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Mifepristone


Special Alerts

Mifepristone: Updated Warnings on Infection, Bleeding, and Ectopic Pregnancy - November 15, 2004

Danco Laboratories, in association with the Food and Drug Administration (FDA), has issued a "Dear Healthcare Professional" letter concerning mifepristone. The letter highlights changes to the product labeling prompted by postmarketing reports of adverse events. The new labeling emphasizes three areas of concern: Bacterial infection following use, prolonged vaginal bleeding, and ectopic pregnancy. With respect to bacterial infections, the manufacturer notes that cases of bacterial infection and sepsis have been reported following use of this product. In rare cases, septic shock has been a complication of these infections. Infections may be severe and sometimes fatal. A causal relationship has not been established. Sustained fever, abdominal pain, or pelvic tenderness should prompt evaluation; however, healthcare professionals are warned that atypical presentations of serious infection without these symptoms have also been noted.

Vaginal bleeding is a common consequence of mifepristone use. Bleeding or spotting occurs in most women for a period of 9-16 days. Up to 8% of women will experience some degree of bleeding or spotting for 30 days or more. In some cases, bleeding may be prolonged and heavy, potentially leading to life-threatening hypovolemic shock. Patients should be counseled to seek medical attention in cases of syncope or excessive bleeding (the manufacturer cites soaking through two thick sanitary pads per hour for two consecutive hours as an example of excessive bleeding).

Finally, the manufacturer notes that reports of ruptured ectopic pregnancy have been received. A causal relationship has not been established. Mifepristone is contraindicated in ectopic pregnancy, and ultrasound is recommended prior to use. However, the new labeling notes that ultrasonography may not identify all ectopic pregnancies, and healthcare providers should be alert for signs and symptoms which may be related to undiagnosed ectopic pregnancy in any patient who receives mifepristone.

Additional information is available at http://www.fda.gov/cder/drug/infopage/mifepristone/, last accessed November 16, 2004.


Pronunciation

 (mi FE pris tone)


U.S. Brand Names

 Mifeprex®


Synonyms

 RU-486; RU-38486


Generic Available

 No


Use

 Medical termination of intrauterine pregnancy, through day 49 of pregnancy. Patients may need treatment with misoprostol and possibly surgery to complete therapy


Use - Unlabeled/Investigational

 Treatment of unresectable meningioma; has been studied in the treatment of breast cancer, ovarian cancer, and adrenal cortical carcinoma


Restrictions

 There are currently no clinical trials with mifepristone in oncology open in the U.S.; investigators wishing to obtain the agent for use in oncology patients must apply for a patient-specific IND from the FDA. Mifepristone will be supplied only to licensed physicians who sign and return a "Prescriber's Agreement." Distribution of mifepristone will be subject to specific requirements imposed by the distributor. Mifepristone will not be available to the public through licensed pharmacies. A patient medication guide is available and must be dispensed with the medication.


Pregnancy Risk Factor

 X


Pregnancy Implications

 This medication is used to terminate pregnancy; there are no approved treatment indications for its use during pregnancy. Prostaglandins (including mifepristone and misoprostol) may have teratogenic effects when used during pregnancy.


Lactation

 Excretion in breast milk unknown/contraindicated


Contraindications

 Hypersensitivity to mifepristone, misoprostol, other prostaglandins, or any component of the formulation; chronic adrenal failure; porphyrias; hemorrhagic disorder or concurrent anticoagulant therapy; pregnancy termination >49 days; intrauterine device (IUD) in place; ectopic pregnancy or undiagnosed adnexal mass; concurrent long-term corticosteroid therapy; inadequate or lack of access to emergency medical services; inability to understand effects and/or comply with treatment


Warnings/Precautions

 Patient must be instructed of the treatment procedure and expected effects. A signed agreement form must be kept in the patient's file. Physicians may obtain patient agreement forms, physician enrollment forms, and medical consultation directly from Danco Laboratories at 1-877-432-7596. Adverse effects (including blood transfusions, hospitalization, ongoing pregnancy, and other major complications) must be reported in writing to the medication distributor. To be administered only by physicians who can date pregnancy, diagnose ectopic pregnancies, provide access to surgical abortion (if needed), and can provide access to emergency care. Medication will be distributed directly to these physicians following signed agreement with the distributor. Must be administered under supervision by the qualified physician. Pregnancy is dated from day 1 of last menstrual period (presuming a 28-day cycle, ovulation occurring midcycle). Pregnancy duration can be determined using menstrual history and clinical examination. Ultrasound should be used if an ectopic pregnancy is suspected or if duration of pregnancy is uncertain. Ultrasonography may not identify all ectopic pregnancies, and healthcare providers should be alert for signs and symptoms which may be related to undiagnosed ectopic pregnancy in any patient who receives mifepristone

Bleeding occurs and should be expected (average 9-16 days, may be 30 days). In some cases, bleeding may be prolonged and heavy, potentially leading to hypovolemic shock. Patients should be counseled to seek medical attention in cases of excessive bleeding; the manufacturer cites soaking through two thick sanitary pads per hour for two consecutive hours as an example of excessive bleeding. Bleeding may require blood transfusion (rare), curettage, saline infusions, and/or vasoconstrictors. Use caution in patients with severe anemia. Confirmation of pregnancy termination by clinical exam or ultrasound must be made 14 days following treatment. Manufacturer recommends surgical termination of pregnancy when medical termination fails or is not complete. Prescriber should determine in advance whether they will provide such care themselves or through other providers. Preventative measures to prevent rhesus immunization must be taken prior to surgical abortion. Prescriber should also give the patient clear instructions on whom to call and what to do in the event of an emergency following administration of mifepristone.

Bacterial infection have been reported following use of this product. In rare cases, these infections may be serious and/or fatal, with septic shock as a potential complication. A causal relationship has not been established. Sustained fever, abdominal pain, or pelvic tenderness should prompt evaluation; however, healthcare professionals are warned that atypical presentations of serious infection without these symptoms have also been noted.

Safety and efficacy have not been established for use in women with chronic cardiovascular, hypertensive, hepatic, respiratory, or renal disease, insulin-dependent diabetes mellitus, severe anemia, or heavy smokers. Women >35 years of age and smokers (>10 cigarettes/day) were excluded from clinical trials. Safety and efficacy in pediatric patients have not been established.


Adverse Reactions

 Vaginal bleeding and uterine cramping are expected to occur when this medication is used to terminate a pregnancy; 90% of women using this medication for this purpose also report adverse reactions. Bleeding or spotting occurs in most women for a period of 9-16 days. Up to 8% of women will experience some degree of bleeding or spotting for 30 days or more. In some cases, bleeding may be prolonged and heavy, potentially leading to hypovolemic shock.

>10%:

Central nervous system: Headache (2% to 31%), dizziness (1% to 12%)

Gastrointestinal: Abdominal pain (cramping) (96%), nausea (43% to 61%), vomiting (18% to 26%), diarrhea (12% to 20%)

Genitourinary: Uterine cramping (83%)

1% to 10%:

Cardiovascular: Syncope (1%)

Central nervous system: Fatigue (10%), fever (4%), insomnia (3%), anxiety (2%), fainting (2%)

Gastrointestinal: Dyspepsia (3%)

Genitourinary: Endometriosis/salpingitis/pelvic inflammatory disease (1%), pelvic pain (2%), uterine hemorrhage (5%), vaginitis (3%)

Hematologic: Decreased hemoglobin >2 g/dL (6%), anemia (2%), leukorrhea (2%)

Neuromuscular & skeletal: Back pain (9%), rigors (3%), leg pain (2%), weakness (2%)

Respiratory: Sinusitis (2%)

Miscellaneous: Viral infection (4%)

<1%: Significant SGOT, SGPT, alkaline phosphatase, and GT changes have been reported rarely

Postmarketing and/or case reports: Allergic reaction, dyspnea, hypotension, lightheadedness, loss of consciousness, MI, ruptured ectopic pregnancy, bacterial infection, post-abortal infection, sepsis, septic shock, tachycardia

In trials for unresectable meningioma, the most common adverse effects included fatigue, hot flashes, gynecomastia or breast tenderness, hair thinning, and rash. In premenopausal women, vaginal bleeding may be seen shortly after beginning therapy and cessation of menses is common. Thyroiditis and effects related to antiglucocorticoid activity have also been noted.


Overdosage/Toxicology

 In studies using 3 times the recommended dose for termination of pregnancy, no serious maternal adverse effects were reported. This medication is supplied in single-dose containers to be given under physician supervision, therefore, the risk of overdose should be low. In case of massive ingestion, treat symptomatically and monitor for signs of adrenal failure.


Drug Interactions

 Substrate of CYP3A4 (minor); Inhibits CYP2D6 (weak), 3A4 (weak)

There are no reported interactions. It might be anticipated that the concurrent administration of mifepristone and a progestin would result in an attenuation of the effects of one or both agents.


Ethanol/Nutrition/Herb Interactions

Food: Do not take with grapefruit juice; grapefruit juice may inhibit mifepristone metabolism leading to increased levels.

Herb/Nutraceutical: Avoid St John's wort (may induce mifepristone metabolism, leading to decreased levels).


Stability

 Store at room temperature of 25°C (77°F).


Mechanism of Action

 Mifepristone, a synthetic steroid, competitively binds to the intracellular progesterone receptor, blocking the effects of progesterone. When used for the termination of pregnancy, this leads to contraction-inducing activity in the myometrium. In the absence of progesterone, mifepristone acts as a partial progesterone agonist. Mifepristone also has weak antiglucocorticoid and antiandrogenic properties; it blocks the feedback effect of cortisol on corticotropin secretion.


Pharmacodynamics/Kinetics

Protein binding: 98% to albumin and 1-acid glycoprotein

Metabolism: Hepatic via CYP3A4 to three metabolites (may possess some antiprogestin and antiglucocorticoid activity)

Half-life elimination: Terminal: 18 hours following a slower phase where 50% eliminated between 12-72 hours

Time to peak: 90 minutes

Excretion: Feces (83%); urine (9%)


Dosage

 Oral:

Adults:

Termination of pregnancy: Treatment consists of three office visits by the patient; the patient must read medication guide and sign patient agreement prior to treatment:

Day 1: 600 mg (three 200 mg tablets) taken as a single dose under physician supervision

Day 3: Patient must return to the healthcare provider 2 days following administration of mifepristone; if termination of pregnancy cannot be confirmed using ultrasound or clinical examination: 400 mcg (two 200 mcg tablets) of misoprostol; patient may need treatment for cramps or gastrointestinal symptoms at this time

Day 14: Patient must return to the healthcare provider ~14 days after administration of mifepristone; confirm complete termination of pregnancy by ultrasound or clinical exam. Surgical termination is recommended to manage treatment failures.

Meningioma (unlabeled use): Refer to individual protocols. The dose used in meningioma is usually 200 mg/day, continued based on toxicity and response.

Elderly: Safety and efficacy have not been established

Dosage adjustment in renal impairment: Safety and efficacy have not been established

Dosage adjustment in hepatic impairment: Safety and efficacy have not been established; use with caution due to CYP3A4 metabolism


Monitoring Parameters

 Clinical exam and/or ultrasound to confirm complete termination of pregnancy; hemoglobin, hematocrit, and red blood cell count in cases of heavy bleeding


Test Interactions

 hCG levels will not be useful to confirm pregnancy termination until at least 10 days following mifepristone treatment


Patient Education

 This medication is used to terminate pregnancy under 7 weeks. It must be administered under direction of a qualified physician. You will need follow-up visits as directed by your prescriber (approximately 3 days and 14 days after treatment). Surgical termination of pregnancy may be required if medication fails; there is a risk of fetal malformation if treatment fails. You may experience vaginal bleeding and cramping that is heavier than a normal menstrual period; report immediately if severe or persistent. You may experience nausea, vomiting, and diarrhea. It is possible to get pregnant before your next period. Once the pregnancy has proved to be ended, contraception should be started before having sexual intercourse. Read carefully all information about this medication provided by your prescriber. Pregnancy/breast-feeding precautions: Your physician will give you a phone number to call for problems, questions, or emergencies; you should not use this medication if you do not have access to emergency care. You will be given a medication guide to help you understand this medication and its effects. It is important to review this carefully. Ask any questions you may have. You will also be required to sign a form saying that you understand the effects of this treatment and are able to return to the physician for follow-up appointments. Do not breast-feed. Discard breast milk for a few days following use of this medication.


Nursing Implications

 Clinical exam and/or ultrasound are needed to confirm complete termination of pregnancy. Vaginal bleeding and cramping are expected to occur and may require medical treatment. Hemoglobin, hematocrit, and red blood cell count should be monitored in cases of heavy bleeding. Patients must be instructed of the treatment procedure and expected effects. A signed agreement must be kept on file. Adverse effects (including blood transfusions, hospitalization, ongoing pregnancy, and other major complications) must be reported in writing to the medication distributor.


Additional Information

 Medication will be distributed directly to qualified physicians following signed agreement with the distributor, Danco Laboratories. It will not be available through pharmacies.


Dental Health: Effects on Dental Treatment

 No significant effects or complications reported


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 No information available to require special precautions


Mental Health: Effects on Mental Status

 May cause dizziness, fatigue, insomnia, or anxiety


Mental Health: Effects on Psychiatric Treatment

 Gastrointestinal side effects are common; use caution with lithium, valproic acid, and SSRIs. Fluoxetine, fluvoxamine, and nefazodone may increase mifepristone serum levels and/or toxicity; monitor. Carbamazepine, phenobarbital, and St John's wort may increase the metabolism of mifepristone, resulting in decreased mifepristone levels and/or effect; monitor.


Oncology: Emetic Potential

 Mild


Oncology: Vesicant

 No


Dosage Forms

 Tablet: 200 mg


References

Grumberg SM, Weiss MH, Spitz IM, et al, "Treatment of Unresectable Meningiomas With the Antiprogesterone Agent Mifepristone," J Neurosurg , 1991, 74(6):861-6.

Perrault D, Eisenhauer EA, Pritchard KI, et al, "Phase II Study of the Progesterone Antagonist Mifepristone in Patients With Untreated Metastatic Breast Carcinoma: A National Cancer Institute of Canada Clinical Trials Group Study," J Clin Oncol , 1996, 14(10):2709-12.

Rocereto TF, Saul HM, Aikins JA, et al, "Phase II Study of Mifepristone (RU486) in Refractory Ovarian Cancer," Gynecol Oncol , 2000, 77(3):429-32.

Spitz IM and Bardin CW, "Mifepristone (RU486) - A Modulator of Progestin and Glucocorticoid Action," N Engl J Med , 1993, 329(6):404-12.


International Brand Names

 Mifegest® (IN); Mifegyne® (CH, DE, DK, ES, FI); Mifégyne® (FR); Mifegyne® (GB, IL, NO, RU, SE)


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