Each extended-release tablet contains: Metformin hydrochloride 1 g.
Pharmacology: Pharmacodynamics: Metformin is a biguanide oral antihyperglycemic agent, which lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycemia. Metformin may act via 3 mechanisms: (1) in the liver, reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis; (2) in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilization and (3) 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).
Metformin is associated with either a stable body weight or modest weight loss. In humans, independently of its action on glycemia, metformin has favorable effects on lipid metabolism. Metformin reduces total cholesterol, LDL cholesterol and triglyceride levels.
Pharmacokinetics: Metformin hydrochloride extended-release tablet comprise of a dual hydrophilic polymer matrix system. Metformin hydrochloride is combined with a drug release controlling polymer to form an "inner" phase, which is then incorporated as discrete particles into an "external" phase of a second polymer. After administration, fluid from the gastrointestinal tract enters the extended-release tablet, causing the polymers to hydrate and swell. The drug is released slowly from the dosage form by a process of diffusion through the gel matrix that is essentially independent of pH. The hydrated polymer system is not rigid and is expected to be broken up by normal peristalsis in the GI tract. The biologically inert components of the extended-release tablet may occasionally remain intact during GI transit and will be eliminated in the feces.
Absorption: Metformin hydrochloride (DIABEMIN XR) bioequivalence study was conducted by combining single and multiple doses in the administration condition. The single dose condition was performed under fasting conditions, while, the multiple doses condition was performed with normal diabetic meals. Following the single dose condition, Cmax is achieved with a median value of 3.5 hours and a range of 1.5 to 4.5 hours, while AUCt, AUCinf and Cmax are similar to the reference drug. Following the multiple doses condition, AUCtau, Cmax and Cmin are similar to the reference drug.
The composition of the meal does not influence the absorption. After repeated administration of up to a dose of 2 g of metformin, metformin does not accumulate in the plasma.
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.
Metabolism: Metformin does not undergo metabolism and it is excreted unchanged in the urine. No metabolites have been identified in humans. There is no biliary elimination.
Elimination: Renal clearance of metformin is >400 mL/minute, 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.
The fast elimination of metformin in patients with normal renal function shows no accumulation of metformin in the body at the recommended dosage.
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 glycemic control.
Metformin may be used as monotherapy or in combination with other oral antidiabetic agents, or with insulin.
Intensive glucose control with metformin as first-line therapy after diet failure in overweight type 2 diabetic patients has been shown to reduce diabetes complications.
Impaired glucose tolerance (IGT) for patients in whom lifestyle interventions (diet and exercise) have failed.
Metformin hydrochloride (DIABEMIN XR) should generally be given once daily with the evening meal or with breakfast and evening meal (twice daily dosage) and should be started at a low dose, with gradual dose escalation. Subsequent dosage should be adjusted according to the patient's therapeutic response, using the lowest possible effective dosage. Metformin hydrochloride (DIABEMIN XR) must be swallowed whole and never crushed or chewed. Metformin hydrochloride (DIABEMIN XR) should always be taken with food. This will avoid the patient having gastrointestinal discomfort.
Patients who have stopped the treatment must contact their doctor. In case the patient has forgotten to take metformin hydrochloride (DIABEMIN XR), the next dose should be taken at the usual time. Do not double the dose of metformin unless otherwise prescribed by the doctor. It is normal that the tablet shells may be present in the feces and this is not linked with a decrease in therapeutic activity.
Metformin hydrochloride (DIABEMIN XR) 1 g: Metformin hydrochloride (DIABEMIN XR) 1 g is intended as a maintenance treatment for patients already treated with either 1 g or 2 g of metformin. The maximum dose is two tablets of metformin hydrochloride (DIABEMIN XR) 1 g once daily, given with the evening meal. If glycemic control is not achieved on maximal daily dose given once daily, then the same dose may be considered but divided along the day according to the following scheme: one tablet during breakfast and one tablet during evening meal.
Combination with insulin: Metformin hydrochloride (DIABEMIN XR) can never be replace insulin in type 1 diabetes but concomitant administration with insulin makes it possible to reduce the insulin doses and obtain more stable blood glucose levels. In case metformin hydrochloride (DIABEMIN XR) is used in combination with insulin the usual starting dose is one tablet metformin hydrochloride (DIABEMIN XR) 500 mg, while insulin dosage is adjusted on the basis of blood glucose measurement.
Elderly and decreased renal function: In the elderly and in patients with decreased renal function, the metformin dosage should be adjusted based on renal function. Regular assessment of renal function is necessary.
Children: Metformin hydrochloride (DIABEMIN XR) is not recommended for use in children.
Symptoms: Hypoglycemia may occur when metformin is used in conjunction with sulfonylurea, insulin, and alcohol.
Lactic acidosis has been reported in metformin overdose cases.
Management of overdosage: Intensive supportive therapy is recommended which should be particularly directed at correcting fluid loss and metabolic disturbances. The most effective method to remove lactate and metformin is hemodialysis.
Known hypersensitivity to metformin hydrochloride.
Diabetic coma and ketoacidosis.
Renal dysfunction (e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females] or abnormal creatinine clearance).
Chronic hepatic disease, cardiac failure, ischemic heart disease (e.g., acute myocardial infarction), alcoholism, history of lactic acidosis or states associated with lactic acidosis such as shock or pulmonary insufficiency, and conditions associated with hypoxia.
Metformin hydrochloride is not recommended for use in pregnancy and nursing mothers.
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. Then 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. It is characterized by acidotic dyspnea, vomiting, abdominal pain with muscle cramps, and/or general feeling of malaise with severe fatigue and hypothermia followed by coma. Lactic acidosis is a medical emergency. If metabolic acidosis is suspected, metformin should be discontinued and the patient should be hospitalized immediately.
Renal function: As metformin is excreted mainly by the kidney, serum creatinine levels or creatinine clearance should be determined before initiating treatment (creatininemia <135 μmol/L in males and <110 μmol/L in females) and regularly thereafter; at least annually in patients with normal renal function and at least two to four times a year in patients with creatinine 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 in the elderly when initiating antihypertensive therapy or diuretic therapy and when starting therapy with a nonsteroidal anti-inflammatory.
Administration of iodinated contrast agent: Intravascular administration of iodinated contrast materials in radiologic studies such as intravenous urography or angiography, may lead to renal failure, resulting in metformin accumulation and a risk of lactic acidosis. Metformin should be discontinued 48 hours prior to or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been reevaluated and found to be normal.
Surgery: If a patient is going to have an elective major surgery, treatment with metformin must be discontinued 48 hours before the surgery. Metformin should not be reinstituted until 48 hours after the surgery and only after ensuring that kidney function is normal.
The use of metformin is not advised in conditions which may cause dehydration or in patients suffering from serious infections or trauma.
Serum B12 levels should annually be evaluated, in long-term therapy.
Metformin therapy in combination with a sulfonylurea should be monitored by blood-glucose readings as hypoglycemia may occur.
Combination therapy with insulin should be done in the hospital, until the correct ratio of the two medicines is determined.
Caution is advised in elderly patients because of the reduced renal function. Hence renal function should be monitored regularly.
Metformin is not recommended in children.
Patients should continue following any dietary advice the doctor has given including some energy-restricted diet for overweight patients. Patients should also get some regular exercise.
Consumption of alcoholic beverages has to be avoided.
The usual laboratory tests for diabetes monitoring should be performed regularly.
Effects on Ability to Drive and Use Machines: Metformin monotherapy does not cause hypoglycemia. However, patients should be alerted to the risk of hypoglycemia when metformin is used in combination with other antidiabetic agents (sulfonylureas, insulin, glinides or other hypoglycemic agents). It is important to be aware of the onset of hypoglycemia. Symptoms of hypoglycemia include weakness, dizziness, increased sweating, fast heartbeat, vision disorders or difficulty in concentration. When a patient starts to feel these symptoms, he should not drive or use machines.
Pregnancy: Metformin is not the appropriate treatment of type 2 diabetes during pregnancy. Women who are pregnant or plan to become pregnant have to consult their doctor for replacement of metformin by insulin.
Lactation: Metformin is contraindicated during breastfeeding. As a general rule, women who are pregnant or breastfeeding should always ask their doctor for advice before taking medicine.
As with all medications, metformin can cause adverse drug reactions. The following adverse drug reactions are presented by frequencies which are defined as follows:
Very common: Gastrointestinal discomfort such as nausea, vomiting, diarrhea, abdominal pain and loss of appetite may occur especially at the beginning of treatment. These symptoms are generally transient and can be reduced by taking metformin with meals. Should these symptoms continue, patients must stop taking the treatment and consult their doctor.
Common: Taste disturbance.
Very rare: Lactic acidosis is a very serious complication, which results in vomiting, abdominal pain with muscle cramps and/or general feeling of malaise with severe fatigue and which requires specific treatment. If this occurs, patients should stop taking metformin hydrochloride (DIABEMIN XR) immediately and consult their doctor promptly. Lactic acidosis is a medical emergency and must be treated in a hospital.
Skin reactions such as erythema (red skin), itching or urticaria (eruption with itching).
Decreased vitamin B
12 levels (to take into consideration if the patient is suffering from megaloblastic anemia).
Isolated cases of liver function test abnormalities or hepatitis resolving upon metformin hydrochloride (DIABEMIN XR) discontinuation.
Any undesirable or distressing effect must be reported to the doctor or pharmacists. If an undesirable effect is severe, occurred suddenly or gets worse rapidly, the doctor must be consulted immediately to prevent serious reactions.
Inadvisable combinations: Alcohol: Increased risk of lactic acidosis in acute alcohol intoxication, particularly in case of fasting or malnutrition and hepatic insufficiency. Avoid consumption of alcohol and alcohol-containing medications.
Associations requiring precautions for use: Glucocorticoids (systemic and local routes) and tetracosactides, beta-2-agonists (e.g. salbutamol, terbutaline), danazol, chlorpromazine at high dosages of 100 mg per day and diuretics have intrinsic hyperglycemic 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.
Diuretics especially loop diuretics, may increase the risk of lactic acidosis due to their potential to decrease renal function.
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.
While taking metformin, patients must not use iodinated contrast agents.
The doctor or pharmacist should be informed about concurrent or recently taken medications such as nonsteroidal anti-inflammatories or even an over-the-counter medication.
There is a possible interaction between anticoagulants and metformin hydrochloride. Patients receiving these two medicines concomitantly need an adjustment of the anticoagulant dosage.
Cimetidine decreases the renal clearance of metformin, therefore a dose reduction should be considered.
Store at temperatures not exceeding 30°C.
A10BA02 - metformin ; Belongs to the class of biguanides. Used in the treatment of diabetes.
Diabemin XR ER tab 1 g
60's (P627/box)
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