Misoprostol

INDICATIONS & USAGE Misoprostol is indicated for reducing the risk of NSAID (nonsteroidal anti-inflammatory drugs, including aspirin)–induced gastric ulcers in patients at high risk of complications from gastric ulcer, e.g., the elderly and patients with concomitant debilitating disease, as well as patients at high risk of developing gastric ulceration, such as patients with a history of ulcer. Misoprostol has not been shown to reduce the risk of duodenal ulcers in patients taking NSAIDs. Misoprostol should be taken for the duration of NSAID therapy. Misoprostol has been shown to reduce the risk of gastric ulcers in controlled studies of 3 months' duration. It had no effect, compared to placebo, on gastrointestinal pain or discomfort associated with NSAID use.

DOSAGE & ADMINISTRATION The recommended adult oral dose of misoprostol for reducing the risk of NSAID-induced gastric ulcers is 200 mcg four times daily with food. If this dose cannot be tolerated, a dose of 100 mcg can be used. (See Clinical Pharmacology: Clinical studies . ) Misoprostol should be taken for the duration of NSAID therapy as prescribed by the physician. Misoprostol should be taken with a meal, and the last dose of the day should be at bedtime. Renal impairment Adjustment of the dosing schedule in renally impaired patients is not routinely needed, but dosage can be reduced if the 200-mcg dose is not tolerated. (See Clinical Pharmacology . )

CONTRAINDICATIONS See boxed WARNINGS . Misoprostol should not be taken by pregnant women to reduce the risk of ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs). Misoprostol should not be taken by anyone with a history of allergy to prostaglandins.

WARNINGS See boxed WARNINGS . For hospital use only if misoprostol were to be used for cervical ripening, induction of labor, or for the treatment of serious post-partum hemorrhage, which are outside of the approved indication.

Drug interactions See Clinical Pharmacology . Misoprostol has not been shown to interfere with the beneficial effects of aspirin on signs and symptoms of rheumatoid arthritis. Misoprostol does not exert clinically significant effects on the absorption, blood levels, and antiplatelet effects of therapeutic doses of aspirin. Misoprostol has no clinically significant effect on the kinetics of diclofenac or ibuprofen. Prostaglandins such as misoprostol may augment the activity of oxytocic agents, especially when given less than 4 hours prior to initiating oxytocin treatment. Concomitant use is not recommended.

ADVERSE REACTIONS The following have been reported as adverse events in subjects receiving misoprostol: Gastrointestinal In subjects receiving misoprostol 400 or 800 mcg daily in clinical trials, the most frequent gastrointestinal adverse events were diarrhea and abdominal pain. The incidence of diarrhea at 800 mcg in controlled trials in patients on NSAIDs ranged from 14–40% and in all studies (over 5,000 patients) averaged 13%. Abdominal pain occurred in 13–20% of patients in NSAID trials and about 7% in all studies, but there was no consistent difference from placebo. Diarrhea was dose related and usually developed early in the course of therapy (after 13 days), usually was self-limiting (often resolving after 8 days), but sometimes required discontinuation of misoprostol (2% of the patients). Rare instances of profound diarrhea leading to severe dehydration have been reported. Patients with an underlying condition such as inflammatory bowel disease, or those in whom dehydration, were it to occur, would be dangerous, should be monitored carefully if misoprostol is prescribed. The incidence of diarrhea can be minimized by administering after meals and at bedtime, and by avoiding coadministration of misoprostol with magnesium-containing antacids. Gynecological Women who received misoprostol during clinical trials reported the following gynecological disorders: spotting (0.7%), cramps (0.6%), hypermenorrhea (0.5%), menstrual disorder (0.3%) and dysmenorrhea (0.1%). Postmenopausal vaginal bleeding may be related to misoprostol administration. If it occurs, diagnostic workup should be undertaken to rule out gynecological pathology. (See boxed WARNINGS . ) Elderly There were no significant differences in the safety profile of misoprostol in approximately 500 ulcer patients who were 65 years of age or older compared with younger patients. Additional adverse events which were reported are categorized as follows: Incidence greater than 1% In clinical trials, the following adverse reactions were reported by more than 1% of the subjects receiving misoprostol and may be causally related to the drug: nausea (3.2%), flatulence (2.9%), headache (2.4%), dyspepsia (2.0%), vomiting (1.3%), and constipation (1.1%). However, there were no significant differences between the incidences of these events for misoprostol and placebo. Causal relationship unknown The following adverse events were infrequently reported. Causal relationships between misoprostol and these events have not been established but cannot be excluded: Body as a whole: aches/pains, asthenia, fatigue, fever, chills, rigors, weight changes. Skin: rash, dermatitis, alopecia, pallor, breast pain. Special senses: abnormal taste, abnormal vision, conjunctivitis, deafness, tinnitus, earache. Respiratory: upper respiratory tract infection, bronchitis, bronchospasm, dyspnea, pneumonia, epistaxis. Cardiovascular: chest pain, edema, diaphoresis, hypotension, hypertension, arrhythmia, phlebitis, increased cardiac enzymes, syncope, myocardial infarction (some fatal), thromboembolic events (e.g., pulmonary embolism, arterial thrombosis, and CVA). Gastrointestinal: GI bleeding, GI inflammation/infection, rectal disorder, abnormal hepatobiliary function, gingivitis, reflux, dysphagia, amylase increase. Hypersensitivity: anaphylactic reaction Metabolic: glycosuria, gout, increased nitrogen, increased alkaline phosphatase. Genitourinary: polyuria, dysuria, hematuria, urinary tract infection. Nervous system/Psychiatric: anxiety, change in appetite, depression, drowsiness, dizziness, thirst, impotence, loss of libido, sweating increase, neuropathy, neurosis, confusion. Musculoskeletal: arthralgia, myalgia, muscle cramps, stiffness, back pain. Blood/Coagulation: anemia, abnormal differential, thrombocytopenia, purpura, ESR increased.

Pregnancy Teratogenic effects See boxed WARNINGS . Congenital anomalies sometimes associated with fetal death have been reported subsequent to the unsuccessful use of misoprostol as an abortifacient, but the drug's teratogenic mechanism has not been demonstrated. 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. Misoprostol is not fetotoxic or teratogenic in rats and rabbits at doses 625 and 63 times the human dose, respectively. Nonteratogenic effects See boxed WARNINGS . Misoprostol may endanger pregnancy (may cause abortion) and thereby cause harm to the fetus when administered to a pregnant woman. Misoprostol may produce uterine contractions, uterine bleeding, and expulsion of the products of conception. Abortions caused by misoprostol may be incomplete. If a woman is or becomes pregnant while taking this drug to reduce the risk of NSAID-induced ulcers, the drug should be discontinued and the patient apprised of the potential hazard to the fetus.