ATC Class:A02BB01

VA Class:GA309

AHFS Class:

• Prostaglandins 56:28.28

Generic Name(s):

• Misoprostol

Chemical Name:

• 11α,13 E )-(±)-11,16-Dihydroxy-16-methyl-9-oxo-prost-13-en-1-oic acid methyl ester

Molecular Formula:

• C₂₂H₃₈O₅

Misoprostol, a synthetic analog of prostaglandin E₁ (alprostadil),1,5,10,11,13,20,25,26,27,31,55,76,78,85,95 is a gastric antisecretory agent with protective effects on the gastroduodenal mucosa;1,2,3,13,15,16,25,26,27,31,35,37,47,57,60,72,76,77,78,79,80,84,85,86,87,88,89,91,94,95,127 the drug also increases the amplitude and frequency of uterine contractions and stimulates uterine bleeding and total or partial expulsion of uterine contents in pregnant women.1,3,23,55

Misoprostol is used for reducing the risk of nonsteroidal anti-inflammatory agent (NSAIA)-induced gastric ulcer in patients at high risk of developing complications from these ulcers and in patients at high risk of developing gastric ulceration.1 Misoprostol has been used for the short-term treatment of active duodenal ulcer† and for the short-term treatment of active, benign gastric ulcer†.2 Misoprostol also has been used as maintenance therapy following healing of gastric ulcer to reduce ulcer recurrence†.72

Misoprostol is used as an adjunct to mifepristone for the medical termination of intrauterine pregnancy (i.e., medical abortion).241 The drug has been used for induction of labor† and for treatment of serious postpartum hemorrhage† in the presence of uterine atony. 1,235,237,238

For information on the use of misoprostol in fixed combination with diclofenac, a NSAIA, see Diclofenac 28:08.04.92.

Prevention of NSAIA-induced Ulcers

Misoprostol is used for reducing the risk of NSAIA-induced gastric ulcers in patients at high risk of developing complications (e.g., bleeding, perforation, death) from these ulcers, such as patients with a concomitant debilitating disease and geriatric patients, and in patients at high risk of developing gastric ulceration, such as those with a history of upper GI ulcer.1,5,56,61,67,68,70,85,95,96,135,233 245 While the drug also has been used for the prevention of NSAIA-induced duodenal ulcers† in a limited number of patients,56,57,59,71 current evidence is insufficient to establish efficacy in these patients.1,95,144

Serious adverse GI effects (e.g., bleeding, ulceration, perforation) can occur at any time in patients receiving chronic NSAIA therapy, and such effects may not be preceded by warning signs or symptoms.66,67,68,95,98,99,103,104,108,110 Results of studies to date are inconclusive concerning the relative risk of various NSAIAs in causing serious GI effects.66,67,68,98,99 In patients receiving prototypical NSAIAs and observed in clinical studies of several months' to 2-years' duration, symptomatic upper GI ulcers, gross bleeding, or perforation appeared to occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of those treated for 1 year.66,98,99 These trends continue with long-term therapy and increase the likelihood of a serious GI event occurring at some time during the course of therapy.231 Studies have shown that patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs have a greater than tenfold higher risk for developing GI bleeding than patients without these risk factors.231 In addition, several comorbid conditions and concomitant therapies have been shown to increase the risk for GI bleeding, including concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAIA therapy, smoking, alcoholism, older age, and poor general health status.231,232 In addition, geriatric or debilitated patients appear to tolerate GI ulceration and bleeding less well than other individuals, and most spontaneous reports of fatal NSAIA-induced GI effects have been in such patients.56,66,95,96,98,99 Therefore, consideration can be given to concomitant preventive therapy with misoprostol in these and other patients deemed at high risk of developing complications resulting from NSAIA-induced gastric ulcer or at high risk of developing such ulcers.1,5,56,67,68,70,95

Clinical Experience

Efficacy of misoprostol for the prevention of NSAIA-induced gastric ulcer has been established principally in short-term studies (up to 3 months' duration).1,56,57,59,60,61,67,69,71,95 Therefore, although continuous misoprostol therapy for the duration of NSAIA use currently is recommended by the manufacturer,1 the long-term safety and efficacy and optimum duration of misoprostol therapy in patients receiving NSAIAs chronically remain to be established.56,73,95,127,135,144,150 In addition, although NSAIA-induced gastric injury is asymptomatic in most patients,67,68,71,95,103,127,135 most studies conducted to date have included only patients with symptomatic injury.1,56,61,95 It also should be recognized that while misoprostol is intended for use in the prevention of NSAIA-induced gastric injury in patients at high risk of complications from such injury,1,95 efficacy of the drug in most high-risk patient groups has not been specifically established.95 Despite the lack of such data, however, high-risk patients are thought to be most likely to benefit from prophylactic therapy with misoprostol.67,68,95,135,144

Misoprostol has reduced the rate of endoscopically documented NSAIA-induced gastroduodenal mucosal injury in healthy individuals.1,56,57,59,60,61,73,74,81,85,95 The drug also has reduced the rate of gastroduodenal ulcer formation in osteoarthritic patients with GI symptoms but no evidence of ulcer prior to initiation of misoprostol.1,61,67,95 Gastroduodenal mucosal injury also has been reduced and healing of gastroduodenal ulcer promoted in patients with rheumatoid arthritis who had GI symptoms and evidence of mucosal injury and/or ulcer when misoprostol was initiated.56,95 However, misoprostol does not appear to be effective in reducing associated GI symptoms (e.g., pain).1,61,70,95

In several short-term (about 1-week duration) studies in a limited number of healthy individuals receiving a NSAIA (e.g., aspirin,59 ibuprofen,1,61,71 naproxen,1,60 tolmetin),1,57,81 reported rates of endoscopically documented gastric1,57,59 or duodenal59 mucosal injury were 10-30% in those receiving oral misoprostol dosages of 100 or 200 mcg 4 times daily and 70-75% in those receiving placebo.1,57,59,60 In a limited number of healthy individuals, misoprostol also has been more effective than sucralfate in preventing aspirin-induced gastroduodenal mucosal injury59 and more effective than cimetidine in preventing tolmetin-induced gastric but not duodenal mucosal injury.81

In a multicenter controlled study in patients with osteoarthritis who were receiving chronic NSAIA therapy (e.g., 3 months or longer with ibuprofen, naproxen, or piroxicam) and had GI symptoms but no endoscopic evidence of gastric ulcer, 100 or 200 mcg of misoprostol 4 times daily reduced the rate of NSAIA-induced gastric ulcer formation; at 12 weeks, 21-30% of patients receiving placebo developed gastric ulcers while only 1.4-3 or 6-8% of patients receiving the 200- or 100-mcg regimen, respectively, developed such ulcers.1,61,67,95 However, the 100-mcg regimen was less effective than the 200-mcg regimen,1,61,95 producing a significant reduction in gastric ulcer formation compared with placebo in only one of the study groups.1,61,95 In addition, misoprostol was not effective in relieving associated GI symptoms (e.g., daytime or nocturnal abdominal pain, nausea, vomiting, anorexia) with either regimen.1,61,70,95

In a study in patients with rheumatoid arthritis who were receiving aspirin therapy for at least 4 weeks and had GI symptoms and endoscopically confirmed gastric and/or duodenal injury, 8 weeks of concomitant misoprostol (200 mcg 4 times daily) therapy promoted gastroduodenal healing, including healing of ulcers.56,95 Healing of gastric or duodenal mucosal injury occurred at 8 weeks in 70 or 86%, respectively, of patients receiving misoprostol compared with 25 or 53%, respectively, of those receiving placebo, and healing of gastroduodenal ulcers occurred in 67% of patients receiving the drug compared with 26% of those receiving placebo.56,95 There was similar evidence of misoprostol-induced healing at 4 weeks.56 Misoprostol also appeared to prevent formation of new ulcers56 and did not interfere with the efficacy of aspirin as determined by relief of pain and stiffness, reduction of swelling, improvement of mobility and grip strength, or erythrocyte sedimentation rate (ESR).1,56,95

Clinical Perspective

The American College of Gastroenterology (ACG) has published guidelines for the prevention of NSAIA-related ulcer complications.245 The guidelines state that misoprostol (administered in full doses of 800 mcg daily) is very effective in preventing ulcers and ulcer complications in patients taking NSAIDs; however, the drug's usefulness is limited by its adverse GI effects.245 There is evidence that lower doses (400-600 mcg daily) may also confer significant protection with a similar adverse effect profile to placebo.245

Gastric Ulcer

Acute Therapy

Misoprostol has been used in the short-term treatment of active, benign, gastric ulcer†.2,55,58,72,76,85,87 However, the drug does not appear to offer any superiority over H₂-receptor antagonists2,76,87,140 and is less effective than these agents in relieving ulcer pain.2,87 Because misoprostol is associated with severe adverse effects (e.g., fetal mortality, premature birth, birth defects),1 it is not considered a drug of choice for the treatment of peptic ulcer disease (e.g., gastric ulcer)140 and is not included in the current American College of Gastroenterology (ACG) guidelines for the treatment of this condition.217

Epidemiologic and clinical evidence supports a strong association between gastric infection with H. pylori and the pathogenesis of gastric ulcers.152,153,155,156,157,158,159,160,161,162,174,194,196,217,218,219,220 The ACG, National Institutes of Health (NIH), and most clinicians currently recommend that all patients with initial or recurrent gastric ulcer and documented H. pylori infection receive anti-infective therapy for treatment of the infection.203,217,218,219,220 The choice of a particular regimen should be based on the rapidly evolving data on optimal therapy, including consideration of the patient's prior exposure to anti-infective agents, the local prevalence of resistance, patient compliance, and costs of therapy.203,217,219,224,225 (See Duodenal Ulcer: Acute Therapy, in Uses.)

Maintenance Therapy

Misoprostol has been used in reduced dosage for up to 14 months in a limited number of patients as maintenance therapy following healing of active gastric ulcer to reduce ulcer recurrence†.72 However, additional studies are needed to evaluate the safety and efficacy of maintenance therapy with the drug.72,144

Duodenal Ulcer

Acute Therapy

Misoprostol has been used for the short-term treatment of endoscopically or radiographically confirmed active duodenal ulcer†.2,23,55,78,79,80,83,84,85,86,89,91,92,93,94 Limited data suggest that misoprostol also may be effective in some patients with duodenal ulcer refractory to H₂-antagonist therapy.85,92 However, misoprostol does not appear to be effective in reducing daytime and nocturnal pain or antacid consumption in patients with duodenal ulcers;23,80,89,91 aluminum-containing antacids have been used concomitantly with the drug as needed for relief of pain.23,79,89,93

Some clinicians state that misoprostol does not appear to offer any superiority over other existing antiulcer therapies for active duodenal ulcers in terms of healing efficacy, dosing schedule, or recurrence after treatment, but is less effective in relieving associated GI pain.23,127,144 Because misoprostol may represent a risk of uterine bleeding and/or abortion when inadvertently used by pregnant women, it is not considered a drug of choice for the treatment of peptic ulcer disease (e.g., duodenal ulcer)140 and is not included in the current ACG guidelines for the treatment of this condition.217

Current epidemiologic and clinical evidence supports a strong association between gastric infection with Helicobacter pylori and the pathogenesis of duodenal and gastric ulcers;152,153,155,156,157,158,159,160,161,162,174,193,194,196,216,218,219,220 long-term H. pylori infection also has been implicated as a risk factor for gastric cancer.155,160,193,194,207,208,209,210,211,212,213,214,215,217 The ACG, NIH, and most clinicians currently recommend that all patients with initial or recurrent duodenal or gastric ulcer and documented H. pylori infection receive anti-infective therapy for treatment of the infection.203,217,218,219,220 Anti- H. pylori regimens that combine one or more anti-infective agents (e.g., clarithromycin, amoxicillin) with a bismuth salt and/or an antisecretory agent (e.g., omeprazole, lansoprazole, H₂-receptor antagonist) have been used successfully for H. pylori eradication.155,156,161,162,163,164,165,166,167,168,169,174,175,176,177,178,179,190,193,194,195,196,197,198,202,204,205,216,217,218,219,220,221,222,223,224,226,227,228,229,230 The choice of a particular regimen should be based on the rapidly evolving data on optimal therapy, including consideration of the patient's prior exposure to anti-infective agents, the local prevalence of resistance, patient compliance, and costs of therapy.203,204,217,219,224,225

Termination of Pregnancy

Misoprostol is used in conjunction with mifepristone for medical termination of an intrauterine pregnancy.241 Although the manufacturer of misoprostol states that it has not conducted and does not intend to conduct research to support such usage,236 mifepristone is labeled by FDA for use with misoprostol for termination of pregnancy and the American College of Obstetricians and Gynecologists (ACOG) states that the medication abortion regimen supported by major medical organizations nationally and internationally includes mifepristone and misoprostol; if mifepristone is unavailable, then a misoprostol-only regimen is an acceptable alternative.244 For additional information on the use of misoprostol with mifepristone for this indication, see Mifepristone 76:00.

Other Obstetric Uses

ACOG states that misoprostol has been used effectively (e.g., 25 mcg every 3-6 hours intravaginally† using tablets formulated for oral administration) to improve cervical inducibility (cervical “ripening”) in pregnant women with a medical or obstetric need for labor induction†.235,237,238 Although the manufacturer of misoprostol states that it has not conducted and does not intend to conduct research to support use in pregnancy (e.g., labor induction),236 some experts state that vaginal administration of misoprostol appears to be safe and effective for induction of labor in appropriately selected women with unfavorable cervices.235,238 However, such use in women with prior uterine surgery or cesarean section should be avoided because of the risk of possible uterine rupture.

Misoprostol also has been used for prevention or treatment of serious postpartum hemorrhage† in the presence of uterine atony.1,237

Other Uses

Misoprostol has been used in a limited number of patients for the management of fat malabsorption† associated with cystic fibrosis,127,133,139 and for the management of hemorrhagic gastritis†,128 reflux esophagitis†,128 alcohol-induced gastritis†,34 and NSAIA-induced nephropathy†.127,141 The drug has been effective in some patients with these conditions,34,128,133,139,141 but further studies are needed.144

Administration

Misoprostol usually is administered orally.1,2,3,4,5

When used to reduce the risk of nonsteroidal anti-inflammatory agent (NSAIA)-induced gastric ulcers, the incidence of misoprostol-induced diarrhea may be minimized by administering the drug in divided doses after meals1,3 and at bedtime1 and by avoiding concomitant administration with a magnesium-containing or other laxative antacid.1

When used in conjunction with mifepristone for the medical termination of pregnancy, misoprostol is administered intrabuccally 24-48 hours following mifepristone administration; patients should be instructed to place 2 misoprostol tablets in each side of the mouth between the cheek and gums for 30 minutes, then swallow any remnants with water or another liquid.241 Misoprostol should be administered in an appropriate setting for the patient, taking into account that expulsion of uterine contents could begin within 2 hours of misoprostol administration.241

Misoprostol also has been administered intravaginally† using tablets formulated for oral administration.1,235,237,238

Dosage

Prevention of NSAIA-Induced Ulcers

For reducing the risk of NSAIA-induced gastric ulcer, the usual adult dosage of misoprostol is 200 mcg 4 times daily.1,56,57,59,76,81,95 Dosage can be reduced to 100 mcg 4 times daily in patients who do not tolerate the usual dosa 1,61,70 however, this reduced dosage may be somewhat less effective in preventing NSAIA-induced gastric ulcers.1,61,67,73,95 Misoprostol dosages of 200 mcg twice daily also have been used for reducing the risk of NSAIA-induced gastric ulcer.60 The optimum duration of misoprostol therapy has not been elucidated and safety and efficacy have been established in controlled studies only for periods up to 3 months' duration;95,144 however, the manufacturer currently recommends that the drug be continued for the duration of NSAIA therapy.1

Termination of Pregnancy

When misoprostol is used in conjunction with mifepristone for the medical termination of an intrauterine pregnancy, 800 mcg of misoprostol is administered intrabuccally (two 200-mcg tablets placed in each cheek pouch) 24-48 hours following mifepristone administration.241 Efficacy of the combined regimen may be reduced if misoprostol is administered less than 24 hours or more than 48 hours after mifepristone.241

If mifepristone is unavailable, ACOG states that misoprostol administration alone† may be an acceptable alternative.244 The recommended dose of misoprostol (when used alone) is 800 mcg administered vaginally, sublingually, or buccally.244 This dose may be repeated every 3 hours for up to 3 doses.244 Of note, although studies have typically used no more than 3 doses for the initial treatment regimen, the World Health Organization (WHO) does not specify a maximum number of misoprostol doses for this medication abortion regimen.244

Gastric Ulcer

For the short-term treatment of active, benign gastric ulcer†, a misoprostol dosage of 100 or 200 mcg 4 times daily for 8 weeks has been used in adults.2,55,58,72,76,87

Duodenal Ulcer

For the short-term treatment of active duodenal ulcer†, misoprostol dosages of 100 or 200 mcg 4 times daily or 400 mcg twice daily for 4-8 weeks have been used in adults.2,23,55,78,80,84,89,91,93

Induction of Labor

Although the optimal misoprostol dosage regimen for cervical ripening and induction of labor† remains to be determined, the American College of Obstetricians and Gynecologists (ACOG) states that misoprostol 25 mcg (¼ of a 100-mcg oral tablet) given intravaginally† can be considered for the initial dose.235,237,238 Subsequent 25-mcg doses have been administered every 3-6 hours.235,237,238

Dosage in Renal Impairment and in Geriatric Patients

Routine reduction of misoprostol dosage in patients with renal impairment or in geriatric patients does not appear to be necessary;1,5 however, if patients are unable to tolerate the usual adult dosage, dosage can be reduced.1,5

Misoprostol generally is well tolerated.2,55 The frequency of adverse effects does not appear to be affected by patient age in adults.1,5 The most frequent adverse effects associated with misoprostol therapy involve the GI tract (e.g., diarrhea, nausea, abdominal pain).2,5,23,55,56,121

GI Effects

Diarrhea is the most common adverse effect of misoprostol.1,3,5,15,22,23,55,56,57,58,59,61,64,76,78,79,80,81,84,85,86,89,91,92,93,121,151 In controlled clinical studies in patients receiving NSAIAs, the incidence of diarrhea associated with a misoprostol dosage of 800 mcg daily was 14-40%.1 In all studies (including those in which the drug was being studied for the treatment of acute duodenal or gastric ulcers), the incidence of diarrhea averaged 13% with dosages of 400-800 mcg daily.1,5,121,143 Diarrhea, which appears to be dose related,1,2,15,23,58,87,89,121 usually is apparent after about 2 weeks of misoprostol therapy,1 and generally is self-limiting,1,58,61,78,80,85,89 often resolving within about a week after onset.1,61 However, diarrhea has been severe enough to require discontinuance of misoprostol therapy in about 2% of patients receiving the drug for the prevention of NSAIA-induced ulcer.1,55,58,78,79 Profound diarrhea (e.g., voluminous, watery diarrhea) and resultant severe dehydration has been reported rarely in patients receiving misoprostol therapy;1,151 such diarrhea also has resulted in severe metabolic acidosis and can be life-threatening.151 Patients with inflammatory bowel disease may be at increased risk of developing such diarrhea during misoprostol therapy1,151 (e.g., secondary to an unmasking or exacerbation of a previously quiescent GI inflammatory condition).151 Misoprostol-induced diarrhea may be minimized by administering the drug in divided doses after meals1,3 and at bedtime1 and by avoiding concomitant administration with a magnesium-containing or other laxative antacid.1

Abdominal pain occurred in about 13-20% of patients receiving misoprostol concomitantly with NSAIAs and in about 7% overall in studies with the drug, but the incidence of this effect did not differ consistently from that reported with placebo.1,5,22,32,55,56,57,61,76,81,91,92,121 Nausea,1,5,15,32,56,57,58,60,61,79,81,91,92,121 flatulence,1,5,57,59,60,61,81,92 dyspepsia, 1,5,15,57,58,61,76,81,91 vomiting,1,15,79,87,92,121 and constipation1,5,59,76,79,121 occur in about 1-4% of patients receiving misoprostol,1 but the incidences of these effects were similar to those reported with placebo.1,5,61 Pancreatitis has been reported rarely in patients receiving the drug.87

GI bleeding, GI inflammation and/or infection, rectal disorder, gingivitis, dysgeusia, reflux, changes in appetite, and dysphagia also have been reported, but a causal relationship to misoprostol has not been established.1,56,91,92 The possibility that preexisting NSAIA-induced gastropathy can progress following initiation of misoprostol therapy should be considered.150

Nervous System Effects

Headache occurs in about 2% of patients receiving misoprostol.1,5,23,32,55,76,78,79,80,87,91,92,121 Asthenia,1 fatigue,1,57,76,91,121 anxiety,1 depression,1 drowsiness,1 dizziness,1,32,78,92 peripheral neuropathy,1 confusion,1 and neurosis also have been reported, but a causal relationship to misoprostol has not been established.1 Vertigo and lethargy have been reported rarely in patients receiving the drug.87

Genitourinary and Renal Effects

Menstrual irregularities (e.g., cramps, dysmenorrhea, hypermenorrhea, spotting) have occurred in 0.1-0.7% of women receiving misoprostol in clinical studies.1,5 Postmenopausal vaginal bleeding may also occur in some women receiving the drug;1,5 if such bleeding occurs, the possibility of an underlying gynecologic abnormality should be ruled out.1 Spontaneous abortions have occurred in pregnant women receiving the drug.1,5 Uterine rupture has been reported in pregnant women following administration of misoprostol to induce labor or to induce abortion beyond the eighth week of pregnancy; death of the fetus has occurred in some cases.1,236

Polyuria, dysuria, hematuria, and urinary tract infection have been reported in patients receiving misoprostol, but a causal relationship to the drug has not been established.1,92

Hematologic Effects

Anemia, abnormal differential blood cell count, thrombocytopenia, and increased erythrocyte sedimentation rate (ESR) have been reported in patients receiving misoprostol, although these effects have not been directly attributed to the drug.1

Ocular and Otic Effects

Visual abnormalities,1,92 conjunctivitis,1 deafness,1 tinnitus,1,15 and earache1 have been reported in patients receiving misoprostol, but a causal relationship to the drug has not been established.1

Dermatologic and Sensitivity Reactions

Rash,1,92,121 dermatitis,1 alopecia,1 pallor,1 purpura,1 and diaphoresis1 have been reported in patients receiving misoprostol, although these effects have not been directly attributed to the drug.1 Anaphylaxis has been reported in patients receiving misoprostol.1

Cardiovascular Effects

Chest pain,1,92 edema,1,57,81 diaphoresis,1 hypotension,1 hypertension,1 arrhythmia,1 phlebitis,1 increased serum concentrations of cardiac enzymes,1 syncope,1,56 myocardial infarction (some fatal), and thromboembolic events (e.g., pulmonary embolism, arterial thrombosis, cerebrovascular accident) have been reported in patients receiving misoprostol, but a causal relationship to the drug has not been established.1

Hepatic Effects

Abnormal hepatobiliary function1 and increased serum alkaline phosphatase1,79,91,121 or aminotransferase14,15,22,32,79,91 concentrations1,14,15,22,32,56,79,91,121 have been reported in patients receiving misoprostol, but these effects have not been directly attributed to the drug.1,121

Respiratory Effects

Upper respiratory tract infection,1 bronchitis,1 bronchospasm,1 dyspnea,1 pneumonia,1 and epistaxis1 have been reported in patients receiving misoprostol, but a causal relationship to the drug has not been established.1

Other Adverse Effects

Fever,1 rigors,1 weight change,1 thirst,1 breast pain,1 impotence,1 loss of libido,1 arthralgia,1 myalgia,1 muscle cramps,1 stiffness,1 and back pain1,79 have been reported in patients receiving misoprostol, but these effects have not been directly attributed to the drug.1

Precautions and Contraindications

Patients receiving misoprostol for reducing the risk of NSAIA-induced gastric ulcer should be advised about such use and that the drug should be used only as directed.1 A copy of the patient information provided by the manufacturer should be given to each patient receiving the drug, and the latest version should be issued with each prescription refill.1 Patients should be instructed to read the patient information before initiation of misoprostol therapy and every time the prescription is refilled, since the information may have been revised.1 It is particularly important that all patients understand misoprostol's abortifacient properties and attendant risks (See Cautions: Pregnancy, Fertility, and Lactation),1,5,23,95 and that the drug is intended only for their use for the specific condition for which it was prescribed.1,5,70 Sharing the drug with another individual, particularly a woman of childbearing potential, could be hazardous.1 Patients should be advised to contact their clinician promptly if they have problems with or questions about misoprostol.1

Because severe adverse cardiovascular effects have been reported with misoprostol, the manufacturer states that the drug should be used with caution in patients with preexisting cardiovascular disease.1

Because misoprostol may exacerbate intestinal inflammation and produce severe diarrhea in patients with inflammatory bowel disease, the drug should be used with extreme caution in these patients and their condition monitored carefully.1,151 Because dehydration rarely may occur secondary to misoprostol-induced diarrhea,1,151 the drug also should be used with careful monitoring in patients prone to dehydration or in whom its consequences would be dangerous.1

Misoprostol should not be used in pregnant women for reducing the risk of NSAIA-induced gastric ulcers.1 Misoprostol also should not be used for reducing the risk of NSAIA-induced gastric ulcers in women of childbearing potential unless the woman is at high risk of developing gastric ulcers or of complications resulting from NSAIA-induced gastric ulcers.1 Misoprostol therapy should not be initiated in such women until the possibility of pregnancy has been excluded and an effective method of contraception has been started.1,5,13,64,70,85

Misoprostol is contraindicated in patients with known hypersensitivity to prostaglandins.1,5

Pediatric Precautions

Safety and efficacy of misoprostol in children <18 years of age have not been established.1

Pregnancy, Fertility, and Lactation

Pregnancy

Misoprostol exhibits abortifacient activity and therefore can cause serious fetal harm when administered to pregnant women.1,5,70 A boxed warning about this risk is included in the prescribing information for the drug.1 Misoprostol should not be used in pregnant women for reducing the risk of NSAIA-induced gastric ulcers.1 The drug also should not be used for reducing the risk of NSAIA-induced gastric ulcers in women of childbearing potential unless the woman is at high risk of developing gastric ulcers or of complications resulting from NSAIA-induced gastric ulcers; such women should not receive misoprostol until pregnancy is excluded and other necessary precautions are ensured.1

Misoprostol has been reported to produce uterine contractions and to stimulate uterine bleeding and total or partial expulsion of the products of conception in pregnant women.1,3,23,55 Spontaneous abortions induced by the drug may be incomplete, may require hospitalization and/or surgery, and can result in dangerous uterine bleeding, premature birth, or birth defects.1,5

Intravaginal use of misoprostol may result in hyperstimulation of the uterus, which may progress to uterine tetany with marked impairment of uteroplacental blood flow, uterine rupture (requiring surgical repair, hysterectomy, and/or salpingo-oophorectomy), or amniotic fluid embolism.1 Pelvic pain, retained placenta, severe genital bleeding, shock, fetal bradycardia, and fetal and maternal death have been reported.1 Use of intravaginal misoprostol dosages exceeding 25 mcg may be associated with an increased risk of uterine tachysystole, uterine rupture, meconium passage, meconium staining of amniotic fluid, and cesarean delivery resulting from uterine hyperstimulation.1,237 The risk of uterine rupture increases with advancing gestational age, prior uterine surgery (including cesarean delivery), and grand multiparity;1,237 the American College of Obstetricians and Gynecologists (ACOG) states that intravaginal use of misoprostol for cervical ripening or labor induction is not recommended in patients with a previous cesarean delivery or prior major uterine surgery. 237

Serious, sometimes fatal, bacterial (e.g., Clostridium sordellii ) infection and sepsis or prolonged heavy vaginal bleeding have been reported following spontaneous, surgical, and medical abortions, including in patients receiving mifepristone and misoprostol for termination of pregnancy; a causal relationship to the regimen has not been established.241,242

Congenital abnormalities, sometimes associated with fetal death, have been reported subsequent to the unsuccessful use of misoprostol as an abortifacient.1 Some data indicate that use of misoprostol during the first trimester of pregnancy has been associated with skull defects, cranial nerve palsies, facial malformations, and limb defects; however, the precise mechanism(s) for these teratogenic effects has not been fully elucidated.1 Effects of misoprostol on later growth, development, and functional maturation of the child whose mother received the drug for cervical ripening or labor induction have not been established.1 The effects of misoprostol on the need for forceps delivery or other intervention are not known.1

Currently, it is recommended that misoprostol be used for reducing the risk of NSAIA-induced gastric ulcers in women of childbearing potential only if they are at high risk of complications resulting from NSAIA-induced gastric ulceration or are at high risk of developing gastric ulceration.1,70 Such therapy should be initiated in such women only after determining that they are reliable and able to comply with effective contraceptive measures and ensuring that they have received both oral and written warnings concerning the hazards associated with misoprostol therapy, the risk of possible contraceptive failure, and the danger to other women of childbearing potential should the drug be taken by them.1 In addition, a reliable, blood pregnancy test must be performed within 2 weeks prior to beginning misoprostol therapy and the drug should not be provided to the patient until the pregnancy test is reported as negative, initiating therapy on the second or third day of the next normal menstrual cycle.1

If misoprostol is inadvertently administered during pregnancy or if the patient becomes pregnant while receiving the drug for reducing the risk of NSAIA-induced gastric ulcer, misoprostol should be discontinued and the patient informed of the potential hazard to the fetus.1

Reproduction studies in rats and rabbits using oral misoprostol dosages up to 10 and 1 mg/kg (625 and 63 times the usual human dosage), respectively, have not revealed evidence of fetotoxicity or teratogenicity.1,5,124 However, increased fetal resorption occurred in rabbits, suggesting possible embryotoxicity.124

Fertility

Reproduction studies in male and female rats using oral misoprostol dosages of 0.1-10 mg/kg daily (6.25-625 times the usual human dosage) have revealed dose-related pre- and post-implantation losses and a decrease in the number of live offspring at the highest dosage administered.1,124 These effects suggest that the drug may impair fertility in both males and females.1

Lactation

It is not known whether misoprostol and/or misoprostol acid cross the placenta.5 The drug is metabolized rapidly to the free acid following oral administration, which is biologically active and distributed into breast milk.1 There are no published reports of adverse effects associated with misoprostol in breast-fed infants.1 Caution is advised if the drug is used during breast-feeding. 1

Food and Antacids

Food and antacids decrease the rate of absorption of misoprostol, resulting in delayed and decreased peak plasma concentrations of misoprostol acid, the active metabolite of the drug.1,3,5,95 Antacids and possibly food also appear to decrease the oral bioavailability of misoprostol;1,5 however, it has been suggested that such decreases may not be clinically important1,5 since misoprostol's activity in protecting the GI mucosa appears to be local rather than systemic.95 Magnesium-containing antacids also may increase the incidence of misoprostol-induced diarrhea.1 Therefore, if concomitant administration of an antacid is necessary, a magnesium-containing or other laxative antacid should be avoided1 and a constipating (e.g., aluminum-containing) antacid used instead.79,89,93

Drugs Metabolized by Hepatic Microsomal Enzymes

Misoprostol does not appear to interfere with the metabolism of drugs, including diazepam1,3,127 or propranolol,1,3,5 by the hepatic cytochrome P-450 (CYP) enzyme system.1,3,5,41,126

Nonsteroidal Anti-inflammatory Agents

No substantial pharmacokinetic interactions between misoprostol and ibuprofen, piroxicam, or diclofenac have been observed to date.1,5,127,129

Absorption or peak plasma concentrations of misoprostol or aspirin do not appear to be affected substantially by concomitant administration,5,44 although AUC of aspirin may be decreased by about 20% when the drugs are administered concomitantly.1,127 This interaction does not appear to be clinically important since misoprostol did not interfere with the efficacy of aspirin as determined by relief of pain and stiffness, reduction of swelling, improvement of mobility and grip strength, or erythrocyte sedimentation rate (ESR) in patients with rheumatoid arthritis who received usual dosages of the drugs concomitantly.1,5,56,127,129

In a study in a limited number of healthy individuals receiving oral indomethacin 75 mg twice daily concomitantly with oral misoprostol 400 mcg twice daily, steady-state plasma indomethacin concentrations reportedly were decreased by 20-60%.63,130 However, reanalysis of data from this study using different statistical methods suggested that oral bioavailability of indomethacin was not affected substantially by concomitant misoprostol.129,130 Further studies are needed to determine whether a potential pharmacokinetic interaction exists between the drugs.63,127,129,130

Pharmacology

GI Effects

Misoprostol, a synthetic prostaglandin E₁ analog, is a gastric antisecretory agent with protective effects on the gastroduodenal mucosa.1,2,3,13,15,16,25,26,27,31,35,37,47,57,60,72,76,77,78,79,80,84,85,86,87,88,89,91,94,95,127 The drug inhibits gastric acid secretion and protects the mucosa from the irritant and/or other (e.g., pharmacologic) effects of certain drugs (e.g., nonsteroidal anti-inflammatory agents [NSAIAs])1,2,3,15,16,25,26,27,31,35,37,47,57,60,77,85 and may have similar antisecretory and mucosal effects in patients with gastric or duodenal ulcer.13,19,72,76,78,79,80,84,85,86,87,88,89,91,92,93,94

The role of endogenous prostaglandins in the GI tract is complex.3,10,12,13,19,26,35,39,106,111,114 Endogenous prostaglandins decrease acid secretion from parietal cells and may have a cytoprotective effect on the gastric mucosa by increasing mucus and bicarbonate secretion, preventing disruption of the gastric mucosal barrier, inhibiting or reducing back diffusion of hydrogen ions, regulating mucosal blood flow, preventing microvascular stasis, and preserving mucosal capacity to regenerate cells.3,7,8,10,12,13,26,35,39,111,114 Enhancement of transmucosal diffusion potential and cellular bicarbonate and chloride exchange, stabilization of lysosomal membranes with a resultant reduction in enzyme release, and modulation of endogenous sulfhydryl concentrations also may contribute to the GI cytoprotective effect of endogenous prostaglandins.3,10,13,26,35,39,114

Inhibition of the synthesis of prostaglandins (e.g., prostaglandins of the E series, prostacyclin) that are believed to exhibit cytoprotective effects on the gastric mucosa has been suggested as a possible mechanism for gastric mucosal damage induced by NSAIAs.1,2,3,5,13,19,26,35,62,88,106 However, the exact relationship between NSAIA-induced GI mucosal damage and prostaglandins has not been fully elucidated.2,13,26,35,39,62,106 NSAIAs may decrease bicarbonate1,2,3,5,31,90,106 and mucus secretion1,2,3,5,52,106 by inhibiting prostaglandin synthesis and decreasing mucosal prostaglandin concentrations.1,3,5,26 NSAIAs also may reduce gastric transmucosal potential difference, decrease gastric blood flow, cause capillary stasis, and selectively increase permeability of the gastric mucosa to cations and thus enhance back diffusion of hydrogen ions into the mucosa.2,3,35,39,62,106 Increased entry of acid into the gastric mucosa causes cellular damage, which leads to additional alterations in mucosal permeability.33,35,106 Gastric mucosal damage induced by NSAIAs can result in ulceration and/or bleeding.3,25,35,39,52,68,103,104,107,108,110 Mucosal prostaglandin synthesis also appears to be reduced in some patients with gastric or duodenal ulceration compared with that in healthy individuals.13,26,88,112,114

The exact mechanisms of the protective effect of misoprostol on the gastroduodenal mucosa have not been fully elucidated, but it appears that several actions may contribute to the drug's activity in the prevention and/or healing of gastroduodenal ulcers.1,2,3,5,9,10,13,19,24,25,26,33,35,47,77,85,90,111 In addition, it appears that the drug's protective effect on the gastroduodenal mucosa is local rather than systemic.1,33,95 However, because the therapeutic GI effects of the drug have been observed principally at antisecretory dosages,1,2,5,23,69,71,79,95,114,127 which are higher than cytoprotective dosages in animals,1,5,23,127 the extent to which the antisecretory and mucosal protective activities contribute to misoprostol's effect in preventing and/or healing gastroduodenal ulcers in humans currently is not known.1,2,5,23,69,71,95,114,127

Inhibition of Gastric Acid Secretion

Misoprostol reduces gastric acid secretion1,2,3,12,14,23,24,27,32,33,47,51,95,109,114 via a direct action at the parietal cells.1,2,3,4,5,9,14,20,24,33,64 Secretion is inhibited under basal conditions1,3,6,12,13,95,114 and also when stimulated by food,1,2,3,9,12,13,14,24,33,36,55,95,114 histamine,1,2,4,12,13,24,33,95,114 pentagastrin,1,2,24,33,48,51,114 betazole,2,24 tetragastrin,2,24 NSAIAs,2,3,27 alcohol,33,47 or caffeine.1,2,12,24,40 Misoprostol also inhibits nocturnal gastric acid secretion1,12,13,24,32 but does not appear to reduce the volume of such secretion.32

In vitro receptor-binding studies have shown that animal parietal cells contain prostaglandin receptors in proximity to histamine H₂ receptors.1,2,23,33,54 It has been postulated that stimulation of prostaglandin receptors may inhibit the activation of the histamine-sensitive enzyme adenylate cyclase,2,10,23,33 and that such inhibition may depend on guanosine-5'-triphosphate (GTP), a regulator in several adenylate cyclase receptor systems.54 Binding to prostaglandin receptors appears to be a saturable, reversible, and stereospecific process.1,20,54 These receptors have high affinity for prostaglandins of the E series, including misoprostol and misoprostol acid (an active metabolite of the drug), but not for prostaglandins of the F or I series or for compounds such as histamine or histamine H₂-receptor antagonists (e.g., cimetidine).1,20 Limited data have shown that the antisecretory activity of misoprostol may be positively correlated with its receptor-site affinity.1,20,54 High affinity for these receptors may allow misoprostol to be effective locally when taken with food despite the lower serum concentrations of the drug that may be attained compared with those attained in the fasted state.1

The degree of inhibition of gastric acid secretion by misoprostol is directly related to dose.1,2,12,24,33,46,55,109 The inhibitory effect of a 50-mcg oral dose of misoprostol generally is considered modest and is relatively short in duration,1,3,13,23,32,55 whereas oral 200-mcg doses are required for substantial inhibitory effects on basal, nocturnal, and food- or histamine-stimulated gastric acid secretion1,2,6,12,14,24,32,36,95 and reportedly are similar in degree although not in duration to those produced by 300-mg oral doses of cimetidine.12,24,144,146 However, other evidence suggests that misoprostol may not be as effective as histamine H₂-antagonists in decreasing gastric acid secretion, particularly nocturnal secretion.144,146 Following oral administration of 100- or 200-mcg of misoprostol in healthy individuals, gastric acid secretion is decreased by 83 or 85-98%, respectively.24 Following oral administration of 200 mcg of the drug, 85 or 75% of meal-stimulated gastric acid secretion is inhibited within 60 or 90 minutes, respectively;13 inhibition persists for at least 3 hours.1,5,12,24,36,95 Following oral administration of a single 200-, 400-, or 800-mcg dose of misoprostol, pentagastrin-stimulated gastric acid secretion is inhibited by 45, 60, or 65%, respectively, for at least 1-2 hours.51 Following oral administration of a single 100- or 200-mcg dose of misoprostol, histamine-stimulated gastric acid secretion is inhibited by 98 or 100%, respectively, for at least 2 hours.12

Mucosal Protective Effects

The mucosal protective effects of misoprostol may contribute to the drug's effect in preventing and/or healing gastroduodenal ulceration and bleeding.1,2,5,10,19,25,26,27,33,35,47,77,109 The exact mechanisms have not been established, but it appears that several actions may contribute to the protective effects of misoprostol on the gastric mucosa.2,5,9,25,26,27,33,35,77 Misoprostol may increase mucus secretion,1,2,3,5,10,23,25,26,27,33,35,51,95 increase bicarbonate secretion from nonparietal cells,1,2,3,5,10,23,25,26,31,33,35,53,95 enhance or maintain blood flow of the mucosa (possibly via direct vasodilation),2,9,10,17,25,26,33,35,95 protect submucosal cell proliferation,23,26 stabilize mucosal membrane systems,23,25,35 prevent mucosal barrier disruption,2,10,33,35 enhance transmucosal diffusion potential,2,117 and inhibit or reduce back diffusion of hydrogen ions into the mucosa.2,3,33 However, the exact relationship between these effects and the mucosal protective activity of misoprostol has not been clearly established.2,33,35,114 Limited data indicate that inhibition of adenyl cyclase does not contribute to the drug's mucosal protective effects.113

In animals, doses smaller than those necessary for inhibition of gastric acid secretion have provided protection of the gastric mucosa.23,77,127 However, a mucosal protective dose has not been established in humans.1,5,23,95,127 In addition, because antisecretory dosages generally appear to be necessary for optimal therapeutic GI effects in humans, it is difficult to determine whether prevention of mucosal injury results from misoprostol-induced gastric acid inhibition, mucosal protection, or both.1,2,5,23,69,71,95,114,127 While it has been suggested that the protective effects of misoprostol on the gastroduodenal mucosa may not depend on inhibition of gastric acid secretion,2,10,25,33,34,47,77,101,106,109,111 current evidence is insufficient to substantiate this suggestion,1,2,5,23,69,71,95,114,127 and further studies are needed to determine the mechanisms and possible therapeutic contribution of the drug's mucosal protective activity.35,48,144

It appears that the extent of increased mucus and bicarbonate secretion induced by misoprostol is directly related to dose.25,51 Following oral administration of single 200-, 400-, or 800-mcg doses in healthy individuals, basal gastric mucus secretion increased by 37, 82, or 95%, respectively.25,51 In one study, following oral administration of 50 mcg of misoprostol 4 times daily for 2 days in healthy individuals who also were receiving aspirin dosages of 975 mg 4 times daily, no appreciable changes in mucus secretion were observed.27

Following oral administration of 100-400 mcg of misoprostol in healthy individuals, dose-related stimulation of basal bicarbonate secretion has been reported;31 lower doses do not appear to produce appreciable effects on bicarbonate secretion.27 Results from studies on the effects of misoprostol on blood flow in the gastric mucosa have been conflicting and species dependent.2,9,33,35,48,118 In a study in dogs, IV misoprostol produced vasodilation and increased the ratio of gastric mucosal blood flow to the rate of acid secretion;9 however, in other animals, the drug had no effect on basal or stimulated mucosal blood flow following intragastric48 or IV116 administration. Further studies are needed to evaluate the relationship, if any, between gastric mucosal blood flow and mucus secretion and the mucosal protective effect of misoprostol.2,33,35

Misoprostol has protected the gastroduodenal mucosa from the irritant and/or other (e.g., pharmacologic) effects of various NSAIAs,1,2,3,25,33,47,57,60,61,81,120 including aspirin,1,2,15,16,22,25,27,37,47,56,59,73,74,77 and those of alcohol,2,25,33,34,47,50,101,111 and from stress-induced effects,2,33,47 as determined by reduction22,25,37 or prevention16 of fecal blood loss16,22,25,37,77 or by endoscopy.15,25,56,57,59,60,61,73 Misoprostol's activity against the irritant effects of taurocholate has been equivocal,33,47,115 and limited evidence suggests that the drug may not protect the gastric mucosa from the effects of systemically administered cytotoxic agents.75

Other GI Effects

Equivocal effects on pepsin secretion have been observed in animals and humans receiving misoprostol.1,4,6,12,24 The drug has produced a moderate reduction in pepsin concentration in gastric juice under basal conditions1,6,24 but not when stimulated by histamine.1,12 In healthy individuals, misoprostol also has inhibited tetragastrin-stimulated and nocturnal pepsin secretion.2 However, in at least one study in animals, misoprostol increased pepsin volume and secretion.132 Misoprostol does not appear to have a substantial effect on intrinsic factor secretion or serum concentrations of polypeptide hormones, including gastrin (basal or meal-stimulated),1,9,28,33,114 somatostatin,1 vasoactive intestinal peptide,1 or motilin.1

At usual dosages, misoprostol can produce diarrhea,1,3,5,15,22,23,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,61,64,76,78,79,80,81,84,85,86,89,91,92,93,121 probably via stimulation of intestinal fluid secretion and effects on motility.137 Following IV administration of the drug in animals, initial (for 1-2 hours after dosing) inhibition of intestinal motility was observed together with stimulation of intestinal fluid secretion, which was followed by the development of organized propulsive spike-burst patterns of motility similar to those associated with other forms of diarrhea.137 Limited evidence suggests that the drug does not affect gastric emptying1,38 or lower esophageal sphincter tone,148 but additional study is necessary.2

Genitourinary and Renal Effects

Misoprostol has been reported to increase the amplitude and frequency of uterine contractions and to stimulate uterine bleeding and total or partial expulsion of uterine contents in pregnant women.1,3,23,55 Other prostaglandins of the E series (e.g., prostaglandin E₂) are known abortifacients.2,23,55 In addition, menstrual irregularities have been reported occasionally in nonpregnant women receiving the drug.1,5,23 Because of the potential abortifacient effect of misoprostol, the drug should not be used in pregnant women for reducing the risk of NSAIA-induced gastric ulcers.1,3,5,13,23,64,70,85

Misoprostol does not appear to have clinically important effects on serum creatinine or uric acid concentrations.1,33,69

Endocrine and Gonadal Effects

Misoprostol does not appear to have clinically important effects on serum concentrations of prolactin (although reductions have been reported in men), thyrotropin (TSH), somatotropin (growth hormone), thyroxine (T₄), follicle-stimulating hormone (FSH, follitropin), luteinizing hormone (lutropin), sex-hormone binding globulin, progesterone (in women, although reductions have been reported), testosterone (in men), estradiol (in women), or gonadotropin.1,12 Although serum cortisol concentrations have been reported to increase in some women receiving misoprostol,12 they remained within the normal range.1,12

Other Effects

In healthy individuals, misoprostol did not inhibit cellular or humoral immune responses.1,18,41,55 The drug also does not appear to affect platelet aggregation1 or to produce clinically important cardiovascular or respiratory effects.1,10,12,30,33,55,80

Pharmacokinetics

Absorption

Misoprostol is rapidly and almost completely absorbed from the GI tract;1,2,5,41,42,45,95 however, the drug undergoes extensive and rapid first-pass metabolism (de-esterification) to form misoprostol acid (the free acid), the principal and active metabolite of the drug.1,2,5,41,42,43,45,95 There is evidence from animal studies that such metabolism may occur at least in part in the GI tract (e.g., in parietal cells).46,143 An average of 88% of a dose of misoprostol reportedly is absorbed following oral administration in healthy individuals,45 but only negligible amounts of unchanged drug are attained in plasma.1,41,45,95

Food and antacids decrease the rate of absorption of misoprostol, resulting in delayed and decreased peak plasma concentrations of misoprostol acid.1,3,95,131 Following oral administration of single 400-mcg doses of misoprostol, average peak plasma misoprostol acid concentrations occur within about 14 minutes in the fasted state compared with about 20 minutes when administered with antacids and about 1 hour when taken with food.1,131 The extent of absorption also appears to be decreased by antacids and possibly by food, but it has been suggested that such decreases may not be clinically important since the GI effects of misoprostol appear to be local rather than systemic.1,33,95

There is considerable interindividual variation in plasma concentrations attained with a given dose of misoprostol;1,5,42 however, it appears that plasma concentrations of the free acid increase linearly with single misoprostol doses of 200-400 mcg.1,5,45 Following oral administration of a single 200- or 400-mcg dose of misoprostol in fasting, healthy individuals, average peak plasma misoprostol acid concentrations occur within 14-20 minutes.2,42,43,44,45,131

Steady-state plasma concentrations of misoprostol acid generally are reached within 48 hours following continuous dosing.1,45 Accumulation of misoprostol acid does not appear to occur during chronic administration of misoprostol.1,5,45

Peak plasma misoprostol acid concentrations and AUC in patients with renal impairment (creatinine clearance of 0.5-37 mL/minute) were about twofold those observed in patients with normal renal function;1,3 however, no clear correlation was established between AUCs achieved and degree of renal impairment.1,5 AUC of misoprostol acid also may be increased in geriatric patients (older than 64 years of age) compared with those in younger adults,1,3,5,43,131 probably secondary to decreased volume of distribution (V_d) in geriatric patients;43,131 however, peak plasma concentrations do not appear to be affected.3,43,131

Following single 50- to 200-mcg oral doses of misoprostol, inhibition of gastric acid secretion under basal and nocturnal conditions and also when stimulated by food, histamine, pentagastrin, or caffeine is apparent within 30 minutes, reaches a maximum within 60-90 minutes, and persists for at least 3 hours.1,5,12,24,36,95 The degree and duration of inhibition of gastric acid secretion produced by misoprostol are directly related to the dose1,2,12,24,33,46,55,109 with single misoprostol doses of 200-400 mcg.12 It appears that misoprostol doses exceeding 400 mcg do not produce further increases in inhibition of gastric acid secretion.12 In animals, doses lower than those necessary for inhibition of gastric acid secretion have provided protection of the gastric mucosa.2,23,77,127 In humans, however, a relationship between dose and mucosal protective activity has not been established since therapeutic effects (e.g., prevention of injury) on the gastroduodenal mucosa have been observed principally with antisecretory doses.1,2,5,23,69,71,79,95,114,127

Distribution

Distribution of misoprostol into human body tissues and fluids has not been fully characterized.2,5,41 Following oral administration of misoprostol in rats, the drug is widely distributed, achieving concentrations in stomach, intestines, liver, blood, and kidneys that are 6-73 times that in plasma.2,5,41

Misoprostol acid is approximately 80-90% bound to serum proteins.1,2,41 Protein binding of the drug does not appear to be affected by plasma concentrations of misoprostol acid or misoprostol in the therapeutic range, age of the patient, or concomitant administration of other highly protein-bound drugs.1,2,41

It is not known whether misoprostol and/or the free acid cross the placenta.5 Misoprostol is metabolized rapidly to the free acid following oral administration, which is distributed into breast milk.1

Elimination

Misoprostol is rapidly metabolized to misoprostol acid (the free acid) following oral administration.1,2,5,41,42,43,45,95 The parent drug reportedly has a half-life of 6 minutes in vitro.41 Plasma concentrations of the free acid and other metabolites of the drug appear to decline in a biphasic manner.2,41,42,45,97 Following oral administration of misoprostol in healthy adults, the elimination half-life of the free acid is about 20-40 minutes.1,5,41,131 Following oral administration of radiolabeled drug in healthy adults, the half-life of misoprostol metabolites averages about 1.5 hours in the initial distribution phase,2,41,42,45 corresponding principally to organic metabolites of the drug, and about 144-177 hours in the terminal elimination phase, corresponding principally to radiolabeled water.2,41,42,45,143

In patients with renal impairment (creatinine clearance of 0.5-37 mL/minute), half-life may be increased twofold compared with that in patients with normal renal function.1,3 It appears that half-life of misoprostol is not increased in geriatric patients.3,43,131

The exact metabolic fate of misoprostol has not been clearly established, but the drug is rapidly and extensively metabolized, principally via de-esterification to form misoprostol acid, which is pharmacologically active.1,2,3,5,41,45,97 Animal evidence suggests that de-esterification of the drug may occur at least in part in the GI tract (e.g., in parietal cells).46,143 Misoprostol acid undergoes extensive, rapid β-oxidation of the α side chain1,2,3,41 to form the tetranor metabolite of misoprostol acid,2,46 and omega -oxidation of the β side chain with subsequent ketone reduction to form prostaglandin F analogs.1,2,3,41 Studies in animals indicate that misoprostol acid is approximately as potent as misoprostol in inhibiting gastric acid secretion;46 the dinor and tetranor metabolites of misoprostol acid appear to be pharmacologically inactive.1,45,127

Following oral or IV administration of misoprostol, the free acid and other metabolites of the drug are excreted mainly in urine;1,45,100 smaller amounts of metabolites are excreted in feces,2,45 probably via biliary elimination.45 Only negligible amounts of unchanged drug are excreted in urine following oral or IV administration.41,45,100 Following a single oral 200-mcg dose of misoprostol in healthy adults, about 73% of the dose is excreted in urine and about 15% in feces within 7 days;2,45 most urinary excretion occurs within 8-24 hours.2,45 The principal urinary metabolites are the dinor and tetranor of misoprostol acid.45 In healthy adults, less than 1% of a single oral dose of misoprostol is excreted in urine as unchanged drug and misoprostol acid.45 Approximately 5% of a single oral dose is excreted in feces within 24 hours as the dinor and tetranor of misoprostol acid.45

Chemistry and Stability

Chemistry

Misoprostol is a synthetic analog of prostaglandin E₁ (alprostadil).1,5,10,11,13,20,25,26,27,31,55,76,78,85,95 Misoprostol differs structurally from prostaglandin E₁ by the presence of a methyl ester at C-1, a methyl group at C-16, and a hydroxy group at C-16 rather than at C-15.2,102 These structural differences appear to increase the antisecretory potency, prolong the duration of action, and improve the safety profile of misoprostol compared with prostaglandin E₁.2,10,11,31,119

Stability

Commercially available misoprostol tablets should be stored in a dry place at a temperature of 25°C or less.1,5

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Pfizer. Cytotec^® (misoprostol) tablets prescribing information. NY, NY; 2018 Feb.

2. Monk JP, Clissold SP. Misoprostol: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of peptic ulcer disease. Drugs . 1987; 33:1-30. [PubMed 3102205]

3. Nicholson PA. A review of the therapeutic efficacy of misoprostol, a prostaglandin E₁ analogue. S Afr Med J . 1988; 74:56-8. [PubMed 3133797]

4. USP DI Update. No. 3. Misoprostol (systemic). Rockville, MD; The United States Pharmacopeial Convention, Inc; 1989:84-9.

5. Searle. Cytotec^® (misoprostol) product information form for the American Hospital Formulary Service. Skokie, IL; 1988 Dec.

6. Nakamura T, Niwa H, Muto H. Misoprostol inhibits basal gastric secretion in humans. Gastroenterology . 1986; 90(5 Part 2):1562.

7. Feldman M. Gastric bicarbonate secretion in humans: effect of pentagastrin, bethanechol, and 11,16,16-trimethyl prostaglandin E₂. J Clin Invest . 1983; 72:295-303. [PubMedCentral][PubMed 6135708]

8. Kauffman GL Jr, Reeve JJ Jr, Grossman MI. Gastric bicarbonate secretion: effect of topical and intravenous 16,16-dimethyl prostaglandin E₂. Am J Physiol . 1980; 239:G44-8.

9. Colton DG, Driskill DR, Phillips EL et al. Effect of SC-29333, an inhibitor of gastric secretion, on canine gastric mucosal blood flow and serum gastrin levels. Arch Int Pharmacodyn Ther . 1978; 236:86-95. [PubMed 747466]

10. Collins PW. Development and therapeutic role of synthetic prostaglandins in peptic ulcer disease. J Med Chem . 1986; 29:437-3. [PubMed 3514911]

11. Collins PW, Pappo R, Dajani EZ. Chemistry and synthetic development of misoprostol. Dig Dis Sci . 1985; 30:114-7S. [PubMed 3967559]

12. Steiner JA. Misoprostol clinical pharmacology: establishment of activity in man. Dig Dis Sci . 1985; 30:136-41S.

13. Wilson DE. Antisecretory and mucosal protective actions of misoprostol: potential role in the treatment of peptic ulcer disease. Am J Med . 1987; 83(Suppl 1A):2-8. [PubMed 3113241]

14. Davis GR, Fordtran JS, Dajani EZ. Dose-response, meal-stimulated gastric antisecretory study of prostaglandin E₁ analog, misoprostol, in man. Dig Dis Sci . 1988; 33:298-302. [PubMed 3125026]

15. Jiranek GC, Kimmey MB, Saunders DR et al. Misoprostol reduces gastroduodenal injury from one week of aspirin: an endoscopic study. Gastroenterology . 1989; 96:656-61. [PubMed 2491827]

16. Cohen MM, Clark L, Armstrong L et al. Reduction of aspirin-induced fecal blood loss with low-dose misoprostol tablets in man. Dig Dis Sci . 1985; 30:605-11. [PubMed 3924533]

17. Sato N, Kawano S, Fukuda M et al. Misoprostol-induced changes in gastric mucosal hemodynamics. Am J Med . 1987; 83(Suppl):15-21. [PubMed 3113240]

18. Clay GA, Goodwin JS. Evaluation of the effects of misoprostol on immunologic competence in normal volunteers. Dig Dis Sci . 1986; 31(Suppl):148-9S.

19. Bright-Asare P, Habte T, Yirgou B et al. Prostaglandins, H₂-receptor antagonists and peptic ulcer disease. Drugs . 1988; 35(Suppl 3):1-9 (IDIS 247642)

20. Tsai BS, Kessler LK, Schoenhard G et al. Demonstration of specific E-type prostaglandin receptors using enriched preparations of canine parietal cells and [³H] misoprostol free acid. Am J Med . 1987; 83(Suppl 1A):9-14. [PubMed 2887113]

21. Fich A, Arber N, Sestieri M et al. Effect of misoprostol and cimetidine on gastric cell turnover. Dig Dis Sci . 1985; 30(Suppl):133-5S.

22. Ryan JR, Vargas R, Clay GA et al. Role of misoprostol in reducing aspirin-induced gastrointestinal blood loss in arthritic patients. Am J Med . 1987; 83(Suppl 1A):41-4. [PubMed 3113245]

23. Lewis JH. Summary of the 29th meeting of the gastrointestinal drugs advisory committee, Food and Drug Administration—June 10, 1985. Am J Gastroenterol . 1985; 80:743-5. [PubMed 3929594]

24. Dajani EZ. Perspective on the gastric antisecretory effects of misoprostol in man. Prostaglandins . 1987; 33(Suppl):68-77. [PubMed 3122277]

25. Dajani EZ. Overview of the mucosal protective effects of misoprostol in man. Prostaglandins . 1987; 33(Suppl):117-29. [PubMed 3122272]

26. Wilson DE. Misoprostol and gastroduodenal mucosal protection (cytoprotection). Postgrad Med J . 1988; 64(Suppl 1):7-11. [PubMed 3138683]

27. Hunt JN, Smith JL, Jiang CL et al. Effect of synthetic prostaglandin E₁ analog on aspirin-induced gastric bleeding and secretion. Dig Dis Sci . 1983; 28:897-902. [PubMed 6604619]

28. McGuigan JE, Chang Y, Dajani EZ. Effect of misoprostol, an antiulcer prostaglandin, on serum gastrin in patients with duodenal ulcer. Dig Dis Sci . 1986; 31(Suppl):120-5S.

29. Wagner BM. Gastric morphology in ulcer patients receiving misoprostol. Dig Dis Sci . 1985; 30(Suppl):129-32S. [PubMed 3838153]

30. Brecht T. Effects of misoprostol on human circulation. Prostaglandins . 1987; 33(Suppl):51-60. [PubMed 3122275]

31. Isenberg JI, Hogan DL, Selling JA et al. Duodenal bicarbonate secretion in humans: role of prostaglandins. Dig Dis Sci . 1986; 31(Suppl):130S. [PubMed 3080284]

32. Akdamar K, Agrawal N, Ertan A. Inhibition of nocturnal gastric secretion in normal human volunteers by misoprostol: a synthetic prostaglandin E₁ methyl ester analog. Am J Gastroenterol . 1982; 77:902-4. [PubMed 6816064]

33. Bauer RF. Misoprostol preclinical pharmacology. Dig Dis Sci . 1985; 30(Suppl):118-25S.

34. Agrawal NM, Godiwala T, Arimura A et al. Cytoprotection by a synthetic prostaglandin against ethanol-induced gastric mucosal damage. Gastrointest Endosc . 1986; 32:67-70. [PubMed 3086177]

35. Miller TA. Protective effects of prostaglandins against gastric mucosal damage: current knowledge and proposed mechanisms. Am J Physiol . 1983; 245:G601-23. [PubMedCentral][PubMed 6195926]

36. Ramage JK, Denton A, Williams JG. Inhibition of food stimulated acid secretion by misoprostol, an orally active synthetic E₁ analogue prostaglandin. Br J Clin Pharmacol . 1985; 19:9-12. [PubMedCentral] [PubMed 3919751]

37. Gullikson G, Anglin C, Kessler L et al. Misoprostol prevents aspirin-induced damage in canine Heidenhain pouches. Gastroenterology . 1983; 84(5 Part 2):1176.

38. Moore JG, Alazraki N, Clay GD. Effect of synthetic prostaglandin E₁ analog on gastric emptying of meals in man. Dig Dis Sci . 1986; 31: 16-20. [PubMed 3079695]

39. Konturek SJ, Pawlik W. Physiology and pharmacology of prostaglandins. Dig Dis Sci . 1986; 31(Suppl):6-19S.

40. Salmon PR, Barton T. Comparative inhibition of coffee-induced gastric acid secretion employing misoprostol and cimetidine. Dig Dis Sci . 1986; 31(Suppl):55-62S.

41. Schoenhard G, Oppermann J, Kohn FE. Metabolism and pharmacokinetic studies of misoprostol. Dig Dis Sci . 1985; 30(Suppl):126-8S.

42. Leese PT, Karim A, Rozek L. Technical and pharmacological considerations in evaluating misoprostol pharmacokinetic data. Dig Dis Sci . 1986; 31(Suppl):147S. [PubMed 3731990]

43. Karim A, Burns TS, Miller MS et al. Pharmacokinetics and safety of the anti-ulcer prostaglandin mosiprostol in elderly male subjects. Clin Pharmacol Ther . 1987; 41:205.

44. Karim A, Rozek LF, Leese PT. Absorption of misoprostol (Cytotec^®), an antiulcer prostaglandin, or aspirin is not affected when given concomitantly to healthy human subjects. Gastroenterology . 1987; 92(5 Part 2):1742.

45. Karim A. Antiulcer prostaglandin misoprostol: single and multiple dose pharmacokinetic profile. Prostaglandins . 1989; 33(Suppl):40-50.

46. Tsai BS, Kessler L, Egofske P et al. Antisecretory activity and metabolism of misoprostol in isolated canine parietal cells. Dig Dis Sci . 1986; 31(Suppl):145-50S. [PubMed 3080277]

47. Bauer RF, Bianchi RG, Casler J et al. Comparative mucosal protective properties of misoprostol, cimetidine, and sucralfate. Dig Dis Sci . 1986; 31(Suppl):81-5S.

48. Leung FW, Miller JC, Guth PH. Dissociated effects of misoprostol on gastric acid secretion and mucosal blood flow. Dig Dis Sci . 1986; 31(Suppl): 86-90S.

49. Smedfors B, Johansson C. Stimulation of duodenal bicarbonate secretion by misoprostol. Dig Dis Sci . 1986; 31(Suppl):96-100S.

50. Liss RH, Letourneau RJ, Schepis JP. Evaluation of cytoprotection against ethanol-induced injury in gastric mucosa pretreated with misoprostol, cimetidine, or placebo. Dig Dis Sci . 1986; 31(Suppl):108-14S.

51. Wilson DE, Quadros E, Rajapaksa T et al. Effects of misoprostol on gastric acid and mucus secretion in man. Dig Dis Sci . 1986; 31(Suppl): 126-9S. [PubMed 3080283]

52. Rainsford KD. The effects of aspirin and other non-steroid anti-inflammatoryanalgesic drugs on gastro-intestinal mucus glycoprotein biosynthesis in vivo : relationship to ulcerogenic actions. Biochem Pharmacol . 1978; 27:877-85. [PubMed 306823]

53. Isenberg JI, Hogan DL, Koss MA et al. Human duodenal mucosal bicarbonate secretion: evidence for basal secretion and stimulation by hydrochloric acid and a synthetic prostaglandin E₁ analogue. Gastroenterology . 1986; 91:370-8. [PubMed 3087810]

54. Shimizu N, Nakamura T. Prostaglandins as hormones. Dig Dis Sci . 1985; 30(Suppl):109-13S.

55. Herting RL, Nissen CH. Overview of misoprostol clinical experience. Dig Dis Sci . 1986; 31(Suppl): 47-54S. [PubMed 3080288]

56. Roth S, Agrawal N, Mahowald M et al. Misoprostol heals gastroduodenal injury in patients with rheumatoid arthritis receiving aspirin. Arch Intern Med . 1989; 149:775-9. [PubMed 2495779]

57. Lanza FL. A double-blind study of prophylactic effect of misoprostol on lesions of gastric and duodenal mucosa induced by oral administration of tolmetin in healthy subjects. Dig Dis Sci . 1986; 31:131-6S. [PubMed 3943440]

58. Agrawal NM, Saffouri B, Kruss DM et al. Healing of benign gastric ulcer: a placebo-controlled comparison of two dosage regimens of misoprostol, a synthetic analog of prostaglandin E₁. Dig Dis Sci . 1985; 30:164-70S.

59. Lanza F, Peace K, Gustitus L et al. A blinded endoscopic comparative study of misoprostol versus sucralfate and placebo in the prevention of aspirin-induced gastric and duodenal ulceration. Am J Gastroenterol . 1988; 83:143-6. [PubMed 3124604]

60. Aadland E, Fausa O, Vatin M et al. Protection by misoprostol against naproxen-induced gastric mucosal damage. Am J Med . 1987; 83(Suppl 1A):37-40.

61. Graham DY, Agrawal NM, Roth SH. Prevention of NSAID-induced gastric ulcer with misoprostol: multicenter, double-blind, placebo-controlled trial. Lancet . 1988; 2:1277-80. [PubMed 2904006]

62. Taha AS, McLaughlin S, Holland PJ et al. Prevention of NSAID-induced gastric ulcer with prostaglandin analogues. Lancet . 1989; 1:52. [PubMed 2563038]

63. Dammann HG, Simon-Schultz J, Bauermeister W et al. Prevention of NSAID-induced gastric ulcer with prostaglandin analogues. Lancet . 1989; 1:52-3. [PubMed 2563038]

64. Shield MJ, Fenn CG. Misoprostol and ulcer prophylaxis. Lancet . 1989; 1:98-9. [PubMed 2562901]

65. Upadhyay R, Taha AS, Sturrock RD et al. Misoprostol and ulcer prophylaxis. Lancet . 1989; 1:212-3. [PubMed 2563111]

66. Nightingale S. Warning changes on NSAIA labeling. JAMA . 1989; 261:1396.

67. Graham DY. Prevention of gastroduodenal injury induced by chronic nonsteroidal antiinflammatory drug therapy. Gastroenterology . 1989; 96:675-81. [PubMed 2642452]

68. Knodel LC. Preventing NSAID-induced gastric ulcers: the role of misoprostol. Hosp Formul . 1989; 24(Suppl A):27-30.

69. Anon. Misoprostol: therapy for the prevention of NSAID-induced gastric ulceration. Hosp Formul . 1989; 24(Suppl A):2-6.

70. Nightingale SL. Approval of misoprostol. JAMA . 1989; 261:1396.

71. Lanza FL, Fakouhi D, Rubin A et al. A double-blind placebo-controlled comparison of the efficacy and safety of 50, 100, and 200 mcg of misoprostol QID in the prevention of ibuprofen-induced gastric and duodenal mucosal lesions and symptoms. Am J Gastroenterol . 1989; 84:633-6. [PubMed 2499187]

72. Ramsey EJ, Harris AE Jr. Prostaglandin E₁ analogue therapy in the treatment of refractory gastric ulcer in an elderly patient. Arch Intern Med . 1988; 148:2275-6. [PubMed 3140754]

73. Silverstein FE, Kimmey MB, Saunders DR et al. Gastric protection by misoprostol against 1,300 mg of aspirin: an endoscopic dose-response study. Am J Med . 1987; 83(Suppl 1A):32-6. [PubMed 3113243]

74. Silverstein FE, Kimmey MB, Saunders DR et al. Gastric protection by misoprostol against 1300 mg of aspirin: an endoscopic study. Dig Dis Sci . 1986; 31:137-41S.

75. Mavligit GM, Faintuch J, Levin B et al. Gastroduodenal injury during hepatic arterial infusion of chemotherapeutic agents: lack of cytoprotection by prostaglandin E₁ analogue. Gastroenterology . 1987; 566-9.

76. Shield MJ. Interim results of a multicenter international comparison of misoprostol and cimetidine in the treatment of out-patients with benign gastric ulcers. Dig Dis Sci . 1985; 30(Suppl):178-84S. [PubMed 2857120]

77. Dajani EZ, Nissen CH. Gastrointestinal cytoprotective effects of misoprostol: clinical efficacy overview. Dig Dis Sci . 1985; 30(Suppl): 194-200S. [PubMed 3932054]

78. Birnie GG, Watkinson G, Shroff NE et al. Double-blind comparison of two dosage regimens of misoprostol in the treatment of duodenal ulceration. Dig Dis Sci . 1988; 33:1269-73. [PubMed 3139379]

79. Brand DL, Roufail WM, Thomson ABR et al. Misoprostol, a synthetic PGE₁ analog, in the treatment of duodenal ulcers: a multicenter double-blind study. Dig Dis Sci . 1985; 30(Suppl): 147-58S.

80. Sontag SJ, Mazure PA, Pontes JF et al. Misoprostol in the treatment of duodenal ulcer: a multicenter double-blind placebo-controlled study. Dig Dis Sci . 1985; 30:159-63S.

81. Lanza FL, Aspinall RL, Swabb EA et al. Double-blind, placebo-controlled endoscopic comparison of the mucosal protective effects of misoprostol versus cimetidine on tolmetin-induced mucosal injury to the stomach and duodenum. Gastroenterology . 1988; 95: 289-94. [PubMedCentral][PubMed 3134266]

82. McGuigan JE, Gugler R. Summary. Dig Dis Sci . 1986; 31(Suppl):143-4S.

83. Hawkey CJ, Walt RP. Misoprostol, smoking, and duodenal ulcer healing rates. Lancet . 1987; 1:393. [PubMed 2880206]

84. Mazure PA. Comparative efficacy of misoprostol and cimetidine in the treatment of acute duodenal ulcer: results of major studies. Am J Med . 1987; 83(Suppl):22-6. [PubMed 3113242]

85. Watkinson G, Hopkins A, Akbar FA. The therapeutic efficacy of misoprostol in peptic ulcer disease. Postgrad Med J . 1988; 64(Suppl):60-73. [PubMedCentral][PubMed 3138682]

86. Lam SK, Lau WY, Choi TK et al. Prostaglandin E₁ (misoprostol) overcomes the adverse effect of chronic cigarette smoking on duodenal ulcer healing. Dig Dis Sci . 1986; 31(Suppl):68-74S.

87. Rachmilewitz D, Chapman JW, Nicholson PA et al. A multicenter international controlled comparison of two dosage regimens of misoprostol with cimetidine in treatment of gastric ulcer in outpatients. Dig Dis Sci . 1986; 31(Suppl):75-80S.

88. Rachmilewitz D. Role of endogenous prostanoids in pathogenesis of peptic ulcer. Postgrad Med . 1985; 78(Suppl):79-83. [PubMed 4048044]

89. Bright-Asare P, Sontag SJ, Gould RJ et al. Efficacy of misoprostol (twice daily dosage) in acute healing of duodenal ulcer: a multicenter double-blind controlled trial. Dig Dis Sci . 1986; 31(Suppl):63-7S.

90. Rees WDW, Gibbons LC, Turnberg LA. Effects of non-steroidal anti-inflammatory drugs and prostaglandins on alkali secretion by rabbit gastric fundus in vitro . Gut . 1983; 24:784-9. [PubMedCentral][PubMed 6576966]

91. Nicholson PA. A multicenter international controlled comparison of two dosage regimes of misoprostol and cimetidine in the treatment of duodenal ulcer in out-patients. Dig Dis Sci . 1985; 30(Suppl):171-7S.

92. Newman RD, Gitlin N, Lacayo EJ et al. Misoprostol in the treatment of duodenal ulcer refractory to H₂ blocker therapy: a placebo-controlled, multicenter, double-blind, randomized trial. Am J Med . 1987; 83(Suppl 1A):27-31. [PubMed 2887112]

93. Simjee AE, Spitaels JM, Pettengell KE et al. A comparative study of misoprostol and ranitidine in the healing of duodenal ulcers. S Afr Med J . 1987; 72: 15-7. [PubMed 3110981]

94. O'Keefe SJD, Spitaels JM, Mannion G et al. Misoprostol, a synthetic prostaglandin E₁ analogue, in the treatment of duodenal ulcers: a double-blind, cimetidine-controlled trial. S Afr Med J . 1985; 67:321-4. [PubMed 3920770]

95. Stern WR. Summary of the 33rd meeting of the Food and Drug Administration's Gastrointestinal Drugs Advisory Committee, September 15-16, 1988. Am J Gastroenterol . 1989; 84:351-3. [PubMed 2494882]

96. Miller SR, Fries JF, Spitz P et al. Patients at high risk for developing upper gastrointestinal complications associated with non-steroidal antiinflammatory drugs. Am J Gastroenterol . 1988; 83:1055.

97. Schoenhard GL, Schmidt RE. Initial pharmacokinetic profile of [³H]-SC-29333, a synthetic prostaglandin E₁ methyl ester analog, in the rhesus monkey and beagle dog. Fed Proc Am Soc Exp Biol Med . 1978; 37:911.

98. Palmer JF. Letter sent to Bathish J, of Wyeth Laboratories regarding labeling revisions about gastrointestinal adverse reactions to Orudis^® (ketoprofen). Rockville, MD: Food and Drug Administration, Division of Oncology and Radiopharmaceutical Drug Products; 1988 Sep.

99. Food and Drug Administration. Labeling revisions for NSAIDs. FDA Drug Bull . 1989; 19:3-4.

100. Schoenhard GL, Schmidt RE. Bioavailability and metabolic fate of SC-29333, a synthetic prostaglandin E₁ methyl ester analog, in the beagle dog. Fed Proc Am Soc Exp Biol Med . 1979; 38:265.

101. Lacy ER. Effects of absolute ethanol, misoprostol, cimetidine, and phosphate buffer on the morphology of rat gastric mucosae. Dig Dis Sci . 1986; 31(Suppl):101-7S.

102. Hamor GH. Nonsteroidal anti-inflammatory drugs. In: Foye WO, ed. Principles of medicinal chemistry. 3rd ed. Philadelphia: Lea & Febiger; 1989:503-31.

103. Roth SH. Nonsteroidal anti-inflammatory drugs: gastropathy, deaths, and medical practice. Ann Intern Med . 1988; 109:353-4. [PubMed 3044208]

104. Griffin MR, Ray WA, Schaffner W. Nonsteroidal anti-inflammatory drug use and death from peptic ulcer in elderly persons. Ann Intern Med . 1988; 109:359-63. [PubMed 3261560]

105. Peoples JB. Peptic ulcer disease and the nonsteroidal anti-inflammatory drugs. Am Surg . 1985; 51:358-62. [PubMed 3994179]

106. Fromm D. How do non-steroidal anti-inflammatory drugs affect gastric mucosal defenses? Clin Invest Med . 1987; 10:251-8.

107. O'Laughlin JC, Hoftiezer JW, Ivey KJ. Effect of aspirin on the human stomach in normals: endoscopic comparison of damage produced one hour, 24 hours, and 2 weeks after administration. Scand J Gastroenterol . 1981; 16(Suppl 67):211-4.

108. Clinch D, Banerjee AK, Ostick G et al. Non-steroidal anti-inflammatory drugs and gastrointestinal adverse effects. J R Coll Phys London . 1983; 17:228-30.

109. Bianchi RG, Casler JJ, Dajani EZ. Gastric antisecretory and antiulcer activity of SC-29333: a synthetic E-prostaglandin analog. Pharmacologist . 1981; 23:121.

110. Levy M. Aspirin use in patients with major upper gastrointestinal bleeding and peptic-ulcer disease. N Engl J Med . 1974; 290:1158-62. [PubMed 4545100]

111. Robert A, Nezamis JE, Lancaster C et al. Cytoprotection by prostaglandins in rats: prevention of gastric necrosis produced by alcohol, HCl, NaOH, hypertonic NaCl, and thermal injury. Gastroenterology . 1979; 77:433-43. [PubMed 456839]

112. Sharon P, Cohen F, Zifroni A et al. Prostanoid synthesis by cultured gastric and duodenal mucosa: possible role in the pathogenesis of duodenal ulcer. Scand J Gastroenterol . 1983; 18:1045-9. [PubMed 6584967]

113. Simon B, Kather H. Human gastric mucosal adenylate cyclase activity: effects of various cytoprotective prostaglandins. Eur J Clin Invest . 1980; 10:481-5. [PubMed 6788566]

114. Hawkey CJ, Rampton DS. Prostaglandins and the gastrointestinal mucosa: are they important in its function, disease, or treatment? Gastroenterology . 1985; 89:1162-88.

115. Fimmel CJ, Müller-Lissner SA, Blum AL. Bile salt-induced, acute gastric mucosal damage in man: time course and effect of misoprostol, a PGI₁-analogue. Scand J Gastroenterol . 1984; 19(Suppl 92):184-8. [PubMed 6609420]

116. Arvidsson S, Falt K, Haglund U. Gastric mucosal damage in sepsis—effects of pretreatment with a synthetic prostaglandin E₁ analogue. Gut . 1985; 26:1025-31. [PubMedCentral] [PubMed 3932138]

117. Colton DG, Callison DA, Dajani EZ. Effects of a prostaglandin E₁ derivative, SC-29333, and aspirin on gastric ionic fluxes and potential difference in dogs. J Pharmacol Exp Ther . 1979; 210:283-8. [PubMed 458634]

118. Larsen KR, Jensen NF, Davis EK et al. The cytoprotective effects of (±)-15-deoxy-16-α, β-hydroxy-16-methyl PGE₁ methyl ester (SC-29333) versus aspirin-shock gastric ulcerogenesis in the dog. Prostaglandins . 1981; 21(Suppl):119-24. [PubMed 6795683]

119. Dajani EZ, Driskill DR, Bianchi RG et al. Influence of the position of the side chain hydroxy group on the gastric antisecretory and antiulcer actions of E₁ prostaglandin analogs. Prostaglandins . 1975; 10:733-45. [PubMed 1215536]

120. Bianchi RG, Bauer RF. Intestinal antiulcer effect of misoprostol. Pharmacologist . 1982; 24:248.

121. Herting RL, Clay GA. Overview of clinical safety with misoprostol. Dig Dis Sci . 1985; 30(Suppl):185-93S.

122. Fakouhi T, Leese P, Nissen C et al. Tolerability of once-daily doses of 800-mcg and 400-mcg misoprostol in healthy volunteers. Curr Ther Res . 1987; 42:357-63.

123. Wildeman RA. Focus on misoprostol: review of worldwide safety data. Clin Invest Med . 1987; 10: 243-5. [PubMed 3113801]

124. Kotsonis FN, Dodd DC, Regnier B et al. Preclinical toxicology profile of misoprostol. Dig Dis Sci . 1985; 30(Suppl):142-6S.

125. Rees WD, Gibbons LC, Warhurst G et al. Studies of bicarbonate secretion by the normal human stomach in vivo: effect of aspirin, sodium taurocholate, and prostaglandin E₂. In: Allen A et al, eds. Mechanisms of mucosal protection in the upper gastrointestinal tract. New York: Raven Press; 1984:119-24.

126. Bennett PN, Fenn GC, Notarianni LJ. Potential drug interactions with misoprostol: effects on the pharmacokinetics of antipyrine and propranolol. Postgrad Med J . 1988; 64(Suppl 1):21-4. [PubMed 3138681]

127. Garris RE, Kirkwood CF. Misoprostol: a prostaglandin E₁ analogue. Clin Pharm . 1989; 8:627-44. [PubMed 2507215]

128. Corboy ED Jr, Clay GA, Fakouhi DT et al. Appendix: humanitarian use of misoprostol in severe refractory upper gastrointestinal disease. Am J Med . 1987; 83(Suppl 1A):49-52. [PubMed 3113246]

129. Rietbrock N, Karim A, Nicholson PA. Prevention of NSAID-induced gastric ulcer with prostaglandin analogues. Lancet . 1989; 1:844-5. [PubMed 2564928]

130. Dammann HG, Simon-Schultz J, Kangah R et al. Prevention of NSAID-induced gastric ulcer with prostaglandin analogues. Lancet . 1989; 1:845. [PubMed 2564929]

131. Karim A, Rozek LF, Burns TS. Pharmacokinetic profile of antiulcer prostaglandin misoprostol in humans. Postgrad Med J . 1988; 64(Suppl 1):80.

132. Okabe S, Takeuchi K, Ueki S et al. [Effects of misoprostol, (±)-methyl(11α,13E)-11,16- dihydroxy-16-methyl-9-oxoprost-13-en-l-oate, on various gastric and duodenal lesions in rats.] (Japanese; with English abstract.) Folia Pharmacol Jpn. 1986; 87: 339-350.

133. Cleghorn GJ, Shepherd RW, Holt TL. The use of a synthetic prostaglandin E₁ analogue (misoprostol) as an adjunct to pancreatic enzyme replacement in cystic fibrosis. Scand J Gastroenterol . 1988; 23(Suppl 143):142-7.

134. Paller MS. The prostaglandin E₁ analog misoprostol reverses acute cyclosporine nephrotoxicity. Transplant Proc . 1988; 20(Suppl 3):634-7. [PubMed 3133856]

135. Hillman AL, Bloom BS. Economic effects of prophylactic use of misoprostol to prevent gastric ulcer in patients taking nonsteroidal anti-inflammatory drugs. Arch Intern Med . 1989; 149:2061-5. [PubMed 2505706]

136. Flower RJ, Moncada S, Vane JR. Analgesic-antipyretics and anti-inflammatory agents: drugs employed in the treatment of gout. In: Gilman AG, Goodman LS, Rall TW et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 7th ed. New York: Macmillan Publishing Company; 1985:674-715.

137. Gullikson GW, Pautsch W, Bianchi RG et al. Comparative effects of misoprostol and 16,16-dimethyl PGE₂ on intestinal fluid transport and myoelectric spike activity in the dog. Dig Dis Sci . 1986; 31(Suppl):148S.

138. Paller MS. Effects of the prostaglandin E₁ analog misoprostol on cyclosporine nephrotoxicity. Transplantation . 1988; 45:1126-31. [PubMed 3132763]

139. Robinson PG, Sly PD, Smith AL. Arch Dis Child . 1988; 63:1081-2.

140. Walt RP. Misoprostol for the treatment of peptic ulcer and antiinflammatory-drug-induced gastroduodenal ulceration. N Engl J Med . 1992; 327:1575-80. [PubMed 1435885]

141. Antillon M, Cominelli F, Lo S et al. Effect of oral prostaglandin in indomethacin induced renal dysfunction in alcoholic cirrhosis: a double-blind randomized study. Gastroenterology . 1988; 94(5 Part 2):A522. [PubMedCentral]

142. Wagner BM. Gastric morphology in ulcer patients receiving misoprostol. Dig Dis Sci . 1985; 30(Suppl):129-32S. [PubMed 3838153]

143. Struthers BJ (Searle, Skokie, IL): Personal Communication; 1989 Oct.

144. Reviewers' comments (personal observations); 1989 Oct.

145. Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal antiinflammatory drugs. N Engl J Med . 1984; 310:563-72. [PubMed 6363936]

146. Savarino V, Scalabrini P, Mela GS et al. Evaluation of antisecretory activity of misoprostol in duodenal ulcer patients using long-term intragastric pH monitoring. Dig Dis Sci . 1988; 33:293-7. [PubMed 3125025]

147. Dajani EZ, Driskill DR, Bianchi RG et al. Effect of a prostaglandin analogue, SC-30249, on canine gastric secretion. Drug Dev Res . 1983; 3:339-47.

148. Ottignon Y, Ethevenaux C, Capron MH et al. The effect of a prostaglandin₁ (PGE₁) on the lower esophageal sphincter (LES) in man. Gastroenterology . 1988; 94(5 Part 2):A338. [PubMedCentral]

149. Mozes M, Moran M, Kotel B et al. Misoprostol (M) improves renal function and reduces the frequency of acute rejection (AR) in cyclosporine-treated (CsA) renal transplant recipients. Proc Am Soc Nephrol . 1988:372A.

150. Blackburn WD Jr, Alarcon GS. Misoprostol treatment of gastropathy due to nonsteroidal anti-inflammatory drugs. Am J Med . 1990; 88:85. [PubMed 2104742]

151. Kornbluth A, Gupta R, Gerson CD. Life-threatening diarrhea after short-term misoprostol use in a patient with Crohn ileocolitis. Ann Intern Med . 1990; 113:474-6. [PubMed 2117413]

152. Peterson WL. Helicobacter pylori and peptic ulcer disease. N Engl J Med . 1991; 324:1043-8. [PubMed 2005942]

153. Marshall BJ. Campylobacter pylori : Its link to gastritis and peptic ulcer disease. Clin Infect Dis . 1990; 12(Suppl 1):S87-93.

154. Reviewers' comments (personal observations); 1993 Oct 26.

155. Blaser MJ. Helicobacter pylori : its role in disease. Clin Infect Dis . 1992; 15:386-91. [PubMed 1520782]

156. Murray DM, DuPont HL, Cooperstock M et al. Evaluation of new antiinfective drugs for the treatment of gastritis and peptic ulcer disease associated with infection by Helicobacter pylori . Clin Infect Dis . 1992; 15(Suppl 1):S268-73.

157. Graham DY, Go MF. Evaluation of new antiinfective drugs for Helicobacter pylori infection: revisited and updated. Clin Infect Dis . 1993; 17:293-4. [PubMed 8399892]

158. Murray DM, DuPont HL. Reply. (Evaluation of new antiinfective drugs for Helicobacter pylori infection: revisited and updated.) Clin Infect Dis . 1993; 17:294-5.

159. George LL, Borody TJ, Andrews P et al. Cure of duodenal ulcer after eradication of H. pylori . Med J Aust . 1990; 153:145-9. [PubMed 1974027]

160. Farrell MK. Dr. Apley meets Helicobacter pylori . J Pediatr Gastroenterol Nutr . 1993; 16:118-9. [PubMed 8450375]

161. Fiocca R, Solcia E, Santoro B. Duodenal ulcer relapse after eradication of Helicobacter pylori . Lancet . 1991; 337:1614. [PubMed 1675746]

162. Graham DY, Lew GM, Evans DG et al. Effect of triple therapy (antibiotics plus bismuth) on duodenal ulcer healing. A randomized controlled trial. Ann Intern Med . 1991; 115:266-9. [PubMed 1854110]

163. Marshall BJ. Treatment strategies for Helicobacter pylori infection. Gastroenterol Clin North Am . 1993; 22:183-98. [PubMed 8449566]

164. Chiba N, Rao BV, Rademaker JW et al. Meta-analysis of the efficacy of antibiotic therapy in eradicating Helicobacter pylori . Am J Gastroenterol . 1992; 87:1716-27. [PubMed 1449132]

165. Glassman MS. Helicobacter pylori infection in children. A clinical overview. Clin Pediatr (Phila) . 1992; 31:487-7.

166. Bianchi Porro G, Parente F, Lazzaroni M. Short and long term outcome of Helicobacter pylori positive resistant duodenal ulcers treated with colloidal bismuth subcitrate plus antibiotics or sucralfate alone. Gut . 1993; 34:466-9. [PubMedCentral][PubMed 8491391]

167. Borody T, Andrews P, Mancuso N et al. Helicobacter pylori reinfection 4 years post-eradication. Lancet . 1992; 339:1295. [PubMed 1349686]

168. Hixson LJ, Kelley Cl, Jones WN et al. Current trends in the pharmacotherapy for peptic ulcer disease. Arch Intern Med . 1992; 152:726-32. [PubMed 1558429]

169. Rauws EAJ, Tytgat GNJ. Cure of duodenal ulcer with eradication of Helicobacter pylori . Lancet . 1990; 335:1233-5. [PubMed 1971318]

170. Hentschel E, Brandstätter G, Dragosics B et al. Effect of ranitidine and amoxicillin plus metronidazole on the eradication of Helicobacter pylori and the recurrence of duodenal ulcer. N Engl J Med . 1993; 328:308-12. [PubMed 8419816]

171. Burette A, Glupczynski Y. On: The who's and when's of therapy for Helicobacter pylori . 1991; 86:924-5. Letter.

172. Bell GD, Powell K, Burridge SM et al. Experience with "triple' anti- Helicobacter pylori eradication thearpy: side effects and the importance of testing the pre-treatment bacterial isolate for metronidazole resistance. Aliment Pharmacol Ther . 1992; 6:427-35. [PubMed 1420735]

173. Sloane R, Cohen H. Common-sense management of Helicobacter pylori -associated gastroduodenal disease. Personal views. Gastroenterol Clin North Am . 1993; 22:199-206. [PubMed 8449567]

174. Ateshkadi A, Lam NP, Johnson CA. Helicobacter pylori and peptic ulcer disease. Clin Pharm . 1993; 12:34-48. [PubMed 8428432]

175. Bayerdorffer E, Mannes GA, Sommer A et al. Long-term follow-up after eradication of Helicobacter pylori with a combination of omeprazole and amoxycillin. Scand J Gastroenterol Suppl . 1993; 196:19-25. [PubMed 8341987]

176. Unge P, Ekstrom P. Effects of combination therapy with omeprazole and an antibiotic on H. pylori and duodenal ulcer disease. Scand J Gastroenterol Suppl . 1993; 196:17-8.

177. Hunt RH. Hp and pH: implications for the eradication of Helicobacter pylori. Scand J Gastroenterol Suppl . 1993; 196:12-6. [PubMed 8341986]

178. Malfertheiner P. Compliance, adverse events and antibiotic resistance in Helicobacter pylori treatment. Scand J Gastroenterol Suppl . 1993; 196:34-7. [PubMed 8341989]

179. Bell GD, Powell U. Eradication of Helicobacter pylori and its effect in peptic ulcer disease. Scand J Gastroenterol Suppl . 1993; 196:7-11. [PubMed 8341990]

180. Bianchi Porro G, Parente F, Lazzaroni M. Short and long term outcome of Helicobacter pylori positive resistant duodenal ulcers treated with colloidal bismuth subcitrate plus antibiotics or sucralfate alone. Gut . 1993; 34:466-9. [PubMedCentral][PubMed 8491391]

181. Graham DY, Go MF. Evaluation of new antiinfective drugs for Helicobacter pylori infection: revisited and updated. Clin Infect Dis . 1993; 17:293-4. [PubMed 8399892]

182. Murray DM, DuPont HL. Reply. (Evaluation of new antiinfective drugs for Helicobacter pylori infection: revisited and updated.) Clin Infect Dis . 1993; 17: 294-5.

183. George LL, Borody TJ, Andrews P et al. Cure of duodenal ulcer after eradication of H. pylori. Med J Aust . 1990; 153:145-9. [PubMed 1974027]

184. Farrell MK. Dr. Apley meets Helicobacter pylori. J Pediatr Gastroenterol Nutr . 1993; 16:118-9. [PubMed 8450375]

185. Fiocca R, Solcia E, Santoro B. Duodenal ulcer relapse after eradication of Helicobacter pylori. Lancet . 1991; 337:1614. [PubMed 1675746]

186. Marshall BJ. Campylobacter pylori: its link to gastritis and peptic ulcer disease. Clin Infect Dis . 1990; 12(Suppl 1):S87-93.

187. Borody T, Andrews P, Mancuso N et al. Helicobacter pylori reinfection 4 years post-eradication. Lancet . 1992; 339:1295. [PubMed 1349686]

188. Hixson LJ, Kelley CL, Jones WN et al. Current trends in the pharmacotherapy for peptic ulcer disease. Arch Intern Med . 1992; 152:726-32. [PubMed 1558429]

189. Rauws EAJ, Tytgat GNJ. Cure of duodenal ulcer with eradication of Helicobacter pylori. Lancet . 1990; 335:1233-5. [PubMed 1971318]

190. Hunt RH. pH and Hp—gastric acid secretion and Helicobacter pylori: implications for ulcer healing and eradication of the organism. Am J Gastroenterol . 1993; 88:481-3. [PubMed 8470623]

191. Hentschel E, Brandstatter G, Dragosics B et al. Effect of ranitidine and amoxicillin plus metronidazole on the eradication of Helicobacter pylori and the recurrence of duodenal ulcer. N Engl J Med . 1993; 328:308-12. [PubMed 8419816]

192. Graham DY, Lew GM, Evans DG et al. Effect of triple therapy (antibiotics plus bismuth) on duodenal ulcer healing: a randomized controlled trial. Ann Intern Med . 1991; 115:266-9. [PubMed 1854110]

193. Reviewers' comments (personal observations) on Helicobacter pylori ; 1993 Oct 26.

194. Marshall BJ. Helicobacter pylori . Am J Gastroenterol . 1994; 89(Suppl):S116-28.

195. Labenz J, Gyenes E, Rühl GH et al. Amoxicillin plus omeprazole versus triple therapy for eradication of Helicobacter pylori in duodenal ulcer disease: a prospective, randomized, and controlled study. Gut . 1993; 34:1167-70. [PubMedCentral][PubMed 8406147]

196. Labenz J, Börsch G. Highly significant change of the clinical course of relapsing and complicated peptic ulcer disease after cure of Helicobacter pylori infection. Am J Gastroenterol . 1994; 89:1785-8. [PubMed 7942667]

197. Wang WM, Chen CY, Jan CM et al. Long-term follow-up and serological study after triple therapy of Helicobacter pylori -associated duodenal ulcer. Am J Gastroenterol . 1994; 89:1793-6. [PubMed 7942669]

198. Anon. Drugs for treatment of peptic ulcers. Med Lett Drugs Ther . 1994; 36:65-7. [PubMed 7912812]

199. Freston JW. Emerging strategies for managing peptic ulcer disease. Scand J Gastroenterol Suppl . 1994; 201:49-54. [PubMed 8047824]

200. Axon ATR. The role of acid inhibition in the treatment of Helicobacter pylori infection. Scand J Gastroenterol Suppl . 1994; 201:16-23. [PubMed 8047818]

201. Labenz J, Rühl GH, Bertrams J et al. Medium- or high-dose omeprazole plus amoxicillin eradicates Helicobacter pylori in gastric ulcer disease. Am J Gastroenterol . 1994; 89:726-30. [PubMed 8172146]

202. Labenz J, Borsch G. Evidence for the essential role of Helicobacter pylori in gastric ulcer disease. Gut . 1994; 35:19-22. [PubMedCentral][PubMed 8307443]

203. NIH Consensus Development Panel on. Helicobacter pylori in Peptic Ulcer Disease. JAMA . 1994; 272:65-9. [PubMed 8007082]

204. Fennerty MB. Helicobacter pylori . Ann Intern Med . 1994: 154:721-7.

205. Adamek RJ, Wegener M, Labenz J et al. Medium-term results of oral and intravenous omeprazole/amoxicillin Helicobacter pylori eradication therapy. Am J Gastroenterol . 1994; 89:39-42. [PubMed 8273795]

206. Bell GD, Powell KU, Burridge SM et al. Helicobacter pylori eradication: efficacy and side effect profile of a combination of omeprazole, amoxycillin and metronidazole compared with four alternative regimens. Q J Med . 1993; 86:743-50. [PubMed 8265776]

207. Nomura A, Stemmermann GN, Chyou PH et al. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med . 1991; 325:1132-6. [PubMed 1891021]

208. Parsonnet J, Friedman GD, Vandersteen DP et al. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med . 1991; 325:1127-31. [PubMed 1891020]

209. The EUROGAST Study Group. An international association between Helicobacter pylori infection and gastric cancer. Lancet . 1993; 341:1359-62. [PubMed 8098787]

210. Talley NJ, Zinsmeister AR, Weaver A et al. Gastric adenocarcinoma and Helicobacter pylori infection. J Natl Cancer Inst . 1991; 83:1734-9. [PubMed 1770552]

211. Forman D, Newell DG, Fullerton F et al. Association between infection with Helicobacter pylori and risk of gastric cancer: evidence from a prospective investigation. BMJ . 1991; 302:1302-5. [PubMedCentral][PubMed 2059685]

212. Forman D. Helicobacter pylori infection: a novel risk factor in the etiology of gastric cancer. J Natl Cancer Inst . 1991; 83:1702-3. [PubMed 1770545]

213. Parsonnet J. Helicobacter pylori and gastric cancer. Gastroenterol Clin North Am . 1993; 22:89-104. [PubMed 8449573]

214. Correa P. Is gastric carcinoma an infectious disease? N Engl J Med . 1991; 325:1170-1.

215. Isaacson PG, Spencer J. Is gastric lymphoma an infectious disease? Hum Pathol . 1993; 24:569-70.

216. Markham A, McTavish D. Clarithromycin and omeprazole: as Helicobacter pylori eradication therapy in patients with H. pylori-associated gastric disorders. Drugs . 1996; 51:161-78. [PubMed 8741237]

217. Soll AH. Medical treatment of peptic ulcer disease. JAMA . 1996; 275:622-9. [PubMed 8594244]

218. Walsh JH, Peterson WL. The treatment of Helicobacter pylori infection in the management of peptic ulcer disease. N Engl J Med . 1995; 333:984-91. [PubMed 7666920]

219. Hackelsberger A, Malfertheiner P. A risk-benefit assessment of drugs used in the eradication of Helicobacter pylori infection. Drug Saf . 1996; 15:30-52. [PubMed 8862962]

220. Rauws EAJ, van der Hulst RWM. Current guidelines for the eradication of Helicobacter pylori in peptic ulcer disease. Drugs . 1995; 6:984-90.

221. van der Hulst RWM, Keller JJ, Rauws EAJ et al. Treatment of Helicobacter pylori infection: a review of the world literature. Helicobacter . 1996; 1:6-19. [PubMed 9398908]

222. Lind T, Veldhuyzen van Zanten S, Unge P et al. Eradication of Helicobacter pylori using one-week triple therapies combining omeprazole with two antimicrobials: the MACH I study. Helicobacter . 1996; 1:138-44. [PubMed 9398894]

223. Anon. The choice of antibacterial drugs. Med Lett Drugs Ther . 1996; 38:25-34. [PubMed 8598824]

224. Fennerty MB. Practice guidelines for treatment of peptic ulcer disease. JAMA . 1996; 276:1135. [PubMed 8827957]

225. Soll AH. Practice guidelines for treatment of peptic ulcer disease. JAMA . 1996; 276:1136-7.

226. Langtry HD, Wilde MI. Lansoprazole: an update of its pharmacological properties and clinical efficacy in the management of acid-related disorders. Drugs . 1997; 54:473-500. [PubMed 9279507]

227. TAP Pharmaceuticals, Inc. Prevacid^® (lansoprazole) delayed-release capsules prescribing information. Deerfield, IL; 1997 Aug.

228. Garnett RG. Lansoprazole: a proton pump inhibitor. Ann Pharmacother . 1996; 30:1425. [PubMed 8968456]

229. Zimmerman AE, Katona BG. Lansoprazole: a comprehensive review. Pharmacotherapy . 1997; 17:308-26. [PubMed 9085323]

230. Hatlebakk JG, Nesje LB, Hausken T et al. Lansoprazole capsules and amoxicillin oral suspension in the treatment of peptic ulcer disease. Scand J Gastroenterol . 1995; 11:1053-7.

231. Merck. Vioxx (rofecoxib) tablets and oral suspension prescribing information. West Point, PA; 1999 Sep.

232. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med . 1999; 340:1888-99. [PubMed 10369853]

233. Lanza FL. A guideline for the treatment and prevention of NSAIA-induced ulcers. Am J Gastroenterol . 1998; 93:2037-46. [PubMed 9820370]

235. Anon. ACOG committee opinion: induction of labor with misoprostol. Obstet Gynecol . 1999; 94:1-2.

236. Cullen M, Searle. Dear health care provider: Important drug warning concerning unapproved use of intravaginal or oral misoprostol in pregnant women for induction of labor or abortion. Skokie, IL; 2000 Aug 23.

237. American College of Obstetricians and Gynecologists. News release: ACOG issues letter on safety of misoprostol. Washington, DC; 2000 Oct 12.

238. American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins. Induction of labor. Practice Bulletin No. 10. Washington, DC: American College of Obstetricians and Gynecologists; 1999 Nov.

239. Anon. Mifepristone (RU486). Med Lett Drugs Ther . 1994; 36:78-80. [PubMed 7914667]

240. Christine-Maitre S, Bouchard P, Spitz IM. Medical termination of pregnancy. N Engl J Med . 2000; 946-56.

241. Danco Laboratories, LLC. Mifeprex^® (mifepristone) oral tablets prescribing information. New York, NY; 2020 Oct.

242. Food and Drug Administration. Questions and answers on Mifeprex. Silver Spring, MD; 2019 Apr 12. From FDA website. [Web]

243. Anon. Drugs for treatment of peptic ulcers. Med Lett Drugs Ther . 1997; 39:1-4. [PubMed 8996458]

244. American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins. Medical abortion up to 70 days of gestation. Practice Bulletin No. 225. Washington, DC: American College of Obstetricians and Gynecologists; 2014 Mar. [Web]

245. Lanza FL, Chan FK, Quigley EM; Practice Parameters Committee of the American College of Gastroenterology. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol. 2009 Mar;104(3):728-38. Epub 2009 Feb 24. [PubMed 19240698]