Symptoms
Hypoglycaemia has not been seen with Xigduo (Metformin hydrochloride) hydrochloride doses of up to 85g, although lactic acidosis has occurred in such circumstances. High overdose of Xigduo (Metformin hydrochloride) 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 Xigduo (Metformin hydrochloride) is haemodialysis.
Hypoglycaemia has not been seen with Xigduo (Metformin hydrochloride) doses of up to 85 g, although lactic acidosis has occurred in such circumstances. High overdose of Xigduo (Metformin hydrochloride) 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 Xigduo (Metformin hydrochloride) is haemodialysis.
Not applicable.
Not applicable
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 Xigduo (Metformin hydrochloride) in 2 or 3 daily doses and to increase the doses slowly.
Adverse events are which have been associated with Xigduo (Metformin hydrochloride) 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 Xigduo (Metformin hydrochloride). 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).
| System organ class | Frequency | Undesirable effects |
| Metabolism and nutrition disorders | Very rare | Lactic acidosis ( serious metabolic complication, most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis) |
| Nervous system disorders | Common | Taste disturbance |
| Gastrointestinal disorders | Very common | nausea, vomiting, diarrhoea, abdominal pain and loss of appetite i |
| Hepatobiliary disorders | Very rare | liver function test abnormalities or hepatitisii |
| Skin and subcutaneous tissue disorders | Very rare | Skin reactions such as erythema, pruritus, urticaria |
i) These undesirable effects occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent them, it is recommended that Xigduo (Metformin hydrochloride) 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 Xigduo (Metformin hydrochloride) 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.
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.
Pharmacotherapeutic group: Blood glucose lowering drugs, Biguanides
ATC Code: A10B A02
Mechanism of action
Xigduo (Metformin hydrochloride) 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
Xigduo (Metformin hydrochloride) 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.
Xigduo (Metformin hydrochloride) hydrochloride stimulates intracellular glycogen synthesis by acting on glycogen synthase.
Xigduo (Metformin hydrochloride) hydrochloride increases the transport capacity of all types of membrane glucose transporters (GLUT) known to date.
In clinical studies, use of Xigduo (Metformin hydrochloride) was associated with either a stable body weight or modest weight loss.
In humans, independently of its action on glycaemia, Xigduo (Metformin hydrochloride) has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: Xigduo (Metformin hydrochloride) 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 Xigduo (Metformin hydrochloride) after failure of diet alone showed:
- a significant reduction of the absolute risk of any diabetes-related complication in the Xigduo (Metformin hydrochloride) 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: Xigduo (Metformin hydrochloride) 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: Xigduo (Metformin hydrochloride) 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: Xigduo (Metformin hydrochloride) 11 events/1000 patient-years, diet alone 18 events/1000 patient-years (p=0.01).
Benefit regarding clinical outcome has not been shown for Xigduo (Metformin hydrochloride) used as second-line therapy, in combination with a sulfonylurea.
In type 1 diabetes, the combination of Xigduo (Metformin hydrochloride) 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
Xigduo (Metformin 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.
Xigduo (Metformin 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 utilization
(3) and delay of intestinal glucose absorption.
Xigduo (Metformin hydrochloride) stimulates intracellular glycogen synthesis by acting on glycogen synthase.
Xigduo (Metformin hydrochloride) increases the transport capacity of all types of membrane glucose transporters (GLUTs) known to date.
In humans, independently of its action on glycaemia, Xigduo (Metformin hydrochloride) has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: Xigduo (Metformin hydrochloride) 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 Xigduo (Metformin hydrochloride) after failure of diet alone showed:
o a significant reduction of the absolute risk of any diabetes-related complication in the Xigduo (Metformin hydrochloride) 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: Xigduo (Metformin hydrochloride) 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: Xigduo (Metformin hydrochloride) 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: Xigduo (Metformin hydrochloride) 11 events/ 1000 patient-years, diet alone 18 events/ 1000 patient-years (p=0.01)
Benefit regarding clinical outcome has not been shown for Xigduo (Metformin hydrochloride) used as second-line therapy, in combination with a sulfonylurea.
In type 1 diabetes, the combination of Xigduo (Metformin 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.
Absorption:
After an oral dose of Xigduo (Metformin hydrochloride) hydrochloride, Tmax is reached approximately in 2.5 hours. Absolute bioavailability of a 500mg or 850mg Xigduo (Metformin hydrochloride) 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, Xigduo (Metformin hydrochloride) hydrochloride absorption is saturable and incomplete. It is assumed that the pharmacokinetics of Xigduo (Metformin hydrochloride) absorption is non-linear.
At the recommended Xigduo (Metformin hydrochloride) 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 Xigduo (Metformin hydrochloride) hydrochloride plasma levels (Cmax) did not exceed 5μg/ml, even at maximum doses.
Food decreases the extent and slightly delays the absorption of Xigduo (Metformin hydrochloride). 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. Xigduo (Metformin hydrochloride) 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:
Xigduo (Metformin hydrochloride) hydrochloride is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination:
Renal clearance of Xigduo (Metformin hydrochloride) is >400ml/min, indicating that Xigduo (Metformin hydrochloride) 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 Xigduo (Metformin hydrochloride) 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 Xigduo (Metformin hydrochloride) 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 Xigduo (Metformin hydrochloride) 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 (Cmax) 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 Xigduo (Metformin hydrochloride) maximum plasma concentration (Cmax) is reached in approximately 2.5 hours (Tmax). Absolute bioavailability of a 500 mg or 850 mg Xigduo (Metformin 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, Xigduo (Metformin hydrochloride) absorption is saturable and incomplete. It is assumed that the pharmacokinetics of Xigduo (Metformin hydrochloride) absorption is non-linear.
At the recommended Xigduo (Metformin hydrochloride) 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 Xigduo (Metformin hydrochloride) plasma levels (Cmax) did not exceed 4 microgram/ml, even at maximum doses.
Food decreases the extent and slightly delays the absorption of Xigduo (Metformin hydrochloride). 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. Xigduo (Metformin 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 63-276 l.
Biotransformation:
Xigduo (Metformin hydrochloride) is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination:
Renal clearance of Xigduo (Metformin hydrochloride) is >400 ml/min, indicating that Xigduo (Metformin hydrochloride) 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 Xigduo (Metformin hydrochloride) in plasma.
Pediatric population
Single dose study: After single doses of Xigduo (Metformin hydrochloride) 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 (Cmax) and systemic exposure (AUC0-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.
Xigduo (Metformin hydrochloride) has no influence on the ability to drive and use machines.
Xigduo (Metformin hydrochloride) 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 Xigduo (Metformin hydrochloride) is used in combination with other antidiabetic agents (e.g. sulphonylureas, insulin, meglitinides).
Xigduo (Metformin hydrochloride) 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).
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.
