mifepristone and misoprostol

Action and Spectrum

Actions and Spectrum: 

Action:  

When mifepristone is taken, it interferes with the progesterone receptors in the uterine lining, causing a decrease in progesterone activity. This results in the thinning of the uterine lining and the detachment of the embryo from the uterine wall, effectively disrupting the pregnancy. 

misoprostol is a synthetic prostaglandin E1 analog, its primary function is to induce uterine contractions. 

Action:  

When misoprostol is taken after mifepristone, usually 24 to 48 hours later, it causes muscular contractions of the uterine muscles, expulsing the embryo and other pregnancy tissues from the uterus. These contractions also help to ensure that the uterus is emptied. 

Combination: The combination of mifepristone and misoprostol is highly effective for ending early pregnancies, usually up to 10 weeks gestation. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Abdominal pain 

Fatigue 

Asthenia 

Dizziness 

Diarrhea 

Fever 

Gastric distress 

Nausea 

Pain 

Headache 

Uterine contractions 

Vomiting 

Uterine cramps 

Abnormal vaginal bleeding 

1-10% 

Syncope 

endometritis 

Abdominal cramps 

Breast tenderness 

<1% 

Salpingitis 

Bronchospasm 

Hot flash 

Black Box Warning

Black Box Warning: 

• Serious infections: mifepristone has been associated with serious bacterial infections that have resulted in death. Infections may include sepsis, which can be life-threatening. The risk of infection increases in certain situations, such as when the product is used beyond the recommended gestational age or when it is used in the presence of certain medical conditions. 
• Risk of uterine rupture with previous cesarean section: misoprostol can increase the risk of uterine rupture in women who have had a previous cesarean section (C-section) and are attempting to undergo a medical abortion. 

Contraindication / Caution

Contraindication/Caution: 

Contraindication 

• Ectopic pregnancy: mifepristone and misoprostol are ineffective in terminating ectopic pregnancies, which occur when the fertilized egg implants outside the uterus, generally in the fallopian tube. Ectopic pregnancies are life-threatening and require immediate medical attention, typically through surgical intervention. 
• Chronic adrenal failure: Individuals with chronic adrenal failure (Addison’s disease) should avoid using mifepristone, as it may interfere with their cortisol replacement therapy. 
• Anticoagulant therapy: mifepristone can potentially increase the risk of bleeding, so it is generally not recommended for individuals receiving anticoagulant therapy or with bleeding disorders. 
• Inherited porphyria: mifepristone can trigger acute attacks in individuals with inherited porphyria, a group of rare metabolic disorders. 
• Allergy or hypersensitivity: If a person is known to be allergic to mifepristone, misoprostol, or other prostaglandins, they should not use these medications. 
• Intrauterine device (IUD): If a woman has an IUD in place, it should be removed before starting medical abortion with mifepristone and misoprostol. 
• Chronic use of corticosteroids: Long-term use of corticosteroids may reduce the effectiveness of mifepristone. 
• Severe anemia: mifepristone and Misoprostol can cause significant bleeding, so individuals with severe anemia may not be suitable candidates for medical abortion. 
• Women with certain medical conditions: Women with some medical conditions, such as particular heart, liver, kidney, or lung diseases, may not be appropriate candidates for medical abortion due to potential risks associated with the medications. 

Caution 

• Gestational age: Medical abortion using mifepristone and misoprostol is typically recommended for pregnancies up to 10 weeks gestation. Beyond this point, the effectiveness of the medications may decrease, and the risk of complications may increase. 
• Presence of an IUD: If a woman has an intrauterine device (IUD), it should be removed before starting medical abortion with mifepristone and misoprostol. 
• Ectopic pregnancy: Medical abortion is ineffective for terminating ectopic pregnancies (pregnancies outside the uterus). Ectopic pregnancies require immediate medical attention and typically need surgical intervention. 
• Ultrasound confirmation: Before starting medical abortion, an ultrasound is usually performed to confirm the pregnancy’s location (intrauterine) and gestational age. 
• Bleeding disorders or anticoagulant therapy: mifepristone and misoprostol can cause significant bleeding, so caution is necessary for individuals with bleeding disorders or those taking anticoagulant medications. 
• Allergy or hypersensitivity: Individuals with a known allergy or hypersensitivity to mifepristone, misoprostol, or prostaglandins should avoid using these medications. 
• Chronic adrenal failure: People with chronic adrenal failure (Addison’s disease) should use mifepristone cautiously, as it may interfere with their cortisol replacement therapy. 
• Chronic use of corticosteroids: Long-term use of corticosteroids may reduce the effectiveness of mifepristone. 
• Inherited porphyria: mifepristone can trigger acute attacks in individuals with inherited porphyria, a group of rare metabolic disorders. 
• Infection or sepsis: Pre-existing infections or sepsis may increase the risk of complications during medical abortion. Infections should be treated before the procedure. 
• Emotional and psychological considerations: Medical abortion can have significant emotional and psychological effects. Women should have access to appropriate counseling and support during and after the process. 
• Access to emergency medical care: Before starting medical abortion, individuals should have access to transportation and emergency medical care if complications arise. 
• Follow-up care: It is essential to follow up with a healthcare provider after the medical abortion to ensure the procedure was successful and to address any concerns or complications. 

Pregnancy / Lactation

Pregnancy consideration:  

US FDA pregnancy category: Not assigned 

Lactation:   

Excreted into human milk: Yes. 

Pregnancy category: 

• Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 
• Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 
• Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    
• Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    
• Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    
• Category N: There is no data available for the drug under this category. 

Pharmacology

Pharmacology: 

mifepristone is an anti-progesterone medication that competitively binds to progesterone receptors, inhibiting progesterone’s biological actions. Consequently, the uterine lining thins and the embryo detaches from the uterine wall, leading to the termination of pregnancy during a medical abortion. mifepristone also has partial glucocorticoid receptor antagonist activity, contributing to its use in Cushing’s syndrome.

On the other hand, misoprostol is a synthetic prostaglandin E1 analog that binds to specific receptors on the uterine smooth muscle cells, inducing powerful contractions and cervical softening. In combination with mifepristone, misoprostol enhances uterine contractions, expulsing the embryo and other pregnancy tissues from the uterus. misoprostol is also utilized for cervical ripening, labor induction, and preventing postpartum hemorrhage. 

Pharmacodynamics: 

Mechanism of action: The mechanism of action of mifepristone and misoprostol is distinct, but when used together, they work synergistically to induce medical abortion.  

• mifepristone: mifepristone is an anti-progesterone drug that acts on progesterone receptors in the body. Progesterone is crucial for maintaining the uterine lining and supporting the embryo’s growth during early pregnancy. mifepristone competitively binds to progesterone receptors, blocking the action of progesterone. As a result, the uterine lining begins to thin, and the embryo’s attachment to the uterine wall is disrupted. This leads to a decrease in the supply of nutrients and also oxygen to the developing embryo, ultimately causing its detachment and death. 

mifepristone’s anti-progesterone activity also leads to the softening and dilation of the cervix, which prepares the uterus for the expulsion of pregnancy tissues. 

• misoprostol: It is a synthetic prostaglandin E1 analog. Prostaglandins are chemical compounds that play various roles in the body, including inducing uterine contractions. misoprostol binds to specific receptors on uterine smooth muscle cells, causing powerful and coordinated contractions of the uterus. These contractions help expel the detached embryo and other pregnancy tissues from the uterus. 

When used together: The combination of mifepristone and misoprostol for medical abortion is highly effective. mifepristone’s anti-progesterone action prepares the uterus for abortion by detaching the embryo and softening the cervix. Then, misoprostol induces muscular contractions, effectively expelling the contents of the uterus. 

Pharmacokinetics: 

Absorption 

mifepristone is well-absorbed after oral administration. Its absorption is enhanced when taken with food. 

misoprostol is rapidly absorbed following oral administration. It is also available in a sublingual and vaginal formulation, where absorption can be more direct. 

Distribution 

mifepristone has a high protein-binding capacity (about 98%) and distributes extensively throughout the body. 

misoprostol is highly protein-bound (around 80-90%) and widely distributed in tissues. 

Metabolism 

mifepristone undergoes extensive hepatic metabolism primarily by the liver enzyme CYP3A4, forming active and inactive metabolites. 

misoprostol undergoes extensive metabolism, primarily in the liver, to produce several metabolites, including the active metabolite misoprostol acid. 

Elimination and Excretion 

Most mifepristone and its metabolites are eliminated via feces (approximately 83%) and a smaller proportion via urine (approximately 9%). 

The excretion of misoprostol and its metabolites primarily occurs through the urine. The elimination half-life is relatively short, clearing the drug from the body relatively quickly. 

Adminstartion

Administration: 

The administration of mifepristone and misoprostol for medical abortion typically involves a two-step process, and it is essential to follow the healthcare provider’s instructions carefully. Medical abortion using these medications is most effective when started early in pregnancy, usually up to 10 weeks gestation.  

mifepristone Administration 

• Medical Assessment: Before starting the medical abortion process, a woman undergoes a medical assessment to confirm the pregnancy and assess her overall health, including any contraindications or cautions. 
• Ultrasound Confirmation: An ultrasound determines the pregnancy’s location (intrauterine) and gestational age. This helps ensure that the pregnancy is eligible for medical abortion. 
• mifepristone Intake: On the first day of the procedure, the woman takes the mifepristone pill under medical supervision. mifepristone is usually taken orally. 
• Action of mifepristone: mifepristone blocks the action of progesterone, which is necessary for maintaining the pregnancy. It causes the thinning of the uterine lining and also detaches the embryo from the uterine wall. 

misoprostol Administration 

• Timing: The woman will administer the misoprostol pills within 24 to 48 hours after taking mifepristone. The exact timing might vary based on the healthcare provider’s instructions. 
• Route of Administration: misoprostol can be taken orally (by placing the pills under the tongue) or vaginally (inserting the pills into the vagina). The healthcare provider will advise on the preferred method. 
• Number of Doses: The number of misoprostol pills may vary, but it is usually multiple pills taken in one or two doses. 
• Action of misoprostol: misoprostol causes muscular contractions of the uterine muscles, expelling the embryo and other pregnancy tissues from the uterus. The contractions also help ensure the uterus is emptied. 
• Pain Relief and Support: During this step, women may experience cramping and bleeding as the uterus contracts and the pregnancy is expelled. Pain relief medications and emotional support are often provided to manage discomfort and provide reassurance. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: mifepristone and misoprostol 

Why do we use mifepristone and misoprostol? 

Uses of mifepristone: 

• Medical Abortion: mifepristone is primarily used with misoprostol for medical abortion (non-surgical abortion) up to 10 weeks of gestation. It blocks the action of progesterone, leading to the detachment of the embryo from the uterine wall and initiating the process of abortion. 
• Cushing’s Syndrome: mifepristone is sometimes prescribed to manage hyperglycemia (high blood sugar levels) in patients with Cushing’s syndrome.  
• Preoperative Cervical Ripening: In some cases, mifepristone is used to prepare the cervix for specific gynecological procedures or surgeries, such as terminating a second-trimester pregnancy or the induction of labor. 
• Endometriosis: mifepristone has been investigated as a treatment option for endometriosis, where the tissue lining the uterus grows outside the uterus and causes pain and inflammation. 

Uses of misoprostol: 

• Medical Abortion: As mentioned earlier, misoprostol is used with mifepristone for medical abortion. It induces uterine contractions, leading to the expulsion of the pregnancy tissues. 
• Cervical Ripening and Labor Induction: misoprostol is used to ripen cervix and induce labor in pregnant women, especially in cases where labor needs to be initiated or enhanced. 
• Prevention and Treatment of Postpartum Hemorrhage: misoprostol effectively prevents and treats postpartum hemorrhage (excessive bleeding after childbirth) in resource-limited settings. 
• Induction of Labor in Fetal Demise: misoprostol may induce labor in cases of fetal demise (when a baby dies in the womb) to facilitate delivery. 
• Treatment of Peptic Ulcers: misoprostol is used with other medications to prevent and treat peptic ulcers caused by nonsteroidal anti-inflammatory drugs (NSAIDs).