Misoprostol

Food slows the absorption of misoprostol, reducing the peak concentration (C_max) and increasing the time to reach C_max after a 400 μg dose. This interaction is clinically insignificant since misoprostol’s ability to protect the GI mucosa appears to be local rather than systemic.

Misoprostol is rapidly de-esterified in the liver to its active metabolite, misoprostol acid. It is not metabolized by the hepatic CYP450 enzyme system and neither induces or inhibits it. See Misoprostol.

Oral: Tablets should be swallowed whole. Misoprostol may be administered with meals.

Vaginal: Oral tablets placed high in the vagina. Studies have shown that moistening the tablets prior to insertion does not improve efficacy.

Sublingual: Oral tablets are kept under the tongue until dissolved or for at least 20 minutes and then swallowed. Some patients have reported unpleasant taste and sense of numbness across mouth and throat with this route.

Buccal: Oral tablets are placed between the teeth and cheek and allowed to dissolve (usually 10-20 minutes).

Rectal: Oral tablets are placed in the rectum and allowed to dissolve.

Treatment and Prevention of NSAID-induced Gastroduodenal Ulcers and Treatment of Duodenal Ulcers Caused by Peptic Ulcer Disease: 200 μg orally 4 times daily with food. The last dose of the day should be taken at bedtime. If not tolerated, may decrease dose to 100 μg 4 times daily or 200 μg twice daily. Alternatively, start slow and titrate up to a tolerable therapeutic dose. Administer for the duration of NSAID therapy.

Medical Termination of Pregnancy: In combination with methotrexate up to 56 days gestation: 800 µg vaginal misoprostol 5-7 days after methotrexate 50 mg/m² orally or intramuscularly, may repeat misoprostol dose in 24 h if needed. Misoprostol alone up to 56 days gestation: 800 µg vaginally Q24-48H max 3 doses. Second trimester termination by induction of labour: 200 µg vaginally Q12H for up to 48 h [SOGC Induced Abortion Guidelines 2006].

Cervical Ripening Prior to Surgical Abortion: ≤13 weeks gestation: 400 µg oral or vaginal misoprostol 4-12 h prior to procedure; for gestations 14-16 weeks 600 µg buccally 2-4 h prior to procedure (if misoprostol is administered vaginally more than 4 h prior to procedure there is potential for unexpected and therefore unsupervised delivery) [SOGC Induced Abortion Guidelines 2006].

Evacuation of the Uterus Due to Miscarriage or Fetal Demise: 200 µg vaginally Q12H up to 48 h [SOGC Induced Abortion Guidelines 2006].

Prevention of Postpartum Hemorrhage: 600 µg orally or sublingually to be given immediately after delivery of the baby only in situations in which use of injectable oxytocin or ergot alkaloids is not possible. In the event of continued hemorrhage, a minimum of 2 hours should elapse before a second dose is given. This interval should be increased to 6 hours if the initial dose was associated with pyrexia or marked shivering. [Int J Gynaecol Obstet 2007;99(Suppl 2):S198-201].

Induction of Labour at Term: The Federation of International Gynecologists and Obstetricians (FIGO) suggests the following dosage options: 25 µg misoprostol vaginally Q4H (max 6 doses), 50 µg misoprostol orally Q4H (max 6 doses), 20 µg misoprostol solution (made by dissolving tablet in water) orally Q2H (max 12 doses). Contraindicated in women with previous caesarean sections due to reports of uterine rupture [Int J Gynaecol Obstet 2007;99(Suppl 2):S194-7].

Facilitation of Transcervical Procedures: For cervical priming prior to instrumentation (e.g., dilatation and curettage, hysteroscopy, intrauterine device insertion) FIGO suggests 400 µg misoprostol vaginally or sublingually 3 hours before the procedure [Int J Gynaecol Obstet 2007;99(Suppl 2):S168-71].

Administer with food to minimize the incidence of diarrhea.

In older adults, start slow and titrate up to avoid the potential for diarrhea. The following recommendation can be made: start at 100 μg/day orally and increase by 100 μg/day at 3-day intervals until the desired dose is achieved.

No dosage adjustment is necessary in renal impairment. If the dose is not tolerated, the dose may be reduced. Alternatively, start slow (100 μg four times daily) and titrate up.

For obstetric/gynecologic use, choice of route of administration may depend on clinical situation. (See Action and Clinical Pharmacology, Pharmacokinetics.)

Reported rarely and not necessarily causally linked to misoprostol are: anaphylaxis, anxiety, appetite changes, arrhythmia, arterial thrombosis, bronchospasm, confusion, cramps, depression, drowsiness, edema, fever, GI bleeding, GI inflammation, gingivitis, gout, hypertension, hypotension, impotence, loss of libido, menstrual irregularities, MI, neuropathy, neurosis, pulmonary embolism, purpura, rash, reflux, rigors, thrombocytopenia, weakness, and weight change.

When tablets are used sublingually or buccally unpleasant taste has been reported. Sense of numbness over the mouth and throat has been reported with sublingual use. Skin rash occurs occasionally and usually resolves within several hours. Uterine rupture is a rare complication reported mostly when misoprostol is used for medical termination of pregnancy between 13 and 26 weeks gestation, and may even occur in women who do not have a uterine scar.

Safety and efficacy of misoprostol in children below the age of 18 have not been established.

Reports of profound diarrhea such as voluminous, watery diarrhea resulting in severe dehydration have been documented. Such diarrhea has resulted in severe metabolic acidosis and can be life-threatening. Patients with inflammatory bowel disease may be at increased risk of developing diarrhea. Misoprostol can also exacerbate intestinal inflammation in these patients; careful monitoring is essential in this patient population.

Misoprostol is a potent uterine stimulant that induces abortion in early pregnancy, and labour in advanced pregnancy. Premature labor or birth defects can also result when misoprostol is administered to pregnant women. See Contraindications.

To date, there have been no studies evaluating the passage of misoprostol or its active metabolite, misoprostol acid, into breast milk. Because of the potential for severe, drug-induced diarrhea in the nursing infant, a decision should be made whether to discontinue nursing, or the drug, taking into account the importance of the drug to the mother.

Only 7% of the dose is systemically bioavailable as the acid following oral administration. Approximately 85% of the misoprostol acid is bound to serum albumin.

Misoprostol, an ester, undergoes rapid de-esterification to its pharmacologically active metabolite, misoprostol acid, in the stomach after oral administration. Absorption of misoprostol acid is rapid, with peak plasma concentrations occurring within 15 to 30 minutes and rapidly declining within 120 minutes. The plasma half-life of the acid is 13 to 40 minutes. Plasma steady state is achieved within 2 days. Misoprostol acid does not accumulate when misoprostol is taken chronically.

Inactive metabolites are secreted in the urine.

The pharmacokinetic profile of the various routes of administration is important when using misoprostol for obstetric/gynecologic applications. Sublingual administration has the shortest T_max (30 min) and is perhaps useful in situations where a fast onset of action is required such as postpartum hemorrhage or cervical priming. Vaginal misoprostol exhibits longer T_max (75 min), but high bioavailability and sustained serum levels (≥6 hours) making it useful for situations that require long duration of effect such as medical abortion.

Misoprostol acid is metabolized by the liver but it does not inhibit or induce the hepatic CYP450 system.