Metformin STELLA 500 mg

Rx

Indications

• 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, metformin 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, metformin may be used as monotherapy or in combination with insulin.
• A reduction of diabetic complications has been shown in overweight type 2 diabetic adult patients treated with metformin as first-line therapy after diet failure.

Dosage

• Adults with normal renal function (GFR ≥ 90 ml/min)
  Monotherapy and combination with other oral antidiabetic agents:
  The usual starting dose is 500 mg or 850 mg metformin hydrochloride 2 or 3 times daily given during or after meals.
  After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability.
  The maximum recommended dose of metformin hydrochloride is 3 g daily, taken as 3 divided doses.
  If transfer from another oral antidiabetic agent is intended: discontinue the other agent and initiate metformin at the dose indicated above.
  Metformin and insulin combination
  Metformin hydrochloride is given at the usual starting dose of 500 mg or 850 mg 2 or 3 times daily, while insulin dosage is adjusted on the basis of blood glucose measurements.
• Elderly
  The metformin dosage should be adjusted based on renal function.
• Renal impairment
  GFR = 60 – 89 ml/min: Total maximum daily dose 3000 mg (to be divided into 2 – 3 daily doses). Dose reduction may be considered in relation to declining renal function.
  GFR = 45 – 59 ml/min: Total maximum daily dose 2000 mg (to be divided into 2 – 3 daily doses).
  GFR = 30 – 44 ml/min: Total maximum daily dose 1000 mg (to be divided into 2 – 3 daily doses).
  Factors that may increase the risk of lactic acidosis should be reviewed before considering initiation of metformin. The starting dose is at most half of the maximum dose.
  GFR < 30 ml/min: Metformin is contraindicated.
• Children from 10 years of age and adolescents
  The usual starting dose is 500 mg or 850 mg metformin hydrochloride once daily, given during or after meals.
  After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability.
  The maximum recommended dose of metformin hydrochloride is 2 g daily, taken as 2 or 3 divided doses.
• Discontinue metformin at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/minute/1.73 m², in patients with a history of liver disease, alcoholism, or heart failure, or in patients who will be administered intraarterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, restart metformin if renal function is stable.

Usage

• Metformin STELLA 500 mg is orally administered with or after meals.

• Patients with a history of a hypersensitivity reaction to metformin or any excipients.
• Severe renal impairment (eGFR below 30 ml/minute/1.73 m²)
• Patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis.
• Diabetic pre-coma.
• Acute conditions with the potential to alter renal function such as: Dehydration, severe infection, shock.
• Disease which may cause tissue hypoxia (especially acute disease, or worsening of chronic disease) such as:
• Decompensated heart failure, respiratory failure, recent myocardial infarction, shock.
• Hepatic insufficiency, acute alcohol intoxication, alcoholism.

Very common

• Gastrointestinal disorders such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite.
• 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.

Common

• Taste disturbance.

Lactic acidosis

• There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases, hypothermia, hypotension, resistant bradyarrhythmias. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (> 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate/pyruvate ratio, metformin plasma levels generally > 5 µg/mL.
• Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
• Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see 6. Administration and dosage, 7. Contraindications, 8. Special warnings and precautions for use, 11. Interactions and incompatibilities with other drugs].
• If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of metformin. In patients treated with metformin with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 ml/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.
• Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue metformin and report these symptoms to their healthcare provider.
• For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:
  Renal impairment
  The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include [see 6. Administration and dosage]:
  – Before initiating metformin, obtain an eGFR.
  – Metformin is contraindicated in patients with an eGFR less than 30 ml/minute/1.73 m² [see 7. Contraindications].
  – Obtain an eGFR at least annually in all patients taking metformin. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
  – In patients taking metformin whose eGFR later falls below 45 ml/minute/1.73 m², assess the benefit and risk of continuing therapy.
  Drug interactions
  The concomitant use of metformin with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see 11. Interactions and incompatibilities with other drugs]. Therefore, consider more frequent monitoring of patients.
  Age 65 or greater
  The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.
  Radiological studies with contrast
  Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop metformin at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 ml/minute/1.73 m², in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart metformin if renal function is stable.
  Surgery and other procedures
  Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment. Metformin should be temporarily discontinued while patients have restricted food and fluid intake.
  Hypoxic states
  Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue metformin.
  Excessive alcohol intake
  Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving metformin.
  Hepatic impairment
  Patients with hepatic impairment have developed metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of metformin in patients with clinical or laboratory evidence of hepatic disease.

Other precautions

• Patients should be advised that dietary regulation is the principal consideration in the management of diabetes, and that metformin therapy is used only as an adjunct to, and not a substitute for proper dietary regulation.
• The administration of oral antidiabetic drugs has been reported to be associated with increased cardiovascular mortality as compared to the treatment with diet alone or the combination of insulin with diet.
• Determination of fetal concentrations of metformin hydrochloride suggest that a partial placental barrier to the drug exists. Since abnormal maternal blood glucose concentrations during pregnancy may be associated with a higher incidence of congenital abnormalities, most experts recommend that insulin be used during pregnancy to maintain optimum control of blood glucose concentration.
• Metformin hydrochloride is excreted into breast milk. A decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman. If metformin hydrochloride is discontinued in a nursing mother and dietary therapy is inadequate for glycemic control, insulin therapy should be considered.
• 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 metformin hydrochloride is used in combination with other antidiabetic agents (sulfonylureas, insulin, repaglinide).