Pharmacology: Pharmacodynamics: Metformin is a biguanide with antihyperglycaemic effects which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia. Metformin may act via 3 mechanisms: Reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis; in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilisation; and delay of intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase.
Metformin increases the transport capacity of all types of membrane glucose transporters (GLUT). In humans, independently of its action on glycaemia, immediate-release metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium- or long-term clinical studies: Immediate-release metformin reduces total cholesterol, low-density lipoprotein (LDL)-cholesterol and triglyceride levels. A similar action has not been demonstrated with the prolonged-release formulation, possibly due to the evening administration and an increase in triglycerides may occur.
Pharmacokinetics: Absorption: After an oral dose of the prolonged-release tablet, metformin absorption is significantly delayed compared to the immediate-release tablet with a time to maximum plasma concentration (Tmax) at 7 hrs (Tmax for the immediate-release tablet is 2.5 hrs). Peak plasma levels are approximateLy 20% lower compared to the same dose of immediate release. However, the extend of absorption [as measured by area under the concentration-time curve (AUC)] is similar to immediate released.
At steady state, similar to the immediate-release formulation, maximum plasma concentration (Cmax) and AUC are not proportionally increased to the administered dose.The AUC after a single oral administration of metformin 2000 mg prolonged-release tablets is similar to that observed after administration of metformin 1000 mg immediate-release tablets twice daily.
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.
Distribution: Plasma 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 volume of distribution (Vd) ranged between 63-276 L.
Metabolism: Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination: Renal 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 hrs.
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.
Treatment of type 2 diabetes mellitus in adults, particularly in overweight patients, when dietary management and exercise alone does not result in adequate glycaemic control. Glumet XR may be used as monotherapy, or in combination with other oral antidiabetic agents or with insulin.
Monotherapy and Combination with Other Oral Antidiabetics: Usual Starting Dose: 1 tab daily with the evening meal.
After 10-15 days, the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability.
Maximum Recommended Dose: Glumet XR 500 mg: 4 tabs of Glumet XR 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.
Glumet 750 mg:2 tabs of Glumet XR 750 mg once daily with the evening meal.
In patients already treated with metformin tablets, the starting dose of Glumet XR should be equivalent to the daily dose of metformin immediate-release tablets.
If transfer from another oral antidiabetic agent is intended, discontinue the other agent and initiate Glumet XR at the dose indicated previously.
Combination with Insulin: Metformin and insulin may be used in combination therapy to achieve better blood glucose control. The usual starting dose of Glumet XR is 1 tab of 500 mg once daily with the evening meal, while insulin dosage is adjusted on the basis of blood glucose measurements.
Hypoglycaemia has not been seen with metformin doses of up to 85 g, although lactic acidosis has occurred in such circumstances. High overdosage or concomitant risks of metformin 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 metformin is haemodialysis.
Hypersensitivity to metformin hydrochloride or to any of the excipients of Glumet XR.
Diabetic ketoacidosis or diabetic precoma; renal failure or renal dysfunction [creatinine clearance (CrCl) <60 mL/min]; acute conditions with the potential to alter renal function eg, dehydration, severe infection, shock and intravascular administration of iodinated contrast agents; acute or chronic disease which may cause tissue hypoxia eg, cardiac or respiratory failure, recent myocardial infarction and shock; hepatic insufficiency, acute alcohol intoxication, alcoholism.
Use in lactation: Metformin is excreted into human breast milk. No adverse effects were observed in breastfed newborns/infants. However, as only limited data are available, breastfeeding is not recommended during metformin treatment. A decision on whether to discontinue breastfeeding should be made, taking into account the benefit of breastfeeding and the potential risk to adverse effect on the child.
Lactic Acidosis: Lactic acidosis is 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 eg, poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia.
Diagnosis: The risk of lactic acidosis must be considered in the event of nonspecific signs eg, muscle cramps with digestive disorders as abdominal pain and severe asthenia.
Lactic acidosis is characterised by acidotic dyspnea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels >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.
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 or at least 2-4 times a year in patients with creatinine clearance levels at the upper 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 eg, when initiating antihypertensive or diuretic therapy and when starting therapy with nonsteroidal anti-inflammatory drug (NSAID).
Administration of Iodinated Contrast Agent: As the intravascular administration of iodinated contrast materials in radiologic studies can lead to renal failure. This may lead to metformin accumulation and risk of lactic acidosis. Metformin should be discontinued prior to or at the time of the test and not reinstituted until 48 hrs, afterwards and only after renal function has been re-evaluated and found to be normal.
Surgery: Metformin hydrochloride should be discontinued 48 hrs before elective surgery under general, spinal or peridural anaesthesia. Therapy should be restarted no earlier than 48 hrs following surgery or resumption of oral nutrition and only if renal function has been established.
Others: All patients should continue the diet with 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 other oral antidiabetics (eg, sulphonylureas, insulin or meglitinides).
Effects on the Ability to Drive or Operate Machinery: Glumet XR 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 metformin is used in combination with other antidiabetic agents (sulphonylureas, insulin, meglitinides).
Use in pregnancy: Uncontrolled diabetes during pregnancy (gestational or permanent) is associated with increased risk of congenital abnormalities and perinatal mortality.
A limited amount of data from the use of metformin in pregnant women does not indicate an increased risk of congenital abnormalities. Animal studies do not indicate harmful effects with respect to pregnancy, embryonic or fetal development, parturition or postnatal development.
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.
Use in children: In the absence of available data, Glumet XR should not be used in children.
Use in the 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.
Use in pregnancy: Uncontrolled diabetes during pregnancy (gestational or permanent) is associated with increased risk of congenital abnormalities and perinatal mortality.
A limited amount of data from the use of metformin in pregnant women does not indicate an increased risk of congenital abnormalities. Animal studies do not indicate harmful effects with respect to pregnancy, embryonic or fetal development, parturition or postnatal development.
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.
Use in lactation: Metformin is excreted into human breast milk. No adverse effects were observed in breastfed newborns/infants. However, as only limited data are available, breastfeeding is not recommended during metformin treatment. A decision on whether to discontinue breastfeeding should be made, taking into account the benefit of breastfeeding and the potential risk to adverse effect on the child.
In post-marketing data and in controlled clinical studies, adverse event reporting in patients treated with Glumet XR was similar in nature and severity to that reported in patients treated with metformin immediate-release.
The following undesirable effects may occur with metformin. Frequencies are defined as follows: Very common >1/10; common ≥1/100, <1/10; uncommon ≥1/1000, <1/100; rare ≥1/10,000, <1/1000; very rare <1/10,000; not known (cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Metabolism and Nutrition Disorders: Very 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.
Nervous System Disorders: Common: Taste disturbance.
Gastrointestinal Disorders: Very Common: Gastrointestinal disorders eg, 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 Disorders: Not Known: Isolated reports of liver function tests abnormalities or hepatitis resolving upon metformin discontinuation.
Skin and Subcutaneous Tissue Disorders: Very Rare: Skin reactions eg, erythema, pruritus, urticaria.
Concomitant Use is not Recommended: Alcohol: Increased 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 Agents: Intravascular 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 hrs afterwards, and only after renal function has been re-evaluated and found to be normal.
Associations Requiring Precautions for Use: Glucocorticoids (systemic and local routes) β2-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.
Angiotensin-converting enzyme (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.
A10BA02 - metformin ; Belongs to the class of biguanides. Used in the treatment of diabetes.
Glumet XR tab 500 mg
100's
Glumet XR tab 750 mg
100's
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