those in whom dehydration, were it to occur, would be dangerous, should be monitored carefully if misoprostol tablets is prescribed. the incidence of diarrhea can be minimized by administering after meals and at bedtime, and by avoiding coadministration of misoprostol tablets with magnesium-containing antacids. gynecological women who received misoprostol tablets during clinical trials reported the following gynecological disorders: spotting (0.7%), cramps (0.6%), hypermenorrhea (0.5%), menstrual disorder (0.3%) and dysmenorrhea (0.1%). postmenopausal vaginal bleeding may be related to misoprostol tablets administration. if it occurs, diagnostic workup should be undertaken to rule out gynecological pathology. (see boxed warnings .) elderly there were no significant differences in the safety profile of misoprostol tablets in approximately 500 ulcer patients who were 65 years of age or older compared with younger patients. additional adverse events which were reported are categorized as follows: incidence greater than 1% in clinical trials, the following adverse reactions were reported by more than 1% of the subjects receiving misoprostol tablets and may be causally related to the drug: nausea (3.2%), flatulence (2.9%), headache (2.4%), dyspepsia (2.0%), vomiting (1.3%), and constipation (1.1%). however, there were no significant differences between the incidences of these events for misoprostol tablets and placebo. causal relationship unknown the following adverse events were infrequently reported. causal relationships between misoprostol tablets and these events have not been established but cannot be excluded: body as a whole: aches/pains, asthenia, fatigue, fever, chills, rigors, weight changes. skin: rash, dermatitis, alopecia, pallor, breast pain. special senses: abnormal taste, abnormal vision, conjunctivitis, deafness, tinnitus, earache. respiratory: upper respiratory tract infection, bronchitis, bronchospasm, dyspnea, pneumonia, epistaxis. cardiovascular: chest pain, edema, diaphoresis, hypotension, hypertension, arrhythmia, phlebitis, increased cardiac enzymes, syncope, myocardial infarction (some fatal), thromboembolic events (e.g., pulmonary embolism, arterial thrombosis, and cva). gastrointestinal: gi bleeding, gi inflammation/infection, rectal disorder, abnormal hepatobiliary function, gingivitis, reflux, dysphagia, amylase increase. hypersensitivity: anaphylactic reaction metabolic: glycosuria, gout, increased nitrogen, increased alkaline phosphatase. genitourinary: polyuria, dysuria, hematuria, urinary tract infection. nervous system/psychiatric: anxiety, change in appetite, depression, drowsiness, dizziness, thirst, impotence, loss of libido, sweating increase, neuropathy, neurosis, confusion. musculoskeletal: arthralgia, myalgia, muscle cramps, stiffness, back pain. blood/coagulation: anemia, abnormal differential, thrombocytopenia, purpura, esr increased.

e taking this drug to reduce the risk of nsaid-induced ulcers, the drug should be discontinued and the patient apprised of the potential hazard to the fetus.

total availability of misoprostol acid is reduced by use of concomitant antacid. clinical trials were conducted with concomitant antacid, however, so this effect does not appear to be clinically important. mean ± sd cmax(pg/ml) auc(0–4)(pg∙hr/ml) tmax(min) fasting 811 ± 317 417 ± 135 14 ± 8 with antacid 689 ± 315 349 ± 108 comparisons with fasting results statistically significant, p<0.05. 20 ± 14 with high fat breakfast 303 ± 176 373 ± 111 64 ± 79 after oral administration of radiolabeled misoprostol, about 80% of detected radioactivity appears in urine. pharmacokinetic studies in patients with varying degrees of renal impairment showed an approximate doubling of t1/2, cmax , and auc compared to normals, but no clear correlation between the degree of impairment and auc. in subjects over 64 years of age, the auc for misoprostol acid is increased. no routine dosage adjustment is recommended in older patients or patients with renal impairment, but dosage may need to be reduced if the usual dose is not tolerated. drug interaction studies between misoprostol and several nonsteroidal anti-inflammatory drugs showed no effect on the kinetics of ibuprofen or diclofenac, and a 20% decrease in aspirin auc, not thought to be clinically significant. pharmacokinetic studies also showed a lack of drug interaction with antipyrine and propranolol when these drugs were given with misoprostol. misoprostol given for 1 week had no effect on the steady state pharmacokinetics of diazepam when the two drugs were administered 2 hours apart. the serum protein binding of misoprostol acid is less than 90% and is concentration-independent in the therapeutic range. after a single oral dose of misoprostol to nursing mothers, misoprostol acid was excreted in breast milk. the maximum concentration of misoprostol acid in expressed breast milk was achieved within 1 hour after dosing and was 7.6 pg/ml (cv 37%) and 20.9 pg/ml (cv 62%) after single 200 mg and 600 mg misoprostol administration, respectively. the misoprostol acid concentrations in breast milk declined to < 1 pg/ml at 5 hours post-dose. pharmacodynamics misoprostol has both antisecretory (inhibiting gastric acid secretion) and (in animals) mucosal protective properties. nsaids inhibit prostaglandin synthesis, and a deficiency of prostaglandins within the gastric mucosa may lead to diminishing bicarbonate and mucus secretion and may contribute to the mucosal damage caused by these agents. misoprostol can increase bicarbonate and mucus production, but in man this has been shown at doses 200 mcg and above that are also antisecretory. it is therefore not possible to tell whether the ability of misoprostol to reduce the risk of gastric ulcer is the result of its antisecretory effect, its mucosal protective effect, or both. in vitro studies on canine parietal cells using tritiated misoprostol acid as the ligand have led to the identification and characterization of specific prostaglandin receptors. receptor binding is saturable, reversible, and stereospecific. the sites have a high affinity for misoprostol, for its acid metabolite, and for other e type prostaglandins, but not for f or i prostaglandins and other unrelated compounds, such as histamine or cimetidine. receptor-site affinity for misoprostol correlates well with an indirect index of antisecretory activity. it is likely that these specific receptors allow misoprostol taken with food to be effective topically, despite the lower serum concentrations attained. misoprostol produces a moderate decrease in pepsin concentration during basal conditions, but not during histamine stimulation. it has no significant effect on fasting or postprandial gastrin nor on intrinsic factor output. effects on gastric acid secretion misoprostol, over the range of 50 to 200 mcg, inhibits basal and nocturnal gastric acid secretion, and acid secretion in response to a variety of stimuli, including meals, histamine, pentagastrin, and coffee. activity is apparent 30 minutes after oral administration and persists for at least 3 hours. in general, the effects of 50 mcg were modest and shorter lived, and only the 200-mcg dose had substantial effects on nocturnal secretion or on histamine and meal-stimulated secretion. uterine effects misoprostol tablets has been shown to produce uterine contractions that may endanger pregnancy. (see boxed warnings .) other pharmacologic effects misoprostol tablets does not produce clinically significant effects on serum levels of prolactin, gonadotropins, thyroid-stimulating hormone, growth hormone, thyroxine, cortisol, gastrointestinal hormones (somatostatin, gastrin, vasoactive intestinal polypeptide, and motilin), creatinine, or uric acid. gastric emptying, immunologic competence, platelet aggregation, pulmonary function, or the cardiovascular system are not modified by recommended doses of misoprostol tablets. clinical studies in a series of small short-term (about 1 week) placebo-controlled studies in healthy human volunteers, doses of misoprostol were evaluated for their ability to reduce the risk of nsaid-induced mucosal injury. studies of 200 mcg q.i.d. of misoprostol with tolmetin and naproxen, and of 100 and 200 mcg q.i.d. with ibuprofen, all showed reduction of the rate of significant endoscopic injury from about 70 to 75% on placebo to 10 to 30% on misoprostol. doses of 25 to 200 mcg q.i.d. reduced aspirin-induced mucosal injury and bleeding. reducing the risk of gastric ulcers caused by nonsteroidal anti-inflammatory drugs (nsaids) two 12-week, randomized, double-blind trials in osteoarthritic patients who had gastrointestinal symptoms but no ulcer on endoscopy while taking an nsaid compared the ability of 200 mcg of misoprostol tablets, 100 mcg of misoprostol tablets, and placebo to reduce the risk of gastric ulcer (gu) formation. patients were approximately equally divided between ibuprofen, piroxicam, and naproxen, and continued this treatment throughout the 12 weeks. the 200-mcg dose caused a marked, statistically significant reduction in gastric ulcers in both studies. the lower dose was somewhat less effective, with a significant result in only one of the studies. reduction of risk of gastric ulcers induced by ibuprofen, piroxicam, or naproxen [no. of patients with ulcer(s) (%)] therapy duration therapy 4 weeks 8 weeks 12 weeks study no. 1 misoprostol tablets 200 mcg q.i.d. (n=74) 1 (1.4) 0 0 1 (1.4) statistically significantly different from placebo at the 5% level. misoprostol tablets 100 mcg q.i.d. (n=77) 3 (3.9) 1 (1.3) 1 (1.3) 5 (6.5) placebo (n=76) 11 (14.5) 4 (5.3) 4 (5.3) 19 (25.0) study no. 2 misoprostol tablets 200 mcg q.i.d. (n=65) 1 (1.5) 1 (1.5) 0 2 (3.1) misoprostol tablets 100 mcg q.i.d. (n=66) 2 (3.0) 2 (3.0) 1 (1.5) 5 (7.6) placebo (n=62) 6 (9.7) 2 (3.2) 3 (4.8) 11 (17.7) studies no. 1 & no. 2 combined data from study no. 1 and study no. 2. misoprostol tablets 200 mcg q.i.d. (n=139) 2 (1.4) 1 (0.7) 0 3 (2.2) misoprostol tablets 100 mcg q.i.d. (n=143) 5 (3.5) 3 (2.1) 2 (1.4) 10 (7.0) placebo (n=138) 17 (12.3) 6 (4.3) 7 (5.1) 30 (21.7) in these trials there were no significant differences between misoprostol tablets and placebo in relief of day or night abdominal pain. no effect of misoprostol tablets in reducing the risk of duodenal ulcers was demonstrated, but relatively few duodenal lesions were seen. in another clinical trial, 239 patients receiving aspirin 650 to 1300 mg q.i.d. for rheumatoid arthritis who had endoscopic evidence of duodenal and/or gastric inflammation were randomized to misoprostol 200 mcg q.i.d. or placebo for 8 weeks while continuing to receive aspirin. the study evaluated the possible interference of misoprostol tablets on the efficacy of aspirin in these patients with rheumatoid arthritis by analyzing joint tenderness, joint swelling, physician's clinical assessment, patient's assessment, change in ara classification, change in handgrip strength, change in duration of morning stiffness, patient's assessment of pain at rest, movement, interference with daily activity, and esr. misoprostol tablets did not interfere with the efficacy of aspirin in these patients with rheumatoid arthritis.

misoprostol acid is reduced by use of concomitant antacid. clinical trials were conducted with concomitant antacid, however, so this effect does not appear to be clinically important. mean ± sd cmax(pg/ml) auc(0–4)(pg∙hr/ml) tmax(min) fasting 811 ± 317 417 ± 135 14 ± 8 with antacid 689 ± 315 349 ± 108 comparisons with fasting results statistically significant, p<0.05. 20 ± 14 with high fat breakfast 303 ± 176 373 ± 111 64 ± 79 after oral administration of radiolabeled misoprostol, about 80% of detected radioactivity appears in urine. pharmacokinetic studies in patients with varying degrees of renal impairment showed an approximate doubling of t1/2, cmax , and auc compared to normals, but no clear correlation between the degree of impairment and auc. in subjects over 64 years of age, the auc for misoprostol acid is increased. no routine dosage adjustment is recommended in older patients or patients with renal impairment, but dosage may need to be reduced if the usual dose is not tolerated. drug interaction studies between misoprostol and several nonsteroidal anti-inflammatory drugs showed no effect on the kinetics of ibuprofen or diclofenac, and a 20% decrease in aspirin auc, not thought to be clinically significant. pharmacokinetic studies also showed a lack of drug interaction with antipyrine and propranolol when these drugs were given with misoprostol. misoprostol given for 1 week had no effect on the steady state pharmacokinetics of diazepam when the two drugs were administered 2 hours apart. the serum protein binding of misoprostol acid is less than 90% and is concentration-independent in the therapeutic range. after a single oral dose of misoprostol to nursing mothers, misoprostol acid was excreted in breast milk. the maximum concentration of misoprostol acid in expressed breast milk was achieved within 1 hour after dosing and was 7.6 pg/ml (cv 37%) and 20.9 pg/ml (cv 62%) after single 200 mg and 600 mg misoprostol administration, respectively. the misoprostol acid concentrations in breast milk declined to < 1 pg/ml at 5 hours post-dose.

nant. the misoprostol tablets package the patient receives from the pharmacist will include a leaflet containing patient information. the patient should read the leaflet before taking misoprostol tablets and each time the prescription is renewed because the leaflet may have been revised. keep misoprostol tablets out of the reach of children. special note for women: misoprostol tablets may cause abortion (sometimes incomplete), premature labor, or birth defects if given to pregnant women. misoprostol tablets is available only as a unit-of-use package that includes a leaflet containing patient information. see patient information at the end of this labeling.