Mifepristone

Mifepristone is a selective progesterone receptor modulator (SPRM)belonging to the pharmacological class of anti-progesterone agents.

Mifepristone is FDA-approved and used for terminating intrauterine pregnancy through 70 days' gestation.

Mifepristone quickly absorbs, reaching peak plasma levels within 1-2 hours for single doses or 1-4 hours for multiple doses, with 69% bioavailability. It extensively binds to plasma proteins like α1-acid glycoprotein and albumin, distributes in tissues, undergoes liver metabolism via CYP3A4, and predominantly exits through faeces (90%) and urine (10%). Its terminal elimination half-life spans 18 hours for single doses and extends to 85 hours for multiple doses, involving a slower elimination phase of 50% between 12-72 hours.

The common side effects of mifepristone includes nausea, vomiting, diarrhoea and stomach cramps.

Mifepristone is available in the form of tablets.

The molecule is available in India, the United States, Canada, the United Kingdom, Australia, Germany, France, Italy, Japan, Brazil and Mexico.

Mifepristone is a selective progesterone receptor modulator (SPRM)belonging to the pharmacological class of anti-progesterone agents.

Due to its competitive interaction with progesterone at progesterone-receptor sites, mifepristone has anti-progestational activity. According to experiments conducted on mice, rats, rabbits, and monkeys using different oral doses, the chemical inhibits Exogenous or endogenous progesterone. This leads to the pregnancy's termination.

Mifepristone inhibits cortisol's ability to attach to its receptor, offering relief from Cushing's syndrome. Though the effects of excess cortisol, including elevated blood sugar, are lessened, the generation of cortisol is not decreased.

The peak plasma time for a single dose is approximately 1-2 hours, while it extends to 1-4 hours for multiple doses. Peak plasma concentration ranges between 2-8 hours.

Mifepristone is available in the form of oral tablets.

Tablets: To be placed under the buccal cavity. Do not chew, crush or break it.

As the physician recommends, take the medication orally once daily; it can be taken with or without food as directed.

Mifepristone can be used for the following health conditions:

Mifepristone effectively terminates early pregnancies (up to 10 weeks) by blocking progesterone, causing the uterus lining to break down and the pregnancy to cease, providing a safe, non-invasive alternative to surgical procedures.

Mifepristone reduces problems such as high blood sugar and hypertension in Cushing's syndrome by inhibiting cortisol receptors, therefore improving symptoms. It provides an effective therapy option for individuals with persistent hypercortisolism, effectively managing weight gain, reducing fatigue, and improving overall quality of life.

Orally: Administer mifepristone orally at a 200 mg dose, followed by buccal administration of Misoprostol 24-48 hours later. Healthcare follow-up should occur within 7-14 days post-Mifepristone intake. Discuss an appropriate setting for Misoprostol's use, considering potential expulsion starting within 2 hours of administration. Administer 800 mcg buccally within 24-48 hours after mifepristone. Optimal effectiveness is achieved by placing Misoprostol in the cheek pouch for 30 minutes and then swallowing. Patients may require medication for post-administration cramps or gastrointestinal symptoms.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Mifepristone is available in the form of tablets.

Day 1: One dosage of 200 mg of mifepristone PO

Days 2–3: 800 mcg of Misoprostol buccal once as a single dosage; this must be given at least 24 hours and up to 48 hours after the first day's dose of mifepristone.

Consult a physician again 7–14 days following mifepristone use

Days 7–14

A follow-up appointment is required to verify that a clinical examination, hCG testing, ultrasound scanning, or medical history has completed the termination process.

Women who have not experienced complete expulsion but are not pregnant may receive a follow-up dosage of 800 mcg of Misoprostol buccal with a follow-up in about seven days.

After treatment, bleeding stops most of the time, but severe or persistent bleeding does not always mean that the abortion was successful.

Following a medical abortion, surgical evacuation is advised to treat continuing pregnancies.

The first day of the last menstrual period marks the beginning of pregnancy.

Medical practitioners may estimate pregnancy duration through menstrual history and clinical assessment.

Utilize ultrasonography for pregnancy evaluation if the duration or ectopic pregnancy is unclear.

Ensure the removal of an intrauterine device (IUD) before treatment.

Discuss with the patient a suitable location for taking Misoprostol, considering that pregnancy expulsion might commence within 2 hours of administration, with most expulsions occurring within 2-24 hours.

Initiate dose of 300 mg PO qDay; may dose up to 1200 mg/day, but should not exceed 20 mg/kg/day.

Dosage increases should be based on the evaluation of glucose control, the need for anti-diabetic medicine, insulin levels, and psychological effects, and should not happen more frequently than every 2-4 weeks.

Avoid grapefruit and related products when using mifepristone due to potential effects on its efficacy. Limit caffeine intake to prevent possible drug interactions and adverse effects. Integrate a diet abundant in whole grains, fruits, vegetables, and low-fat dairy products. Abstain from smoking and alcohol to reduce complications. Include heart-healthy omega-3 fatty acid-containing foods or beverages daily. Employ low-fat cooking oils like olive, soybean, canola, or coconut oil to manage elevated blood pressure.

The dietary restriction should be individualized as per patient requirements.

Mifepristone may be contraindicated in the following conditions:-

Infection and Sepsis: Post-therapy, severe bacterial infection and occasional fatal septic shock have been reported with Mifepristone use during pregnancy termination. Healthcare providers must monitor for potential infection signs. Indications like sustained fever, intense abdominal pain, or pelvic tenderness warrant attention. Rare Clostridium sordellii infections are linked to mifepristone, childbirth, and gynecologic conditions.

Mifepristone REMS Program: The Mifepristone REMS Program manages the distribution of 200 mg of Mifepristone tablets due to severe complications. Requirements include prescriber certification through completing the Prescriber Agreement Form, patient agreement signature, and dispensing by certified prescribers or pharmacies under their supervision.

Uterine Bleeding: Uterine bleeding is experienced by almost all patients during medical abortion. Prompt medical or surgical intervention is necessary for prolonged heavy bleeding, indicating incomplete abortion or complications, to prevent hypovolemic shock. Immediate medical attention is crucial for prolonged heavy vaginal bleeding post-abortion.

Ectopic Pregnancy: Patients with confirmed or suspected ectopic pregnancy should avoid this drug as it does not effectively terminate such pregnancies. Healthcare providers should remain vigilant as symptoms of a medical abortion (abdominal pain, uterine bleeding) may mimic those of a ruptured ectopic pregnancy. Despite prior ultrasonography, the presence of an ectopic pregnancy might be overlooked. Evaluate women who conceived with an IUD in place for ectopic pregnancy.

Rhesus Immunization: 200 mg Mifepristone tablets may necessitate the same precautions against rhesus vaccination as those adopted before and after surgical abortion.

The adverse reactions related to mifepristone can be categorized as

The clinically relevant drug interactions of mifepristone are briefly summarized here.

Drugs that May Reduce Mifepristone: The primary enzyme involved in mifepristone metabolism is CYP450 3A4. Mifepristone metabolism can be induced by CYP3A4 inducers such as rifampin, dexamethasone, St. John's Wort, and several anticonvulsants like phenytoin, phenobarbital, and carbamazepine, which lowers serum concentrations of mifepristone. It is unknown if this action affects the dosage regimen's effectiveness.

Drugs that May Increase Mifepristone: Since CYP 3A4 is responsible for the drug's metabolism, ketoconazole, itraconazole, erythromycin, and grapefruit juice may impede this metabolism, hence raising serum concentrations of mifepristone, even though specific drug or food interactions with mifepristone have not been investigated. Patients receiving CYP 3A4 inhibitor therapy now or recently should utilize 200 mg mifepristone tablets with caution.

Effects on CYP 3A4Substrates: Coadministration of mifepristone may raise the serum concentrations of medications that are CYP 3A4 substrates, according to data on in vitro inhibition. Such an interaction may be seen for a long time after mifepristone is used because of how slowly the drug leaves the body. As a result, when mifepristone is used with medications that are CYP 3A4 substrates and have a limited therapeutic range, caution should be taken.

The common side effects of mifepristone include:-

Weakness

Nausea

Uterine cramps

Heavy menstrual bleeding, or menorrhagia

Vomiting

Diarrhoea

Dizziness

Infection after having an abortion.

Pregnancy Category X (FDA): When pregnant, avoid using. The risks outweigh the potential benefits. There are safer alternatives available.

Pregnancy tests are necessary before therapy or interruptions exceeding 14 days in potentially fertile females due to the drug's pregnancy loss effects. As it affects hormonal contraceptives, non-hormonal birth control is recommended during and a month post-treatment.

Administering mifepristone during organogenesis resulted in pregnancy loss across mice, rats, and rabbits at relevant doses. Its impact on endogenous and exogenous progesterone led to pregnancy loss. Using it in pregnancy or conception alerts to potential fetal hazards. Patients with active Cushing's syndrome face an increased risk of fetal loss (24-30%). Background risks for congenital disabilities and miscarriage in the general U.S. population are estimated at 2-4% and 15-20%, respectively.

Consideration of mifepristone's impact on a breastfed child, milk production, and infant effects remains unknown. While acknowledging breastfeeding benefits, assess maternal necessity versus potential drug impact on the infant. To reduce exposure, consider pumping and discarding milk for 18-21 days after treatment cessation.

As per the FDA, Mifepristone is not intended for use in this population.

Renal impairment: The initial dose is unchanged; the maximum dose is limited to 600 mg PO qDay.

Mild-to-moderate: The initial dose is unchanged; the maximum dose is limited to 600 mg PO qDay.

Severe: Do not use

The use of Mifepristone in a regimen with misoprostol disrupts pregnancy by causing decidual necrosis, myometrial contractions, and cervical softening, leading to the expulsion of the products of conception. Mifepristone dosages of at least 1 mg/kg have been demonstrated to counteract progesterone's effects on the endometrium and myometrium in females. The substance makes the myometrium more sensitive to prostaglandins' ability to induce contractions during pregnancy. Additionally, mifepristone has modest antiandrogenic and anti-glucocorticoid properties. After 10 to 25 mg/kg of Mifepristone dosages, the glucocorticoid dexamethasone was less active in rats. In humans, 4.5 mg/kg or more doses caused cortisol and adrenocorticotropic hormone (ACTH) to rise in response.

Absorption: Mifepristone is swiftly absorbed upon administration, exhibiting a bioavailability of around 69%. When taken as a single dose, it reaches peak plasma concentration within 1-2 hours, while in multiple doses, this peak occurs within 1-4 hours.

Distribution: This drug extensively binds to plasma proteins, mainly α1-acid glycoprotein and albumin, with a binding capacity of 98%. It efficiently crosses into various tissues, including the central nervous system, and is found in minimal amounts in breast milk.

Metabolism: The liver primarily metabolizes mifepristone, undergoing processes facilitated by CYP3A4 enzymes through N-demethylation and terminal hydroxylation. These actions result in the formation of three distinct metabolites.

Excretion: After metabolism, the drug is primarily eliminated, with approximately 90% excreted through faeces and the remaining 10% through urine. Its elimination half-life ranges from 18 hours for a single dose, exhibiting a slower phase where 50% is eliminated between 12-72 hours, to a more extended period of 85 hours for multiple doses.