Document: spc-doc_PL 30306-0568 change

• spc-doc_PL 04569-1620
• spc-doc_PL 30306-0568
• spc-doc_PL 43059-0002

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SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Acarbose 100 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 100 mg acarbose.

For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Tablet.

Acarbose 100 mg Tablets are an off-white, round, convex tablet, with ‘AR’ over ‘100’ on one side and ‘>’ on the other side.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Indications

Acarbose Tablets are recommended for the treatment of non-insulin dependent (NIDDM) diabetes mellitus in patients inadequately controlled on diet alone, or on diet and oral hypoglycaemic agents.

Mode of action

Acarbose is a competitive inhibitor of intestinal alpha-glucosidases with maximum specific inhibitory activity against sucrase. Acarbose dose-dependently delays the digestion of starch and sucrose into absorbable monosaccharides in the small intestine. In patients with diabetes, this results in a lowering of postprandial hyperglycaemia and a smoothing effect on fluctuations in the daily blood glucose profile.

In contrast to sulphonylurea drugs, acarbose has no stimulatory action on the pancreas.

Treatment with Acarbose Tablets also results in a reduction of fasting blood glucose and to modest changes in levels of glycated haemoglobin (HbAj, HbA_1c). The changes may be a reduction or reduced deterioration in HbA₁ or HbA_1c levels, depending upon the patient's clinical status and disease progression. These parameters are affected in a dose-dependent manner by acarbose.

Following oral administration, only 1-2% of the active inhibitor is absorbed.

4.2 Posology and method of administration

Acarbose Tablets are administered 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 a 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 of 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.

If distressing complaints develop in spite of strict adherence to the diet, the dose should not be increased further and if necessary should be reduced according to the severity of the side-effects and the clinical judgment of the prescriber.

Acarbose is intended for continuous long-term treatment.

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.

4.3 Contraindications

□    Hypersensitivity to acarbose or any of the excipients

□    Use during pregnancy and in nursing mothers.

Acarbose Tablets are also contra-indicated in patients with colonic ulceration, inflammatory bowel disease, partial intestinal obstruction or in patients predisposed to intestinal obstruction.

In addition, Acarbose Tablets 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 Tablets are contra-indicated in patients with severe hepatic impairment (e.g. liver

cirrhosis).

As acarbose has not been studied in patients with severe renal impairment, it should not be used in patients with a creatinine clearance of less than 25 ml/min/1.73m².

4.4 Special warnings and precautions for use

Cases of fulminant hepatitis have been reported during acarbosetherapy. The mechanismis unknown but acarbose may contribute to a multi factorial pathophysiology of liver injury.

Liver enzyme monitoring should be considered during the first six 6 to twelve 12 months of treatment (see

section 4.8).

The safety and efficacy of acarbose has not been established in patients under 18 years of age.

Acarbose has an antihyperglycaemic effect, but does not itself induce hypoglycaemia. If acarbose is prescribed in addition to other blood glucose lowering drugs (e.g sulphonylureas metformin, or insulin) a fall of the blood glucose values into the hypoglycaemic range may require a dose adaption of the respective co-medication. If acute hypoglycemia develops glucose should be used for rapid correction of hypoglycaemia (see section 4.5).

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.

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.

Acarbose has an anti-hyperglycaemic effect but, by itself, does not cause hypoglycaemia. In patients treated simultaneously with acarbose and sulphonylurea, metformin or insulin, the glycaemia values may drop to hypoglycaemic levels and so dose adjustment of these medicinal products may be necessary. Isolated reports of hypoglycaemic shock have been received.

In the event of acute hypoglycaemia, it should be considered that the biotransformation of sucrose intofructose and glucose is slower during treatment; for this reason, sucrose is not suitable for fast relief from hypoglycaemia and glucose should be used instead.

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 gastro-intestinal 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 Tablets, 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.

4.6 Fertility, Pregnancy and lactation

The use of acarbose is contra-indicated in pregnancy and in nursing mothers.

After the administration of radioactively marked acarbose to nursing rats, a small amount of radioactivity was recovered in the milk. To date there have been no similar findings in humans.

Nevertheless, as the possibility of drug induced effects on nursing infants cannot be excluded, the prescription of acarbose is not recommended during breastfeeding.

4.7    Effects on ability to drive and use machines

None known.

4.8    Undesirable effects

The frequencies of adverse drug reactions (ADRs) reported with acarbose 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 summarised in the table below.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100) and rare (> 1/10,000 to < 1/1,000).

The ADRs identified during postmarketing surveillance only (status: 31 Dec 2005) and for which a frequency could not be estimated, are listed under “Not known”.

System Organ Class	Very common	Common	Uncommon	Rare	Not known
Blood Rnd lymphatic system					Thrombocytopenia
Immune system disorders					Allergic reaction (rash, erythema,
Vascular disorder				Oedema
Gastrointestin al disorders	Flatulence	Diarrhoea Gastrointestina l and abdominal	Nausea Vomiting Dyspepsia		Subileus/Ileu s Pneumatosi s cystoides
Hepatobiliar y			Increase in liver	Jaundice	Hepatitis

>

In addition, events reported as liver disorder, hepatic function abnormal and liver injury have been received, particularly from Japan.

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 therapy with acarbose. (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 4-6 hours.

Diarrhoea should be treated by standard conservative measures.

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.

5.2 Pharmacokinetic properties

Following 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 hours. 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 comprised 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

Acute toxicity

LD₅₀ studies were performed in mice, rats and dogs. Oral LD₅₀ values were estimated to be >10g/kg body-weight. Intravenous LD₅₀ values ranged from 3.8g/kg (dog) to 7.7g/kg (mouse).

Sub-chronic toxicity

Three month studies have been conducted in rats and dogs in which acarbose was administered orally by gavage.

In rats, daily doses of up to 450mg/kg body-weight were tolerated without drug-related toxicity.

In the dog study, daily doses of 50-450mg/kg were associated with decreases in body-weight. This occurred due to the fact that dosing of the animals took place shortly before their feed was administered, resulting in the presence of acarbose in the gastrointestinal tract at the time of feeding. The pharmacodynamic action of acarbose led to a reduced availability of carbohydrate from the feed, and hence to weight loss in the animals. A greater time interval between dosing and feeding in the rat study resulted in most of the drug being eliminated prior to feed intake, and hence no effect on body-weight development was observed.

Owing to a shift in the intestinal a-amylase synthesis feedback mechanism a reduction in serum a-amylase activity was also observed in the dog study. Increases in blood urea concentrations in acarbose-treated dogs also occurred, probably as a result of increased catabolic metabolism associated with the weight loss.

Chronic toxicity

In rats treated for one year with up to 4500ppm acarbose in their feed, no drug-related toxicity was observed. In dogs, also treated for one year with daily doses of up to 400mg/kg by gavage, a pronounced reduction in body-weight development was observed, as seen in the sub-chronic study. Again this effect was due to an excessive pharmacodynamic activity of acarbose and was reversed by increasing the quantity of feed.

Carcinogenicity studies

In a study in which Sprague-Dawley rats received up to 4500ppm acarbose in their feed for 24-26 months, malnutrition was observed in animals receiving the drug substance. A dose-dependent increase in tumours of the renal parenchyma (adenoma, hypernephroid carcinoma) was also observed against a background of a decrease in the overall tumour rate. When this study was repeated, an increase in benign tumours of testicular Leydig cells was also observed. Owing to the malnutrition and excessive decrease in bodyweight gain these studies were considered inadequate to assess the carcinogenic potential of acarbose.

In further studies with Sprague-Dawley rats in which the malnutrition and glucose deprivation were avoided by either dietary glucose supplementation or administration of acarbose by gavage, no drug-related increases in the incidences of renal or Leydig cell tumours were observed.

In an additional study using Wistar rats and doses of up to 4500ppm acarbose in the feed, neither drug-induced malnutrition nor changes in the tumour profile occurred. Tumour incidences were also unaffected in hamsters receiving up to 4000ppm acarbose in the feed for 80 weeks (with and without dietary glucose supplementation).

Reproductive toxicity

There was no evidence of a teratogenic effect of acarbose in studies with oral doses of up to 480mg/kg/day in rats and rabbits.

In rats no impairment of fertility was observed in males or females at doses of up to 540mg/kg/day. The oral administration of up to 540mg/kg/day to rats during foetal development and lactation had no effect on parturition or on the young.

Mutagenicity

The results of a number of mutagenicity studies show no evidence of a genotoxic potential of acarbose.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Cellulose, Microcrystalline Maize Starch Croscarmellose Sodium Silica, Colloidal Anhydrous Magnesium Stearate

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

2 years.

6.4    Special precautions for storage

Store in the original package in order to protect from light.

6.5    Nature and contents of container

PVC/Aclar®/Aluminium blisters containing 10, 21, 30, 42, 84, 90, 100, 105, 420 and 500 tablets.*

* Not all pack sizes may be marketed

6.6    Special precautions for disposal

Not relevant.

7 MARKETING AUTHORISATION HOLDER

Actavis Group PTC ehf Reykjavikurvegi 76-78,

220 Hafnarfjordur,

Iceland

8    MARKETING AUTHORISATION NUMBER(S)

PL 30306/0568

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

1/11/2010

10 DATE OF REVISION OF THE TEXT

20/01/2015