MIFEPRISTONE + MISOPROSTOL

Indications

• Medical termination of intrauterine pregnancy up to 84 days gestation
• Cervical ripening before mechanical cervical dilatation
• Management of Cushing's syndrome

Dosage

Adults: For medical termination of pregnancy: 200 mg orally for one dose, taken 36-48 hours before the procedure. Alternatively, 600 mg orally for one dose, followed by 200 mg 36-48 hours later unless abortion is already complete. For cervical ripening: 200 mg orally followed by prostaglandin as per national protocols.

Mechanism of action

Mifepristone exhibits its anti-progestational activity through competitive binding to progesterone receptors. This interaction inhibits the effects of endogenous or exogenous progesterone, leading to the termination of pregnancy. In cases of Cushing's syndrome, it blocks cortisol from binding to its receptor, mitigating the effects of elevated cortisol levels without affecting cortisol production.

Pharmacodynamics

Mifepristone is a synthetic steroid with significant antiprogestational effects, particularly effective in terminating early intrauterine pregnancies. It sensitizes the myometrium to prostaglandin-induced contractions and promotes cervical softening, facilitating the expulsion of products of conception. Mifepristone also has antiglucocorticoid activity, which can inhibit the action of glucocorticoids like dexamethasone.

Pharmacokinetics

The pharmacokinetics of mifepristone include rapid absorption after oral administration, with peak plasma concentrations occurring within 1-2 hours. It undergoes extensive hepatic metabolism, primarily by cytochrome P450 enzymes, and has a half-life of approximately 20-30 hours. The metabolites are excreted in urine and feces. Caution is advised in patients with hepatic or renal impairment, as specific data for these populations are lacking.

Contra-indications

• Acute porphyrias
• Chronic adrenal failure
• Suspected ectopic pregnancy
• Uncontrolled severe asthma
• History of endocarditis
• Prosthetic heart valve
• Hemorrhagic disorders

Adverse effects

• Abdominal cramps
• Diarrhoea
• Infection
• Nausea
• Pelvic inflammatory disease
• Vaginal haemorrhage (sometimes severe)
• Vomiting
• Hypotension
• Angioedema
• Chills
• Dizziness
• Erythema nodosum
• Fever
• Headache
• Hot flush
• Malaise
• Skin reactions
• Toxic epidermal necrolysis
• Toxic shock syndrome
• Uterine rupture

Interactions

• Corticosteroids (decreases efficacy)
• Posaconazole (increases exposure)
• Avatrombopag (increases exposure)
• Cobicistat (increases exposure)
• Warfarin (increases exposure)
• Dabrafenib (decreases exposure)
• Bosentan (decreases exposure)
• Ergotamine (increases exposure)
• Everolimus (increases exposure)
• Grapefruit juice (increases exposure)

Precautions

• Adrenal suppression (may require corticosteroid)
• Anticoagulant therapy
• Existing cardiovascular disease
• Risk factors for cardiovascular disease

Pregnancy

Mifepristone is indicated for the medical termination of intrauterine pregnancy up to 49 days gestation under close medical supervision.

Breast-feeding

Use is not recommended during breastfeeding due to potential effects on the nursing infant.

Storage

Store at room temperature, protected from light and moisture.

Formulations

• Mifepristone 200 mg tablets
• Mifepristone 200 mg oral tablet in Medabon® Combipack with misoprostol 200 micrograms vaginal tablets

Indications

• Gastric ulcer
• Duodenal ulcer
• NSAID-induced peptic ulcer
• Termination of pregnancy following mifepristone
• Management of miscarriage

Dosage

Children: Oral preparations are not licensed for use in children under 3 years. For children aged 1–5 months, the dose is 1 mg/kg 3 times a day. For children aged 6 months to 2 years

Adults: For gastric and duodenal ulcers, the typical adult dose is 150 mg orally twice daily. For termination of pregnancy following mifepristone, the recommended dose is 400 micrograms orally.

Mechanism of action

Misoprostol stimulates prostaglandin E1 receptors on parietal cells in the stomach to reduce gastric acid secretion. It increases mucus and bicarbonate secretion, thickening the mucosal bilayer, and promotes the generation of new cells. In the uterus, Misoprostol binds to smooth muscle cells to enhance the strength and frequency of contractions, while also degrading collagen and reducing cervical tone.

Pharmacodynamics

Misoprostol acts as a prostaglandin E1 analog which is effective in reducing the risk of NSAID-induced gastric ulcers and is utilized in obstetric applications such as miscarriage management and abortion. Its onset of action varies by route: oral (8 minutes), sublingual (11 minutes), vaginal (20 minutes), and rectal (100 minutes), with durations of action ranging from approximately 2 to 4 hours.

Pharmacokinetics

Misoprostol is rapidly absorbed after oral administration, with bioavailability affected by food. It undergoes extensive first-pass metabolism, leading to a half-life of about 20-40 minutes. The drug is metabolized in the liver and its metabolites are eliminated primarily through the urine. The pharmacokinetic profile varies with administration route and formulation.

Contra-indications

• Hypersensitivity to misoprostol or any of its components
• Pregnancy (for certain indications such as termination)
• History of uterine rupture
• Severe cardiovascular disease
• Conditions where hypotension might precipitate severe complications

Adverse effects

• Diarrhea
• Abdominal pain
• Nausea
• Vomiting
• Headache
• Dizziness
• Uterine rupture (rare)
• Chills
• Fever
• Hot flushes
• Hypotension
• Malaise
• Toxic shock syndrome (rare)

Interactions

• Oxytocin (unknown additive effect)
• NSAIDs may have diminished efficacy when misoprostol is used concurrently

Precautions

• Monitor for coagulopathy during treatment
• Use with caution in patients with a history of inflammatory bowel disease
• Caution in patients with cardiovascular disease
• Patients should be informed about potential for diarrhea and other gastrointestinal side effects

Pregnancy

Not recommended during pregnancy except for specific medical indications such as termination of pregnancy following mifepristone, as it may induce contractions and lead to miscarriage.

Breast-feeding

Misoprostol is excreted in breast milk; caution is advised when administered to nursing mothers.

Storage

Store below 25°C. Protect from light and moisture.

Formulations

• Tablets: 200 micrograms, 400 micrograms
• Pessaries: 100 micrograms
• Oral solution

Mechanism of action

The anti-progestational activity of mifepristone results from competitive interaction with progesterone at progesterone-receptor sites. Based on studies with various oral doses in several animal species (mouse, rat, rabbit and monkey), the compound inhibits the activity of endogenous or exogenous progesterone. The termination of pregnancy results. In the treatment of Cushing's syndrome, Mifepristone blocks the binding of cortisol to its receptor. It does not decrease cortisol production but reduces the effects of excess cortisol, such as high blood sugar levels. Mifepristone competitively inhibits the actions of progesterone at progesterone-receptor sites, resulting in termination of pregnancy.The combination of mifepristone and misoprostol causes expulsion of the products of conception through decidual necrosis, myometrial contractions, and cervical softening. When administered in the early stages of pregnancy, mifepristone causes decidual breakdown by blockade of uterine progesterone receptors. This leads to detachment of the blastocyte, which decreases hCG production. This in turn causes a decrease in progesterone secretion from the corpus luteum, which further accentuates decidual breakdown. Decreased endogenous progesterone coupled with blockade of progesterone receptors in the uterus increases prostaglandin levels and sensitizes the myometrium to the contractile actions of prostaglandins. In addition, mifepristone promotes uterine contractions and softening of the cervix and sensitizes the myometrium to effects of prostaglandins (e.g., misoprostol) that stimulate uterine contraction and expulsion of the products of conception. In the absence of progesterone, mifepristone acts as a partial progestin agonist. At dosages higher than those used for termination of pregnancy, mifepristone also exhibits antiglucocorticoid activity. The drug also has been shown to have weak antiandrogenic activity.

Pharmacodynamics

Mifepristone is a synthetic steroid with antiprogestational effects indicated for the medical termination of intrauterine pregnancy through 49 days' pregnancy. Doses of 1 mg/kg or greater of mifepristone have been shown to antagonize the endometrial and myometrial effects of progesterone in women. During pregnancy, the compound sensitizes the myometrium to the contraction-inducing activity of prostaglandins. Mifepristone also exhibits antiglucocorticoid and weak antiandrogenic activity. The activity of the glucocorticoid dexamethasone in rats was inhibited following doses of 10 to 25 mg/kg of mifepristone. Doses of 4.5 mg/kg or greater in human beings resulted in a compensatory elevation of adrenocorticotropic hormone (ACTH) and cortisol.

Mechanism of action

Misoprostol is a synthetic prostaglandin E1 analog that stimulates prostaglandin E1 receptors on parietal cells in the stomach to reduce gastric acid secretion. Mucus and bicarbonate secretion are also increased along with thickening of the mucosal bilayer so the mucosa can generate new cells. Misoprostol binds to smooth muscle cells in the uterine lining to increase the strength and frequency of contractions as well as degrade collagen and reduce cervical tone. Misoprostol enhances natural gastromucosal defense mechanisms and healing in acid-related disorders, probably by increasing production of gastric mucus and mucosal secretion of bicarbonate. Misoprostol inhibits basal and nocturnal gastric acid secretion by direct action on the parietal cells; also inhibits gastric acid secretion stimulated by food, histamine, and pentagastrin. It decreases pepsin secretion under basal, but not histamine stimulation. Misoprostol has no significant effect on fasting or postprandial gastrin or intrinsic factor output.

Pharmacodynamics

Misoprostol is a prostaglandin E1 analog used to reduce the risk of NSAID induced gastric ulcers by reducing secretion of gastric acid from parietal cells. Misoprostol is also used to manage miscarriages and used alone or in combination with mifepristone for first trimester abortions. An oral dose of misoprostol has an 8 minute onset of action and a duration of action of approximately 2 hours, a sublingual dose has an 11 minute onset of action and a duration of action of approximately 3 hours, a vaginal dose has a 20 minute onset of action and a duration of action of approximately 4 hours, and a rectal dose has a 100 minute onset of action and a duration of action of approximately 4 hours.