No pediatric clinical studies have been conducted with FORTAMET®. In a double-blind, placebo-controlled study in pediatric patients aged 10 to 16 years with type 2 diabetes (mean FPG 182.2 mg/dL), treatment with immediate-release metformin (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) resulted in a significant mean net reduction in FPG of 64.3 mg/dL compared with placebo (Table 5).
|FPG (mg/dL)||(n = 37)||(n = 36)|
|Change at FINAL VISIT||-42.9||21.4||less than 0.001|
|Body Weight (lbs)||(n = 39)||(n = 38)|
|Change at FINAL VISIT||-3.3||-2.0||NS**|
* All patients on diet therapy at Baseline
** Not statistically significant
Fortamet Indications and Usage
FORTAMET® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
FORTAMET® is contraindicated in patients with:
- Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females] or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (see WARNINGS and PRECAUTIONS).
- Known hypersensitivity to metformin.
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
FORTAMET® should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function (see also PRECAUTIONS).
Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with FORTAMET® (metformin hydrochloride) Extended-Release Tablets; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/ L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 μg/mL are generally found.
The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/ surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient’s age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking FORTAMET® (metformin hydrochloride) Extended-Release Tablets and by use of the minimum effective dose of FORTAMET®. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. FORTAMET® treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, FORTAMET® should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, FORTAMET® should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking FORTAMET® , since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, FORTAMET® should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS).
The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient’s physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see also PRECAUTIONS). FORTAMET® should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose and, if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of FORTAMET® , gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking FORTAMET® do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling (see also PRECAUTIONS).
Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).
Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking FORTAMET® , the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery (see also CONTRAINDICATIONS and PRECAUTIONS).
Monitoring of renal function – Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive FORTAMET®. In patisents with advanced age, FORTAMET® should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those ≥80 years of age, renal function should be monitored regularly and, generally, FORTAMET® should not be titrated to the maximum dose (see WARNINGS and DOSAGE AND ADMINISTRATION).
Before initiation of FORTAMET® therapy and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and FORTAMET® discontinued if evidence of renal impairment is present.
Macrovascular Outcomes –
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with FORTAMET® or any other anti-diabetic drug.
Use of concomitant medications that may affect renal function or metformin disposition – Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion (see PRECAUTIONS: Drug Interactions), should be used with caution.
Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials) – Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see CONTRAINDICATIONS). Therefore, in patients in whom any such study is planned, FORTAMET® should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.
Hypoxic states – Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on FORTAMET® therapy, the drug should be promptly discontinued.
Surgical procedures – FORTAMET® therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient’s oral intake has resumed and renal function has been evaluated as normal.
Alcohol intake – Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving FORTAMET®.
Impaired hepatic function – Since impaired hepatic function has been associated with some cases of lactic acidosis, FORTAMET® should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
Vitamin B12 levels – In controlled clinical trials of immediate-release metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum Vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12 -intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of immediate-release metformin or Vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on FORTAMET® and any apparent abnormalities should be appropriately investigated and managed (see PRECAUTIONS: Laboratory Tests). Certain individuals (those with inadequate Vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B12 levels. In these patients, routine serum Vitamin B12 measurements at two- to three-year intervals may be useful.
Change in clinical status of patients with previously controlled type 2 diabetes – A patient with type 2 diabetes previously well controlled on FORTAMET® who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, FORTAMET® must be stopped immediately and other appropriate corrective measures initiated (see also WARNINGS).
Hypoglycemia – Hypoglycemia does not occur in patients receiving FORTAMET® alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.
Loss of control of blood glucose – When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold FORTAMET® and temporarily administer insulin. FORTAMET® may be reinstituted after the acute episode is resolved.
The effectiveness of oral antidiabetic drugs in lowering blood glucose to a targeted level decreases in many patients over a period of time. This phenomenon, which may be due to progression of the underlying disease or to diminished responsiveness to the drug, is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective during initial therapy. Should secondary failure occur with FORTAMET® or sulfonylurea monotherapy, combined therapy with FORTAMET® and sulfonylurea may result in a response. Should secondary failure occur with combined FORTAMET® /sulfonylurea therapy, it may be necessary to consider therapeutic alternatives including initiation of insulin therapy.
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