Misoprostol oral tablets contain 200 mcg of misoprostol, a synthetic prostaglandin E 1analog.

Misoprostol contains approximately equal amounts of the two diastereomers presented below with their enantiomers indicated by (±):

Misoprostol is a water-soluble, viscous liquid.

Inactive ingredients of tablets are hydrogenated castor oil, hypromellose, microcrystalline cellulose, and sodium starch glycolate.

Misoprostol, over the range of 50 mcg to 200 mcg, inhibits basal and nocturnal gastric acid secretion, and acid secretion in response to a variety of stimuli, including meals, histamine, pentagastrin, and coffee. Activity is apparent 30 minutes after oral administration and persists for at least 3 hours. In general, the effects of 50 mcg were modest and shorter lived, and only the 200-mcg dose had substantial effects on nocturnal secretion or on histamine and meal-stimulated secretion.

Misoprostol has been shown to produce uterine contractions that may endanger pregnancy. (See boxed WARNINGS.)

Misoprostol does not produce clinically significant effects on serum levels of prolactin, gonadotropins, thyroid-stimulating hormone, growth hormone, thyroxine, cortisol, gastrointestinal hormones (somatostatin, gastrin, vasoactive intestinal polypeptide, and motilin), creatinine, or uric acid. Gastric emptying, immunologic competence, platelet aggregation, pulmonary function, or the cardiovascular system are not modified by recommended doses of misoprostol.

In a series of small short-term (about 1 week) placebo-controlled studies in healthy human volunteers, doses of misoprostol were evaluated for their ability to reduce the risk of NSAID-induced mucosal injury. Studies of 200 mcg q.i.d. of misoprostol with tolmetin and naproxen, and of 100 mcg and 200 mcg q.i.d. with ibuprofen, all showed reduction of the rate of significant endoscopic injury from about 70–75% on placebo to 10–30% on misoprostol. Doses of 25 mcg to 200 mcg q.i.d. reduced aspirin-induced mucosal injury and bleeding.

Two 12-week, randomized, double-blind trials in osteoarthritic patients who had gastrointestinal symptoms but no ulcer on endoscopy while taking an NSAID compared the ability of 200 mcg of misoprostol, 100 mcg of misoprostol, and placebo to reduce the risk of gastric ulcer (GU) formation. Patients were approximately equally divided between ibuprofen, piroxicam, and naproxen, and continued this treatment throughout the 12 weeks. The 200-mcg dose caused a marked, statistically significant reduction in gastric ulcers in both studies. The lower dose was somewhat less effective, with a significant result in only one of the studies.

Reduction of Risk of Gastric Ulcers Induced by Ibuprofen, Piroxicam, or Naproxen

[No. of patients with ulcer(s) (%)]

* Statistically significantly different from placebo at the 5% level.

** Combined data from Study No. 1 and Study No. 2.

In these trials there were no significant differences between misoprostol and placebo in relief of day or night abdominal pain. No effect of misoprostol in reducing the risk of duodenal ulcers was demonstrated, but relatively few duodenal lesions were seen.

In another clinical trial, 239 patients receiving aspirin 650 mg to 1300 mg q.i.d. for rheumatoid arthritis who had endoscopic evidence of duodenal and/or gastric inflammation were randomized to misoprostol 200 mcg q.i.d. or placebo for 8 weeks while continuing to receive aspirin. The study evaluated the possible interference of misoprostol on the efficacy of aspirin in these patients with rheumatoid arthritis by analyzing joint tenderness, joint swelling, physician’s clinical assessment, patient’s assessment, change in ARA classification, change in handgrip strength, change in duration of morning stiffness, patient’s assessment of pain at rest, movement, interference with daily activity, and ESR. Misoprostol did not interfere with the efficacy of aspirin in these patients with rheumatoid arthritis.

Misoprostol tablets are 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.

See boxed WARNINGS.

Misoprostol Tablets 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.

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.

Caution should be employed when administering misoprostol to patients with pre-existing cardiovascular disease.

A reversible increase in the number of normal surface gastric epithelial cells occurred in the dog, rat, and mouse. No such increase has been observed in humans administered Misoprostol Tablets for up to 1 year.

An apparent response of the female mouse to Misoprostol Tablets in long-term studies at 100 to 1000 times the human dose was hyperostosis, mainly of the medulla of sternebrae. Hyperostosis did not occur in long-term studies in the dog and rat and has not been seen in humans treated with Misoprostol Tablets.

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 to 40% and in all studies (over 5,000 patients) averaged 13%. Abdominal pain occurred in 13 to 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.

The toxic dose of misoprostol in humans has not been determined. Cumulative total daily doses of 1600 mcg have been tolerated, with only symptoms of gastrointestinal discomfort being reported. In animals, the acute toxic effects are diarrhea, gastrointestinal lesions, focal cardiac necrosis, hepatic necrosis, renal tubular necrosis, testicular atrophy, respiratory difficulties, and depression of the central nervous system. Clinical signs that may indicate an overdose are sedation, tremor, convulsions, dyspnea, abdominal pain, diarrhea, fever, palpitations, hypotension, or bradycardia. Symptoms should be treated with supportive therapy.

It is not known if misoprostol acid is dialyzable. However, because misoprostol is metabolized like a fatty acid, it is unlikely that dialysis would be appropriate treatment for overdosage.

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.

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.)

Misoprostol Tablets, 200 mcg are white to off-white, round, flat, beveled edge tablet, debossed with “10" and “07" on either side of score line, on one side and plain on the other side and are supplied as:

NDC 50268-555-60 in bottle of 60 tablets

Pharmacist: Dispense in this child-resistant container with Patient Leaflet attached.

Store at or below 25°C (77°F), in a dry area.

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AvKARE

Pulaski, TN 38478

20769562 05/2024

Read this leaflet before taking misoprostol tablets and each time your prescription is renewed, because the leaflet may be changed.

Misoprostol tablets are being prescribed by your doctor to decrease the chance of getting stomach ulcers related to the arthritis/pain medication that you take.

Do not take misoprostol tablets to reduce the risk of NSAID- induced ulcers if you are pregnant. (See boxed WARNINGS.)

Misoprostol tablets can cause abortion (sometimes incomplete which could lead to dangerous bleeding and require hospitalization and surgery), premature birth, or birth defects. It is also important to avoid pregnancy while taking this medication and for at least one month or through one menstrual cycle after you stop taking it. Misoprostol tablets may cause the uterus to tear (uterine rupture) during pregnancy. The risk of uterine rupture increases as your pregnancy advances and if you have had surgery on the uterus, such as a Cesarean delivery. Rupture (tearing) of the uterus can result in severe bleeding, hysterectomy, and/or maternal or fetal death.

If you become pregnant during misoprostol therapy, stop taking misoprostol tablets and contact your physician immediately. Remember that even if you are on a means of birth control it is still possible to become pregnant. Should this occur, stop taking misoprostol tablets and contact your physician immediately.

Misoprostol tablets may cause diarrhea, abdominal cramping, and/or nausea in some people. In most cases these problems develop during the first few weeks of therapy and stop after about a week. You can minimize possible diarrhea by making sure you take misoprostol tablets with food.

Because these side effects are usually mild to moderate and usually go away in a matter of days, most patients can continue to take misoprostol tablets. If you have prolonged difficulty (more than 8 days), or if you have severe diarrhea, cramping and/or nausea, call your doctor.

Take misoprostol tablets only according to the directions given by your physician.

Do not give misoprostol tablets to anyone else. It has been prescribed for your specific condition, may not be the correct treatment for another person, and would be dangerous if the other person were pregnant.

This information sheet does not cover all possible side effects of misoprostol tablets. This patient information leaflet does not address the side effects of your arthritis/pain medication. See your doctor if you have questions.

Keep out of reach of children.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Manufactured for:

AvKARE

Pulaski, TN 38478

20769562 Rev. 05/2024