of these agents should be made. very rarely, individual cases of hypoglycemic shock have been reported in patients receiving acarbose tablets therapy in combination with sulfonylureas and/or insulin. intestinal adsorbents (e.g., charcoal) and digestive enzyme preparations containing carbohydrate-splitting enzymes (e.g., amylase, pancreatin) may reduce the effect of acarbose tablets and should not be taken concomitantly. acarbose tablets have been shown to change the bioavailability of digoxin when they are coadministered, which may require digoxin dose adjustment. (see clinical pharmacology, drug-drug interactions ).

to glucose and fructose is inhibited by acarbose tablets, is unsuitable for the rapid correction of hypoglycemia. severe hypoglycemia may require the use of either intravenous glucose infusion or glucagon injection. elevated serum transaminase levels: in long-term studies (up to 12 months, and including acarbose tablets doses up to 300 mg t.i.d.) conducted in the united states, treatment-emergent elevations of serum transaminases (ast and/or alt) above the upper limit of normal (uln), greater than 1.8 times the uln, and greater than 3 times the uln occurred in 14%, 6%, and 3%, respectively, of acarbose tablets-treated patients as compared to 7%, 2%, and 1%, respectively, of placebo-treated patients. although these differences between treatments were statistically significant, these elevations were asymptomatic, reversible, more common in females, and, in general, were not associated with other evidence of liver dysfunction. in addition, these serum transaminase elevations appeared to be dose related. in us studies including acarbose tablets doses up to the maximum approved dose of 100 mg t.i.d., treatment-emergent elevations of ast and/or alt at any level of severity were similar between acarbose tablets-treated patients and placebo-treated patients (p ≥ 0.496). in approximately 3 million patient-years of international postmarketing experience with acarbose tablets, 62 cases of serum transaminase elevations > 500 iu/l (29 of which were associated with jaundice) have been reported. forty-one of these 62 patients received treatment with 100 mg t.i.d. or greater and 33 of 45 patients for whom weight was reported weighed < 60 kg. in the 59 cases where follow-up was recorded, hepatic abnormalities improved or resolved upon discontinuation of acarbose tablets in 55 and were unchanged in two. cases of fulminant hepatitis with fatal outcome have been reported; the relationship to acarbose is unclear. 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.

our 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. 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.

toms 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 b 6 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 .) pneumatosis cystoides intestinalis: there have been rare postmarketing reports of pneumatosis cystoides intestinalis associated with the use of alpha-glucosidase inhibitors, including acarbose tablets. pneumatosis cystoides intestinalis may present with symptoms of diarrhea, mucus discharge, rectal bleeding and constipation. complications may include pneumoperitoneum, volvulus, intestinal obstruction, intussusception, intestinal hemorrhage and intestinal perforation. if pneumatosis cystoides intestinalis is suspected, discontinue acarbose tablets and perform the appropriate diagnostic imaging.

of these agents should be made. very rarely, individual cases of hypoglycemic shock have been reported in patients receiving acarbose tablets therapy in combination with sulfonylureas and/or insulin. intestinal adsorbents (e.g., charcoal) and digestive enzyme preparations containing carbohydrate-splitting enzymes (e.g., amylase, pancreatin) may reduce the effect of acarbose tablets and should not be taken concomitantly. acarbose tablets have been shown to change the bioavailability of digoxin when they are coadministered, which may require digoxin dose adjustment. (see clinical pharmacology, drug-drug interactions ).

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.

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 absorption: in a study of 6 healthy men, less than 2% of an oral dose of acarbose was absorbed as active drug, while approximately 35% of total radioactivity from a 14 c-labeled oral dose 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 14 c-labeled 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 (that is, sulfate, methyl, and glucuronide conjugates). one metabolite (formed by cleavage of a glucose molecule from acarbose) also has alpha-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 intravenously, 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 (this is, 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 three times a day (t.i.d.) oral dosing. special populations: 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. patients with severe renal impairment (clcr < 25 ml/min/1.73m 2 ) attained about 5 times higher peak plasma concentrations of acarbose and 6 times larger aucs than volunteers with normal renal function. no studies of acarbose pharmacokinetic parameters according to race have been performed. in u.s. controlled clinical studies of acarbose tablets in patients with type 2 diabetes mellitus, reductions in glycosylated hemoglobin levels were similar in caucasians (n=478) and african-americans (n=167), with a trend toward a better response in latinos (n=132). 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 c max 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.

ract, 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 (that is, sulfate, methyl, and glucuronide conjugates). one metabolite (formed by cleavage of a glucose molecule from acarbose) also has alpha-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 intravenously, 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 (this is, 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 three times a day (t.i.d.) oral dosing. special populations: 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. patients with severe renal impairment (clcr < 25 ml/min/1.73m 2 ) attained about 5 times higher peak plasma concentrations of acarbose and 6 times larger aucs than volunteers with normal renal function. no studies of acarbose pharmacokinetic parameters according to race have been performed. in u.s. controlled clinical studies of acarbose tablets in patients with type 2 diabetes mellitus, reductions in glycosylated hemoglobin levels were similar in caucasians (n=478) and african-americans (n=167), with a trend toward a better response in latinos (n=132).

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.

-0.74 0.0001 200 mg t.i.d. although studies utilized a maximum dose of 200 or 300 mg t.i.d., 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. 231 -0.86 0.0001 300 mg t.i.d. 53 -1.00 0.0001 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.)* figure 1 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. table 2: effect of acarbose tablets on hba1c hba1c(%) hba1c normal range: 4 to 6% study treatment mean baseline mean change from baseline after four months treatment in study 1, and six months in studies 2, 3, and 4 treatment difference p-value 1 placebo plus diet 8.67 +0.33 - - acarbose tablets 100 mg t.i.d. plus diet 8.69 -0.45 -0.78 0.0001 2 placebo plus sfu sfu, sulfonylurea, maximum dose 9.56 +0.24 - - acarbose tablets 50 to 300 although studies utilized a maximum dose of up to 300 mg t.i.d., 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. mg t.i.d. plus sfu 9.64 -0.30 -0.54 0.0096 3 placebo plus metformin metformin dosed at 2000 mg/day or 2500 mg/day 8.17 +0.08 results are adjusted to a common baseline of 8.33% - - acarbose tablets 50 to 100 mg t.i.d plus metformin 8.46 -0.57 -0.65 0.0001 4 placebo plus insulin mean dose of insulin 61 u/day 8.69 +0.11 - - acarbose tablets 50 to 100 mg t.i.d. plus insulin 8.77 -0.58 -0.69 0.0001 table 3: effect of acarbose tablets on postprandial glucose one-hour postprandial glucose (mg/dl) study treatment mean baseline mean change from baseline after four months treatment in study 1, and six months in studies 2, 3, and 4 treatment difference p-value 1 placebo plus diet 297.1 +31.8 - - acarbose tablets 100 mg t.i.d. plus diet 299.1 -42.6 -74.4 0.0001 2 placebo plus sfu sfu, sulfonylurea, maximum dose 308.6 +6.2 - - acarbose tablets 50 to 300 although studies utilized a maximum dose of up to 300 mg t.i.d., 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. mg t.i.d. plus sfu 311.1 -27.3 -33.5 0.0017 3 placebo plus metformin metformin dosed at 2000 mg/day or 2500 mg/day 263.9 +3.3 results are adjusted to a common baseline of 273 mg/dl - - acarbose tablets 50 to 100 mg t.i.d plus metformin 283.0 -31.0 -34.3 0.0001 4 placebo plus insulin mean dose of insulin 61 u/day 279.2 +8.0 - - acarbose tablets 50 to 100 mg t.i.d. plus insulin 277.8 -28.0 -36.0 0.0178 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. figure 2

les of 30 ndc 71205-856-30 bottles of 60 ndc 71205-856-60 bottles of 90 ndc 71205-856-90 bottles of 100 ndc 71205-856-00 bottles of 120 ndc 71205-856-72 bottles of 180 ndc 71205-856-78 bottles of 500 ndc 71205-856-55 bottles of 1000 ndc 71205-856-11 store at 20° to 25 ° c (68° to 77 ° f) [see usp controlled room temperature]. protect from moisture. keep container tightly closed. keep this and all drugs out of the reach of children. rev: may 2018 distributed by: virtus pharmaceuticals, llc langhorne, pa 19047 1-888-848-3593 manufactured by: bluepharma indústria farmacêutica, s.a. s. martinho do bispo 3045-016 coimbra, portugal repackaged and relabeled by: proficient rx lp thousand oaks, ca 91320

nd 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.