Glucophage

Metformin HCl.

Pharmacology: Pharmacodynamics: Mode of Action: 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.
Metformin hydrochloride 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 utilization; delay of intestinal glucose absorption.
Metformin hydrochloride stimulates intracellular glycogen synthesis by acting on glycogen synthase.
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, metformin hydrochloride has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: Metformin hydrochloride 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.
Effect on Body Weight: In the clinical studies, use of metformin was associated with either a stable body weight or modest weight loss.
Clinical Efficacy: The prospective randomized study (UKPDS) 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 metformin hydrochloride after failure of diet alone showed a significant reduction of the absolute risk of any diabetes-related complication in the 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]; a significant reduction of the absolute risk of diabetes-related mortality [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 [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); a significant reduction in the absolute risk of myocardial infarction [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 metformin hydrochloride used as 2nd-line therapy, in combination with a sulfonylurea.
In type 1 diabetes, the combination of metformin hydrochloride and insulin has been used in selected patients, but the clinical benefit of this combination has not been formally established.
Controlled clinical studies in a limited pediatric population 10-16 years treated for 1 year demonstrated a similar response in glycemic control to that seen in adults.
Pharmacokinetics: Absorption: After an oral dose of metformin hydrochloride, T_max is reached in 2.5 hrs. Absolute bioavailability of metformin hydrochloride 500- or 850-mg tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in feces was 20-30%.
After oral administration, metformin hydrochloride absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin hydrochloride absorption is nonlinear.
At the recommended metformin hydrochloride doses and dosing schedules, steady-state plasma concentrations are reached within 24-48 hrs and are generally <1 mcg/mL. In controlled clinical trials, maximum metformin hydrochloride plasma levels (C_max) did not exceed 4 mcg/mL, even at maximum doses.
Food decreases the extent and slightly delays the absorption of metformin hydrochloride. Following administration of a 850 mg dose, a 40% lower plasma peak concentration, a 25% decrease in area under the curve (AUC) and a 35 min prolongation of the time to peak plasma concentration were observed. The clinical relevance of these findings is unknown.
Distribution: Plasma protein-binding is negligible. 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.
Metabolism: Metformin hydrochloride is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination: Renal clearance of metformin hydrochloride is >400 mL/min, indicating that metformin hydrochloride 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 hydrochloride in plasma.
Children and Adolescents: Single-Dose Study: After single doses of metformin hydrochloride 500 mg, pediatric patients have shown similar pharmacokinetic profile to that observed in healthy adults.
Multiple-Dose Study: Data are restricted to 1 study. After repeated doses of 500 mg twice daily for 7 days in pediatric 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.
Toxicology: Preclinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies on safety, pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential and reproductive toxicity.

Treatment of type 2 diabetes mellitus, particularly in overweight patients, when dietary management and exercise alone does not result in adequate glycaemic control.
In adults, Glucophage film-coated tablet may be used as monotherapy or in combination with other oral antidiabetic agents or with insulin.
In children from 10 years of age and adolescents, Glucophage film-coated tablet may be used as monotherapy or in combination with insulin.

One 500-mg tab 3 times daily or one 850-mg tab 2 times daily.
Note: In combination therapy with either a sulphonylurea or insulin, diabetic control should be checked by blood sugar readings, because of the possibility of hypoglycaemia.
Usual Starting Dose: One 500- or 850-mg tab 2-3 times daily. The dose should be increased gradually. One 500 mg tab 3 or 4 times daily, or one 850 mg tab 2 times daily is often enough to give a good diabetic control.
This may be achieved within a few days, but it is not unusual for the full effect to be delayed for up to 2 weeks. If control is incomplete, a cautious increase in dosage by increments of one 500- or 850-mg tab is justified. Maximum Daily Recommended Dose: 3 g daily in 3 divided doses. Once control has been obtained, it may be possible to reduce the dosage.
When combined with existing sulphonylurea therapy which is not giving adequate control, 1-3 Glucophage 500- or 850-mg tab should be added initially, with the dosage of Glucophage being gradually increased until optimal control is obtained. Often the sulphonylurea may be reduced and in some patients even withdrawn. Glucophage can then be continued as the sole therapy.
When used with insulin, the guidelines are as follows: When the dosage of insulin is <60 units daily, 1-3 Glucophage 500 or 850 mg tab may be added initially, followed by a gradual reduction of insulin (4 units every 2-4 days). The tablets may be increased at weekly intervals.
When the dosage of insulin is >60 units daily, the addition of Glucophage may occasionally cause a rapid fall in the blood sugar level. Careful observation of such patients is advised in the first 24 hrs after the introduction of Glucophage. After this, the recommendations stated previously should be followed.
Adolescents and Children: Monotherapy and Combination with Insulin: The 1000 mg FC tab can be used in adolescents and children >10 years.
Usual Starting Dose: 500 mg or 850 mg once daily, given during or after meals.
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: 2 g daily in 2 or 3 divided doses.
Elderly: Due to the potential for decreased renal function in elderly subjects, the dosage should be adjusted based on renal function. Regular assessment of renal function is necessary.

Hypoglycaemia has not been seen with doses of metformin hydrochloride up to 85 g, although lactic acidosis has occurred in such circumstances. High overdose of 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 metformin hydrochloride is haemodialysis.

Hypersensitivity to metformin hydrochloride or to any of the excipients of Glucophage. Diabetic ketoacidosis and 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, intravascular administration of iodinated contrast agents. Acute or chronic disease which may cause tissue hypoxia eg, cardiac or respiratory failure, recent myocardial infarction, shock. Major surgery. Hepatic insufficiency, acute alcohol intoxication, alcoholism.

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 hydrochloride accumulation. Reported cases of lactic acidosis in patients on metformin hydrochloride have occurred primarily in diabetic patients with significant renal failure. It is possible and recommended that the incidence of lactic acidosis 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 (<7.25), plasma lactate levels (>5 mmol/L), and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, metformin hydrochloride should be discontinued and the patient should be hospitalized immediately.
Renal Function: As metformin hydrochloride is excreted by the kidney, it is recommended that creatinine clearance (CrCl) levels be determined before initiating treatment and regularly thereafter: At least annually in patients with normal renal function and at least 2-4 times a year in patients with CrCl at the lower limit of normal and in elderly subjects.
Decreased renal function in elderly subjects is frequent and symptomatic. Special caution is recommended in situations where renal function may become impaired eg, when initiating antihypertensive therapy or diuretic therapy, and when starting therapy with a nonsteroidal anti-inflammatory drug (NSAID).
Administration of Iodinated Contrast Agent: Intravascular administration of iodinated contrast materials in radiologic studies can lead to renal failure. This may induce metformin metformin accumulation and may expose to lactic acidosis. Therefore, depending on the renal function, metformin must be discontinued 48 hrs before the test or from the time of the test and may not be reinstituted until 48 hrs afterwards, and only after renal function has been re-evaluated and found to be normal.
Surgery: Metformin hydrochloride must be discontinued 48 hrs before elective major surgical interventions and may not be reinstituted until 48 hrs afterwards, and only after renal function has been reevaluated and found to be normal.
Other Precautions: It is recommended that all patients continue their diet with a regular distribution of carbohydrate intake during the day and that overweight patients should continue their energy-restricted diet.
It is recommended that the usual laboratory tests for diabetes monitoring be performed regularly.
Metformin hydrochloride alone does not cause hypoglycaemia, but caution is advised when it is used in combination with insulin or sulfonylureas.
Effects on Ability to Drive or Operate Machinery: 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 hypoglycemia when metformin hydrochloride is used in combination with other antidiabetic agents (sulfonylureas, insulin, meglitinides).
Use in pregnancy & lactation: Uncontrolled diabetes during pregnancy (gestational or permanent) is associated with increased 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.
However, when the patient plans to become pregnant and during pregnancy, it is recommended that diabetes is not treated with metformin, but insulin be used to maintain blood glucose levels as close to normal as possible.
Metformin is excreted into milk in lactating rats and 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 of adverse effects on the child.
Use in children: The diagnosis of type 2 diabetes mellitus should be confirmed before treatment with metformin hydrochloride is initiated. No effect of metformin hydrochloride on growth and puberty has been detected during controlled clinical studies of 1 year duration but no long-term data on these specific points are available. Therefore, a careful follow-up of the effect of metformin hydrochloride on these parameters in metformin hydrochloride treated children, especially pre-pubescent children, is recommended.
Children between 10 and 12 years: Only 15 subjects between 10 and 12 years were included in the controlled clinical studies conducted in children and adolescents. Although efficacy and safety of metformin hydrochloride in older children and adolescents, particular caution is recommended when prescribing to children between 10 and 12 years.

Uncontrolled diabetes during pregnancy (gestational or permanent) is associated with increased 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.
However, when the patient plans to become pregnant and during pregnancy, it is recommended that diabetes is not treated with metformin, but insulin be used to maintain blood glucose levels as close to normal as possible.
Metformin is excreted into milk in lactating rats and 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 of adverse effects on the child.

The undesirable effects listed as follows may occur under treatment with metformin HCl.
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).
Nervous System Disorders: Common: Taste disturbance.
Gastrointestinal Disorders: Very Common: Gastrointestinal disorders eg, nausea, vomiting, diarrhea, 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 hydrochloride be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.
Skin and Subcutaneous Tissue Disorders: Very Rare: Skin reactions eg, erythema, pruritus, urticaria.
Metabolism and Nutrition Disorders: Very Rare: Lactic acidosis. Decrease of vitamin B12 absorption with decrease of serum levels during long-term use of metformin hydrochloride. Consideration of such aetiology is recommended if a patient presents with megaloblastic anaemia.
Hepatobiliary Disorders: Isolated reports of liver function tests abnormalities or hepatitis resolving upon metformin hydrochloride discontinuation.
Children and Adolescents: In published and post-marketing data and in controlled clinical studies in a limited pediatric population 10-16 years treated for 1 year, adverse event reporting was similar in nature and severity to that reported in adults.

Contraindicated Combinations: Depending on the renal function, metformin must be discontinued 48 hrs before or from the time of IV administration of iodinated contrast media.
Combinations to be Used with Caution: Medicinal Products with Intrinsic Hyperglycaemic Activity [eg, Glucocorticoids and Tetracosactides (Systemic and Local Routes), β₂-Agonists, Danazol, and Chlorpromazine at High Dosages of 100 mg Daily, Diuretics): More frequent blood glucose monitoring may be required, especially at the beginning of treatment. If necessary, adjust the metformin dosage during therapy with the respective medicinal product and upon its discontinuation.
Diuretics, especially loop diuretics, may increase the risk of lactic acidosis due to the potential to decrease renal function (further to the intrinsic hyperglycemic effect, see previously mentioned).
Angiotensin-Converting Enzyme (ACE) Inhibitors: May decrease the blood glucose levels. If necessary, adjust the metformin dosage during therapy with an ACE inhibitor and upon its discontinuation.
Interaction with Alcohol: The risk of lactic acidosis is increased in acute alcohol intoxication, particularly in case of fasting or malnutrition or hepatic insufficiency. It is recommended that consumption of alcohol and alcohol-containing medicinal product be avoided.

Store in a dry place below 30°C. 

Antidiabetic Agents

A10BA02 - metformin ; Belongs to the class of biguanides. Used in the treatment of diabetes.

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