GLYBEK

Acarbose is a complex oligosaccharide that acts as an inhibitor of several enzymes responsible for the breakdown of complex carbohydrates in the intestines.

It inhibits both pancreatic alpha-amylase and membrane-bound alpha-glucosidases.

• including intestinal glucoamylase, sucrase, maltase, and isomaltase.

• which are responsible for the metabolism of complex starches and oligo-, tri-, and disaccharides into absorbable simple sugars. 7, 4 By inhibiting the activity of these enzymes, acarbose limits the absorption of dietary carbohydrates and the subsequent postprandial increase in blood glucose and insulin levels.

Acarbose is therefore used in conjunction with diet, exercise, and other pharmacotherapies for the management of blood sugar levels in patients with type 2 diabetes. 6, 7 Acarbose is one of only two approved alpha-glucosidase inhibitors (the other being miglitol ), receiving its first FDA approval in 1995 under the brand name Precose (since discontinued).

This class of antidiabetic therapy is not widely used due to their relatively modest impact on A1c, their requirement for thrice-daily dosing, and the potential for significant gastrointestinal adverse effects.

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

Acarbose is a complex oligosaccharide that competitively inhibits the ability of brush-border alpha-glucosidase enzymes to break down ingested carbohydrates into absorbable monosaccharides, reducing carbohydrate absorption and subsequent postprandial insulin levels.

Acarbose requires the co-administration of carbohydrates in order to exert its therapeutic effect, and as such should be taken with the first bite of a meal three times daily.

Given its mechanism of action, acarbose in isolation poses little risk of contributing to hypoglycemia.

• this risk is more pronounced, however, when acarbose is used in conjunction with other antidiabetic therapies (e.g. sulfonylureas, insulin).

Patients maintained on acarbose in addition to other antidiabetic agents should be aware of the symptoms and risks of hypoglycemia and how to treat hypoglycemic episodes.

There have been rare post-marketing reports of the development of pneumatosis cystoides intestinalis following treatment with alpha-glucosidase inhibitors.

• patients experiencing significant diarrhea/constipation, mucus discharge, and/or rectal bleeding should be investigated and, if pneumatosis cystoides intestinalis is suspected, should discontinue therapy.

The oral bioavailability of acarbose is extremely minimal, with less than 1-2% of Oral administered parent drug reaching the systemic circulation.

Despite this, approximately 35% of the total radioactivity from a radiolabeled and Oral administered dose of acarbose reaches the systemic circulation, with peak plasma radioactivity occurring 14-24 hours after dosing.

• this delay is likely reflective of metabolite absorption rather than absorption of the parent drug.

As acarbose is intended to work within the gut, its minimal degree of oral bioavailability is therapeutically desirable.

Acarbose is extensively metabolized within the gastrointestinal tract, primarily by intestinal bacteria and to a lesser extent by digestive enzymes, into at least 13 identified metabolites.

Approximately 1/3 of these metabolites are absorbed into the circulation where they are subsequently renally excreted.

The major metabolites appear to be methyl, sulfate, and glucuronide conjugates of 4-methylpyrogallol.

Only one metabolite.

• resulting from the cleavage of a glucose molecule from acarbose.

• has been identified as having alpha-glucosidase inhibitory activity.

Roughly half of an

Oral administered dose is excreted in the feces within 96 hours of administration.

What little drug material is absorbed into the systemic circulation (approximately 34% of an Oral administered dose) is excreted primarily by the kidneys, suggesting renal excretion would be a significant route of elimination if the parent drug was more readily absorbed.

• this is further supported by data in which approximately 89% of an Intravenous administered dose of acarbose was excreted in the urine as active drug (in comparison to <2% following oral administration) within 48 hours.

In healthy volunteers, the plasma elimination half-life of acarbose is approximately 2 hours.

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The symptoms of acarbose overdose are likely to be consistent with its adverse effect profile and may therefore include significant gastrointestinal (GI) symptoms (flatulence, distension, etc), although an overdose on an empty stomach (i.e. when not co-administered with food) is less likely to result in these GI symptoms.

In the event of an overdose, patients should be instructed to avoid carbohydrate-containing foods for 4-6 hours following administration as these can precipitate the aforementioned GI symptoms.

Acarbose tablets are contraindicated in patients with known hypersensitivity to the drug.

Acarbose tablets are contraindicated in patients with diabetic ketoacidosis or cirrhosis.

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 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.

There is no fixed dosage regimen for the management of diabetes mellitus with acarbose tablets or any other pharmacologic agent.

Dosage of acarbose tablets 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 tablets should be taken three times daily at the start (with the first bite) of each main meal.

Acarbose tablets 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, one-hour postprandial plasma glucose may be used to determine the therapeutic response to acarbose tablets 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 tablets, either as monotherapy or in combination with sulfonylureas, insulin or metformin.

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.

Once a 25 mg t.i.d. dosage regimen is reached, dosage of acarbose tablets should be adjusted at 4-8 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. .

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.

The maximum recommended dose for patients ≤ 60 kg is 50 mg t.i.d.

The maximum recommended dose for patients > 60 kg is 100 mg t.i.d.

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.

Tablets, USP are supplied as follows: For 50 mg: White to yellow-tinged, round, biconvex tablets, debossed with "HP" and "148" on one side and plain on other side.

NDC: 71335-9725-1: 30 Tablets in a BOTTLE NDC: 71335-9725-2: 90 Tablets in a BOTTLE NDC: 71335-9725-3: 100 Tablets in a BOTTLE Store at 20o to 25oC (68oto 77oF) .

Protect from moisture.

For bottles, keep container tightly closed.

Repackaged/Relabeled by: Bryant Ranch Prepack, Inc.

Burbank, CA 91504.

The safety of acarbose tablets 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 acarbose tablets 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.

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.

Safety and effectiveness of acarbose tablets in pediatric patients have not been established.

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