Acarbose 100mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Acarbose 100mg tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 100mg Acarbose.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablet.
Acarbose 100mg tablets are round, biconvex, white to off-white tablets, with a score-line on one side and bossing “ACA 100” on the other side. The scoreline is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Acarbose is recommended for the treatment of non-insulin dependent (NIDDM) diabetes mellitus in patients inadequately controlled on diet alone, or on diet and (i) metformin and / or (ii) a sulphonylurea.
4.2 Posology and method of administration
Acarbose tablets are taken orally and should be chewed with the first mouthful of food, or swallowed whole with a little liquid directly before the meal. Owing to the great individual variation of glucosidase activity in the intestinal mucosa, there is no fixed dosage regimen, and patients should be treated according to clinical response and tolerance of intestinal side effects.
Adults
The recommended initial dose is 50mg three times a day. However, some patients may benefit from more gradual initial dose titration to minimise gastrointestinal side effects. This may be achieved by initiating treatment at 50mg once or twice a day, with subsequent titration to a three times a day regimen.
If after six to eight weeks' treatment patients show an inadequate clinical response, the dosage may be increased to 100mg three times a day. A further increase in dosage to a maximum of 200mg three times a day may occasionally be necessary.
Acarbose is intended for continuous long-term treatment.
If adverse events occur in spite of strict adherence to the diabetic diet, the dose should not be increased and if necessary should be reduced (see section 4.8).
Elderly patients
No modification of the normal adult dosage regimen is necessary.
Children and adolescents under 18 years
The efficacy and safety of acarbose in children and adolescents have not been established. Acarbose is not recommended for patients under the age of 18 years.
Renal or hepatic impairment
See section 4.3.
4.3 Contraindications
Hypersensitivity to acarbose or any of the excipients. Acarbose is also contraindicated in patients with inflammatory bowel disease, colonic ulceration, partial intestinal obstruction or in patients predisposed to intestinal obstruction. In addition, Acarbose should not be used in patients who have chronic intestinal diseases associated with marked disorders of digestion or absorption and in patients who suffer from states which may deteriorate as a result of increased gas formation in the intestine, e.g. larger hernias.
Acarbose is contraindicated in patients with hepatic impairment.
As Acarbose has not been studied in patients with severe renal impairment, it should not be used in patients with a creatinine clearance < 25 ml/min/1.73m2.
4.4 Special warnings and precautions for use
Hypoglycaemia: When administered alone, Acarbose does not cause hypoglycaemia. It may, however, act to potentiate the hypoglycaemic effects of insulin and sulphonylurea drugs, and the dosages of these agents may need to be modified accordingly. In individual cases hypoglycaemic shock may occur (i.e. clinical sequelae of glucose levels < 1 mmol/L such as altered conscious levels, confusion or convulsions).
Episodes of hypoglycaemia occurring during therapy must, where appropriate, be treated by the administration of glucose, not sucrose. This is because acarbose will delay the digestion and absorption of disaccharides, but not monosaccharides.
Transaminases: Patients treated with acarbose may, on rare occasions, experience an idiosyncratic response with either symptomatic or asymptomatic hepatic dysfunction. In the majority of cases this dysfunction is reversible on discontinuation of acarbose therapy. It is recommended that liver enzyme monitoring is considered during the first six to twelve months of treatment. If elevated transaminases are observed, withdrawal of therapy may be warranted, particularly if the elevations persist. In such circumstances, patients should be monitored at weekly intervals until normal values are established.
The administration of antacid preparations containing magnesium and aluminium salts, e.g. hydrotalcite, has been shown not to ameliorate the acute gastrointestinal symptoms of Acarbose in higher dosage and should, therefore, not be recommended to patients for this purpose.
If ileus or sub-ileus is suspected, treatment must be stopped immediately (see section 4.8).
It is essential to adhere to a strict diabetic diet when taking Acarbose.
Regular use of Acarbose should not be interrupted without medical advice as this may lead to a rise in blood glucose.
Since the information available on its effects and tolerability in children and adolescents is still insufficient, Acarbose should not be used in patients under 18 years of age.
4.5 Interaction with other medicinal products and other forms of interaction
Sucrose (cane sugar) and foods containing sucrose often cause abdominal discomfort or even diarrhoea during treatment with Acarbose as a result of increased carbohydrate fermentation in the colon.
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 therefore be taken concomitantly.
The concomitant administration of neomycin may lead to enhanced reductions of postprandial blood glucose and to an increase in the frequency and severity of gastrointestinal side effects. If the symptoms are severe, a temporary dose reduction of Acarbose may be warranted.
The concomitant administration of colestyramine may enhance the effects of Acarbose, particularly with respect to reducing postprandial insulin levels. Simultaneous administration of Acarbose and colestyramine should, therefore, be avoided. In the rare circumstance that both Acarbose and colestyramine therapy are withdrawn simultaneously, care is needed as a rebound phenomenon has been observed with respect to insulin levels in non-diabetic subjects.
In individual cases Acarbose may affect digoxin bioavailability, which may require dose adjustment of digoxin. Monitoring of serum digoxin levels should be considered.
In a pilot study to investigate a possible interaction between Acarbose and nifedipine, no significant or reproducible changes were observed in the plasma nifedipine profiles.
Several therapeutic agents including thiazide and other diuretics, corticosteroids, phenothiazines, thyroid hormones, oestrogens and oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers and isoniazid can cause hyperglycaemia, which may attenuate the pharmacodynamic effects of Acarbose. Blood glucose levels should be closely monitored if any of these agents are used by patients receiving Acarbose, or if treatment with Acarbose is contemplated in patients already receiving any of these agents.
If Acarbose is prescribed in addition to other oral hypoglycaemic agents (e.g. a sulphonylurea or metformin), a fall of the blood glucose into the hypoglycaemic range may necessitate a decrease in the dose of the concomitant medication.
4.6 Fertility, Pregnancy and lactation
Pregnancy
The safety of this medicinal product for use in human pregnancy has not been established. An evaluation of experimental animal studies does not indicate direct or indirect harmful effects with respect to reproduction, development of the embryo or fetus, the course of gestation, and peri- and postnatal development.
Acarbose is not recommended during pregnancy.
When the patient plans to become pregnant and during pregnancy, diabetes should be treated with insulin to maintain blood glucose levels as close to normal as possible in order to lower the risk of fetal malformations associated with abnormal blood glucose levels.
Lactation
It is unknown whether acarbose is excreted in human breast milk. Animal studies have shown excretion of acarbose in breast milk. Acarbose should not be used during breast-feeding.
4.7 Effects on ability to drive and use machines
Acarbose monotherapy does not cause hypoglycaemia and is therefore unlikely to have effects on the ability to drive or to use machines. However, patients should be alerted to the risk of hypoglycaemia when acarbose is used in combination with metformin and / or a sulphonylurea.
4.8 Undesirable effects
Adverse drug reactions (ADRs) based on placebo-controlled studies with acarbose sorted by CIOMS III categories of frequency (placebo-controlled studies in clinical trial database: acarbose N = 8,595; placebo N = 7,278; status: 10 Feb 2006) are listed below.
Frequencies are defined as very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1000 to <1/100); rare (>1/10 000 to <1/1000); very rare (<1/10 000).
Blood and the lymphatic system disorders:
Not known (cannot be estimated from the available data): Thrombo-cytopenia*
Immune System Disorders:
Not known (cannot be estimated from the available data): Allergic reaction (rash, erythema, exanthema, urticaria)*
Vascular Disorders:
Rare: Oedema
Gastrointestinal Disorders:
Very common: Flatulence
Common: Diarrhoea, Gastrointestinal and abdominal pains Uncommon: Nausea, Vomiting, Dyspepsia
Not known (cannot be estimated from the available data): Subileus/ileus, Pneumatosis cystoides intestinalis*
Hepatobiliary Disorders:
Uncommon: Transient increase in liver enzymes Rare: Jaundice
Not known (cannot be estimated from the available data): Hepatitis*
*ADRs derived from post marketing reports (status: 31 Dec 2005).
If ileus or subileus is suspected, treatment must be stopped immediately.
Individual cases of fulminant hepatitis with fatal outcome have been reported in Japan. The relationship to acarbose is unclear.
If the prescribed diabetic 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.
In patients receiving the recommended daily dose of 150 to 300 mg Acarbose, clinically relevant abnormal liver function tests (three times above upper limit of normal range) were rarely observed. Abnormal values may be transient under ongoing Acarbose therapy. (See Section 4.4).
4.9 Overdose
When Acarbose tablets are taken with drinks and/or meals containing carbohydrates overdose may lead to meteorism, flatulence and diarrhoea. If Acarbose tablets are taken independently of food, excessive intestinal symptoms need not be anticipated.
No specific antidotes to Acarbose are known.
Intake of carbohydrate-containing meals or beverages should be avoided for 46 hours.
Diarrhoea should be treated by standard conservative measures.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Alpha glucosidase inhibitors ATC code: A10BF01
In all species tested, acarbose exerts its activity in the intestinal tract. The action of acarbose is based on the competitive inhibition of 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. Glucose derived from these carbohydrates is released and taken up into the blood more slowly. In this way, acarbose reduces the postprandial rise in blood glucose, thus reducing blood glucose fluctuations.
In contrast to sulphonylureas acarbose has no stimulatory action on the pancreas.
Treatment with acarbose also results in a reduction of fasting blood glucose and to modest changes in levels of glycated haemoglobin (HbA1, HbA1c). The changes may be a reduction or reduced deterioration in HbA1 or HbA1c levels, depending upon the patient's clinical status and disease progression. These parameters are affected in a dose-dependent manner by acarbose.
5.2 Pharmacokinetic properties
Following oral administration, only 1-2% of the active inhibitor is absorbed.
The pharmacokinetics of acarbose were investigated after oral administration of the 14C-labelled substance (200mg) to healthy volunteers. On average, 35% of the total radioactivity (sum of the inhibitory substance and any degradation products) was excreted by the kidneys within 96 h. The proportion of inhibitory substance excreted in the urine was 1.7% of the administered dose. 50% of the activity was eliminated within 96 hours in the faeces. The course of the total radioactivity concentration in plasma was comprised of two peaks. The first peak, with an average acarbose-equivalent concentration of 52.2 ± 15.7pg/l after 1.1 ± 0.3 h, is in agreement with corresponding data for the concentration course of the inhibitor substance (49.5 ± 26.9pg/l after 2.1 ± 1.6 h). The second peak is on average 586.3 ± 282.7pg/l and is reached after 20.7 ± 5.2 h. The second, higher peak is due to the absorption of bacterial degradation products from distal parts of the intestine. In contrast to the total radioactivity, the maximum plasma concentrations of the inhibitory substance are lower by a factor of 10-20. The plasma elimination half-lives of the inhibitory substance are 3.7 ± 2.7 h for the distribution phase and 9.6 ± 4.4 h for the elimination phase.
A relative volume of distribution of 0.32 l/kg body-weight has been calculated in healthy volunteers from the concentration course in the plasma.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.
A markedly reduced body weight gain in rats and dogs after repeated administration of acarbose was considered as pharmacodynamic effect (loss of carbohydrates) and could be counteracted by increase of food or glucose supplementation.
Carcinogenicity was studied in Sprague-Dawley rats, Wistar rats and hamsters. An increased tumour incidence in certain tissues (kidney, testis) was observed if malnutrition due to acarbose was not corrected. No increase in tumour rate was observed if the body weight gain was kept normal by food or glucose supplementation.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Cellulose, microcrystalline Starch pregelatinized, maize Silica, colloidal anhydrous Magnesium stearate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4
Special precautions for storage
Do not store above 25 °C. Store in the original packaging in order to protect from moisture.
6.5 Nature and contents of container
20, 21, 30, 40, 50, 60, 90, 100, 105, 120, 270 tablets in PVC/PE/PVDC aluminium blisters. Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
GeneVida GmbH, Heinrich Strater Str. 49a 44229 DORTMUND, Germany
8 MARKETING AUTHORISATION NUMBER(S)
PL 43059/0002
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 28/06/2011
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DATE OF REVISION OF THE TEXT
13/05/2014