ACARBOSE
DESCRIPTION:
(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)-alpha- D-glucopyranosyl -
(1 ---> 4)-O-(alpha)-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 C25H43NO18.
ACTIONS/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,
acarbose 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.
MECHANISM OF ACTION: In contrast to sulfonylureas, acarbose 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 acarbose to
enhance 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 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 1C-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 1C-
labeled acarbose, peak plasma concentrations of radioactivity were attained 14-
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 bacterial, 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 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
(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 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(squared)) 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 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 has no effect on either the pharmacokinetics or pharmacodynamics of digoxin,
nifedipine, propranolol, or ranitidine. PRECOSE(R) did not interfere with the
absorption or disposition of the sulfonylurea glyburide in diabetic patients.
CLINICAL STUDIES:
CLINICAL TRIALS
CLINICAL EXPERIENCE IN TYPE 2 DIABETES MELLITUS PATIENTS ON DIETARY TREATMENT
ONLY: Results from six controlled, fixed-dose, monotherapy studies of acarbose in the treatment of type 2 diabetes mellitus, involving 769 acarbose-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:
TABLE 1 MEAN CHANGE IN HBA1C IN FIXED-DOSE MONOTHERAPY STUDIES
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DOSE OF acarbose * N CHANGE IN HBA1C P-VALUE
%
___________________________________________________________________________________________________________
25 mg t.i.d. 110 -0.44 0.0307
50 mg t.i.d. 131 -0.77 0.0001
100 mg t.i.d. 244 -0.74 0.0001
200 mg t.i.d.** 231 -0.86 0.0001
300 mg t.i.d.** 53 -1.00 0.0001
___________________________________________________________________________________________________________
*acarbose was statistically significantly different from placebo at all doses. Although there were no statistically significant differences among the mean results for doses ranging from 50 to 300 mg t.i.d., some patients may derive benefit by increasing the dosage from 50 to 100 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.
____________________________________________________________________________________________________________
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 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. acarbose regimen was superior to lower doses, but there
were no statistically significant differences from 50 to 200 mg t.i.d.
CLINICAL EXPERIENCE IN TYPE 2 DIABETES MELLITUS PATIENTS RECEIVING
SULFONYLUREAS: acarbose was studied as adjunctive therapy to sulfonylurea
treatment in two large, placebo-controlled, double-blind, randomized studies
conducted in the United States in which 540 patients were included in the
efficacy analysis. In addition, acarbose was studied as adjunctive therapy to
sulfonylurea treatment in a third study, conducted in Canada, in which patients
were stratified according to background therapy. Study 1 (Table 2) involved
patients under treatment at entry with diet alone who were subsequently
randomized to four treatment groups. At the end of the study, patients in the
acarbose + tolbutamide group showed a mean treatment effect on glycosylated
hemoglobin (HbA1c) of -1.78% and were receiving a significantly lower mean daily
dose of tolbutamide than patients in the tolbutamide- alone group. Also, the
efficacy in the acarbose + tolbutamide group was significantly better than in
the other three treatment groups. Study 2 (Table 2) involved patients taking
background treatment with maximum daily doses of sulfonylureas. At the end of
this study, the mean effect of the addition of acarbose to maximum
sulfonylurea therapy was a change in HbA1c of -0.54%. In addition, there was a
significantly greater proportion of patients in the acarbose + sulfonylurea
group who reduced their sulfonylurea dose as compared to patients in the placebo
+ sulfonylurea group. In Study 3 (Table 2), the addition of acarbose to a
background treatment of sulfonylurea produced an additional change in mean HbA1c
of -0.8%.
TABLE 2
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HBA1C(%)
STUDY TREATMENT MEAN MEAN CHANGE TREATMENT P-VALUE
BASELINE* FROM BASELINE DIFFERENCE**
____________________________________________________________________________________________________________
1 Placebo 9.48 + 0.05 - -
acarbose 200*/* mg t.i.d. 9.19 -0.71 -0.76 0.0005
Tolbutamide 250-1000 mg t.i.d. 9.28 -1.22 -1.27 0.0001
(mean dose 2.4 g/d)
acarbose 200*/* mg t.i.d.+ 8.99 -1.73 -1.78 0.0001
Tolbutamide 250-1000 mg t.i.d.
(mean dose 1.9 g/d)
2 Sulfonylurea + Placebo 9.56 + 0.24 - -
Sulfonylurea + acarbose 9.64 -0.30 -0.54 0.0096
50-300*/* mg t.i.d.
3 Sulfonylurea + Placebo 8.00 + 0.10 - -
Sulfonylurea + acarbose 8.10 -0.80 -0.90 0.0020
50-200*/* mg t.i.d.
___________________________________________________________________________________________________________
*Normal Range: 4-6%
**The result of subtracting the placebo group average.
*/* 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.
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INDICATIONS AND USAGE:
acarbose, as monotherapy, is indicated as an adjunct to diet to lower blood
glucose in patients with type 2 diabetes mellitus whose hyperglycemia cannot be
managed on 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 to enhance glycemic control
is additive to that of sulfonylureas when used in combination, presumably
because its mechanism of action is different.
In initiating treatment for type 2 diabetes mellitus, 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.
CONTRAINDICATIONS:
Acarbose is contraindicated in patients with known hypersensitivity to the
drug and in patients with diabetic ketoacidosis or cirrhosis.It is also
contraindicated in patients with inflammatory bowel disease, colonic ulceration,
partial intestinal obstruction or in patients predisposed to intestinal
obstruction. In addition, it 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.
PRECAUTIONS:
GENERAL
HYPOGLYCEMIA: Because of its mechanism of action, it when administered
alone should not cause hypoglycemia in the fasted or postprandial state.
Sulfonylurea agents may cause hypoglycemia. Because it is given in
combination with a sulfonylurea will cause a further lowering of blood glucose,
it may increase the hypoglycemic potential or 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 intravenous glucose infusion or
glucagon injection.
ELEVATED SERUM TRANSAMINASE LEVELS: In long-term studies (up to 12 months, and
including acarbose doses up to 300 mg t.i.d.) conducted in the United Stated,
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-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 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-treated patients and
placebo-treated patients (p >= 0.496).
In approximately 3 million patient-years of international post-marketing
experience with acarbose, 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 in 55 and were unchanged in two. Two patients in
Japan died of fulminant hepatitis; 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.
INFORMATION FOR PATIENTS: Patients should be told to take acarbose 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 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 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. 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
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 acarbose in combination with a sulfonylurea or insulin.
If side effects occur with PRECOSE(R), 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 should be monitored by
periodic blood glucose tests. Measurement of glycosylated hemoglobin levels is
recommended for the monitoring of long-term glycemic control.
acarbose particularly at doses in excess of 50mg t.i.d., may give rise to
elevations of serum transaminases and, in rare instances, hyperbilirubinemia. It
is recommended that serum transminase levels be checked every 3 months during
the first year of treatment with it and periodically thereafter. If
elevated transaminases are observed, a reduction in dosage or withdrawal of
therapy may be indicated, particularly if the elevations persist.
RENAL IMPAIRMENT: 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 (serum creatinine >2.0 mg/dL) have not been conducted.
Therefore, treatment of these patients with acarbose 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, 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 or insulin, patients should be
observed closely for any evidence of hypoglycemia.
Intestinal adsorbents (e.g., charcoal) and digestive enzyme preparations
containing carbohydrate-splitting enzymes (e.g., amylase, pancreatin) may reduce
the effect of acarbose and should not be taken concomitantly.
CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY: Nine chronic
toxicity/carcinogenicity studies were conducted in three animal species (rat,
hamster, dog) including two rat strains (Sprague-Dawley and Wistar).
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 showed no mutagenic activity when tested in six IN VITRO and three IN
VIVO assays.
Fertility studies conducted in rats after oral administration produced no
untoward effect on fertility or on the overall capability to reproduce.
PREGNANCY:
TERATOGENIC EFFECTS: Pregnancy Category B. The safety of acarbose 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 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.
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 should not be administered to a nursing woman.
PEDIATRIC USE: Safety and effectiveness of acarbose in pediatric patients have
not been established.
ADVERSE REACTIONS:
DIGESTIVE TRACT: Gastrointestinal symptoms are the most common reactions to
acarbose. In the U.S. placebo-controlled trials, the incidences of abdominal
pain, diarrhea, and flatulence were 21%, 33%, and 77% respectively in 1075
patients treated with acarbose 50-300 mg t.i.d., whereas the corresponding
incidences were 9%, 12%, and 32% in 818 placebo-treated patients. 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 is a
manifestation of the mechanism of action of acarbose and is related to the
presence of undigested carbohydrate in the lower GI tract. Rarely, these
gastrointestinal events may be severe and might be confused with paralytic
ileus.
ELEVATED SERUM TRANSAMINASE LEVELS: See PRECAUTIONS.
OTHER ABNORMAL LABORATORY FINDINGS: Small reductions in hematocrit occurred more
often in 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 it's therapy but were thought to be
either spurious or of no clinical significance.
OVERDOSAGE:
Unlike sulfonylureas or insulin, an overdose it will not result in
hypoglycemia. An overdose may result in transient increases in flatulence,
diarrhea, and abdominal discomfort which shortly subside.
DOSAGE AND ADMINISTRATION:
There is no fixed dosage regimen for the management of diabetes mellitus with
It or any other pharmacologic agent. Dosage of acarbose 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 should be
taken three times daily at the start (with the first bite) of each main meal.
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), one-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 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, either as monotherapy
or in combination with sulfonylureas.
INITIAL DOSAGE: The recommended starting dosage of acarbose 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 should be adjusted at 4-8 week intervals based on one- hour
postprandial glucose 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 patients (=) 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: Sulfonylurea agents may cause hypoglycemia.
acarbose given in combination with a sulfonylurea will cause a further
lowering of blood glucose and may increase the hypoglycemic potential of the
sulfonylurea. If hypoglycemia occurs, appropriate adjustments in the dosage of
these agents should be made.