 %) of women aborted successfully within 24 hours and were considered as day cases with small complication rate, as compared to hospitalized patients.  In nulliparous patients, the time for complete abortion was longer than in other groups (p < 0.0019).  Nulliparous women and women with gestation more than 16 weeks required opiate analgesia more often (p = 0.003 and < 0.001, respectively).  The authors concluded that women with previous live-births aborted more often within 8 hours than women with no previous births.  They stated that mifepristone and misoprostol is a safe and effective method for 2nd-trimester pregnancy termination; and 2nd-trimester medical abortion can be provided by a nurse-midwife with the back-up of a gynecologist.

Louie and co-workers (2017) evaluated the efficacy and acceptability of a regimen using mifepristone and buccal misoprostol with unlimited dosing for 2nd trimester abortion in Armenia.  Women seeking to terminate 13 to 22 week pregnancies were enrolled in the study.  Participants swallowed 200 mg mifepristone in the clinic and were instructed to return to the hospital for induction 24 to 48 hours later.  During induction, women were given 400 μg buccal misoprostol every 3 hours until the fetus and placenta were expelled.  The abortion was considered a success if complete uterine evacuation was achieved without oxytocin or surgery.  A total of 120 women with a median gestational age of 18 weeks participated in the study.  All women began misoprostol induction around 24 hours after taking mifepristone.  Complete uterine evacuation was achieved in 119 (99.2 %) women.  The median induction-to-abortion interval was 10.3 hours (range of 4 to 17.4) with a mean of 9.5 ± 2.5 hours.  A median of 4 misoprostol doses (range of 2 to 6) with a mean of 4 ± 1 misoprostol doses were administered.  The induction-to-abortion interval, number of misoprostol doses, pain score and analgesia use increased as gestational age advanced.  Acceptability of the method was high among both patients and providers.  The authors concluded that the medical abortion regimen of 200-mg mifepristone followed 24 hours later by induction with 400 μg buccal misoprostol administered every 3 hours, with no limit on the number of doses used for the termination of pregnancies of 13 to 22 weeks' gestation was an effective and acceptable option for women.

Lerma and Shaw (2017) reviewed recent literature on 2nd trimester abortion with medical methods.  Across studies published in the recent past, it is apparent that women prefer shorter procedures and procedure times.  Several randomized controlled trials have confirmed adding mifepristone to the 2nd trimester medication abortion regimen results in shorter abortion intervals from first misoprostol administration to complete fetal expulsion.  A study of simultaneous administration of mifepristone and misoprostol yielded shorter mean 'total' abortion times, presenting several logistical advantages.  Recent studies on the continuous dosing of misoprostol have produced critical evidence to support continued dosing until expulsion.  These studies had a more practical design compared with previous protocols that capped the number of misoprostol doses.  The authors concluded that 2nd trimester surgical abortion is well-tolerated and increasingly expeditious.  Further research is needed to refine second trimester medical abortion methods, specific to the mifepristone, misoprostol dosing interval.  A 12-hour mifepristone to misoprostol interval may be the optimal interval balancing patient preferences and logistical considerations.  Pragmatic dosing, including continuous dosing of misoprostol, could yield results that better inform clinical guidelines and reduce burden on patient, provider, and health facility.

Ovarian Cancer Metastasis:

Zheng and colleagues (2017) noted that SDF-1/CXCR4 signaling axis determines the proliferative potential and site-specific cancer metastasis.  Recent studies suggested involvement of the axis and steroidal hormone in ovarian cancer metastasis.  These researchers hypothesized that mifepristone might interfere this axis and inhibit ovarian cancer metastasis.  Mifepristone at concentrations of less than IC50 inhibited expression of CXCR4 on cell surface of ovarian cancer SKOV-3 and IGROV-1, and reduced expression of the intracellular CXCR4 protein and its related mRNA activated by SDF-1.  SDF-1 significantly stimulated proliferation of SKOV-3 and IGROV-1 cells with concomitant increases in intracellular phosphorylation of Akt and ERK.  SDF-1 activated cell chemotactic migration and actin polymerization, and up-regulated expression of MMP-2, MMP-9, COX-2, VEGF without influencing the adhesion molecules ICAM-1 and integrins β1, α1, α3, α5, and α6.  The afore-mentioned effects of SDF-1 could be antagonized by mifepristone concentration-dependently, and CXCR4 antagonist AMD3100.  Mifepristone suppressed the SDF-1-induced migration, invasion and adhesion of the cancer cells to extracellular matrixes.  Three-day pre-treatment of nude mice with mifepristone (5 and 20 mg/kg/day) followed by a single intraperitoneal IGROV-1 inoculation, along with repeated SDF-1 and mifepristone administrations in turn every other day for 36 days significantly reduced ascitic fluid, metastatic foci, tumor weight and immunoreactivity of CXCR4 in comparison with the SDF-1-treated control.  The authors concluded that these findings suggested that mifepristone inhibit SDF-1/CXCR4 signaling axis, may have preventive and therapeutic effects on ovarian cancer metastasis.

Appendix

Dosing Information:

200 mg mifepristone (Mifeprex) on Day 1, followed 24 to 48 hours after Mifeprex dosing by 800 mcg buccal misoprostol.  Highlights of Prescribing Information.

Greene and Drazen (2016) stated that “the study conditions in the two U.S. trials conducted in 1994 - 1995 for submission to the FDA were very conservative.  The maximum gestational age for pregnancies among women allowed into the studies was relatively early, less than 63 days of amenorrhea, to both maximize the probability of success and minimize the potential risk of excessive bleeding.  The relatively high dose of mifepristone used (600 mg) maximized the probability of efficacy, and the dose of the second medication (misoprostol, 400 μg) needed to complete the procedure was administered under direct supervision and required a stay of a minimum of 4 hours in the prescribing medical care facility to minimize the risk of adverse events …. On March 30, 2016, the FDA released the new label for mifepristone (www.accessdata.fda.gov/drugsatfda_docs/label/2016/020687s020lbl.pdf), which included three important revisions: recommending the 200-mg dose (1 pill) rather than the originally approved 600-mg dose (3 pills), extending the indication for use to pregnancies of less than 70 days’ duration, and formally eliminating the requirement that the dose of misoprostol be given in a medical facility, including a protracted stay for observation”.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

Other CPT codes related to the CPB:

76801 - 76817 Ultrasound, pregnant uterus
84702 - 84703 Gonadotropin, chorionic (hCH): quantitative or qualitative

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-10 codes covered if selection criteria are met:

D39.2 Neoplasm of uncertain behavior of placenta [hydatidiform mole]
E24.0 - E24.1, E24.43, E24.8 - E24.9 Cushing's syndrome [covered for endogenous only] [who have type 2 diabetes or glucose intolerance and are not candidates for surgery or who have not responded to prior surgery]
O01.0 - O01.9 Hydatidiform mole
O04.5 - O04.89 Complications following (induced) termination of pregnancy
Z30.012 Encounter for prescription of emergency contraception
Z33.2 Encounter for elective termination of pregnancy
Z64.0 Problems related to unwanted pregnancy

ICD-10 codes not covered for indications listed in the CPB (not all inclusive):

C00.0 - D09.9 Malignant neoplasm
C34.00 - C34.92 Malignant neoplasm of bronchus and lung [non-small cell lung cancer]
D25.0 - D25.9 Leiomyoma of uterus
D32.0 Benign neoplasm of cerebral meninges
E24.3 Ectopic ACTH syndrome
F06.4 Anxiety disorder due to known physiological condition
F10.20 - F10.29 Alcohol dependence
F14.20 - F14.29 Cocaine dependence
F20.0 - F21 Schizophrenia
F32.0 - F32.9 Major depressive disorder, single episode
F33.0 - F33.9 Major depressive disorder, recurrent episode
F41.0 - F41.9 Other anxiety disorders
F43.10 - F43.12 Post-traumatic stress disorder
G30.0 - G30.9 Alzheimer's disease
N80.1 - N80.9 Endometriosis
O42.00 - O42.92 Premature rupture of membranes
O60.00 - O60.14x9 Preterm labor

ICD-10 codes contraindicated for this CPB for endogenous Cushing syndrome:

C54.1 Malignant neoplasm of endometrium
D07.0 Carcinoma in situ of endometrium
N85.02 Endometrial intraepithelial neoplasia [EIN]
N93.0, N93.8 - N93.9 Other abnormal uterine and vaginal bleeding [unexplained]
O00.00 - 09A.53 Pregnancy, childbirth, and the puerperium
Z33.1 Pregnancy state, incidental
Z34.00 - Z34.93 Encounter for supervision of normal pregnancy
Z79.51 Long‐term (current) use of inhaled steroids [corticosteroids]
Z79.52 Long‐term (current) use of systemic steroids [corticosteroids]

The above policy is based on the following references:

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