Precose Information
Precose () Description
Precose () (acarbose tablets) is an oral alpha-glucosidase inhibitor for use in the management of type 2 diabetes mellitus. Acarbose is an oligosaccharide which is obtained from fermentation processes of a microorganism, Actinoplanes utahensis, and is chemically known as O-4,6-dideoxy- 4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl]amino]-α-D-glucopyranosyl-(1 → 4)-O-α-D-glucopyranosyl-(1 → 4)-D-glucose. It is a white to off-white powder with a molecular weight of 645.6. Acarbose is soluble in water and has a pKa of 5.1. Its empirical formula is CHNO and its chemical structure is as follows:
Precose () is available as 25 mg, 50 mg and 100 mg tablets for oral use. The inactive ingredients are starch, microcrystalline cellulose, magnesium stearate, and colloidal silicon dioxide.
Precose () Clinical Pharmacology
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, Precose () 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, Precose () does 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 Precose () to enhance glycemic control is additive to that of sulfonylureas, insulin or metformin when used in combination. In addition, Precose () diminishes 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.
Precose () Clinical Trials
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:
* Precose () 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. Precose () regimen was superior to lower doses, but there were no statistically significant differences from 50 to 200 mg t.i.d.
Study 1 (n=109) involved patients on background treatment with diet only. The mean effect of the addition of Precose () 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 Precose () 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 Precose () 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 Precose () 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 Precose () 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 Precose () was statistically significant at six months, and this effect was persistent at one year. In the Precose () -treated patients on insulin, there was a statistically significant reduction in HbA1c at six months, and a trend for a reduction at one year.
Precose () Indications And Usage
Precose () is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Precose () Contraindications
Precose () is contraindicated in patients with known hypersensitivity to the drug. Precose () is contraindicated in patients with diabetic ketoacidosis or cirrhosis. Precose () is also contraindicated in patients with inflammatory bowel disease, colonic ulceration, partial intestinal obstruction or in patients predisposed to intestinal obstruction. In addition, Precose () is 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.
Precose () Precautions
Patients should be told to take Precose () 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.
Precose () 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 Precose () 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 Precose () 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 Precose () 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 Precose () in combination with a sulfonylurea or insulin.
If side effects occur with Precose () , 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 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.
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 Precose () , the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from patients receiving Precose () in combination with sulfonylureas or insulin, patients should be observed closely for any evidence of hypoglycemia.
Patients Receiving Sulfonylureas or Insulin: Sulfonylurea agents or insulin may cause hypoglycemia. Precose () given in combination with a sulfonylurea or insulin may 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. Very rarely, individual cases of hypoglycemic shock have been reported in patients receiving Precose () therapy in combination with sulfonylureas and/or insulin.
Intestinal adsorbents (for example, charcoal) and digestive enzyme preparations containing carbohydrate-splitting enzymes (for example, amylase, pancreatin) may reduce the effect of Precose () and should not be taken concomitantly.
Precose () has been shown to change the bioavailability of digoxin when they are coadministered, which may require digoxin dose adjustment. (See CLINICAL PHARMACOLOGY, .
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 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.
Precose () Adverse Reactions
Gastrointestinal symptoms are the most common reactions to Precose () . 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 Precose () 50–300 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 Precose () are a manifestation of the mechanism of action of Precose () 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
Precose () Overdosage
Unlike sulfonylureas or insulin, an overdose of Precose () 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 4–6 hours.
Precose () Dosage And Administration
There is no fixed dosage regimen for the management of diabetes mellitus with Precose () or any other pharmacologic agent. Dosage of Precose () must be individualized on the basis of both effectiveness and tolerance while not exceeding the maximum recommended dose of 100 mg t.i.d. Precose () should be taken three times daily at the start (with the first bite) of each main meal. Precose () 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. 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.
During treatment initiation and dose titration (see below), one-hour postprandial plasma glucose may be used to determine the therapeutic response to Precose () 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 Precose () , either as monotherapy or in combination with sulfonylureas, insulin or metformin.
Precose () How Supplied
Precose () is available as 25 mg, 50 mg or 100 mg round, unscored tablets. Each tablet strength is white to yellow-tinged in color. The 25 mg tablet is coded with the word “Precose () ” on one side and “25” on the other side. The 50 mg tablet is coded with the word “Precose () ” and “50” on the same side. The 100 mg tablet is coded with the word “Precose () ” and “100” on the same side. Precose () is available in bottles of 100 and 50 mg strength in unit dose packages of 100.
Precose () Mg Tablets
80498595 50419-863-51
(acarbose tablets)
100 Tablets
Rx
Precose () Mg Tablets
80498609 50419-861-51
(acarbose tablets)
100 Tablets
Rx
Precose () Mg Tablets
80498625 50419-862-51
(acarbose tablets)
100 Tablets
Rx
Precose () Mg Tablets Unit Dose Package
80498617 50419-861-48
(acarbose tablets)
100 Tablets
Rx
