Mifepristone + Misoprostol

Mifepristone + Misoprostol is an abortion agent or abortifacient belonging to the pharmacological class of anti-progesterone and Prostaglandin E1 Analogue.

The FDA commonly approves Mifepristone + misoprostol for the medical termination of intrauterine pregnancy through 70 days gestation.

Mifepristone: 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.

Misoprostol: Misoprostol taken orally is quickly absorbed. The active metabolite of misoprostol, misoprostol acid, has less than 90% plasma protein binding that is concentration-independent within the therapeutic range. The quick and thorough metabolism of misoprostol produces misoprostol acid. About 70% of the measured radioactivity is discovered in the urine after administering a radio-labelled dosage. Misoprostol acid has an elimination half-life of roughly half an hour.

The common side effects associated with Mifepristone + misoprostol include nausea, vomiting, diarrhoea and stomach cramps.

Mifepristone + Misoprostol is available in tablets.

The Mifepristone + misoprostol is available in India, the USA, France, China, Germany, Italy, the United Kingdom, Japan, and Australia.

Mifepristone + Misoprostol is an abortion agent or abortifacient belonging to the pharmacological class of anti-progesterone and Prostaglandin E1 Analogue.

Due to its competitive interaction with progesterone at progesterone-receptor sites, Mifepristone has anti-progestational activity. The chemical inhibits Exogenous or endogenous progesterone, according to experiments conducted on mice, rats, rabbits, and monkeys using different oral doses. 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.

Misoprostol's ability to shield the mucosa contributes to its effectiveness in treating ulcers. The secretion of mucus and bicarbonate, the prevention of the mucus bilayer breaking down, the reduction of hydrogen ion backflow, the control of mucosal blood flow, and the maintenance of the mucosal capacity to produce new cells are some of the theories that link the cytoprotective impact. Misoprostol decreases pepsin levels at baseline but does not affect histamine-stimulated release. Because prostaglandins affect a range of tissues, misoprostol has been found to have additional effects. Misoprostol also stops stomach acid production during the day and at night by directly targeting the parietal cell. Parietal cell receptors exhibit a significant affinity for prostaglandins of the E series. The suppression of gastric acid secretion, triggered by food, histamine, pentagastrin, and coffee, is enhanced by misoprostol at higher rates. Misoprostol suppresses stomach acid production more than H2 antagonists do, especially at night. In conclusion, misoprostol increases the frequency of uterine contractions, which increases the risk of miscarriages.

Synergistic Benefits: Mifepristone + Misoprostol combination has synergistic effects to terminate pregnancies by blocking progesterone effects and inducing uterine contractions efficiently. By inhibiting progesterone, a hormone essential for maintaining pregnancy, Mifepristone causes the uterine lining to break down, much like a menstrual cycle, stopping the development of pregnancy. Misoprostol, an analogue of prostaglandin, facilitates the ejection of aborted pregnancy tissue by inducing uterine contractions. Together, they provide a safer, more dependable, and more effective way of termination while reducing the risks associated with surgery.

Mifepristone + Misoprostol is available in tablet.

Tablets: When taken orally, to be swallowed whole with water/liquid. Do not chew, crush or break it. If taken vaginally, insert the tablet deeply in a lie-down or squat, and remain supine for 30 minutes.

As the physician recommends, take the medication orally once daily, preferably before or after meals.

Mifepristone + Misoprostol can be used as follows:

In early pregnancy, misoprostol + Mifepristone can result in abortions up until week 10 (70 days after the last menstrual cycle). The combination inhibits progesterone, which is essential for sustaining pregnancy. Mifepristone suppresses progesterone, which causes the uterine lining to rupture and causes the pregnancy to end. Uterine bleeding occurs after 24-48 hours of using Mifepristone + misoprostol. The second medication, misoprostol, induces uterine contractions by relaxing the cervix. When combined, they provide a 90% non-surgical pregnancy termination rate. Misoprostol is given orally or vaginally 24-36 hours after Mifepristone.

Mifepristone + Misoprostol are commonly indicated in medical abortion to terminate pregnancies within the first 10 weeks. Mifepristone blocks progesterone, vital for pregnancy, leading to uterine lining breakdown. Misoprostol, a prostaglandin analogue, prompts uterine contractions and softens the cervix, non-surgically terminating the pregnancy. This combination adheres to specific medical guidelines for administration.

Orally and Vaginally: Mifepristone is initially administered orally, taken with a glass of water and usually in a clinical setting to block progesterone's vital effects for pregnancy. Subsequently, misoprostol is taken orally or inserted vaginally, usually 24-48 hours after the Mifepristone dose. In case of vomiting within 30 minutes of tablet intake, inform your doctor or take another tablet. The medication's effects might take 24-48 hours to manifest, leading to spotting or bleeding. After 36-48 hours, a second dose of misoprostol, either orally or vaginally, should be taken, with recommended rest due to potential severe stomach pain or vaginal bleeding, resulting in abortion. Misoprostol is usually taken in a series of doses, often 800 mcg, either orally or vaginally.

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

Mifepristone + Misoprostol is available in tablets.

The combination should be given orally once daily with or after meals.

200 mg OP daily. Blocks progesterone effects crucial for pregnancy.

Timing: 24–48 hours after initial Mifepristone intake.

If vomiting occurs within 30 minutes after tablet intake, consulting a doctor or taking another tablet is advisable.

Action: Effects might take 24-48 hours, often causing potential effects like spotting or bleeding.

Timing: 36–48 hours, usually taken orally or vaginally following the first dose of Mifepristone

Resting is advised post-administration since severe stomach discomfort or vaginal bleeding could result in an abortion.

Consider cooking oils such as olive, soybean, canola, or coconut oil to help lower high blood pressure and include omega-3 fatty acids in your diet for heart health. To avoid possible drug interactions and adverse effects, avoid grapefruit and its derivatives and limit caffeine intake. To reduce difficulties, avoid alcohol, quit smoking and maintain a diet high in whole grains, fruits, vegetables, and low-fat dairy products. By avoiding extreme stress and physically demanding activities like jogging, one can lower the risk of experiencing significant vaginal bleeding.

The dietary restriction should be individualized as per patient requirements.

Mifepristone + Misoprostol may be contraindicated in the following conditions:-

Caution is advised for those with certain medical conditions, such as anaemia, bleeding disorders, or using an IUD, as they may increase the risk of complications.

It is known to cause sleepiness, so driving or operating machinery should not be done.

Although they are uncommon, these drugs may result in severe infections following pregnancy termination. Monitor infection-related symptoms such as fever, chills, or recurrent stomach pain; if any appear, get medical attention immediately.

There is a risk of incomplete abortion. It is crucial to attend follow-up visits to confirm the termination and ensure no tissue remains in the uterus.

The adverse reactions related to Mifepristone + misoprostol can be categorized as

The clinically relevant drug interactions of Mifepristone + misoprostol is briefly summarized here.

Drug-Drug Interactions: Mifepristone + misoprostol interacts with corticosteroids (dexamethasone), antifungals (ketoconazole, itraconazole), antibiotics (erythromycin, rifampicin), anti-epileptics (phenytoin, phenobarbital, carbamazepine), immunosuppressants (cyclosporine, tacrolimus, sirolimus), and migraine medications (ergotamine). Consequently, it is not recommended to use Mifepristone + misoprostol together.

Drug-Food Interactions: It is essential to inform the doctor about all vitamins, herbs, and supplements used, since Mifepristone and misoprostol may interact with them and cause unwanted side effects. Additionally, it is known that grapefruit juice and St. John's Wort, a natural treatment for mild depression, interact with Mifepristone + misoprostol.

Drug-Disease Interactions: Caution should be exercised when using Mifepristone and Misoprostol in individuals with bleeding disorders, confirmed or suspected ectopic pregnancy, heart problems, liver or kidney disease, vaginal bleeding, or porphyria (a blood disorder that is inherited and can cause issues with the nervous system or skin).

The common side of Mifepristone + Misoprostol include the following

Nausea

Uterine cramps and bleeding

Diarrhoea

Vomiting

Stomach cramp

Menorrhagia (heavy menstrual bleeding)

Dizziness

Infection following abortion

The use of Mifepristone + Misoprostol should be prudent in the following group of special populations:

Mifepristone: Pregnancy Category X (FDA)- Not for use in pregnancy.

Mifepristoneuse during pregnancy leads to pregnancy loss; risks of birth abnormalities remain unknown.

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.

Misoprostol: Pregnancy Category X (FDA) - Not for use in pregnancy.

When misoprostol is given to a pregnant woman, it can harm the pregnancy (causing an abortion) and injure the fetus. Misoprostol has not been approved for use in inducing labour in the third trimester because it has been linked to uterine hyperstimulation, which can alter the fetal heart rate and cause fetal death.

Several reports in the literature associate the use of misoprostol during the first trimester of pregnancy with skull defects, cranial nerve palsies, facial malformations, and limb defects.

Mifepristone: 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.

Misoprostol: Misoprostol is quickly metabolized by the mother into misoprostol acid, which is physiologically active and excreted in breast milk. While there are no documented cases of misoprostol's adverse effects on nursing infants, caution should be used when misoprostol is given to breastfeeding women.

As per FDA, safety and effectiveness in the pediatric population have yet to be established.

Kidney impairment (Mild to Severe): Be cautious when taking it, particularly if one has a history of kidney problems. The dose may be adjusted as required.

Hepatic Impairment Mild to moderate): Be cautious when taking it, particularly if one has a history of Liver diseases/conditions. The dose may be adjusted as required.

Severe: Do not use

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Mifepristone + Misoprostol.

Overconsumption of Mifepristone + misoprostol could lead to severe vaginal bleeding, intense abdominal pain, dizziness, or persistent vomiting.

There is no specific antidote or treatment for excessive Mifepristone + Misoprostol intake, so treatment typically involves symptomatic and supportive measures. Activated charcoal may limit absorption if the ingestion is recent. Management consists of monitoring vital signs, addressing severe bleeding or abdominal pain, and administering medication to control bleeding or manage symptoms. Severe bleeding may require blood transfusions, while persistent complications could need surgical intervention to remove retained products or manage excessive bleeding. Intravenous fluids combat dehydration from blood loss. Close vital sign monitoring is crucial, emphasizing timely medical intervention to mitigate potential risks from Mifepristone + Misoprostol overdose.

A synthetic steroid with antiprogestational properties called Mifepristone is prescribed for the medical termination of intrauterine pregnancy up to 49 days, along with other medical conditions. 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.

Misoprostol is a synthetic PGE1 analogue with mucosal protection and antisecretory effects on the stomach. NSAIDs prevent the synthesis of prostaglandins. The mucosal damage brought on by NSAIDs may be exacerbated by a lack of prostaglandins inside the stomach and duodenal mucosa. This may result in decreased bicarbonate and mucus output.

Misoprostol is both antisecretory and stimulates bicarbonate and mucus formation at doses of 200 mcg and higher. Therefore, it is impossible to determine whether misoprostol's capacity to lower the incidence of gastric and duodenal ulcers is due to its mucosal protective impact, its antisecretory activity, or both.

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.

Absorption: Misoprostol is absorbed rapidly after oral administration.

Distribution: The plasma protein binding of misoprostol acid, the active metabolite of misoprostol, is less than 90% and is concentration-independent in the therapeutic range.

Metabolism: Misoprostol is rapidly and extensively metabolized to misoprostol acid.

Excretion: After administration of a radio-labeled dosage, approximately 70% of detected radioactivity appears in the urine. The elimination half-life of misoprostol acid is about 30 minutes.

Mifepristone blocks progesterone, which is crucial for maintaining pregnancy, while misoprostol induces uterine contractions, leading to the termination of the pregnancy.