Oral Antidiabetic Agent – Alpha-glucosidase Inhibitor
Action And Clinical Pharmacology: Acarbose is a complex oligosaccharide that inhibits a-glucosidase activity in the brush border membrane of the small intestine. This delays the digestion of ingested carbohydrates, thereby resulting in a smoothing and lowering of blood glucose concentration following meals (postprandial). As a consequence of decreases in plasma glucose postprandial increases, acarbose reduces levels of glycosylated hemoglobin in patients with Type II (non-insulin dependent) diabetes mellitus. Systemic nonenzymatic protein glycosylation, as reflected by levels of glycosylated hemoglobin, is a function of average blood glucose concentration over time.
Mechanism of Action: Acarbose does not enhance insulin secretion. The antihyperglycemic action of acarbose results from a competitive, reversible inhibition of pancreatic a-amylase and membrane bound intestinal a-glucoside hydrolase enzymes. Pancreatic a-amylase hydrolyzes complex starches to oligosaccharides in the lumen of the small intestine, while the membrane-bound intestinal a-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 smoothing and lowering of postprandial hyperglycemia, resulting in improved glycemic control.
Because its mechanism of action is different, the effect of acarbose in enhancing glycemic control is additive to that of sulfonylureas when used in combination. In addition, acarbose diminishes the insulinotropic and weight-increasing effects of sulfonylureas.
Acarbose has no inhibitory activity against lactase and consequently does not induce lactose intolerance.
Pharmacokinetics: Absorption: One to 2% of an oral dose of acarbose is absorbed from the gastrointestinal tract as unchanged drug. When 4-labelled acarbose was administered orally, approximately 35% of the total radioactivity (changed and unchanged drug) was absorbed. An average of 51% of an oral dose was excreted in the feces as unabsorbed drug-related radioactivity within 96 hours of ingestion. Because acarbose acts locally within the gastrointestinal tract, this low systemic bioavailability of parent compound is therapeutically desired. Following oral dosing of healthy volunteers with 4-labelled acarbose, peak plasma concentrations of radioactivity were attained 14 to 24 hours after dosing, while peak plasma concentrations of active drug were attained at approximately 1 hour. The delayed absorption of acarbose-related radioactivity reflects the absorption of metabolites that may be formed by either intestinal bacteria or intestinal enzymatic hydrolysis.
Metabolism: Acarbose is metabolized exclusively within the gastrointestinal tract, principally by intestinal bacteria, but also by digestive enzymes. A fraction of these metabolites (approximately 34% of the dose) was absorbed and subsequently excreted in the urine. At least 13 metabolites have been separated chromatographically from urine specimens. The major metabolites have been identified as 4-methylpyrogallol derivatives (i.e., sulfate, methyl, and glucuronide conjugates). One metabolite (formed by cleavage of a glucose molecule from acarbose) also has a-glucosidase inhibitory activity. This metabolite, together with the parent compound, recovered from the urine, accounts for less than 2% of the total administered dose.
Excretion: The fraction of acarbose that is absorbed as intact drug is almost completely excreted by the kidneys. When acarbose was given i.v., 89% of the dose was recovered in the urine as active drug within 48 hours. In contrast, less than 2% of an oral dose was recovered in the urine as active (i.e., parent compound and active metabolite) drug. This is consistent with the low bioavailability of the parent drug. The plasma elimination half-life of acarbose activity is approximately 2 hours in healthy volunteers. Consequently, drug accumulation does not occur with 3 times a day (t.i.d.) oral dosing.
Indications And Clinical Uses: As monotherapy, acarbose is indicated as adjunct to prescribed diet for the management of blood glucose levels in non-insulin dependent diabetic patients who are inadequately controlled by diet alone.
Acarbose may also be used in combination with a sulfonylurea when diet plus either acarbose or a sulfonylurea do not result in adequate glycemic control. The effect of acarbose in enhancing glycemic control is additive to that of sulfonylureas when used in combination because of its different mechanism of action.
In initiating treatment for NIDDM, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling blood glucose and symptoms of hyperglycemia. The importance of regular physical activity when appropriate should also be stressed. If this treatment program fails to result in adequate glycemic control, the use of acarbose should be considered. The use of acarbose must be viewed by both the physician and patient as a treatment in addition to diet, and not as a substitute for diet or as a convenient mechanism for avoiding dietary restraint. Acarbose should be considered as complementary to dietary therapy and physical exercise before resorting to other forms of treatment, such as oral hypoglycemics.
Contra-Indications: Patients with hypersensitivity to acarbose and patients with diabetic ketoacidosis. It is also contraindicated in patients with inflammatory bowel disease, colonic ulceration, partial intestinal obstruction or in patients predisposed to intestinal obstruction. In addition, acarbose should not be used in patients who have chronic intestinal diseases associated with marked disorders of digestion or absorption and in patients who suffer from states which may deteriorate as a result of increased gas formation in the intestine, e.g. larger hernias. tag_WarningWarnings
Manufacturers’ Warnings In Clinical States: Transaminases: Acarbose may give rise to elevations of serum transaminases and, in rare instances, hyperbilirubinemia. If elevated transaminase levels are observed, a reduction in dosage or withdrawal of therapy may be indicated, particularly if the elevations persist.
Precautions: General: Increased use of sucrose (cane sugar) and food that contains sucrose can lead to gastrointestinal symptoms (e.g., flatulence and bloating) and also loose stools and occasionally diarrhea as a result of increased carbohydrate fermentation in the colon during acarbose treatment.
Acarbose delays glucose absorption and lowers hyperglycemia following meals. Regular intake of acarbose should not be interrupted without the physician’s knowledge, since such interruption can cause a rise in blood glucose.
Hypoglycemia: Because of its mechanism of action, acarbose when administered alone will not cause hypoglycemia in the fasted or postprandial state. Sulfonylurea agents may cause hypoglycemia. Because acarbose given with a sulfonylurea will cause a further lowering of blood glucose, it may increase the hypoglycemic potential of the sulfonylurea. Oral glucose (dextrose), whose absorption is not inhibited by acarbose, 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 acarbose, is unsuitable for the rapid correction of hypoglycemia. Severe hypoglycemia may require the use of either i.v. glucose infusion or glucagon injection.
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.
Geriatrics: No special precautions are necessary with acarbose treatment in the elderly. Elderly patients receiving acarbose may require more intensive supervision and follow-up.
Children: Safety and effectiveness of acarbose in patients
Pregnancy: There are no adequate and well-controlled studies of acarbose in pregnant women and its use in these patients is not recommended.
Lactation : A small amount of radioactivity has been found in the milk of lactating rats after administration of radiolabelled acarbose. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, acarbose should not be administered to a nursing woman.
Patients with Special Diseases and Conditions: See Warnings regarding elevated serum transaminases.
Renal: Plasma concentrations of acarbose 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 (creatinine clearance
In one species of rats studied an increased incidence of renal tumors was observed. This was not seen in any other species of rats or other animals studied. When malnutrition was prevented in these rats, acarbose did not increase the incidence of renal tumors.
Drug Interactions: General: Certain drugs tend to produce hyperglycemia and may lead to loss of blood glucose control. These drugs include diuretics (thiazides, furosemide), corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics and isoniazid. When such drugs are administered to a patient receiving acarbose, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from patients receiving acarbose in combination with sulfonylureas, patients should be observed closely for evidence of hypoglycemia.
Intestinal Absorbents: Intestinal absorbents (e.g., charcoal) and digestive enzyme preparations containing carbohydrate-splitting enzymes (amylase, pancreatin) may reduce the effect of acarbose and should not be taken concomitantly.
Antacids: The concomitant administration of acarbose and an antacid does not alter the effect of acarbose. The administration of antacid preparations is unlikely to ameliorate the gastrointestinal symptoms of acarbose and therefore should not be recommended to patients for this purpose.
Cholestyramine: The concomitant administration of cholestyramine may enhance the effects of acarbose, particularly with respect to reducing postprandial insulin levels. In healthy volunteers, a rebound phenomenon with respect to the postprandial insulin response was observed when both acarbose and cholestyramine therapy were withdrawn simultaneously.
Other Drugs: Studies in healthy volunteers have shown that acarbose has no effect on either the pharmacokinetics or pharmacodynamics of digoxin, nifedipine, propranolol or ranitidine.
Acarbose did not interfere with the absorption or disposition of the sulfonylurea glyburide in diabetic patients.
Acarbose delays the intestinal absorption of metformin but does not reduce its overall bioavailability.
Laboratory Tests: Therapeutic response to acarbose should be monitored by periodic postprandial blood glucose tests. Measurement of glycosylated hemoglobin levels is recommended for the monitoring of long-term glycemic control.
Adverse Reactions: In placebo controlled pivotal studies of Â³6 months duration, adverse experiences were reported in 53% of patients receiving placebo and in 77% of patients treated with acarbose. The majority of adverse experiences were gastrointestinal symptoms which result from the pharmacodynamic action of the drug. The majority of symptoms were of mild or moderate intensity and were dose-dependent. The symptoms occurred early (within 1 to 2 months of treatment) and improved tolerability with longer duration of treatment was observed. Rarely, these gastrointestinal events may be severe and might be confused with ileus/ileus-like symptoms. Therapy was discontinued prematurely due to adverse events in 14% of acarbose-treated patients and 5% of placebo-treated patients.
The following adverse events (>3%) were reported at acarbose doses of 50 to 300 mg given 3 times daily (see Table I). The maximum recommended daily dose is 100 mg 3 times daily.
The only significant difference in the incidence of adverse events between acarbose and placebo were gastrointestinal symptoms (e.g., flatulence, diarrhea and abdominal pain) which can be minimized by starting on a low dose and titrating slowly (see Dosage).
Rarely, hypersensitive skin reactions, such as erythema, exanthema and urticaria and cases of hepatitis and jaundice have been reported.
Laboratory Tests: In clinical trials, at doses of 50 mg t.i.d. and 100 mg t.i.d., the incidence of serum transaminase elevations with acarbose was the same as with placebo. In approximately 3 million patient-years of international postmarketing experience with acarbose, 62 cases of serum transaminase elevations Â³500 IU/L have been reported, 29 of which were associated with jaundice. In most cases where followup was reported, hepatic dysfunction improved or resolved upon discontinuation of acarbose. Therefore, when appropriate, liver enzyme monitoring should be considered during the first 6 to 12 months.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Unlike sulfonylureas, an overdose of acarbose will not result in hypoglycemia. When acarbose is taken with drinks and/or meals containing carbohydrates (polysaccharides, oligosaccharides or disaccharides), overdosage can lead to abdominal distention, flatulence and diarrhea. In the event of acarbose being taken in an overdose independent of food, excessive intestinal symptoms need not be anticipated.
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.
Dosage And Administration: There is no fixed dosage regimen for the management of diabetes mellitus with acarbose or any other pharmacologic agent. Dosage of acarbose must be individualized on the basis of both effectiveness and tolerance while not exceeding 100 mg t.i.d. 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), 2-hour postprandial plasma glucose should be used to determine the therapeutic response to acarbose and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately 3 months. The therapeutic goal should be to decrease both postprandial plasma glucose and glycosylated hemoglobin levels to optimal or near optimal by using the lowest effective dose of acarbose.
Initial Dosage: The usual starting dosage is 50 mg given orally once daily. After 1 to 2 weeks, the dosage should be increased to 50 mg b.i.d. with a subsequent increase to 50 mg t.i.d. after a further 1 to 2 weeks. Each dose should be taken with the first bite of a main meal.
Maintenance Dosage: Once a maintenance dose of 50 mg t.i.d. has been reached, 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. The dosage should be adjusted at 4 to 8 week intervals based on 2-hour postprandial glucose levels and on tolerance. Consideration should be given to lowering the dose if no further reduction in postprandial glucose or glycosylated hemoglobin levels is observed after titration to 100 mg t.i.d. Once an effective and tolerated dosage is established, it should be maintained.
Maximum Dosage: Dosages above 100 mg t.i.d. are not recommended.
Patients Receiving Sulfonylureas: Sulfonylurea agents may cause hypoglycemia. Therefore, acarbose given in combination with a sulfonylurea may also cause hypoglycemia. If hypoglycemia occurs, appropriate adjustment in the sulfonylurea dosage should be made.
Availability And Storage: 50 mg: Each round, off-white, scored tablet, marked with “G50” on one side and the Bayer cross on the other, contains: acarbose 50 mg. Nonmedicinal ingredients: cornstarch, magnesium stearate, microcrystalline cellulose and silicon dioxide. Preservative- and dye-free. Blister packs in cartons of 120.
100 mg: Each round, off-white, scored tablet, marked with “G100” on one side and the Bayer cross on the other, contains: acarbose 100 mg. Nonmedicinal ingredients: cornstarch, magnesium stearate, microcrystalline cellulose and silicon dioxide. Preservative- and dye-free. Blister packs in cartons of 120.
Store between 15 and 25Â°C. At temperatures >25Â°C and at a relative humidity of >75%, discoloration may occur in tablets that have been removed from the pack. The tablets should therefore not be removed from the foil until immediately before use.
PRANDASEÂ® Bayer Acarbose Oral Antidiabetic Agent – Alpha-glucosidase Inhibitor