Amophage

Treatment of type 2 diabetes mellitus, particularly in overweight patients, when dietary management and exercise alone does not result in adequate glycaemic control.

Adults

- In adults, Amophage hydrochloride may be used as monotherapy or in combination with other oral anti-diabetic agents or with insulin.

A reduction of diabetic complications has been shown in overweight type 2 diabetic adult patients treated with Amophage as first-line therapy after diet failure.

Paediatric population

- In children from 10 years of age and adolescents, Amophage hydrochloride may be used as monotherapy or in combination with insulin.

Treatment of type 2 diabetes mellitus, particularly in over weight patients, when dietary management and exercise alone does not result in adequate glycemic control.

- In adults, Metformin film-coated tablets may be used as monotherapy or in combination with other oral anti-diabetic agents or with insulin.

- In children from 10 years of age and adolescents, Amophage film-coated tablets may be used as monotherapy or in combination with insulin.

A reduction of diabetic complications has been shown in overweight type 2 diabetic adult patients treated with Amophage as first-line therapy after diet failure.

Posology

Adults (with normal renal function, GFR> 90 mL/min):

Monotherapy and combination with other oral antidiabetic agents:

- The usual starting dose is 500mg (5ml) or 850mg (8.5ml) Amophage hydrochloride 2 or 3 times daily given during or after meals.

- After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability. In patients receiving a high Amophage hydrochloride dose (2 to 3 grams per day), it is possible to replace two Amophage hydrochloride 500mg doses (5ml) with one Amophage hydrochloride 1000mg (10ml) dose. The maximum recommended dose of Amophage is 3g (30ml) daily, taken as 3 divided doses.

- If transfer from another oral antidiabetic agent is intended, discontinue the other agent and initiate Amophage at the dose indicated above.

Combination with insulin:

Amophage and insulin may be used in combination therapy to achieve better blood glucose control. Amophage hydrochloride is given at the usual starting dose of 500mg (5ml) or 850mg (8.5ml) 2-3 times daily, while insulin dosage is adjusted on the basis of blood glucose measurements.

Patients with renal impairment

A GFR should be assessed before initiation of treatment with Amophage containing products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months.

Amophage may be used in patients with moderate renal impairment, stage 3a (creatinine clearance [CrCl] 45-59 ml/min or estimated glomerular filtration rate [eGFR] 45-59 ml/min/1.73m2) only in the absence of other conditions that may increase the risk of lactic acidosis and with the following dose adjustments:

Amophage is contraindicated in patients with severe renal failure (GFR <30 mL/min).

Elderly:

Due to the potential for decreased renal function in elderly subjects, the Amophage dosage should be adjusted based on renal function. Regular assessment of renal function is necessary.

Paediatric population

Monotherapy and combination with insulin

- Amophage hydrochloride can be used in children from 10 years of age and adolescents.

- The usual starting dose is 500mg (5ml) or 850mg (8.5ml) once daily, given during meals or after meals.

- After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability. The maximum recommended dose of Amophage is 2g (20ml) daily, taken as 2 or 3 divided doses.

Method of administration

Amophage oral solution is for oral administration.

Posology

Adults:

Adults with normal renal function (GFR> 90 mL/min)

Monotherapy and combination with other oral antidiabetic agents:

- The usual starting dose is 500mg or 850mg Amophage 2 or 3 times daily given during or after meals.

After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability.

The maximum recommended dose of Amophage is 3 g daily, taken as 3 divided doses.

If transfer from another oral antidiabetic agent is intended: discontinue the other agent and initiate Amophage at the dose indicated above.

Combination with insulin:

Amophage and insulin may be used in combination therapy to achieve better blood glucose control. Amophage is given at the usual starting dose of 500mg or 850mg Amophage 2or3 times daily, while insulin dosage is adjusted on the basis of blood glucose measurements.

Elderly:

Due to the potential for decreased renal function in elderly subjects, the Amophage dosage should be adjusted based on renal function. Regular assessment of renal function is necessary.

Renal impairment

A GFR should be assessed before initiation of treatment with metformin containing products and at least annually thereafter. In patients at an increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months.

Paediatric population:

Monotherapy and combination with insulin

- Amophage film-coated tablets can be used in children from 10 years of age and adolescents.

- The usual starting dose is 500 mg or 850 mg Amophage once daily, given during meals or after meals.

After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability. The maximum recommended dose of Amophage is 2 g daily, taken as 2 or 3 divided doses.

-

- Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis.)

- Severe renal failure (GFR <30 mL/min)

- Acute conditions with the potential to alter renal function such as:

- Disease which may cause tissue hypoxia (especially acute disease, or worsening of chronic disease) such as:

- Hepatic insufficiency, acute alcohol intoxication, alcoholism.

- Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis)

- Severe renal failure (GFR <30 mL/min)

- Acute conditions with the potential to alter renal function such as:

o dehydration,

o severe infection,

o shock,

- Acute or chronic disease which may cause tissue hypoxia such as:

o cardiac or respiratory failure,

o recent myocardial infarction,

o shock

- Hepatic insufficiency, acute alcohol intoxication, alcoholism

Lactic acidosis

Lactic acidosis, a very rare, but serious metabolic complication, most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis. Amophage accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis.

Reported cases of lactic acidosis in patients on Amophage have occurred primarily in diabetic patients with impaired renal failure or acute worsening of renal function. Special caution should be paid to situations where renal function may become impaired, for example in case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake), or when initiating antihypertensive therapy or diuretic therapy and when starting therapy with a non-steroidal anti-inflammatory drug (NSAID). In the acute conditions listed, Amophage should be temporarily discontinued.

Other associated risk factors should be considered to avoid lactic acidosis such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia (such as decompensated heart failure, acute myocardial infarction).

The risk of lactic acidosis must be considered in the event of non-specific signs such as muscle cramps, digestive disorders as abdominal pain and severe asthenia. Patients should be instructed to notify these signs immediately to their physicians if they occur, notably if patients had a good tolerance to Amophage before. Amophage should be discontinued, at least temporarily, until the situation is clarified. Reintroduction of Amophage should then be discussed taking into account the benefit/risk ratio in an individual basis as well as renal function.

Diagnosis:

Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be initiated with caution in Amophage treated patients. Other risk factors for lactic acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis.

Patients and/or care-givers should be informed on the risk of lactic acidosis.

Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH (< 7.35), increased plasma lactate levels (>5 mmol/l) and an increased anion gap and lactate/pyruvate ratio. In case of lactic acidosis, the patient should be hospitalised immediately.

Physicians should alert the patients on the risk and on the symptoms of lactic acidosis.

Renal function

As Amophage is excreted by the kidney, creatinine clearance (this can be estimated from serum creatinine levels by using the Cockcroft-Gault formula) or eGFR should be determined before initiating treatment and regularly thereafter:

- at least annually in patients with normal renal function;

- at least two to four times a year in patients with serum creatinine levels at the lower limit of normal and in elderly subjects.

Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive therapy, diuretic therapy or when starting therapy with a non-steroidal anti-inflammatory drug (NSAID).

In these cases, it is also recommended to check renal function before initiating treatment with Amophage.

Cardiac function

Patients with heart failure are more at risk of hypoxia and renal insufficiency. In patients with stable chronic heart failure, Amophage may be used with a regular monitoring of cardiac and renal function.

For patients with acute and unstable heart failure, Amophage is contraindicated.

Administration of iodinated contrast media

Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy, resulting in Amophage accumulation and an increased risk of lactic acidosis.5.

In patients with moderate renal impairment (eGFR between 45 and 60 ml/min/1.73m²), Amophage must be discontinued 48 hours before administration of iodinated contrast media and not be reinstituted until at least 48 hours afterwards and only after renal function has been re-evaluated and has not deteriorated further.

Surgery

Amophage must be discontinued at the time of surgery under general, spinal or epidural anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and provided that renal function has been re-evaluated and found to be stable.

Paediatric population

The diagnosis of type 2 diabetes mellitus should be confirmed before treatment with Amophage is initiated.

No effect of Amophage on growth and puberty has been detected during controlled clinical studies of one year duration, but no long term data on these specific points are available. Therefore, a careful follow-up of the effect of Amophage hydrochloride on these parameters, in Amophage hydrochloride treated children, especially pre-pubescent children, is recommended.

Children aged between 10 and 12 years:

Only 15 subjects aged between 10 and 12 years were included in the controlled clinical studies conducted in children and adolescents. Although efficacy and safety of Amophage in these children did not differ from efficacy and safety in older children and adolescents, particular caution is recommended when prescribing to children aged between 10 and 12 years.

Other precautions

All patients should continue their diet with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet.

The usual laboratory tests for diabetes monitoring should be performed regularly.

Amophage hydrochloride alone does not cause hypoglycaemia, but caution is advised when it is used in combination with insulin or other oral antidiabetics (e.g. sulphonylureas or meglitinides).

Excipient warnings

This product contains:

- Sodium methyl and propyl parahydroxybenzoates. These may cause allergic reactions (possibly delayed).

- Liquid maltitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

- Sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine. Sucrose may also be harmful to teeth.

- Sodium - 7mg per 5ml dose. To be taken into consideration by patients on a controlled sodium diet.

- Potassium - 14.5mg per 5ml dose. To be taken into consideration by patients with reduced kidney function or patients on controlled potassium diets.

- Sodium sulphite. This may rarely cause severe hypersensitivity (allergic) reactions and bronchospasm.

- Ethanol. This medicinal product contains small amounts of ethanol (alcohol), less than 100mg per 10ml.

Lactic acidosis:

Lactic acidosis, a very rare but serious metabolic complication, most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis.

In case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake), metformin should be temporarily discontinued and contact with a health care professional is recommended.

Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be initiated with caution in metformin-treated patients. Other risk factors for lactic acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis.

Patients and/or care-givers should be informed of the risk of lactic acidosis. Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. In case of suspected symptoms, the patient should stop taking metformin and seek immediate medical attention. Diagnostic laboratory findings are decreased blood pH (< 7.35), increased plasma lactate levels (>5 mmol/L) and an increased anion gap and lactate/pyruvate ratio.

Administration of iodinated contrast agents

Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy, resulting in metformin accumulation and an increased risk of lactic acidosis.5.

Renal function

Surgery

Metformin must be discontinued at the time of surgery under general, spinal or epidural anesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and provided that renal function has been re-evaluated and found to be stable.

Paediatric population

The diagnosis of type 2 diabetes mellitus should be confirmed before treatment with Amophage is initiated.

No effect of Amophage on growth and puberty has been detected during controlled clinical studies of one-year duration but no long-term data on these specific points are available. Therefore, a careful follow-up of the effect of Amophage on these parameters in Amophage-treated children, especially pre-pubescent children, is recommended.

Children aged between 10 and 12 years:

Only 15 subjects aged between 10 and 12 years were included in the controlled clinical studies conducted in children and adolescents. Although efficacy and safety of Amophage in these children did not differ from efficacy and safety in older children and adolescents, particular caution is recommended when prescribing to children aged between 10 and 12 years.

Other precautions:

All patients should continue their diet with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet.

The usual laboratory tests for diabetes monitoring should be performed regularly.

Amophage alone does not cause hypoglycaemia, but caution is advised when it is used in combination with insulin or oral antidiabetics (e.g. sulfonylureas or meglitinides).

Amophage has no influence on the ability to drive and use machines.

Amophage monotherapy does not cause hypoglycaemia and therefore has no effect on the ability to drive or to use machines.

However, patients should be alerted to the risk of hypoglycaemia when Amophage is used in combination with other antidiabetic agents (e.g. sulphonylureas, insulin, meglitinides).

Amophage monotherapy does not cause hypoglycaemia and therefore has no effect on the ability to drive or to use machines.

However, patients should be alerted to the risk of hypoglycaemia when meformin hydrochloride is used in combination with other antidiabetic agents (sulfonylureas, insulin or meglitinides).

During treatment initiation, the most common adverse reactions are nausea, vomiting, diarrhoea, abdominal pain and loss of appetite which resolve spontaneously in most cases. To prevent them, it is recommended to take Amophage in 2 or 3 daily doses and to increase the doses slowly.

Adverse events are which have been associated with Amophage are given below, listed by system organ class and frequency. Undesirable effects are especially likely to occur at treatment onset or at dose increase.

The following adverse reactions may occur under treatment with Amophage. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness:

very common (>1/10),

common (>1/100 to <1/10),

uncommon (>1/1000 to<1/100),

rare (>1/10000 to<1/1000),

very rare (<1/10000),

not known (cannot be estimated from the available data).

i) These undesirable effects occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent them, it is recommended that Amophage be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.

ii) Isolated reports of liver function test abnormalities or hepatitis resolving upon Amophage discontinuation

Paediatric population

In published and post marketing data and in controlled clinical studies in a limited paediatric population aged 10-16 years treated during 1 year, adverse event reporting was similar in nature and severity to that reported in adults.

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 Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

During treatment initiation, the most common adverse reactions are nausea, vomiting, diarrhoea, abdominal pain and loss of appetite which resolve spontaneously in most cases. To prevent them, it is recommended to take metformin in 2 or 3 daily doses and to increase slowly the doses.

The following adverse reactions may occur under treatment with metformin. Frequencies are defined as follows: very common: >1/10; common >1/100, <1/10; uncommon >1/1,000, <1/100; rare >1/10,000, <1/1,000; very rare <1/10,000.

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Metabolism and nutrition disorders:

very rare:

Lactic acidosis.

Decrease of vitamin B12 absorption with decrease of serum levels during long-term use of metformin. Consideration of such aetiology is recommended if a patient presents with megaloblastic anaemia.

Nervous system disorders:

Common: Taste disturbance

Gastrointestinal disorders:

very common: Gastrointestinal disorders such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite. These undesirable effects occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent them, it is recommended that metformin be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.

Hepatobiliary disorders:

very rare: Isolated reports of liver function tests abnormalities or hepatitis resolving upon metformin discontinuation.

Skin and subcutaneous tissue disorders:

very rare: Skin reactions such as erythema, pruritus, urticaria

Paediatric population

In published and post marketing data and in controlled clinical studies in a limited paediatric population aged 10-16 years treated during 1 year, adverse event reporting was similar in nature and severity to that reported in adults.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Symptoms

Hypoglycaemia has not been seen with Amophage hydrochloride doses of up to 85g, although lactic acidosis has occurred in such circumstances. High overdose of Amophage or concomitant risks may lead to lactic acidosis.

Management

Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and Amophage is haemodialysis.

Hypoglycaemia has not been seen with Amophage doses of up to 85 g, although lactic acidosis has occurred in such circumstances. High overdose of Amophage or concomitant risks may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and Amophage is haemodialysis.

Pharmacotherapeutic group: Blood glucose lowering drugs, Biguanides

ATC Code: A10B A02

Mechanism of action

Amophage hydrochloride is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.

Pharmacodynamic effect

Amophage hydrochloride may act via 3 mechanisms:

(1) reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis (2) in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilisation (3) delay of intestinal glucose absorption.

Amophage hydrochloride stimulates intracellular glycogen synthesis by acting on glycogen synthase.

Amophage hydrochloride increases the transport capacity of all types of membrane glucose transporters (GLUT) known to date.

In clinical studies, use of Amophage was associated with either a stable body weight or modest weight loss.

In humans, independently of its action on glycaemia, Amophage has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: Amophage hydrochloride reduces total cholesterol, LDL cholesterol and triglyceride levels.

Clinical efficacy and safety:

The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood glucose control in adult patients with type 2 diabetes.

Analysis of the results for overweight patients treated with Amophage after failure of diet alone showed:

- a significant reduction of the absolute risk of any diabetes-related complication in the Amophage group (29.8 events/1000 patient-years) versus diet alone (43.3 events/1000 patient-years), p=0.0023, and versus the combined sulphonylurea and insulin monotherapy groups (40.1 events/1000 patient-years), p=0.0034;

- a significant reduction of the absolute risk of diabetes-related mortality: Amophage 7.5 events/1000 patient-years, diet alone 12.7 events/1000 patient-years, p=0.017;

- a significant reduction of the absolute risk of overall mortality: Amophage 13.5 events/1000 patient-years versus diet alone 20.6 events/1000 patient-years (p=0.011), and versus the combined sulphonylurea and insulin monotherapy groups 18.9 events/1000 patient-years (p=0.021);

- a significant reduction in the absolute risk of myocardial infarction: Amophage 11 events/1000 patient-years, diet alone 18 events/1000 patient-years (p=0.01).

Benefit regarding clinical outcome has not been shown for Amophage used as second-line therapy, in combination with a sulfonylurea.

In type 1 diabetes, the combination of Amophage hydrochloride and insulin has been used in selected patients, but the clinical benefit of this combination has not been formally established.

Paediatric population

Controlled clinical studies in a limited paediatric population aged 10-16 years treated during 1 year demonstrated a similar response in glycaemic control to that seen in adults.

Pharmacotherapeutic group: Blood Glucose lowering drugs, excl Insulins, Biguanides ATC code: A10BA02

Mechanism of action

Amophage is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.

Amophage may act via 3 mechanisms:

(1) reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis

(2) in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilization

(3) and delay of intestinal glucose absorption.

Amophage stimulates intracellular glycogen synthesis by acting on glycogen synthase.

Amophage increases the transport capacity of all types of membrane glucose transporters (GLUTs) known to date.

In humans, independently of its action on glycaemia, Amophage has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: Amophage reduces total cholesterol, LDL cholesterol and triglyceride levels.

In clinical studies, use of metformin was associated with either a stable body weight or modest weight loss.

Clinical efficacy:

The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood glucose control in adult patients with type 2 diabetes.

Analysis of the results for overweight patients treated with Amophage after failure of diet alone showed:

o a significant reduction of the absolute risk of any diabetes-related complication in the Amophage group (29.8 events/ 1000 patient-years) versus diet alone (43.3 events/ 1000 patient-years), p=0.0023, and versus the combined sulfonylurea and insulin monotherapy groups (40.1 events/ 1000 patient-years), p=0.0034;

o a significant reduction of the absolute risk of diabetes-related mortality: Amophage 7.5 events/1000 patient-years, diet alone 12.7 events/1000 patient-years, p=0.017;

o a significant reduction of the absolute risk of overall mortality: Amophage 13.5 events/ 1000 patient-years versus diet alone 20.6 events/ 1000 patient -years (p=0.011), and versus the combined sulfonylurea and insulin monotherapy groups 18.9 events/ 1000 patient-years (p=0.021);

o a significant reduction in the absolute risk of myocardial infarction: Amophage 11 events/ 1000 patient-years, diet alone 18 events/ 1000 patient-years (p=0.01)

Benefit regarding clinical outcome has not been shown for Amophage used as second-line therapy, in combination with a sulfonylurea.

In type 1 diabetes, the combination of Amophage and insulin has been used in selected patients, but the clinical benefit of this combination has not been formally established.

Paediatric population

Controlled clinical studies in a limited paediatric population aged 10-16 years treated during 1 year demonstrated a similar response in glycaemic control to that seen in adults.

Absorption:

After an oral dose of Amophage hydrochloride, T_max is reached approximately in 2.5 hours. Absolute bioavailability of a 500mg or 850mg Amophage hydrochloride tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30%.

After oral administration, Amophage hydrochloride absorption is saturable and incomplete. It is assumed that the pharmacokinetics of Amophage absorption is non-linear.

At the recommended Amophage doses and dosing schedules, steady state plasma concentrations are reached within 24 to 48 hours and are generally less than 1μg/ml. In controlled clinical trials, maximum Amophage hydrochloride plasma levels (C_max) did not exceed 5μg/ml, even at maximum doses.

Food decreases the extent and slightly delays the absorption of Amophage. Following administration of a dose of 850mg, a 40% lower plasma peak concentration, a 25% decrease in AUC (area under the curve) and a 35 minute prolongation of time to peak plasma concentration were observed. The clinical relevance of these findings is unknown.

Distribution:

Plasma protein binding is negligible. Amophage hydrochloride partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean volume of distribution (Vd) ranged between 63-276L.

Biotransformation:

Amophage hydrochloride is excreted unchanged in the urine. No metabolites have been identified in humans.

Elimination:

Renal clearance of Amophage is >400ml/min, indicating that Amophage is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours.

When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of Amophage in plasma.

Characteristics in specific groups of patients

Renal impairment

The available data in subjects with moderate renal insufficiency are scarce and no reliable estimation of the systemic exposure to Amophage in this subgroup as compared to subjects with normal renal function could be made. Therefore, the dose adaptation should be made upon clinical efficacy/tolerability considerations.

Paediatric population:

Single dose study: After single doses of Amophage hydrochloride 500mg, paediatric patients have shown similar pharmacokinetic profiles to that observed in healthy adults.

Multiple dose study: Data are restricted to one study. After repeated doses of 500mg twice daily for 7 days, in paediatric patients, the peak plasma concentration (C_max) and systemic exposure (AUC0-t) were reduced by approximately 33% and 40%, respectively, compared to diabetic adults who received repeated doses of 500mg twice daily for 14 days. As the dose is individually titrated based on glycaemic control, this is of limited clinical relevance.

Absorption:

After an oral dose of Amophage maximum plasma concentration (C_max) is reached in approximately 2.5 hours (T_max). Absolute bioavailability of a 500 mg or 850 mg Amophage tablet is approximately 50-60 % in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30 %.

After oral administration, Amophage absorption is saturable and incomplete. It is assumed that the pharmacokinetics of Amophage absorption is non-linear.

At the recommended Amophage doses and dosing schedules, steady state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 microgram/ml. In controlled clinical trials, maximum Amophage plasma levels (C_max) did not exceed 4 microgram/ml, even at maximum doses.

Food decreases the extent and slightly delays the absorption of Amophage. Following administration of a dose of 850 mg, a 40 % lower plasma peak concentration, a 25 % decrease in AUC (area under the curve) and a 35 minute prolongation of time to peak plasma concentration were observed. The clinical relevance of these findings is unknown.

Distribution:

Plasma protein binding is negligible. Amophage partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean volume of distribution (Vd) ranged between 63-276 l.

Biotransformation:

Amophage is excreted unchanged in the urine. No metabolites have been identified in humans.

Elimination:

Renal clearance of Amophage is >400 ml/min, indicating that Amophage is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours.

When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of Amophage in plasma.

Pediatric population

Single dose study: After single doses of Amophage 500 mg, paediatric patients have shown similar phamacokinetic profile to that observed in healthy adults.

Multiple dose study: Data are restricted to one study. After repeated doses of 500 mg twice daily for 7 days in paediatric patients the peak plasma concentration (C_max) and systemic exposure (AUC_0-t) were reduced by approximately 33% and 40%, respectively compared to diabetic adults who received repeated doses of 500 mg twice daily for 14 days. As the dose is individually titrated based on glycaemic control, this is of limited clinical relevance.

Non clinical data reveal no special hazard for humans based on conventional studies on safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, reproductive toxicity.

Preclinical data reveal no special hazard for humans based on conventional studies on safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and reproductive toxicity.

Not applicable.

Not applicable

Any unused product or waste material should be disposed of in accordance with local requirements.

Any unused product or waste material should be disposed off in accordance with local requirements.