Metformin Boston 850

POSOLOGY, METHOD OF ADMINISTRATION

Method of administration

Oral route. Should be swallowed whole, must not be chewed, taken with or after meals. For example, with a dose of 2 tablets per day, take 1 tablet for breakfast and another one for dinner.

Posology

Adults

Monotherapy and combination with other oral antidiabetic agents

The usual starting dose of metformin hydrochloride is 500 mg twice daily or 850 mg once daily, taken with meals. Dosage may be increased by 500 mg weekly or 850 mg every 2 weeks, up to 2000 mg daily in divided doses. The dose of metformin hydrochloride should be individually tailored based on efficacy and tolerability.

Patients may be titrated from 500 mg twice daily to 850 mg twice daily after 2 weeks. In patients requiring glycemic control, a maximum dose of 2550 mg per day may be used. Doses above 2000 mg may be better tolerated when taken in 3 divided doses a day with meals.

Combination with insulin

Metformin and insulin may be used in combination therapy to achieve better blood glucose control. 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

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.

Patients with renal impairment

A GFR should be assessed before initiation of treatment with metformin-containing products and at least annually thereafter.

Metformin is contraindicated in patients with an eGFR less than 30 ml/min/1.73 m2. Initiation of metformin therapy is not recommended in patients with an eGFR between 30 and 45 ml/min/1.73 m2.

In patients taking metformin and whose eGFR falls below 45 ml/min/1.73 m2, assess the risk-benefit of continuing treatment.

Discontinue metformin if the patient's eGFR falls below 30 ml/min/1.73 m2.

Children from 10 years of age and adolescents

The usual initial dose is 850 mg of metformin hydrochloride, once daily, with or after a meal.

After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. Maximum 2 tablets/day to be taken in the morning and evening.

Discontinue metformin during iodinated contrast media

In patients with an eGFR between 30 - 60 ml/min/1.73 m2, in patients with a history of liver disease, alcoholism, or heart failure, or in patients who will receive a contrast agent containing Intra-arterial iodine, discontinue metformin before or at the time of imaging with iodinated contrast media. Reassess eGFR index 48 hours after screening, reinstitute metformin if renal function is stable.

CONTRAINDICATIONS

Hypersensitivity to metformin or to any of the other ingredients of this medicine.

Acute or chronic metabolic acidosis including diabetic ketoacidosis.

Diabetic pre-coma.

Severe renal failure (GFR <30 mL/min)

Acute conditions with the potential to alter renal function such as dehydration, severe infection, and shock.

The disease which may cause tissue hypoxia (especially acute disease, or worsening of chronic disease) such as decompensated heart failure, respiratory failure, recent myocardial infarction, or shock.

Hepatic insufficiency, acute alcohol intoxication, alcoholism.

WARNINGS AND PRECAUTIONS

Lactic acidosis

There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and increased lactate: pyruvate ratio; metformin plasma levels were generally >5 mcg/mL.

Risk factors include renal impairment, concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate), age >65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states (for example 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  (section Posology, method of administration, Contraindications, Warnings and Precautions, Drug Interactions and Use in Special Populations)

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 metformin-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in the 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: 

- Before initiating metformin, obtain an estimated glomerular filtration

rate (eGFR).

- Metformin is contraindicated in patients with an eGFR less than                     30 L/min/1.73 m2.

- Initiation of metformin is not recommended in patients with an eGFR between 30 and 45 mL/min/1.73 m2. 

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.

- For patients taking metformin whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefits and risks of continuing treatment.

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. 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/min/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. Reevaluate 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 pre-renal 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 the use of metformin in patients with clinical or laboratory evidence of hepatic disease.

Patients with heart failure are more at risk of hypoxia and renal insufficiency. In patients with chronic stable heart failure, metformin may be used with regular monitoring of cardiac and renal function.

Patients should be advised of the need for nutritional therapy and that metformin is only an aid, not a substitute for a proper diet.

Women during pregnancy.

SHELF-LIFE

36 months. Do not use the products over the expiry date.

Box of 5 blisters x 20 film-coated tablets