GLUCOBAY^®

Acarbose tablets 50mg and 100mg

Qualitative and Quantitative Composition

Glucobay 50 1 tablet contains 50mg acarbose

Glucobay 100 1 tablet contains 100mg acarbose

Pharmaceutical Form

Indications

Glucobay is indicated for the additional treatment of insulin dependent and non-insulin dependent diabetes mellitus in association with diet.

Posology and Method of Administration

Recommended usual dose:

Because efficacy and tolerability vary, the dosage must be adjusted by the doctor to suit each individual patient.

Range of dose:

Unless otherwise prescribed the recommended dosage is as follows:

A further increase in dosage to 3 × 200 mg acarbose/day may occasionally be necessary.

The dose may be increased after 4 - 8 weeks. An increase can also be made later in the course of the treatment if the patient shows an inadequate clinical response. If side effects occur in spite of strict adherence to the diet, the dose should not be increased, and if necessary should be reduced. The average dose is 300mg acarbose/day (corresponding to 3 × 2 tablets of Glucobay 50 /day, or 3 × 1 tablet of Glucobay 100 /day).

Method of Administration

Acarbose tablets are effective only if swallowed whole with a little liquid directly before the meal or chewed with the first few mouthfuls of the meal.

Special monitoring of advice

(see Special Warnings and Precautions for Use)

Elderly (above 65 years)

No alteration of dosage or dosing frequency is necessary for elderly patients.

Children

(see contraindications)

Hepatic impairment

No dose adjustment is required in patients with pre-existing impaired hepatic function

Renal impairment

(see contraindications)

Contraindications

Hypersensitivity to acarbose and/or to inactive constituents.

Since the information on its effects and tolerability in children and adolescents is still insufficient, acarbose tablets should not be used in patients under 18 years of age.

Chronic intestinal disorders associated with distinct disturbances of digestion and absorption.

States which may deteriorate as a result of increased gas formation in the intestine (e.g. Roemheld's syndome, major hernias, intestinal obstructions, and intestinal ulcers).

Acarbose tablets should not be used in patients with severe renal impairment (creatinine clearance < 25 mL/min).

Special Warnings and Precautions or Use

Asymptomatic liver enzyme elevations may occur in individual cases. Therefore liver enzyme monitoring should be considered during the first 6 to 12 months of treatment. In evaluable cases these changes were reversible on discontinuation of acarbose therapy.

Interaction with Other Medicaments and Other Forms of Interaction

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

Glucobay has an antihyperglycaemic effect, but does not itself induce hypoglycaemia. If Glucobay is prescribed in addition to sulphonylurea, metformin or insulin, a fall of the blood glucose into the hypoglycaemic range may necessitate a decrease in the sulphonylurea, metformin or insulin dose. In individual cases hypoglycaemic shock may occur.

If acute hypoglycaemia develops it should be borne in mind that sucrose (cane sugar) is broken down into fructose and glucose more slowly during treatment with Glucobay; for this reason sucrose is unsuitable for a rapid alleviation of hypoglycaemia and glucose should be used instead.

In individual cases Glucobay may affect digoxin bioavailability, which may require dose adjustment of digoxin.

Because they may possibly influence the action of Glucobay simultaneous administration of cholestyramine, intestinal absorbents and digestive enzyme products should be avoided. No interaction was observed with dimethicone/simethicone.

Pregnancy and Lactation

Glucobay should not be administered during pregnancy, as no information is available on its use in pregnant women.

After administration of radiolabelled acarbose to lactating rats a small quantity of the radioactivity 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 the breastfeeding period.

Undesirable Effects

(i.e. very common >10%, common > 1% and < 10%, uncommon > 0.1% and < 1%, rare > 0.01 % and < 0.1%, very rare < 0.01%)

Adverse Events Observed in Controlled Clinical Trials

Very common, flatulence. Commonly, diarrhoea and abdominal pain. Uncommonly, nausea.

If the prescribed diabetic diet is not observed the intestinal side effects may be intensified. If severe symptoms develop in spite of adherence to the prescribed diabetic diet the doctor must be consulted and the dose temporarily or permanently reduced.

In patients receiving the recommended daily dose of 150 to 300 mg acarbose/day, rarely were clinically relevant abnormal liver function tests (three times above upper limit or normal range) observed. Abnormal values may be transient with ongoing acarbose therapy.

(See also Special Warnings and Precautions for Use).

Adverse Events from Spontaneous Reports

Very rarely hypersensitive skin reactions may occur e.g. rash, erythema, exanthema and urticaria.

Very rarely oedema was observed.

Very rarely subileus/ileus may occur.

Very rarely cases of jaundice and/or hepatitis and associated liver damage have been reported.

Overdose

When Glucobay is taken with drinks and/or meals containing carbohydrates (polysaccharides, oligosaccharides, or disaccharides), overdosage can lead to meteorism, flatulence, and diarrhoea. If an overdose of Glucobay is taken without food excessive intestinal symptoms are unlikely.

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.

Pharmacodynamic Properties

The active ingredient of the tablets is acarbose, a pseudotetrasaccharide of microbial origin. Acarbose can be used for the treatment of insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetes.

In all species tested acarbose exerts its activity in the intestinal tract. The action of acarbose is based on inhibition of the intestinal enzymes (a-glucosidases) involved in the degradation of disaccharides, oligosaccharides, and polysaccharides. This leads to a dose-dependent delay in the digestion of these carbohydrates. Most importantly, glucose derived from carbohydrates is released and taken up into the blood more slowly. In this way acarbose postpones and reduces the postprandial rise in blood glucose. As a result of the balancing effect on the uptake of glucose from the intestine, the blood glucose fluctuations over the day are reduced and the mean blood glucose values decrease.

Acarbose lowers abnormally high concentrations of glycosylated haemoglobin.

Pharmacokinetic Properties

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

Absorption

Since on average 35% of the total radioactivity (sum of the inhibitory substance and any degradation 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 course of the total radioactivity concentration in plasma went through two peaks. The first peak, with an average acarbose-equivalent concentration of 52.2 ± 15.7 mcg/l after 1.1 ± 0.3 hours, is in agreement with corresponding data for the concentration course of the inhibitor substance (49.5 ± 26.9 mcg/l after 2.1 ± 1.6 hours). The second peak is on average 586.3 ± 282.7 mcg/l and is reached after 20.7 ± 5.2 hours. 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 hours is believed to be due to absorption of bacterial degradation products from deeper parts of the intestine.

Distribution

A relative volume of distribution of 0.32 L/kg bodyweight has been calculated in healthy volunteers from the concentration course in the plasma (intravenous dosing, 0.4 mg/kg b.w.)

Bioavailability

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

Excretion

The plasma elimination half-lives of the inhibitory substance are 3.7 ± 2.7 hours for the distribution phase and 9.6 ± 4.4 hours for the elimination phase.

The proportion of inhibitory substance excreted in the urine was 1.7% of the administered dose. 51% of the activity was eliminated within 96 hours in the faeces.

Preclinical Safety Data

Acute toxicity

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

On the basis of these results acarbose may be described as non-toxic after single oral doses; even after doses of 10g/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

Tolerability 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 histo-pathological investigations similarly 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, changes due to the test substance were demonstrated in the gain of body weight, a-amylase activity in the serum, and the blood urea concentration. In all dose groups, when the constant quantity of 350g feed/day was given, the body weight gain mean group values fell markedly during the first 4 weeks of the study. When the quantity of feed provided had been increased to 500 g/day in the 5^th 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 a-amylase activity can also be interpreted as a sign of increased pharmacodynamic effect.

Chronic toxicity

Chronic studies have been conducted in rats, dogs, and hamsters, with respective treatment durations of 24 months, 12 months, and 80 weeks. 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.

Sprague-Dawley rats received up to 4500 ppm acarbose in feed over a period of 24-26 months. Administration of acarbose in the feed caused considerable malnutrition in the animals. Under these study conditions, tumours of the renal parenchyma (adenoma, hypernephroid carcinoma) were found dose-dependently compared 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 Leydig cells of 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.

Wistar rats received 0-4500 ppm acarbose for 30 months in feed or via a stomach tube. 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.

Hamsters received 0-4000 ppm acarbose in feed over 80 weeks, with and without glucose substitution. Increased blood glucose concentrations were seen in animals of the highest dose group. Tumour incidences were not elevated.

Reproduction toxicology

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 6^th to the 15^th day of gestation, and in the rabbits from the 6^th to the 18^th 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.

Pharmaceutical Particulars

List of Excipients

Microcrystalline cellulose, highly dispersed silicon dioxide, magnesium stearate, maize starch.

Shelf-life

Blister pack, PVC. 36 months from date of manufacture.

Blister pack, polypropylene. 36 months from date of manufacture, stored below 25°C.

Special Precautions for Storage

None

Nature and Contents of Container

Glucobay 50 - packs of 90 tablets.

Glucobay 100 - packs of 90 tablets.

Instruction for Use / Handling

At storage conditions 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 or bottle immediately prior to use.

   Inhouse Pharmacy (UK)