Due to national registration procedure for acarbose, the product information may vary in different countries.
The following product information refers only to the German market.

Glucobay® 50 (Tablets)
Glucobay® 100 (Tablets)

Glucobay 50:
1 tablet contains 50 mg acarbose.
Glucobay 100:
1 tablet contains 100 mg acarbose.

Tablets

A supplement to dietary therapy in patients with diabetes mellitus.

Dosage
The dosage must be adjusted by the doctor to suit each patient, because efficacy and tolerance vary from one individual to another. Treatment should begin with:
     3 x 1 Glucobay 50 tablet daily
or 3 x ½ Glucobay 100 tablet daily
     (equivalent to 150 mg acarbose per day).
In some patients, a gradual increase in the dosage of Glucobay has helped to reduce gastrointestinal side effects, starting with:
     1 to 2 x 1 Glucobay 50 tablet daily
     (equivalent to 50 to 100 mg acarbose per day).
The dose can be gradually increased depending on the patient's blood glucose level, and also as treatment progresses if it is not effective enough, up to:
     3 x 1 Glucobay 100 tablet daily
     (equivalent to 300 mg acarbose per day).
The average dose is 150 to 300 mg acarbose/day depending on the requirements of the individual patient. It may be necessary to increase the dose further to
     3 x 2 Glucobay 100 tablets daily
     (equivalent to 600 mg acarbose per day).
in exceptional cases (see also section Side effects).

If distressing complaints develop in spite of strict adherence to the diet, the dose should not be increased further, but if necessary should be somewhat reduced.

Type of administration
The maximum effect of Glucobay tablets is attained if they are swallowed whole with a little liquid directly before the meal or with the first mouthful of food.

Duration of use
It is not envisaged that there will be any time restriction on the use of Glucobay.
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• Hypersensitivity to acarbose or any of the other ingredients.
• Chronic intestinal disorders associated with marked impairment of digestion and absorption.
• Conditions which can worsen as a result of gas build-up in the intestine (e.g. Roemheld's syndrome, serious hernias, intestinal obstructions and intestinal ulcers)
• Glucobay should not be used in patients with severe renal impairment (creatinine clearance <25 ml/min).
• Pregnancy and breast-feeding (see section Pregnancy and breast-feeding).

Elevation of liver enzymes, including clinically significant values (up to 3 times the upper limit of normal), has been observed in isolated cases. As a rule, the liver enzyme elevation was reversible both after discontinuation and continuation of the treatment. For this reason liver values should be monitored at regular intervals in the first 6 - 12 months of treatment.

Other precautions

• A diabetic diet must naturally also be strictly maintained when taking Glucobay.
• Regular treatment with Glucobay should not be interrupted without consulting a doctor because this can result in an increase in blood sugar levels.
• Glucobay does not induce hypoglycaemia in patients treated by diet alone. If hypoglycaemia develops during Glucobay treatment because of the lower insulin requirement in patients being treated in addition with insulin, sulphonylureas or metformin, glucose must be taken (not household sugar [cane sugar]) (see also section Interactions with other medicines and other forms of interaction).
• Treatment with Glucobay should be recorded on the diabetes card.

Interactions with other medicines and other forms of interaction

Household sugar (cane sugar) and foods containing sucrose
Household sugar (cane sugar) and foods containing household sugar often cause abdominal discomfort or even diarrhoea during treatment with Glucobay as a result of increased carbohydrate fermentation in the colon (see section Side effects).

Sulphonylureas, metformin preparations or insulin
Glucobay has an antihyperglycaemic effect, but does not itself induce hypoglycaemia. If Glucobay is prescribed in addition to drugs containing sulphonylureas or metformin, or in addition to insulin, a drop in blood sugar levels bringing them into the hypoglycaemic range may necessitate a corresponding reduction in the dose of sulphonylurea, metformin or insulin. Hypoglycaemic shock may occur in isolated cases. If acute hypoglycaemia develops it should be borne in mind that household sugar (cane sugar) is broken down into fructose and glucose more slowly during treatment with Glucobay; for this reason household sugar is unsuitable for rapid alleviation of hypoglycaemia and glucose should be used instead.

Digoxin
In isolated cases, acarbose may affect digoxin bioavailability, which may require adjustment of the digoxin dose.

Cholestyramine, intestinal adsorbents and digestive enzyme preparations
Because they may possibly weaken the action of acarbose, concomitant administration of cholestyramine, intestinal adsorbents and digestive enzyme preparations should be avoided.

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Pregnancy and breast-feeding

Glucobay should not be administered during pregnancy since there is no experience available on use in pregnant women.
After administration of radiolabelled acarbose to lactating rats a small quantity of the radioactive substance was found in the milk. There are as yet no corresponding findings in humans. However, as drug induced effects of acarbose in milk have not been excluded in babies, in principle it is advisable not to prescribe Glucobay during breastfeeding.

Not applicable.

Side effects

Especially if the prescribed diabetic diet is not observed, intestinal side effects may be intensified. If painful symptoms develop in spite of strict adherence to the diabetic diet prescribed, the doctor must be consulted and the dose temporarily or permanently reduced.
Gastrointestinal symptoms may be severe and pronounced. A decision must be made in such cases as to whether treatment with Glucobay 50/100 can be continued.

The following undesirable effects were reported after administration of acarbose. The frequency is indicated as follows:

Very frequently:	>	10%
Frequently:	>	1%	to	≤	10%
Occasionally:	>	0.1%	to	≤	1%
Rarely:	>	0.01%	to	≤	0.1%
Very rarely:				≤	0.01%

Very frequently:	Flatulence, abdominal noise,
Frequently:	Diarrhoea, abdominal pain,
Occasionally:	Nausea,
Rarely:	Elevated liver enzymes (also clinically significant),
Very rarely:	Constipation, ileus, subileus, hypersensitivity reactions (e.g. rash, erythema, exanthema and urticaria), hepatitis and/or jaundice, oedema (mainly peripheral).

Isolated cases of severe liver failure have been observed in Japan with no established relationship with acarbose treatment.

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When Glucobay is taken with drinks and/or meals containing carbohydrates (polysaccharides, oligosaccharides, or disaccharides), overdosage can lead to meteorism, flatulence and diarrhoea. In the event of an overdose of Glucobay being taken independently of food, excessive intestinal symptoms should not be expected.

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.

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Acarbose is an oral antidiabetic belonging to the class of alpha-glucosidase inhibitors (ATC Code A10BF01).

Acarbose delays the enzymatic breakdown of carbohydrates in the small intestine by means of reversible inhibition of intestinal alpha-glucosidases and thus reduces the level of post-prandial blood glucose increases. As a result of the lower rate of post-prandial glucose absorption, the absorbed glucose can be metabolised more effectively and the area under the post-prandial blood glucose curve is reduced. Acarbose does not stimulate insulin secretion but reduces the burden on the beta cells by reducing the extent to which the blood glucose level increases. Compensatory postprandial hyperinsulinaemia is avoided. Acarbose therapy does not lead to an increase in body weight. Improved insulin sensitivity has been observed in people with impaired glucose tolerance and in elderly diabetics. Fasting blood glucose concentrations and levels of glycosylated haemoglobin (HbA1, HbA1c) decrease markedly during treatment with acarbose.
The point in time when acarbose is taken determines its efficacy: the maximum effect is attained when it is taken with the first mouthful of the main meal; taking acarbose even about 15 minutes before the meal already considerably reduces its efficacy.
In studies with a duration of several years, the effect of acarbose remained constant over the entire period of treatment: the enzymes in the small intestine lose none of their activity and their susceptibility to inhibition by acarbose is maintained.
In a prospective, randomised, placebo-controlled, double-blind, comparative study (duration of treatment 3 - 5 years, on average 3.3 years) involving 1,429 persons with postprandial sugar values at the beginning of the study between 7.8 and 11.1 mmol/l (140 - 200 mg/dl) and fasting values between 5.6 and 7.8 mmol/l (100 - 140 mg/dl), the incidence of all cardiovascular events including myocardial infarction and new manifestation of hypertension decreased significantly. In these patients, the relative risk of type II diabetes developing was reduced by up to 36% regardless of sex in all age and weight groups.

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The pharmacokinetics of Glucobay was investigated after oral administration of the labelled substance (200 mg) to healthy volunteers.

Absorption
Since a mean value of 35% of the total radioactivity (sum of the inhibitory active substance and any breakdown products) was excreted by the kidneys within 96 hours, it can be assumed that the degree of absorption is at least in this range.
The total radioactivity plasma concentration curve exhibited two peaks. The first peak, with a mean acarbose-equivalent concentration of 52.2 ± 15.7 µg/l after 1.1 ± 0.3 h, is in agreement with corresponding data for the concentration curve of the inhibitory active substance (49.5 ± 26.9 µg/l after 2.1 ± 1.6 h). The second mean peak is 586.3 ± 282.7 µg/l and is reached after 20.7 ± 5.2 h. In contrast to the total radioactivity, the maximum plasma concentrations of the inhibitory substance are lower by a factor of 10 - 20. The second, higher peak after about 14 - 24 h is believed to be due to absorption of bacterial breakdown products from lower-lying sections of the intestine.

Distribution
A relative volume of distribution of 0.32 l/kg bodyweight has been calculated in healthy volunteers from the plasma concentration curve (intravenous administration, 0.4 mg/kg body weight).

Elimination
The plasma elimination half-lives of the inhibitory active substance are 3.7 ± 2.7 h for the distribution phase and 9.6 ± 4.4 h for the elimination phase.
The percentage of the inhibitory active substance eliminated in the urine was 1.7% of the administered dose. 51% of the activity was eliminated in the faeces within 96 hours.

Bioavailability
The bioavailability is 1 - 2%. This extremely low systemically available percentage of inhibitory active substance is desirable and has no relevance to the therapeutic effect.

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Acute toxicity
Acute toxicity studies after oral and intravenous administration of acarbose have been conducted on mice, rats and dogs. The results of the acute toxicity studies are summarised in the following table.

Species	Sex	Route of administration	LD50SIU/kg(3)		Confidence limits for p<0.05
Mouse	m(1)	per os	>	1000000
Mouse	m	i.v.	>	500000
Rat	m	per os	>	1000000
Rat	m	i.v.		478000	(421000 - 546000)
Rat	f (2)	i.v.		359000	(286000 - 423000)
Dog	m and f	per os	>	650000
Dog	m and f	i.v.	>	250000

(1) male
(2) female
(3) 65000 SIU correspond to about 1 g of the product
(SIU = saccharase inhibitory units)

On the basis of these results acarbose may be described as non toxic after single oral doses; even after doses of 10 g/kg an LD50 could not be determined. Moreover, no symptoms of intoxication were observed in any of the test species in the dose range under investigation. The substance is also practically non toxic after i.v. administration.

Subchronic toxicity
Tolerance studies have been conducted in rats and in dogs over periods of 3 months.
In rats acarbose has been investigated in doses of 50 - 450 mg/kg p.o. All haematological and clinicochemical parameters remained unchanged compared to a control group receiving no acarbose. Subsequent histopathological investigations also yielded no evidence of damage at any dose.
Doses of 50 - 450 mg/kg p.o. have also been investigated in dogs. Compared to a control group which received no acarbose, the aim was to look for changes induced by the test substance in the development of the animals' body weight, alpha-amylase activity in the serum and blood urea concentration. Bodyweight development was influenced in all dose groups in that when a constant quantity of 350 g feed/day had been given, the average group values fell appreciably during the first 4 weeks of the study. When the quantity of feed provided had been increased to 500 g/day in the 5th week of the study, the animals remained at the same weight level. These weight changes induced by acarbose in quantities exceeding the therapeutic dose should be regarded as an expression of increased pharmacodynamic activity of the test substance due to an isocaloric feed imbalance (loss of carbohydrates); they do not represent an actual toxic effect. The slight increases in the urea concentration should also be regarded as an indirect result of the treatment, i.e. of a catabolic metabolic situation developing with the loss in weight. The diminished alpha-amylase activity can also be interpreted as a sign of an increased pharmacodynamic effect.

Chronic toxicity
Chronic studies have been conducted in rats, dogs and hamsters, with treatment durations of 24 months, 12 months and 80 weeks, respectively. In addition to the question of damage caused by chronic administration, the studies in rats and hamsters were also intended to address possible carcinogenic effects.

Carcinogenicity
A number of studies are available on carcinogenicity.

	a)	Sprague-Dawley rats received up to 4500 ppm acarbose in feed over a period of 24 - 26 months. Administration of acarbose in the feed resulted in considerable malnutrition in the animals. Under these study conditions, dose-dependent tumours of the renal parenchyma (adenoma, hypernephroid carcinoma) were found in comparison to the controls, while the overall tumour rate (in particular the rate for hormone-dependent tumours) decreased. To prevent malnutrition, in subsequent studies the animals received glucose substitution. At a dose of 4500 ppm acarbose plus glucose substitution, the body weight was 10% lower than in the control group. An increased incidence of renal tumours was not observed. When the study was repeated without glucose substitution over a 26-month period, an increase in benign tumours of the Leydig cells in the testes was also observed. In all groups receiving glucose substitution the glucose values were (sometimes pathologically) elevated (alimentary diabetes on administration of large quantities of glucose). On administration of acarbose via a stomach tube the body weights were within the control range and with this study design, elevated pharmacodynamic activity was avoided. The tumour rate was normal.
	b)	Wistar rats received 0 - 4500 ppm acarbose for 30 months in feed or via probang. Administration of acarbose in the feed did not lead to any pronounced weight loss. From 500 ppm acarbose the caecum was enlarged. The overall tumour rate decreased and there was no evidence of an increased incidence of tumours.
	c)	Hamsters received 0 - 4000 ppm acarbose in feed over 80 weeks, with and without glucose substitution. Increased blood sugar levels were found in animals of the highest dose group. The incidence of tumours was not increased.

Reproduction toxicity
Investigations for teratogenic effects were conducted in rats and in rabbits, using doses of 0, 30, 120 and 480 mg/kg p.o. in both species. In the rats the treatment was administered from the 6th to the 15th day of gestation and in the rabbits from the 6th to the 18th day of gestation. There was no evidence of teratogenic effects due to acarbose in either species in the range of doses under test.
No impairment of fertility was observed in male or female rats up to a dose of 540 mg/kg/day. Administration of up to 540 mg/kg/day during foetal development and lactation in rats had no effect on the birth process or the young. No data are available on the use of acarbose during pregnancy and lactation in humans.

Mutagenicity
According to a number of mutagenicity studies, there is no evidence of any genotoxic action of acarbose. Top

Microcrystalline cellulose, magnesium stearate, maize starch, colloidal silicon dioxide.

Incompatibilities

Not applicable.

Shelf-life

5 years.

Special storage instructions

Under storage conditions of up to 25°C and below 60% relative humidity, the unpacked tablets can be stored for up to two weeks. At higher temperatures and/or higher relative humidity, discoloration can occur in tablets that are not in the pack. The tablets should therefore only be removed from the foil immediately prior to use.

Type and contents of container

Folding box with blisters made from polypropylene (colourless) and aluminium.

Glucobay 50:
21 tablets (N1; starter pack)
105 tablets (N2)
Hospital packs: 240 tablets

Glucobay 100:
21 tablets (N1)
105 tablets (N2)
Hospital packs: 240 tablets

Instructions for use and disposal

No special instructions.

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Product License Holder

Bayer Vital GmbH
D-51368 Leverkusen
Telephone: (0214) 30-5 13 48
Telefax: (0214) 30-5 15 98
E-mail address: bayer-vital@bayerhealthcare.com

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Registration Number

Glucobay 50: 9835.00.00
Glucobay 100: 9835.01.00

Date of Extension of the Registration

12.06.2000

Date of Preparation

December 2003

Prescription/Pharmacy Status

Prescription only

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