- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
ExcipientsEach prolonged release tablet contains up to 10.8mg sodium (0.5mmol) For a full list of excipients, see section 6.1
Monotherapy and combination with other oral antidiabetic agents: The usual starting dose is one tablet of 500 mg once daily. After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastro-intestinal tolerability. The maximum recommended dose is 4 tablets of 500 mg daily. Dosage increases should be made in increments of 500 mg every 10-15 days, up to a maximum of 2000 mg once daily with the evening meal. If glycaemic control is not achieved on 2000 mg of Glucient SR once daily, 1000 mg of Glucient SR twice daily should be considered, with both doses being given with food. If glycaemic control is still not achieved, patients may be switched to standard metformin tablets to a maximum dose of 3000 mg daily. In patients already treated with metformin tablets, the starting dose of Glucient SR should be equivalent to the daily dose of metformin immediate-release tablets. In patients treated with metformin at a dose above 2000 mg daily, switching to Glucient SR is not recommended. If transfer from another oral antidiabetic agent is intended: discontinue the other agent and initiate Glucient SR at the dose indicated above.
Combination with insulin:Metformin and insulin may be used in combination therapy to achieve better blood glucose control. The usual starting dose of Glucient SR is one tablet of 500 mg once 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 metformin dosage should be adjusted based on renal function. Regular assessment of renal function is necessary (see section 4.4).Children: In the absence of available data, Glucient SR should not be used in children.
Method of administrationThe tablets should be swallowed whole with a drink of water. They should not be chewed or crushed.
Lactic acidosis:Lactic acidosis is a rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by assessing also other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia.Diagnosis:Lactic acidosis is characterised by acidotic dyspnea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/l, and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, metformin should be discontinued and the patient should be hospitalised immediately (see section 4.9).
Renal function:As metformin is excreted by the kidney, creatinine clearance and/or serum creatinine levels 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 creatinine clearance levels at the 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 or diuretic therapy and when starting therapy with an NSAID.
Administration of iodinated contrast agent:As the intravascular administration of iodinated contrast materials in radiologic studies can lead to renal failure, metformin should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal.
Surgery:Metformin hydrochloride should be discontinued 48 hours before elective surgery under general, spinal or peridural anaesthesia. Therapy should be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and only if renal function has been established.
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. Metformin alone never causes hypoglycaemia, although caution is advised when it is used in combination with insulin or sulphonylureas. Excipients Each tablet contains up to 10.8mg sodium (0.5mmol) which should be taken into consideration for patients on a controlled sodium diet
Concomitant use not recommended
AlcoholIncreased risk of lactic acidosis in acute alcohol intoxication, particularly in case of: fasting or malnutrition, hepatic insufficiency.Avoid consumption of alcohol and alcohol-containing medications.
Iodinated contrast agentsIntravascular administration of iodinated contrast agents may lead to renal failure, resulting in metformin accumulation and a risk of lactic acidosis.Metformin should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see section 4.4).
Associations requiring precautions for useGlucocorticoids (systemic and local routes), beta-2-agonists, and diuretics have intrinsic hyperglycaemic activity. Inform the patient and perform more frequent blood glucose monitoring, especially at the beginning of treatment. If necessary, adjust the dosage of the antidiabetic drug during therapy with the other drug and upon its discontinuation.ACE-inhibitors may decrease the blood glucose levels. If necessary, adjust the dosage of the antidiabetic drug during therapy with the other drug and upon its discontinuation.
PregnancyTo date, no relevant epidemiological data are available. Animal studies do not indicate harmful effects with respect to pregnancy, embryonal or fetal development, parturition or postnatal development (see also section 5.3)When the patient plans to become pregnant and during pregnancy, diabetes should not be treated with metformin but insulin should be used to maintain blood glucose levels as close to normal as possible in order to lower the risk of fetal malformations associated with abnormal blood glucose levels.
LactationMetformin is excreted into milk in lactating rats. Similar data are not available in humans and a decision should be made whether to discontinue nursing or to discontinue metformin, taking into account the importance of the compound to the mother.
Metabolism and nutrition disordersVery rare: Decrease of vitamin B12 absorption with decrease of serum levels during long-term use of metformin. Consideration of such an aetiology is recommended if a patient presents with megaloblastic anaemia.Lactic acidosis (see section 4.4.).
Nervous system disordersCommon: Taste disturbance
Gastrointestinal disordersVery 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. A slow increase of the dose may also improve gastrointestinal tolerability.
Hepatobiliary disordersNot known: Isolated reports of liver function tests abnormalities or hepatitis resolving upon metformin discontinuation.
Skin and subcutaneous tissue disordersVery rare: Skin reactions such as erythema, pruritus, urticaria
Clinical efficacy:The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood glucose control in overweight type 2 diabetic patients treated with immediate-release metformin as first-line therapy after diet failure. Analysis of the results for overweight patients treated with metformin after failure of diet alone showed: a significant reduction of the absolute risk of any diabetes-related complication in the metformin 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: metformin 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: metformin 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: metformin 11 events/ 1000 patient-years, diet alone 18 events/ 1000 patient-years (p=0.01)For metformin used as second-line therapy, in combination with a sulphonylurea, benefit regarding clinical outcome has not been shown.In type 1 diabetes, the combination of metformin and insulin has been used in selected patients, but the clinical benefit of this combination has not been formally established.
AbsorptionAfter an oral dose of the prolonged-release tablet, metformin absorption is significantly delayed compared to the immediate-release tablet with a Tmax at 7 hours (Tmax for the immediate-release tablet is 2.5 hours).At steady state, similar to the immediate-release formulation, Cmax and AUC are not proportionally increased to the administered dose. The AUC after a single oral administration of 2000 mg of Metformin prolonged-release tablets is similar to that observed after administration of 1000 mg of Metformin immediate-release tablets b.i.d.Intrasubject variability of Cmax and AUC of Metformin prolonged-release is comparable to that observed with Metformin immediate-release tablets. When the prolonged-release tablet is administered in fasting conditions the AUC is decreased by 30% (both Cmax and Tmax are unaffected).Metformin absorption from the prolonged-release formulation is not altered by meal composition. No accumulation is observed after repeated administration of up to 2000 mg of metformin as prolonged-release tablets.
DistributionPlasma protein binding is negligible. Metformin 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 Vd ranged between 63-276 l.
MetabolismMetformin is excreted unchanged in the urine. No metabolites have been identified in humans.
EliminationRenal clearance of metformin is> 400 ml/min, indicating that metformin 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 metformin in plasma.
Consilient Health Ltd
No. 1 Church Road, Richmond upon Thames, Surrey, TW9 2QE, UK
+44(0)20 3751 1889
+44(0) 20 3751 1888