Acarbose (Acarbose) Tablets are an oral alpha-glucosidase inhibitor for use in the management of type 2 diabetes mellitus. Acarbose (Acarbose) is an oligosaccharide which is obtained from fermentation processes of a microorganism, and is chemically known as 4,6-dideoxy-4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl]amino]-α-D- glucopyranosyl-(1→4)--α-D-glucopyranosyl-(1→4)-D-glucose. It is a white to off-white powder with a molecular weight of 645.6. Acarbose (Acarbose) is soluble in water and has a pK of 5.1. Its molecular formula is CHNO and its chemical structure is as follows:

Acarbose (Acarbose) Tablets are available as 25 mg, 50 mg and 100 mg tablets for oral use. The inactive ingredients are colloidal silicon dioxide, corn starch, magnesium stearate and microcrystalline cellulose.

Acarbose (Acarbose) is a complex oligosaccharide that delays the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals. As a consequence of plasma glucose reduction, Acarbose (Acarbose) reduces levels of glycosylated hemoglobin in patients with type 2 diabetes mellitus. Systemic non-enzymatic protein glycosylation, as reflected by levels of glycosylated hemoglobin, is a function of average blood glucose concentration over time.

In contrast to sulfonylureas, Acarbose (Acarbose) does not enhance insulin secretion. The antihyperglycemic action of Acarbose (Acarbose) results from a competitive, reversible inhibition of pancreatic alpha-amylase and membrane-bound intestinal alpha-glucoside hydrolase enzymes. Pancreatic alpha-amylase hydrolyzes complex starches to oligosaccharides in the lumen of the small intestine, while the membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides in the brush border of the small intestine. In diabetic patients, this enzyme inhibition results in a delayed glucose absorption and a lowering of postprandial hyperglycemia.

Because its mechanism of action is different, the effect of Acarbose (Acarbose) to enhance glycemic control is additive to that of sulfonylureas, insulin or metformin when used in combination. In addition, Acarbose (Acarbose) diminishes the insulinotropic and weight-increasing effects of sulfonylureas.

Acarbose (Acarbose) has no inhibitory activity against lactase and consequently would not be expected to induce lactose intolerance.

Results from six controlled, fixed-dose, monotherapy studies of Acarbose (Acarbose) in the treatment of type 2 diabetes mellitus, involving 769 Acarbose (Acarbose) -treated patients, were combined and a weighted average of the difference from placebo in the mean change from baseline in glycosylated hemoglobin (HbA1c) was calculated for each dose level as presented below:

Results from these six fixed-dose, monotherapy studies were also combined to derive a weighted average of the difference from placebo in mean change from baseline for one-hour postprandial plasma glucose levels as shown in the following figure:

*Acarbose (Acarbose) was statistically significantly different from placebo at all doses with respect to effect on one‑hour postprandial plasma glucose.

**The 300 mg t.i.d. Acarbose (Acarbose) regimen was superior to lower doses, but there were no statistically significant differences from 50 to 200 mg t.i.d.

Acarbose (Acarbose) was studied as monotberapy and as combination therapy to sulfonylurea, metformin, or insulin treatment. The treatment effects on HbA1c levels and one-hour postprandial glucose levels are summarized for four placebo-controlled, double-blind, randomized studies conducted in the United States in Tables 2 and 3, respectively. The placebo-subtracted treatment differences, which are summarized below, were statistically significant for both variables in all of these studies.

Study 1 (N=109) involved patients on background treatment with diet only. The mean effect of the addition of Acarbose (Acarbose) to diet therapy was a change in HbA1c of -0.78%, and an improvement of one-hour postprandial glucose of -74.4 mg/dL.

In Study 2 (N=137), the mean effect of the addition of Acarbose (Acarbose) to maximum sulfonylurea therapy was a change in HbA1c of -0.54%, and an improvement of one-hour postprandial glucose of -33.5 mg/dL.

In Study 3 (N=147), the mean effect of the addition of Acarbose (Acarbose) to maximum metformin therapy was a change in HbA1c of -0.65%, and an improvement of one-hour postprandial glucose of -34.3 mg/dL.

Study 4 (N=145) demonstrated that Acarbose (Acarbose) added to patients on background treatment with insulin resulted in a mean change in HbA1c of -0.69%, and an improvement of one-hour postprandial glucose of -36 mg/dL.

A one year study of Acarbose (Acarbose) as monotherapy or in combination with sulfonylurea, metformin or insulin treatment was conducted in Canada in which 316 patients were included in the primary efficacy analysis (Figure 2). In the diet, sulfonylurea and metformin groups, the mean decrease in HbA1c produced by the addition of Acarbose (Acarbose) was statistically significant at six months, and this effect was persistent at one year. In the Acarbose (Acarbose) -treated patients on insulin, there was a statistically significant reduction in HbA1c at six months, and a trend for a reduction at one year.

Figure 2: Effects of Acarbose (Acarbose) (■) and placebo (●) on mean change in HbA1c levels from baseline throughout a one-year study in patients with type 2 diabetes mellitus when used in combination with: (A) diet alone; (B) sulfonylurea; (C) metformin; or (D) insulin. Treatment differences at 6 and 12 months were tested: *p

Acarbose (Acarbose) Tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Acarbose (Acarbose) Tablets are contraindicated in patients with known hypersensitivity to the drug and in patients with diabetic ketoacidosis or cirrhosis. Acarbose (Acarbose) Tablets are also contraindicated in patients with inflammatory bowel disease, colonic ulceration, partial intestinal obstruction or in patients predisposed to intestinal obstruction. In addition, Acarbose (Acarbose) Tablets are contraindicated in patients who have chronic intestinal diseases associated with marked disorders of digestion or absorption and in patients who have conditions that may deteriorate as a result of increased gas formation in the intestine.

Patients should be told to take Acarbose (Acarbose) orally three times a day at the start (with the first bite) of each main meal. It is important that patients continue to adhere to dietary instructions, a regular exercise program, and regular testing of urine and/or blood glucose.

Acarbose (Acarbose) itself does not cause hypoglycemia even when administered to patients in the fasted state. Sulfonylurea drugs and insulin, however, can lower blood sugar levels enough to cause symptoms or sometimes life-threatening hypoglycemia. Because Acarbose (Acarbose) given in combination with a sulfonylurea or insulin will cause a further lowering of blood sugar; it may increase the hypoglycemic potential of these agents. 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 Acarbose (Acarbose) was added to metformin therapy. The risk of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be well understood by patients and responsible family members. Because Acarbose (Acarbose) prevents the breakdown of table sugar, patients should have a readily available source of glucose (dextrose, D-glucose) to treat symptoms of low blood sugar when taking Acarbose (Acarbose) in combination with a sulfonylurea or insulin.

If side effects occur with Acarbose (Acarbose) , they usually develop during the first few weeks of therapy. They are most commonly mild-to-moderate gastrointestinal effects, such as flatulence, diarrhea, or abdominal discomfort, and generally diminish in frequency and intensity with time.

Therapeutic response to Acarbose (Acarbose) should be monitored by periodic blood glucose tests. Measurement of glycosylated hemoglobin levels is recommended for the monitoring of long-term glycemic control.

Acarbose (Acarbose) , 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 Acarbose (Acarbose) and periodically thereafter. If elevated transaminases are observed, a reduction in dosage or withdrawal of therapy may be indicated, particularly if the elevations persist.

Eight carcinogenicity studies were conducted with Acarbose (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 (Acarbose) in feed at high doses (up to approximately 500 mg/kg body weight) for 104 weeks. Acarbose (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 (Acarbose) from indirect effects resulting from the carbohydrate malnutrition induced by the large doses of Acarbose (Acarbose) employed in the studies. In one study using Sprague-Dawley rats, Acarbose (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 (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 (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 (Acarbose) did not induce any DNA damage in the CHO chromosomal aberration assay, bacterial mutagenesis (Ames) assay, or a DNA binding assay. , 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.

Gastrointestinal symptoms are the most common reactions to Acarbose (Acarbose) . In U.S. placebo-controlled trials, the incidences of abdominal pain, diarrhea, and flatulence were 19%, 31%, and 74% respectively in 1255 patients treated with Acarbose (Acarbose)   50 to 300 mg t.i.d., whereas the corresponding incidences were 9%, 12%, and 29% in 999 placebo-treated patients.

In a one-year safety study, during which patients kept diaries of gastrointestinal symptoms, abdominal pain and diarrhea tended to return to pretreatment levels over time, and the frequency and intensity of flatulence tended to abate with time. The increased gastrointestinal tract symptoms in patients treated with Acarbose (Acarbose) are a manifestation of the mechanism of action of Acarbose (Acarbose) and are related to the presence of undigested carbohydrate in the lower GI tract.

If the prescribed diet is not observed, the intestinal side effects may be intensified. If strongly distressing symptoms develop in spite of adherence to the diabetic diet prescribed, the doctor must be consulted and the dose temporarily or permanently reduced.

Unlike sulfonylureas or insulin, an overdose of Acarbose (Acarbose) will not result in hypoglycemia. An overdose may result in transient increases in flatulence, diarrhea, and abdominal discomfort which shortly subside. In cases of overdosage the patient should not be given drinks or meals containing carbohydrates (polysaccharides, oligosaccharides and disaccharides) for the next 4 to 6 hours.

There is no fixed dosage regimen for the management of diabetes mellitus with Acarbose (Acarbose) or any other pharmacologic agent. Dosage of Acarbose (Acarbose) must be individualized on the basis of both effectiveness and tolerance while not exceeding the maximum recommended dose of 100 mg t.i.d. Acarbose (Acarbose) should be taken three times daily at the start (with the first bite) of each main meal. Acarbose (Acarbose) should be started at a low dose, with gradual dose escalation as described below, both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient.

During treatment initiation and dose titration (see below), one-hour postprandial plasma glucose may be used to determine the therapeutic response to Acarbose (Acarbose) and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately three months.

The therapeutic goal should be to decrease both postprandial plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of Acarbose (Acarbose) , either as monotherapy or in combination with sulfonylureas, insulin or metformin.

Acarbose (Acarbose) Tablets are supplied as round, white to off-white, biconvex tablets. The 25 mg tablet is debossed with the product identification "54 311" on one side and plain on the other side.