Mechanism of Action:

In contrast to sulfonylureas, Acarbose Tablets do not enhance insulin secretion. The antihyperglycemic action of 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 Tablets to enhance glycemic control is additive to that of sulfonylureas, insulin or metformin when used in combination. In addition, Acarbose Tablets diminish the insulinotropic and weight-increasing effects of sulfonylureas.

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

Pharmacokinetics

Drug-Drug Interactions

Studies in healthy volunteers have shown that Acarbose Tablets have no effect on either the pharmacokinetics or pharmacodynamics of nifedipine, propranolol, or ranitidine. Acarbose Tablets did not interfere with the absorption or disposition of the sulfonylurea glyburide in diabetic patients. Acarbose Tablets may affect digoxin bioavailability and may require dose adjustment of digoxin by 16% (90% confidence interval: 8 to 23%), decrease mean Cmax of digoxin by 26% (90% confidence interval: 16 to 34%) and decreases mean trough concentrations of digoxin by 9% (90% confidence limit: 19% decrease to 2% increase). (See PRECAUTIONS, Drug Interactions).

The amount of metformin absorbed while taking Acarbose Tablets was bioequivalent to the amount absorbed when taking placebo, as indicated by the plasma AUC values. However, the peak plasma level of metformin was reduced by approximately 20% when taking Acarbose Tablets due to a slight delay in the absorption of metformin. There is little if any clinically significant interaction between Acarbose Tablets and metformin.

Clinical Experience from Dose Finding Studies in Type 2 Diabetes Mellitus Patients on Dietary Treatment Only

Results from six controlled, fixed-dose, monotherapy studies of Acarbose Tablets in the treatment of type 2 diabetes mellitus, involving 769 Acarbose Tablets-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 Tablets were 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 Tablets regimen was superior to lower doses, but there were no statistically significant differences from 50 to 200 mg t.i.d.

Figure 1 Dose of Acarbose Tablets (t.i.d.)*

Clinical Experience in Type 2 Diabetes Mellitus Patients on Monotherapy, or in Combination with Sulfonylureas, Metformin or Insulin

Acarbose Tablets were studied as monotherapy 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 Tablets 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 Tablets 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 Tablets 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 Tablets 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 -36.0 mg/dL.

A one year study of Acarbose Tablets 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 Tablets was statistically significant at six months, and this effect was persistent at one year. In the Acarbose Tablets-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

Figure 2: Effects of Acarbose Tablets (▪) 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 < 0.01; # p = 0.077.

General

Information for Patients:

Patients should be told to take Acarbose Tablets 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 Tablets 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 Tablets 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 Tablets were 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 Tablets prevent 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 Tablets in combination with a sulfonylurea or insulin.

If side effects occur with Acarbose Tablets, 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.

Laboratory Tests:

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

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

Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking acarbose. Use alternative methods to monitor for glycemic control.

Renal Impairment:

Plasma concentrations of Acarbose Tablets 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 mg/dL) have not been conducted. Therefore, treatment of these patients with Acarbose Tablets is not recommended.

Drug Interactions

Certain drugs tend to produce hyperglycemia and may lead to loss of blood glucose control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel-blocking drugs, and isoniazid. When such drugs are administered to a patient receiving Acarbose Tablets, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from patients receiving Acarbose Tablets in combination with sulfonylureas or insulin, patients should be observed closely for any evidence of hypoglycemia.

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

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, Acarbose Tablets should not be administered to a nursing woman.

Pediatric Use:

Safety and effectiveness of Acarbose Tablets in pediatric patients have not been established.

Geriatric Use:

Of the total number of subjects in clinical studies of Acarbose Tablets in the United States, 27% were 65 and over, while 4% 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.

Digestive Tract:

Gastrointestinal symptoms are the most common reactions to Acarbose Tablets. 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 Tablets 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 Tablets are a manifestation of the mechanism of action of Acarbose Tablets 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.

Elevated Serum Transaminase Levels:

See PRECAUTIONS.

Other Abnormal Laboratory Findings:

Small reductions in hematocrit occurred more often in Acarbose Tablets-treated patients than in placebo-treated patients but were not associated with reductions in hemoglobin. Low serum calcium and low plasma vitamin B6 levels were associated with Acarbose Tablets therapy but are thought to be either spurious or of no clinical significance.

Postmarketing Adverse Event Reports:

Additional adverse events reported from worldwide postmarketing experience include fulminant hepatitis with fatal outcome, hypersensitive skin reactions (e.g. rash, erythema, exanthema and urticaria), edema, ileus/subileus, jaundice and/or hepatitis and associated liver damage, thrombocytopenia, and pneumatosis cystoids intestinalis (see PRECAUTIONS.)

Initial Dosage:

The recommended starting dosage of Acarbose Tablets is 25 mg given orally three times daily at the start (with the first bite) of each main meal. However, some patients may benefit from more gradual dose titration to minimize gastrointestinal side effects. This may be achieved by initiating treatment at 25 mg once per day and subsequently increasing the frequency of administration to achieve 25 mg t.i.d.

Maintenance Dosage:

Once a 25 mg t.i.d. dosage regimen is reached, dosage of Acarbose Tablets should be adjusted at 4 to 8 week intervals based on one-hour postprandial glucose or glycosylated hemoglobin levels, and on tolerance. The dosage can be increased from 25 mg t.i.d. to 50 mg t.i.d. Some patients may benefit from further increasing the dosage to 100 mg t.i.d. The maintenance dose ranges from 50 mg t.i.d. to 100 mg t.i.d. However, since patients with low body weight may be at increased risk for elevated serum transaminases, only patients with body weight > 60 kg should be considered for dose titration above 50 mg t.i.d. (see PRECAUTIONS). If no further reduction in postprandial glucose or glycosylated hemoglobin levels is observed with titration to 100 mg t.i.d., consideration should be given to lowering the dose. Once an effective and tolerated dosage is established, it should be maintained.

Maximum Dosage:

The maximum recommended dose for patient's ≤ 60 kg is 50 mg t.i.d. The maximum recommended dose for patients > 60 kg is 100 mg t.i.d.

Patients Receiving Sulfonylureas or Insulin:

Sulfonylurea agents or insulin may cause hypoglycemia. Acarbose Tablets given in combination with a sulfonylurea or insulin will cause a further lowering of blood glucose and may increase the potential for hypoglycemia. If hypoglycemia occurs, appropriate adjustments in the dosage of these agents should be made.