Miglitol

ADVERSE REACTIONS Gastrointestinal Gastrointestinal symptoms are the most common reactions to miglitol tablets. In U.S. placebo-controlled trials, the incidences of abdominal pain, diarrhea, and flatulence were 11.7%, 28.7%, and 41.5% respectively in 962 patients treated with miglitol tablets, 25 mg to 100 mg 3 times daily, whereas the corresponding incidences were 4.7%, 10.0%, and 12.0% in 603 placebo-treated patients. The incidence of diarrhea and abdominal pain tended to diminish with continued treatment. Dermatologic Skin rash was reported in 4.3% of patients treated with miglitol tablets compared to 2.4% of placebo-treated patients. Rashes were generally transient and most were assessed as unrelated to miglitol tablets by physician investigators. Abnormal Laboratory Findings Low serum iron occurred more often in patients treated with miglitol tablets (9.2%) than in placebo-treated patients (4.2%) but did not persist in the majority of cases and was not associated with reductions in hemoglobin or changes in other hematologic indices. Postmarketing Experience The following adverse reactions have been reported during post-approval use of miglitol tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: ileus (including paralytic ileus), subileus, gastrointestinal pain, nausea, abdominal distention. Pneumatosis Cystoides Intestinalis There have been rare postmarketing reports of pneumatosis cystoides intestinalis associated with the use of alpha-glucosidase inhibitors, including miglitol tablets. Pneumatosis cystoides intestinalis may present with symptoms of diarrhea, mucus discharge, rectal bleeding, and constipation. Complications may include pneumoperitoneum, volvulus, intestinal obstruction, intussusception, intestinal hemorrhage, and intestinal perforation. If pneumatosis cystoides intestinalis is suspected, discontinue miglitol tablets and perform the appropriate diagnostic imaging.

Drug Interactions Several studies investigated the possible interaction between miglitol and glyburide. In six healthy volunteers given a single dose of 5 mg glyburide on a background of 6 days treatment with miglitol (50 mg 3 times daily for 4 days followed by 100 mg 3 times daily for 2 days) or placebo, the mean C max and AUC values for glyburide were 17% and 25% lower, respectively, when glyburide was given with miglitol. In a study in diabetic patients in which the effects of adding miglitol 100 mg 3 times daily for 7 days or placebo to a background regimen of 3.5 mg glyburide daily were investigated, the mean AUC value for glyburide was 18% lower in the group treated with miglitol, although this difference was not statistically significant. Information on a potential interaction with glyburide was obtained from one of the large U.S. clinical trials (Study 7) in which patients were dosed with either miglitol or placebo on a background of glyburide 10 mg twice daily. At the 6-month and 1-year clinic visits, patients taking concomitant miglitol 100 mg 3 times daily exhibited mean C max values for glyburide that were 16% and 8% lower, respectively, compared to patients taking glyburide alone. However, these differences were not statistically significant. Thus, although there was a trend toward lower AUC and C max values for glyburide when co-administered with miglitol tablets, no definitive statement regarding a potential interaction can be made based on the foregoing three studies. The effect of miglitol (100 mg 3 times daily for 7 days) on the pharmacokinetics of a single 1000 mg dose of metformin was investigated in healthy volunteers. Mean AUC and C max values for metformin were 12% to 13% lower when the volunteers were given miglitol as compared with placebo, but this difference was not statistically significant. In a study with healthy volunteers, co-administration of either 50 mg or 100 mg miglitol 3 times daily together with digoxin reduced the average plasma concentrations of digoxin by 19% and 28%, respectively. However, in diabetic patients under treatment with digoxin, plasma digoxin concentrations were not altered by co-administration of miglitol 100 mg 3 times daily for 14 days. Other healthy volunteer studies have demonstrated that miglitol may significantly reduce the bioavailability of ranitidine and propranolol by 60% and 40%, respectively. No effect of miglitol was observed on the pharmacokinetics or pharmacodynamics of either warfarin or nifedipine. Intestinal adsorbents (e.g., charcoal) and digestive enzyme preparations containing carbohydrate-splitting enzymes (e.g., amylase, pancreatin) may reduce the effect of miglitol tablets and should not be taken concomitantly. In 12 healthy males, concomitantly administered antacid did not influence the pharmacokinetics of miglitol.

Pregnancy Teratogenic Effects Pregnancy Category B The safety of miglitol tablets in pregnant women has not been established. Developmental toxicology studies have been performed in rats at doses of 50, 150 and 450 mg/kg, corresponding to levels of approximately 1.5, 4, and 12 times the maximum recommended human exposure based on body surface area. In rabbits, doses of 10, 45, and 200 mg/kg corresponding to levels of approximately 0.5, 3, and 10 times the human exposure were examined. These studies revealed no evidence of fetal malformations attributable to miglitol. Doses of miglitol up to 4 and 3 times the human dose (based on body surface area), for rats and rabbits respectively, did not reveal evidence of impaired fertility or harm to the fetus. The highest doses tested in these studies, 450 mg/kg in the rat and 200 mg/kg in the rabbit promoted maternal and/or fetal toxicity. Fetotoxicity was indicated by a slight but significant reduction in fetal weight in the rat study and slight reduction in fetal weight, delayed ossification of the fetal skeleton and increase in the percentage of non-viable fetuses in the rabbit study. In the peri-postnatal study in rats, the NOAEL (No Observed Adverse Effect Level) was 100 mg/kg (corresponding to approximately four times the exposure to humans, based on body surface area). An increase in stillborn progeny was noted at the high dose (300 mg/kg) in the rat peri-postnatal study, but not at the high dose (450 mg/kg) in the delivery segment of the rat developmental toxicity study. Otherwise, there was no adverse effect on survival, growth, development, behavior, or fertility in either the rat developmental toxicity or peri-postnatal studies. There are however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, miglitol should be used during pregnancy only if clearly needed.