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General

Hypoglycemia: Because of its mechanism of action, PRECOSE® when administered alone should not cause hypoglycemia in the fasted or postprandial state. Sulfonylurea agents or insulin may cause hypoglycemia. Because PRECOSE® given in combination with a sulfonylurea or insulin will cause a further lowering of blood glucose, it may increase the potential for hypoglycemia. Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, and no increased incidence of hypoglycemia was observed in patients when PRECOSE® was added to metformin therapy. Oral glucose (dextrose), whose absorption is not inhibited by PRECOSE®, should be used instead of sucrose (cane sugar) in the treatment of mild to moderate hypoglycemia. Sucrose, whose hydrolysis to glucose and fructose is inhibited by PRECOSE®, is unsuitable for the rapid correction of hypoglycemia. Severe hypoglycemia may require the use of either intravenous glucose infusion or glucagon injection.

Elevated Serum Transaminase Levels: In long-term studies (up to 12 months, and including PRECOSE® doses up to 300 mg t.i.d.) conducted in the United States, treatment-emergent elevations of serum transaminases (AST and/or ALT) above the upper limit of normal (ULN), greater than 1.8 times the ULN, and greater than 3 times the ULN occurred in 14%, 6%, and 3%, respectively, of PRECOSE®-treated patients as compared to 7%, 2%, and 1%, respectively, of placebo-treated patients. Although these differences between treatments were statistically significant, these elevations were asymptomatic, reversible, more common in females, and, in general, were not associated with other evidence of liver dysfunction. In addition, these serum transaminase elevations appeared to be dose related. In US studies including PRECOSE® doses up to the maximum approved dose of 100 mg t.i.d., treatment-emergent elevations of AST and/or ALT at any level of severity were similar between PRECOSE®-treated patients and placebo-treated patients (p ≥ 0.496).

In approximately 3 million patient-years of international post-marketing experience with PRECOSE®, 62 cases of serum transaminase elevations > 500 IU/L (29 of which were associated with jaundice) have been reported. Forty-one of these 62 patients received treatment with 100 mg t.i.d. or greater and 33 of 45 patients for whom weight was reported weighed < 60 kg. In the 59 cases where follow-up was recorded, hepatic abnormalities improved or resolved upon discontinuation of PRECOSE® in 55 and were unchanged in two. A few cases of fulminant hepatitis with fatal outcome have been reported; the relationship to acarbose is unclear.

Loss of Control of Blood Glucose: When diabetic patients are exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of control of blood glucose may occur. At such times, temporary insulin therapy may be necessary.

Laboratory Tests: Therapeutic response to PRECOSE® should be monitored by periodic blood glucose tests. Measurement of glycosylated hemoglobin levels is recommended for the monitoring of long-term glycemic control.

PRECOSE®, particularly at doses in excess of 50 mg t.i.d., may give rise to elevations of serum transaminases and, in rare instances, hyperbilirubinemia. It is recommended that serum transaminase levels be checked every 3 months during the first year of treatment with PRECOSE® and periodically thereafter. If elevated transaminases are observed, a reduction in dosage or withdrawal of therapy may be indicated, particularly if the elevations persist.

Renal Impairment: Plasma concentrations of PRECOSE® in renally impaired volunteers were proportionally increased relative to the degree of renal dysfunction. Long-term clinical trials in diabetic patients with significant renal dysfunction (serum creatinine > 2.0 mg/dL) have not been conducted. Therefore, treatment of these patients with PRECOSE® is not recommended.

Carcinogenesis, Mutagenesis, and Impairment of Fertility: Eight carcinogenicity studies were conducted with acarbose. Six studies were performed in rats (two strains, Sprague-Dawley and Wistar) and two studies were performed in hamsters.

In the first rat study, Sprague-Dawley rats received acarbose in feed at high doses (up to approximately 500 mg/kg body weight) for 104 weeks. Acarbose treatment resulted in a significant increase in the incidence of renal tumors (adenomas and adenocarcinomas) and benign Leydig cell tumors. This study was repeated with a similar outcome. Further studies were performed to separate direct carcinogenic effects of acarbose from indirect effects resulting from the carbohydrate malnutrition induced by the large doses of acarbose employed in the studies. In one study using Sprague-Dawley rats, acarbose was mixed with feed but carbohydrate deprivation was prevented by the addition of glucose to the diet. In a 26-month study of Sprague-Dawley rats, acarbose was administered by daily postprandial gavage so as to avoid the pharmacologic effects of the drug. In both of these studies, the increased incidence of renal tumors found in the original studies did not occur. Acarbose was also given in food and by postprandial gavage in two separate studies in Wistar rats. No increased incidence of renal tumors was found in either of these Wistar rat studies. In two feeding studies of hamsters, with and without glucose supplementation, there was also no evidence of carcinogenicity.

Acarbose did not induce any DNA damage in vitro in the CHO chromosomal aberration assay, bacterial mutagenesis (Ames) assay, or a DNA binding assay. In vivo, no DNA damage was detected in the dominant lethal test in male mice, or the mouse micronucleus test.

Fertility studies conducted in rats after oral administration produced no untoward effect on fertility or on the overall capability to reproduce.

Pregnancy

Teratogenic Effects: Pregnancy Category B. The safety of PRECOSE® in pregnant women has not been established. Reproduction studies have been performed in rats at doses up to 480 mg/kg (corresponding to 9 times the exposure in humans, based on drug blood levels) and have revealed no evidence of impaired fertility or harm to the fetus due to acarbose. In rabbits, reduced maternal body weight gain, probably the result of the pharmacodynamic activity of high doses of acarbose in the intestines, may have been responsible for a slight increase in the number of embryonic losses. However, rabbits given 160 mg/kg acarbose (corresponding to 10 times the dose in man, based on body surface area) showed no evidence of embryotoxicity and there was no evidence of teratogenicity at a dose 32 times the dose in man (based on body surface area). There are, however, no adequate and well-controlled studies of PRECOSE® in pregnant women. Because animal reproduction studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies as well as increased neonatal morbidity and mortality, most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.

Nursing Mothers: A small amount of radioactivity has been found in the milk of lactating rats after administration of radiolabeled acarbose. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, PRECOSE® should not be administered to a nursing woman.

Pediatric Use: Safety and effectiveness of PRECOSE® in pediatric patients have not been established.

Geriatric Use: Of the total number of subjects in clinical studies of PRECOSE® in the United States, 27 percent were 65 and over, while 4 percent were 75 and over. No overall differences in safety and effectiveness were observed between these subjects and younger subjects. The mean steady-state area under the curve (AUC) and maximum concentrations of acarbose were approximately 1.5 times higher in elderly compared to young volunteers; however, these differences were not statistically significant.

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