Akarboza Mylan

Indications

Akarboza Mylan is 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

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

In contrast to sulphonylureas Akarboza Mylan has no stimulatory action on the pancreas.

Treatment with Akarboza Mylan also results in a reduction of fasting blood glucose and to modest changes in levels of glycated haemoglobin (HbA₁, 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 Akarboza Mylan.

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

Indications

Akarboza Mylan 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

Akarboza Mylan is a competitive inhibitor of intestinal alpha-glucosidases with maximum specific inhibitory activity against sucrase. Akarboza Mylan 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, Akarboza Mylan has no stimulatory action on the pancreas.

Treatment with Akarboza Mylan Tablets also results in a reduction of fasting blood glucose and to modest changes in levels of glycated haemoglobin (HbA₁, 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 Akarboza Mylan.

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

Posology

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 50 mg 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 50 mg 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 100 mg three times a day. A further increase in dosage to a maximum of 200 mg 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.

Akarboza Mylan is intended for continuous long-term treatment.

Elderly

No modification of the normal adult dosage regimen is necessary.

Paediatric population

The efficacy and safety of Akarboza Mylan in children and adolescents have not been established. Akarboza Mylan is not recommended for patients under the age of 18 years.

Method of administration

Akarboza Mylan 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.

Akarboza Mylan 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.

Akarboza Mylan 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 Akarboza Mylan in children and adolescents have not been established. Akarboza Mylan is not recommended for patients under the age of 18 years.

Akarboza Mylan is also contra-indicated in patients with inflammatory bowel disease, colonic ulceration, partial intestinal obstruction or in patients predisposed to intestinal obstruction. In addition, Akarboza Mylan 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.

Akarboza Mylan is contra-indicated in patients with severe hepatic impairment.

As Akarboza Mylan has not been studied in patients with severe renal impairment, it should not be used in patients with a creatinine clearance < 25 ml/min/1.73 m².

- Hypersensitivity to Akarboza Mylan or any of the excipients

- Use during pregnancy and in nursing mothers.

Akarboza Mylan 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, Akarboza Mylan 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.

Akarboza Mylan Tablets are contra-indicated in patients with hepatic impairment.

As Akarboza Mylan 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.

Hypoglycaemia: Akarboza Mylan has an antihyperglycaemic effect, but does not itself induce hypoglycaemia. If Akarboza Mylan 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.

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: Cases of fulminant hepatitis have been reported during Akarboza Mylan therapy. The mechanism is unknown, but Akarboza Mylan may contribute to a multifactorial pathophysiology of liver injury. It is recommended that liver enzyme monitoring is considered during the first 6 to 12 months of treatment. If elevated liver enzymes are observed, a reduction in dosage or 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 Akarboza Mylan in higher dosage and should, therefore, not be recommended to patients for this purpose.

Hypoglycaemia: When administered alone, Akarboza Mylan 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 changed 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 Akarboza Mylan will delay the digestion and absorption of disaccharides but not of monosaccharides.

Transaminases: Patients treated with Akarboza Mylan 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 Akarboza Mylan 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 Akarboza Mylan in higher dosage and should, therefore, not be recommended to patients for this purpose.

None known.

None known.

The frequencies of adverse drug reactions (ADRs) reported with Akarboza Mylan, based on placebo-controlled studies (Akarboza Mylan N = 8,595; placebo N = 7,278), 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 and for which a frequency could not be estimated, are listed under “Not known”.

In postmarketing, cases of liver disorder, hepatic function abnormal, and liver injury have been reported. Individual cases of fulminant hepatitis with fatal outcome have also been reported, particularly from Japan.

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

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

The frequencies of adverse drug reactions (ADRs) reported with Akarboza Mylan based on placebo-controlled studies with Akarboza Mylan sorted by CIOMS III categories of frequency (placebo-controlled studies in clinical trial database: Akarboza Mylan 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”.

< The MedDRA preferred term is used to describe a certain reaction and its synonyms and related conditions. ADR term representation is based on MedDRA version 11.1. >

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 Akarboza Mylan 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 Akarboza Mylan, 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 Akarboza Mylan..

When Akarboza Mylan tablets are taken with drinks and/or meals containing carbohydrates overdose may lead to meteorism, flatulence and diarrhoea. If Akarboza Mylan tablets are taken independently of food, excessive intestinal symptoms need not be anticipated.

No specific antidotes to Akarboza Mylan are known.

Intake of carbohydrate-containing meals or beverages should be avoided for 4-6 hours.

Diarrhoea should be treated by standard conservative measures.

When Akarboza Mylan Tablets are taken with drinks and/or meals containing carbohydrates overdose may lead to meteorism, flatulence and diarrhoea. If Akarboza Mylan Tablets are taken independently of food, excessive intestinal symptoms need not be anticipated.

No specific antidotes to Akarboza Mylan are known.

Intake of carbohydrate-containing meals or beverages should be avoided for 4-6 hours.

Diarrhoea should be treated by standard conservative measures.

Pharmacotherapeutic group: drugs used in diabetes, alpha-glusosidase 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 (α-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.

Pharmacotherapeutic group: Alpha glucosidase inhibitors, ATC code: A10BF01

In all species tested, Akarboza Mylan exerts its activity in the intestinal tract. The action of Akarboza Mylan is based on the competitive inhibition of intestinal enzymes (α-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, Akarboza Mylan reduces the postprandial rise in blood glucose, thus reducing blood glucose fluctuations.

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

The pharmacokinetics of Akarboza Mylan were investigated after oral administration of the ¹⁴C-labelled substance (200 mg) 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 ± 15.7μg/l after 1.1 ± 0.3 h, is in agreement with corresponding data for the concentration course of the inhibitor substance (49.5 ± 26.9 μg/l after 2.1 ± 1.6 h). The second peak is on average 586.3 ± 282.7 μg/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.

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

The pharmacokinetics of Akarboza Mylan 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 Akarboza Mylan-equivalent concentration of 52.2 ± 15.7μg/l after 1.1 ± 0.3 h, is in agreement with corresponding data for the concentration course of the inhibitor substance (49.5 ± 26.9μg/l after 2.1 ± 1.6 h). The second peak is on average 586.3 ± 282.7μg/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.

Acute toxicity

LD₅₀ studies were performed in mice, rats and dogs. Oral LD₅₀ values were estimated to be > 10 g/kg body-weight. Intravenous LD₅₀ values ranged from 3.8 g/kg (dog) to 7.7 g/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 450 mg/kg body-weight were tolerated without drug-related toxicity.

In the dog study, daily doses of 50-450 mg/kg were associated with decreases in body-weight. This occurred because dosing of the animals took place shortly before the feed was administered, resulting in the presence of acarbose in the gastro-intestinal 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 α-amylase synthesis feedback mechanism a reduction in serum α-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 4500 ppm acarbose in their feed, no drug-related toxicity was observed. In dogs, also treated for one year with daily doses of up to 400 mg/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 4500 ppm 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 4500 ppm 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 4000 ppm 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 480 mg/kg/day in rats and rabbits.

In rats no impairment of fertility was observed in males or females at doses of up to 540 mg/kg/day. The oral administration of up to 540 mg/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.

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 Akarboza Mylan 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 Akarboza Mylan in the gastro-intestinal tract at the time of feeding. The pharmacodynamic action of Akarboza Mylan 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 α-amylase synthesis feedback mechanism a reduction in serum α-amylase activity was also observed in the dog study. Increases in blood urea concentrations in Akarboza Mylan-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 Akarboza Mylan 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 Akarboza Mylan and was reversed by increasing the quantity of feed.

Carcinogenicity studies

In a study in which Sprague-Dawley rats received up to 4500ppm Akarboza Mylan 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 Akarboza Mylan.

In further studies with Sprague-Dawley rats in which the malnutrition and glucose deprivation were avoided by either dietary glucose supplementation or administration of Akarboza Mylan 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 Akarboza Mylan 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 Akarboza Mylan in the feed for 80 weeks (with and without dietary glucose supplementation).

Reproductive toxicity

There was no evidence of a teratogenic effect of Akarboza Mylan 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 Akarboza Mylan.

None stated.

Not applicable.

None stated.

Not relevant.