Mifepristone

If the compound has been ingested, rapid gastric lavage should be performed using 5% sodium bicarbonate. For skin contact, the skin should be washed with soap and water. If the compound has entered the eyes, they should be washed with large quantities of isotonic saline or water. In serious cases, atropine and/or pralidoxime should be administered. Anti-cholinergic drugs work to counteract the effects of excess acetylcholine and reactivate AChE. Atropine can be used as an antidote in conjunction with pralidoxime or other pyridinium oximes (such as trimedoxime or obidoxime), though the use of '-oximes' has been found to be of no benefit, or possibly harmful, in at least two meta-analyses. Atropine is a muscarinic antagonist, and thus blocks the action of acetylcholine peripherally.

Acute exposure to cholinesterase inhibitors can cause a cholinergic crisis characterized by severe nausea/vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Accumulation of ACh at motor nerves causes overstimulation of nicotinic expression at the neuromuscular junction. When this occurs symptoms such as muscle weakness, fatigue, muscle cramps, fasciculation, and paralysis can be seen. When there is an accumulation of ACh at autonomic ganglia this causes overstimulation of nicotinic expression in the sympathetic system. Symptoms associated with this are hypertension, and hypoglycemia. Overstimulation of nicotinic acetylcholine receptors in the central nervous system, due to accumulation of ACh, results in anxiety, headache, convulsions, ataxia, depression of respiration and circulation, tremor, general weakness, and potentially coma. When there is expression of muscarinic overstimulation due to excess acetylcholine at muscarinic acetylcholine receptors symptoms of visual disturbances, tightness in chest, wheezing due to bronchoconstriction, increased bronchial secretions, increased salivation, lacrimation, sweating, peristalsis, and urination can occur. Certain reproductive effects in fertility, growth, and development for males and females have been linked specifically to organophosphate pesticide exposure. Most of the research on reproductive effects has been conducted on farmers working with pesticides and insecticdes in rural areas. In females menstrual cycle disturbances, longer pregnancies, spontaneous abortions, stillbirths, and some developmental effects in offspring have been linked to organophosphate pesticide exposure. Prenatal exposure has been linked to impaired fetal growth and development. Neurotoxic effects have also been linked to poisoning with OP pesticides causing four neurotoxic effects in humans: cholinergic syndrome, intermediate syndrome, organophosphate-induced delayed polyneuropathy (OPIDP), and chronic organophosphate-induced neuropsychiatric disorder (COPIND). These syndromes result after acute and chronic exposure to OP pesticides.

In large prelicensure clinical trials, medical abortion with mifepristone/misoprostol was safe and not accompanied by abnormalities in laboratory tests or cases of hepatitis or jaundice. Since its licensure and more widescale use, there have been no published reports of liver injury attributed to mifepristone and misoprostol used to induce medical abortion.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 89,000(SRC), determined from a structure estimation method(2), indicates that mifepristone is expected to be immobile in soil(SRC). Volatilization of mifepristone from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 5.0X10-13 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Mifepristone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 8.0X10-14 mm. Biodegradation data were not available(SRC, 2005).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 89,000(SRC), determined from a structure estimation method(2), indicates that mifepristone is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 5.0X10-13 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 2,800(SRC), from an estimated log Kow of 89,000(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is very high(SRC). Biodegradation data were not available(SRC, 2005).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), mifepristone, which has an estimated vapor pressure of 8.0X10-14 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase mifepristone may be removed from the air by wet and dry deposition(SRC). Mifepristone does not contain chromophores that absorb light at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

Mifepristone is metabolized in the liver by CYP3A4; thus, medications that are CYP3A4 inhibitors can result in higher concentrations of mifepristone in the patient. For patients taking multiple doses of mifepristone in managing hyperglycemia in Cushing syndrome, the medication's half-life is reportedly around 85 hours. During this time, the significant symptoms to watch for are cardiogenic. Hypokalemia is very common due to the effects of cortisol on unopposed mineralocorticoid receptors.

Mifepristone is a cholinesterase or acetylcholinesterase (AChE) inhibitor. A cholinesterase inhibitor (or 'anticholinesterase') suppresses the action of acetylcholinesterase. Because of its essential function, chemicals that interfere with the action of acetylcholinesterase are potent neurotoxins, causing excessive salivation and eye-watering in low doses, followed by muscle spasms and ultimately death. Nerve gases and many substances used in insecticides have been shown to act by binding a serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. Acetylcholine esterase breaks down the neurotransmitter acetylcholine, which is released at nerve and muscle junctions, in order to allow the muscle or organ to relax. The result of acetylcholine esterase inhibition is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. Among the most common acetylcholinesterase inhibitors are phosphorus-based compounds, which are designed to bind to the active site of the enzyme. The structural requirements are a phosphorus atom bearing two lipophilic groups, a leaving group (such as a halide or thiocyanate), and a terminal oxygen.

Nearly all of the women who receive mifepristone will report adverse reactions, and many can be expected to report more than one such reaction. About 90% of patients report adverse reactions following administration of misoprostol on day three of the treatment procedure. Side effects include more heavy bleeding than a heavy manstrual period, abdominal pain, uterine cramping, nausea, vomiting, and diarrhea.

Using a structure estimation method based on molecular connectivity indices(1), the Koc for mifepristone can be estimated to be 89,000(SRC). According to a classification scheme(2), this estimated Koc value suggests that mifepristone is expected to be immobile in soil.

/SIGNS AND SYMPTOMS/ Vaginal bleeding that is heavier than associated with a normal menses occurs in almost all women receiving mifepristone and misoprostol. Based on clinical studies, bleeding or spotting should be expected for an average of 9-16 days. ... Excessive bleeding may require treatment with vasoconstrictors, saline infusions, and/or blood transfusions or curettage.

/SIGNS AND SYMPTOMS/ Serious bacterial infections) including very rare cases of fatal septic shock) have been reported following mifepristone administration; a causal relationship to the mifepristone-misoprostol regimen has not been established. Clinicians should consider the possibility of infection if sustained fever (temperature of 38 degrees C or higher persisting for more than 4 hours), severe abdominal pain, or pelvic tenderness occurs within several days of medical abortion. Atypical presentations of serious infection and sepsis (i.e., presence of significant leukocytosis, tachycardia, or hemoconcentration without fever, severe abdominal pain, pelvic tenderness) may also occur.

/HUMAN EXPOSURE STUDIES/ Myocardial infarction occurred in at least one patient 3 days following use of mifepristone and vaginal misoprostol; a causal relationship to the regimen has not been established.

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl mifepristone, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Mifepristone is indicated in combination with misoprostol for the medical termination of intrauterine pregnancy of 49 days duration or less. /Included in US product labeling/

MEDICATION

Mifepristone is indicated in combination with misoprostol for the medical termination of intrauterine pregnancy of 49 days duration or less. /Included in US product labeling/

Calculated removal (%): 86.7

For the medical termination of intrauterine pregnancy through 49 days' pregnancy. Also indicated to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance and are not candidates for surgery or have had unsuccessful surgery.

Commercially available mifepristone must be obtained through a restricted distribution program. Clinicians in institutions must sign a prescriber's agreement form before ordering the drug from the distributor or prescribing the drug; the drug is not available through pharmacies.

Progesterone receptor antagonist with partial agonist activity.

Information available in 2005 indicated that Mifepristone was used in the manufacture of pharmaceutical preparations in the following countries: Denmark, Finland, France, Germany, India, Indonesia, Israel, Norway, Russian Federation, Spain, Sweden, Switzerland, United Kingdom, United States (1,2)