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metformin hcl 850 mg tablet (generic glucophage)

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Uses

Diabetes Mellitus

Metformin is used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. Metformin may also be used in combination with a sulfonylurea or a thiazolidinedione antidiabetic agent as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who do not achieve adequate glycemic control with metformin, sulfonylurea, or thiazolidinedione monotherapy.

Metformin may be used with repaglinide in patients with type 2 diabetes mellitus who have inadequate glycemic control with metformin or repaglinide monotherapy. Metformin is commercially available in fixed combination with repaglinide for use in patients with type 2 diabetes mellitus who are already receiving repaglinide and metformin concurrently as separate components or in those who have inadequate glycemic control with repaglinide or metformin monotherapy. Metformin also may be used concomitantly with nateglinide for the management of type 2 diabetes mellitus in treatment-naive patients (those not previously treated with antidiabetic agents) as well as in those who have previously received antidiabetic therapy.

Metformin is commercially available in fixed combination with glyburide or glipizide for use as an adjunct to diet and exercise to improve glycemic control in adults with diabetes mellitus; such fixed-combination preparations may be used as initial therapy in patients whose hyperglycemia cannot be controlled by diet and exercise alone, or as second-line therapy in patients who do not achieve adequate control of hyperglycemia with metformin or sulfonylurea monotherapy. A thiazolidinedione may be added to metformin in fixed combination with glyburide in patients who have inadequate glycemic control with fixed-combination therapy.

Metformin is commercially available in fixed combination with rosiglitazone for use in the management of type 2 diabetes mellitus when treatment with both rosiglitazone and metformin is appropriate. Metformin is commercially available in fixed combination with pioglitazone (as immediate- or extended-release tablets) for use as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who have inadequate glycemic control with pioglitazone or metformin monotherapy or in those who are already receiving pioglitazone and metformin concurrently as separate components.

Metformin is commercially available in fixed combination with sitagliptin for use when treatment with both sitagliptin and metformin is appropriate.

Metformin also may be used as adjunctive therapy in patients with type 2 diabetes mellitus receiving insulin therapy to improve glycemic control and/or decrease the dosage of insulin needed to obtain optimal glycemic control.

The American Diabetes Association (ADA) currently classifies diabetes mellitus as type 1 (immune mediated or idiopathic), type 2 (predominantly insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance), gestational diabetes mellitus, or that associated with certain conditions or syndromes (e.g., drug- or chemical-induced, hormonal, that associated with pancreatic disease, infections, specific genetic defects or syndromes). Type 1 diabetes mellitus was previously described as juvenile-onset (JOD) diabetes mellitus, since it usually occurs during youth. Type 2 diabetes mellitus previously was described as adult-onset (AODM) diabetes mellitus. However, type 1 or type 2 diabetes mellitus can occur at any age, and the current classification is based on pathogenesis (e.g., autoimmune destruction of pancreatic β cells, insulin resistance) and clinical presentation rather than on age of onset. Many patients' diabetes mellitus does not easily fit into a single classification. Epidemiologic data indicate that the incidence of type 2 diabetes mellitus is increasing in children and adolescents such that 8-45% of children with newly diagnosed diabetes have nonimmune-mediated diabetes mellitus; most of these individuals have type 2 diabetes mellitus, although other types, including idiopathic or nonimmune-mediated type 1 diabetes mellitus, also have been reported.

Patients with type 2 diabetes mellitus have insulin resistance and usually have relative (rather than absolute) insulin deficiency. Most patients with type 2 diabetes mellitus (about 80-90%) are overweight or obese; obesity itself also contributes to the insulin resistance and glucose intolerance observed in these patients. Patients with type 2 diabetes mellitus who are not obese may have an increased percentage of abdominal fat, which is an indicator of increased cardiometabolic risk. While children with immune-mediated type 1 diabetes mellitus generally are not overweight, the incidence of obesity in children with this form of diabetes is increasing with the increasing incidence of obesity in the US population. Distinguishing between type 1 and type 2 diabetes mellitus in children may be difficult since obesity may occur with either type of diabetes mellitus, and autoantigens and ketosis may be present in a substantial number of children with features of type 2 diabetes mellitus (e.g., obesity, acanthosis nigricans).

Metformin is not effective as sole therapy in patients with type 1 diabetes mellitus; insulin is necessary in these patients.

Patients with type 2 diabetes mellitus are not dependent initially on insulin (although many patients eventually require insulin for glycemic control) nor are they prone to ketosis; however, insulin occasionally may be required for correction of symptomatic or persistent hyperglycemia that is not controlled by dietary regulation or oral antidiabetic agents (e.g., sulfonylureas), and ketosis occasionally may develop during periods of severe stress (e.g., acute infection, trauma, surgery). Type 2 diabetes mellitus is a heterogeneous subclass of the disease; hyperglycemia in these patients often is accompanied by other metabolic abnormalities such as obesity, hypertension, hyperlipidemia, and impaired fibrinolysis. Endogenous insulin is present in type 2 diabetic patients, although plasma insulin concentrations may be decreased, increased, or normal. In patients with type 2 diabetes mellitus, glucose-stimulated secretion of endogenous insulin is frequently, but not always, reduced and decreased peripheral sensitivity to insulin is almost always associated with glucose intolerance.

Glycemic Control and Microvascular Complications

Current evidence from epidemiologic and clinical studies supports an association between chronic hyperglycemia and the pathogenesis of microvascular complications in patients with diabetes mellitus, and results of randomized, controlled studies in patients with type 1 diabetes mellitus indicate that intensive management of hyperglycemia with near-normalization of blood glucose and glycosylated hemoglobin (hemoglobin A1c [HbA1c]) concentrations provides substantial benefits in terms of reducing chronic microvascular (e.g., neuropathy, retinopathy, nephropathy) complications associated with the disease. HbA1c concentration reflects the glycosylation of other proteins throughout the body as a result of recent hyperglycemia and is used as a predictor of risk for the development of diabetic microvascular complications (e.g., neuropathy, retinopathy, nephropathy). Microvascular complications of diabetes are the principal causes of blindness and renal failure in developed countries and are more closely associated with hyperglycemia than are macrovascular complications.

In the Diabetes Control and Complications Trial (DCCT), a reduction of approximately 50-75% in the risk of development or progression of retinopathy, nephropathy, and neuropathy was demonstrated during an average 6.5 years of follow-up in patients with type 1 diabetes mellitus receiving intensive insulin treatment (3 or more insulin injections daily with dosage adjusted according to results of at least 4 daily blood glucose determinations, dietary intake, and anticipated exercise) compared with that in patients receiving conventional insulin treatment (1 or 2 insulin injections daily, self-monitoring of blood or urine glucose values, education about diet and exercise). However, the incidence of severe hypoglycemia, including multiple episodes in some patients, was 3 times higher in the intensive-treatment group than in the conventional-treatment group. The reduction in risk of microvascular complications in the DCCT study correlated continuously with the reduction in HbA1c concentration (hemoglobin A1c) produced by intensive insulin treatment (e.g., a 40% reduction in risk of microvascular disease for each 10% reduction in hemoglobin A1c). These data imply that any decrease in HbA1c levels is beneficial and that complete normalization of blood glucose concentrations may prevent diabetic microvascular complications.

The DCCT was terminated prematurely because of the pronounced benefits of intensive insulin regimens, and all treatment groups were encouraged to institute or continue such intensive insulin therapy. In the Epidemiology of Diabetes Interventions and Complications (EDIC) study, the long-term, open-label continuation phase of the DCCT, the reduction in the risk of microvascular complications (e.g., retinopathy, nephropathy, neuropathy) associated with intensive insulin therapy has been maintained throughout 7 years of follow-up. In addition, the prevalence of hypertension (an important consequence of diabetic nephropathy) in those receiving conventional therapy has exceeded that of those receiving intensive therapy. Patients receiving conventional insulin therapy in the DCCT were able to achieve a lower HbA1c when switched to intensive therapy in the continuation study, although the average HbA1c values achieved during the continuation study were higher (i.e., worse) than those achieved during the DCCT with intensive insulin therapy. Patients who remained on intensive insulin therapy during the EDIC continuation study were not able to maintain the degree of glycemic control achieved during the DCCT; by 5 years of follow-up in the EDIC study, HbA1c values were similar in both intensive and conventional therapy groups. The EDIC study demonstrated that the greater the duration of chronically elevated plasma glucose concentrations (as determined by HbA1c values), the greater the risk of microvascular complications. Conversely, the longer patients can maintain a target HbA1c of 7% of less, the greater the delay in the onset of these complications.

In another randomized, controlled study (Stockholm Diabetes Intervention Study) in patients with type 1 diabetes mellitus who were evaluated for up to 7.5 years, blood glucose control (as determined by HbA1c concentrations) was improved, and the incidence of microvascular complications (e.g., decreased visual acuity, retinopathy, nephropathy, decreased nerve conduction velocity) reduced, with intensive insulin treatment (e.g., at least 3 insulin injections daily accompanied by intensive educational efforts) compared with that in patients receiving standard treatment (e.g., generally 2 insulin injections daily without intensive educational efforts).

Data from the United Kingdom Prospective Diabetes Study (UKPDS and the Action in Diabetes and VAscular disease: preterax and diamicroN modified release Controlled Evaluation (ADVANCE) study in patients with type 2 diabetes mellitus generally are consistent with the same benefits of oral hypoglycemic agents on microvascular complications as those observed in type 1 diabetics receiving insulin therapy in the DCCT.

The UKPDS evaluated middle-aged, newly diagnosed, overweight (exceeding 120% of ideal body weight) or non-overweight patients with type 2 diabetes mellitus who received conventional or intensive treatment regimens with an oral sulfonylurea agent and/or insulin; overweight patients also could be allocated to metformin therapy in the same proportions as those allocated to sulfonylureas and insulin. Initial therapy consisted of an oral antidiabetic agent (sulfonylurea or metformin) or insulin, with stepwise addition of metformin (or glyburide in those initially allocated to metformin) in those poorly controlled on initial therapy or conversion to insulin alone in patients not adequately controlled with 2 oral agents. Intensive treatment consisted of antidiabetic therapy targeted to a fasting plasma glucose concentration of less than 108 mg/dL or, in patients receiving insulin, preprandial glucose concentrations of 72-126 mg/dL. Conventional treatment consisted of antidiabetic therapy targeted to a fasting plasma glucose concentration of less than 270 mg/dL without symptoms of hyperglycemia. Results of UKPDS indicate greater beneficial effects on retinopathy, nephropathy, and possibly neuropathy with intensive glucose-lowering therapy (median achieved HbA1c concentration: 7%) in type 2 diabetics compared with that in the conventional treatment group (median achieved HbA1c concentration: 7.9%). The overall incidence of microvascular complications was reduced by 25% with intensive therapy. Epidemiologic analysis of UKPDS results indicates a continuous relationship between the risks of microvascular complications and glycemia, with a 35% reduction in risk for each 1% reduction in HbA1c, and no evidence of a glycemic threshold.

The ADVANCE study also evaluated the relatively short-term effects (median follow-up: 5 years) of conventional or intensive therapy on the development of major vascular complications. The primary end point was the composite of major macrovascular (death from cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke) and major microvascular (new or worsening nephropathy or retinopathy) events. While the incidence of the primary composite end point was reduced by approximately 10% in the ADVANCE study, the beneficial effect was due principally to a 21% reduction in microvascular events (nephropathy); there was no appreciable reduction in macrovascular outcomes. Intensive antidiabetic therapy (mean achieved HbA1c concentration: 6.5%) was associated with a reduction in new or worsening nephropathy compared with conventional treatment (mean achieved HbA1c concentration of 7.3%), but there was no effect on the development of new or worsening retinopathy. Results of the Veterans Affairs Diabetes Trial (VADT), another study similar in design to the ADVANCE study, also indicated that intensive therapy in patients with poorly controlled type 2 diabetes mellitus (median baseline HbA1c concentration of 9.4%) did not lessen the rate of microvascular complications compared with standard antidiabetic therapy.

In UKPDS, fasting plasma glucose concentrations and HbA1c values steadily increased over 10 years in the patients receiving conventional therapy, and more than 80% of these patients eventually required antidiabetic therapy in addition to diet to maintain fasting plasma glucose concentrations within the desired goal of less than 270 mg/dL. In patients receiving intensive therapy initiated with chlorpropamide, glyburide, or insulin, fasting plasma glucose concentrations and HbA1c values decreased during the first year of the study. Subsequent increases in these indices of glycemic control after the first year paralleled that in the conventional therapy group for the remainder of the study, indicating slow decline of pancreatic β-cell function and loss of glycemic control regardless of intensity of therapy. In contrast to UKPDS, no diminution in the effect on HbA1c or fasting blood glucose concentrations with either intensive or conventional therapy was observed in ADVANCE or VADT over a median follow-up of 5 or 5.6 years, respectively.

Data from long-term follow-up (over 10 years) of middle-aged, newly diagnosed UKPDS patients with type 2 diabetes mellitus indicate that strict glycemic control (i.e., maintenance of fasting blood glucose concentrations below 108 mg/dL) was not achieved with initial intensive oral antidiabetic therapy (stepwise introduction of a sulfonylurea [i.e., chlorpropamide, glyburide], then insulin, or an oral sulfonylurea and insulin, or insulin alone to achieve fasting plasma glucose concentrations of 108 mg/dL) in most patients; at 3 and 9 years, 50 and 75%, respectively, of patients required combination therapy with sulfonylureas or initiation of insulin to maintain adequate glycemic control. While strict guidelines for insulin dosage adjustments were used in the DCCT study, adjustments of antidiabetic therapy dosage in UKPDS were not as frequent (dosage adjustments allowed every 3 months); in addition, the definition of secondary treatment failure with sulfonylureas and the time of institution of supplementary antidiabetic therapy changed as the study progressed. Because of the benefits of strict glycemic control, the goal of therapy for type 2 diabetes mellitus is to lower blood glucose to as close to normal as possible, which generally requires aggressive management efforts (e.g., mixing therapy with various antidiabetic agents including sulfonylureas, metformin, insulin, and/or possibly others) over time. For additional information on clinical studies demonstrating the benefits of strict glycemic control on microvascular complications in patients with type 1 or type 2 diabetes mellitus, .

Glycemic Control and Macrovascular Complications

Current evidence indicates that appropriate management of dyslipidemia, blood pressure, and vascular thrombosis provides substantial benefits in terms of reducing macrovascular complications associated with diabetes mellitus; intensive glycemic control generally has not been associated with appreciable reductions in macrovascular outcomes in controlled trials. Reduction in blood pressure to a mean of 144/82 mm Hg (''tight blood pressure control'') in patients with diabetes mellitus and uncomplicated mild to moderate hypertension in UKPDS substantially reduced the incidence of virtually all macrovascular (e.g., stroke, heart failure) and microvascular (e.g., retinopathy, vitreous hemorrhage, renal failure) outcomes and diabetes-related mortality; blood pressure and glycemic control were additive in their beneficial effects on these end points. While intensive antidiabetic therapy titrated with the goal of reducing HbA1c to near-normal concentrations (6-6.5% or less) has not been associated with appreciable reductions in cardiovascular events during the randomized portion of controlled trials examining such outcomes, results of long-term follow-up (10-11 years) from DCCT and UKPDS indicate a delayed cardiovascular benefit in patients treated with intensive antidiabetic therapy early in the course of type 1 or type 2 diabetes mellitus.

Treatment Goals

The ADA currently states that it is reasonable to attempt to achieve in patients with type 2 diabetes mellitus the same blood glucose and HbA1c goals recommended for patients with type 1 diabetes mellitus. Based on target values for blood glucose and HbA1c used in clinical trials (e.g., DCCT) for type 1 diabetic patients, modified somewhat to reduce the risk of severe hypoglycemia, ADA currently recommends target preprandial (fasting) and peak postprandial (1-2 hours after the beginning of a meal) plasma glucose concentrations of 70-130 and less than 180 mg/dL, respectively, and HbA1c concentrations of less than 7% (based on a nondiabetic range of 4-6%) in general in patients with type 1 or type 2 diabetes mellitus who are not pregnant. HbA1c concentrations of 7% or greater should prompt clinicians to initiate or adjust antidiabetic therapy in nonpregnant patients with the goal of achieving HbA1c concentrations of less than 7%. Patients with diabetes mellitus who have elevated HbA1c concentrations despite having adequate preprandial glucose concentrations should monitor glucose concentrations 1-2 hours after the start of a meal. Treatment with agents (e.g., α-glucosidase inhibitors, exenatide, pramlintide) that principally lower postprandial glucose concentrations to within target ranges also should reduce HbA1c.

More stringent treatment goals (i.e., an HbA1c less than 6%) can be considered in selected patients. An individualized HbA1c concentration goal that is closer to normal without risking substantial hypoglycemia is reasonable in patients with a short duration of diabetes mellitus, no appreciable cardiovascular disease, and a long life expectancy. Less stringent treatment goals may be appropriate in patients with long-standing diabetes mellitus in whom the general HbA1c concentration goal of less than 7% is difficult to obtain despite adequate education on self-management of the disease, appropriate glucose monitoring, and effective dosages of multiple antidiabetic agents, including insulin. Achievement of HbA1c values of less than 7% is not appropriate or practical for some patients, and clinical judgment should be used in designing a treatment regimen based on the potential benefits and risks (e.g., hypoglycemia) of more intensified therapy.

Considerations in Initiating and Maintaining Antidiabetic Therapy

When initiating therapy for patients with type 2 diabetes mellitus who do not have severe symptoms, most clinicians recommend that diet be emphasized as the primary form of treatment; caloric restriction and weight reduction are essential in obese patients. Although appropriate dietary management and weight reduction alone may be effective in controlling blood glucose concentration and symptoms of hyperglycemia, many patients receiving dietary advice fail to achieve and maintain adequate glycemic control with dietary modification alone.

Recognizing that lifestyle interventions often fail to achieve or maintain the target glycemic goal within the first year of initiation of such interventions, ADA currently suggests initiation of metformin concurrently with lifestyle interventions at the time of diagnosis of type 2 diabetes mellitus. Other experts suggest concurrent initiation of lifestyle interventions and antidiabetic agents only when HbA1c levels of 9% or greater are present at the time of diagnosis of type 2 diabetes mellitus. ADA and other clinicians state that lifestyle interventions should remain a principal consideration in the management of diabetes even after pharmacologic therapy is initiated. In addition, loss of blood glucose control on diet alone can be temporary in some patients, requiring only short-term management with drug therapy. The importance of regular physical activity also should be emphasized, and cardiovascular risk factors should be identified and corrective measures employed when feasible.

If lifestyle interventions alone are initiated and these interventions fail to reduce symptoms and/or blood glucose concentrations within 2-3 months of diagnosis, initiation of monotherapy with an oral antidiabetic agent (e.g., metformin, sulfonylurea) or insulin should be considered.

Metformin Monotherapy

Clinical studies indicate that metformin is as effective (approximately 1.5% decrease in HbA1c values) as a sulfonylurea antidiabetic agent (e.g., chlorpropamide, glyburide, glipizide, tolbutamide) for the management of type 2 diabetes mellitus. Although metformin often has been used in patients who did not achieve adequate glycemic control with sulfonylurea monotherapy and who did not have symptoms of severe insulin deficiency (e.g., ketosis, uncontrolled weight loss), many clinicians recommend either metformin or a sulfonylurea as initial monotherapy in patients with type 2 diabetes mellitus whose hyperglycemia is not controlled despite dietary modification and exercise. Potential advantages of metformin compared with sulfonylurea antidiabetic agents or insulin include a minimal risk of hypoglycemia, more favorable effects on serum lipids, reduction of hyperinsulinemia, and weight loss or lack of weight gain. Type 2 diabetic patients who are very obese or who have baseline fasting blood glucose concentrations exceeding 200 mg/dL may be less likely to respond to therapy with sulfonylurea antidiabetic agents. Therefore, since metformin may stabilize or even decrease body weight, the drug may be particularly useful as initial monotherapy in obese individuals who might gain weight while receiving a sulfonylurea. Metformin is equally effective in lean or obese patients with type 2 diabetes mellitus. Metformin may be effective as replacement monotherapy in some patients with primary or secondary failure to sulfonylureas.(See Diabetes Mellitus: Combination Therapy, in Uses.)

In controlled studies of up to 8 months' duration in adults with type 2 diabetes mellitus, therapy with metformin hydrochloride (0.5-3 g daily) reduced fasting and postprandial glucose concentrations and HbA1c substantially more than did placebo. The antihyperglycemic effect of metformin does not appear to correlate with duration of diabetes, age, obesity, race, fasting insulin concentrations, or baseline plasma lipid concentrations. In a placebo-controlled study in pediatric (10-16 years of age), treatment-naive (i.e., those receiving diet therapy only), obese patients with type 2 diabetes mellitus, the net difference in fasting plasma glucose concentrations in patients receiving metformin hydrochloride (up to 2 g daily) or placebo for up to 16 weeks was 64.3 mg/dL, reflecting an increase in fasting plasma glucose concentrations in the placebo group and an improvement in glycemic control with metformin therapy. The improvement in glycemic control with metformin in these pediatric patients was similar to that observed in clinical studies with the drug in adults. A small, similar weight loss occurred in patients receiving either metformin or placebo in this study. In a multicenter, randomized, controlled study in newly diagnosed, asymptomatic patients with type 2 diabetes mellitus, the efficacy of metformin therapy in reducing fasting plasma glucose (target value: less than 108 mg/dL) and HbA1c concentrations in a subgroup of obese patients was similar to that of therapy with a sulfonylurea (chlorpropamide, glyburide, or glipizide) or insulin in nonobese patients; all drug regimens improved glycemic control compared with conventional (diet only) therapy. However, unlike sulfonylurea or insulin therapy, metformin therapy generally decreased plasma insulin concentrations and was not associated with weight gain or an increased incidence of hypoglycemia. In this long-term study, gradual deterioration in glycemic control occurred with all therapies over the study period despite increases in drug dosage or combined drug therapy; HbA1c concentrations generally had increased to baseline levels after 4-5 years of therapy with any of the drug regimens. Such deterioration in glycemic control has been attributed to a progressive decline in pancreatic β-cell function rather than a reduction in insulin sensitivity.

Oral antidiabetic agents, including metformin, are not effective as sole therapy in patients with diabetes mellitus complicated by acidosis, ketosis, or coma; management of these conditions requires the use of insulin. Metformin is not recommended for use in hospitalized patients with diabetes mellitus, as such patients may be at greater risk for the development of lactic acidosis; management of such patients usually requires the use of insulin.

Combination Therapy

Metformin may be used concomitantly with one or more oral antidiabetic agents (e.g., a sulfonylurea, a thiazolidinedione, a meglitinide, and/or an α-glucosidase inhibitor) or insulin to improve glycemic control in patients with type 2 diabetes.

Primary or secondary failure may occur with metformin as well as with other antidiabetic therapy (e.g., sulfonylureas). In patients receiving initial monotherapy with metformin, the incidence of primary and secondary failures appears to be less than or similar to that in patients receiving sulfonylurea monotherapy. Secondary failure to metformin is characterized by progressively decreasing diabetic control following 1 month to several years of good control. Combined therapy with metformin and another oral antidiabetic agent generally is used in patients with longstanding type 2 diabetes mellitus who have poor glycemic control with monotherapy; the sequence in which metformin or a sulfonylurea is used at initiation of therapy does not appear to alter the effectiveness of combined therapy with the drugs. However, ADA and other clinicians currently recommend initiating therapy with metformin and adding another antidiabetic agent, such as a sulfonylurea, insulin, or a thiazolidinedione, if patients fail to achieve or maintain target HbA1c goals. Optimum benefit generally is obtained by addition of a second antidiabetic agent as soon as monotherapy with metformin no longer provides adequate glycemic control (i.e., when the target glycemic goal is not achieved within 2-3 months of initiation of metformin therapy or at any other time when the HbA1c goal is not achieved).

Combination Therapy with Oral Antidiabetic Agents

Combined therapy with metformin and other oral antidiabetic agents in patients not adequately controlled with monotherapy may reduce symptoms or allow reduced insulin dosages; some clinicians consider use of combination oral antidiabetic therapy as a means to delay or avoid institution of insulin. When glycemic control cannot be improved after 1-3 months of combined therapy with oral antidiabetic agents (e.g., a sulfonylurea) at maximal doses or if the effectiveness of such combined therapy declines, the manufacturer recommends switching to insulin therapy with or without continuance of metformin therapy. However, ADA considers the choice of additional second-line therapy to depend on the degree of glycemic control achieved during metformin monotherapy. In patients with HbA1c exceeding 8.5% or symptomatic hyperglycemia despite metformin monotherapy, ADA states that consideration should be given to adding insulin.(See Combination Therapy with Insulin under Uses: Diabetes Mellitus.)

When glycemic control is closer to the target HbA1c goal with metformin monotherapy (e.g., HbA1c less than 7.5%), an agent with a lesser potential to lower glycemia and/or slower onset of action may be considered (e.g., sulfonylurea, thiazolidinedione) as additional therapy to metformin. ADA states that other antidiabetic agents such as α-glucosidase inhibitors, meglitinides, exenatide, or pramlintide generally are less effective, less well studied, and/or more expensive than recommended therapies (i.e., metformin, a sulfonylurea, a thiazolidinedione, insulin). However, these agents may be appropriate for treatment of type 2 diabetes mellitus in selected patients.

Metformin is commercially available in fixed combination with glyburide or glipizide for use as initial therapy in the management of patients with type 2 diabetes mellitus whose hyperglycemia cannot be controlled by diet and exercise alone. In several comparative trials in such patients, therapy with metformin in fixed combination with glyburide or glipizide was more effective in improving glycemic control (as determined by HbA1c values, fasting plasma glucose concentrations) than monotherapy with either component. A greater percentage of patients receiving metformin in fixed combination with glipizide or glipizide achieved strict glycemic control (e.g., HbA1c values less than 7%) than patients receiving monotherapy with metformin, glyburide, or glipizide.

Metformin in fixed combination with glyburide or glipizide also is used to improve glycemic control in patients with type 2 diabetes mellitus who are inadequately controlled with either sulfonylurea or metformin monotherapy. In several comparative studies in such patients, greater glycemic control (as determined by HbA1c values, fasting plasma glucose concentrations) was achieved with the fixed combination of metformin and glyburide or glipizide than with metformin, glyburide, or glipizide monotherapy. Strict glycemic control (e.g., HbA1c values less than 7%) was achieved in a greater percentage of patients receiving fixed combinations of metformin with a sulfonylurea (glyburide or glipizide) than with sulfonylurea or metformin monotherapy. In a comparative clinical trial in pediatric patients (9-16 years of age) with type 2 diabetes mellitus, therapy with metformin in fixed combination with glyburide (titrated to a final mean daily dosage of 3.1 mg of glyburide and 623 mg of metformin hydrochloride) was no more effective in improving glycemic control (as determined by reductions in HbA1c values) than monotherapy with either component (titrated to final mean daily dosages of 6.5 mg of glyburide or 1.5 g of metformin hydrochloride).

Metformin (immediate- or extended-release) is used in fixed combination with pioglitazone in patients with type 2 diabetes mellitus who have inadequate glycemic control with pioglitazone or metformin monotherapy or in those who are already receiving pioglitazone and metformin concurrently as separate components. No clinical trials have evaluated the fixed combination of metformin and pioglitazone; efficacy and safety of the fixed combination has been established based on concurrent administration of the 2 agents given separately. Safety and efficacy of the fixed combination of metformin and pioglitazone in patients with type 2 diabetes mellitus are extrapolated from clinical trials evaluating pioglitazone as add-on therapy to metformin.

Metformin also is used in combination with rosiglitazone (either as a fixed-combination preparation or as individual drugs given concurrently) in patients with type 2 diabetes mellitus when treatment with both metformin and rosiglitazone is appropriate.

The fixed-combination preparation containing metformin and rosiglitazone has not been specifically studied in patients previously receiving metformin monotherapy; however, clinical trials have evaluated rosiglitazone (4 or 8 mg once daily) as add-on therapy in patients who had inadequate glycemic control with metformin (2.5 g once daily). In these studies, substantial improvements in fasting plasma glucose and HbA1c concentrations were observed with the combination of rosiglitazone and metformin compared with metformin alone. In a dose-ranging trial evaluating rosiglitazone 4 or 8 mg as add-on therapy to the maximum daily dosage of metformin hydrochloride, 28.1% of patients receiving the higher dosage of rosiglitazone concurrently with metformin achieved HbA1c values of 7% or less.

A thiazolidinedione may be added to metformin in fixed combination with glyburide in patients with type 2 diabetes mellitus who have inadequate glycemic control with the fixed combination. In such patients, the addition of rosiglitazone to combined therapy with metformin and glyburide has reduced fasting glucose concentrations and HbA1c values. Strict glycemic control (e.g., HbA1c values less than 7%) was achieved in 42.4% of patients of receiving the triple combination of metformin, glyburide, and rosiglitazone compared with 13.5% of those receiving metformin and glyburide.

Metformin in fixed combination with repaglinide is used in patients with type 2 diabetes mellitus who have inadequate glycemic control with repaglinide or metformin monotherapy or in those who are already receiving repaglinide and metformin concurrently as separate components. In a double-blind, controlled trial in patients with type 2 diabetes mellitus who had inadequate glycemic control with metformin monotherapy, add-on therapy with repaglinide resulted in greater glycemic control (as determined by HbA1c values, fasting plasma glucose concentrations) than metformin or repaglinide monotherapy. Combined therapy with metformin and repaglinide resulted in a greater reduction in HbA1c and fasting plasma glucose concentrations at a lower repaglinide dosage than with repaglinide monotherapy. However, the incidence of hypoglycemia with combined metformin and repaglinide therapy was higher than with repaglinide monotherapy. In addition, body weight increased in patients receiving repaglinide alone or combined with metformin but remained stable in those receiving metformin monotherapy.

In a clinical trial in patients who had inadequate glycemic control (HbA1c exceeding 7.1%) with metformin monotherapy, addition of repaglinide to metformin therapy produced reductions in fasting plasma glucose concentrations and HbA1c averaging 39.6 mg/dL and 1.4%, respectively, compared with reductions averaging 4.5 mg/dL and 0.33%, respectively, with metformin alone; patients receiving repaglinide therapy alone had an increase in fasting plasma glucose concentrations of 8.8 mg/dL and a reduction of 0.38% in HbA1c. In a clinical trial in treatment-naive patients or patients who had previously received antidiabetic therapy (followed by a washout period of at least 2 months), combined therapy with metformin hydrochloride and nateglinide resulted in greater reductions in HbA1c and fasting plasma glucose concentrations than metformin or nateglinide monotherapy.

In another clinical trial in patients with type 2 diabetes mellitus who had inadequate glycemic control with metformin, a sulfonylurea, or insulin, the combination of pioglitazone (30 mg daily) and metformin (and withdrawal of other antidiabetic therapy) reduced fasting plasma glucose concentrations and HbA1c values compared with metformin therapy alone, regardless of whether patients were receiving lower (less than 2 g daily) or higher (2 g daily or more) dosages of metformin hydrochloride.

In a multicenter, controlled study in patients whose hyperglycemia was inadequately controlled by diet and metformin therapy, the addition of acarbose produced appreciable improvement in postprandial plasma glucose concentrations and modest improvement in HbA1c. Fasting plasma glucose concentrations generally are not reduced by addition of acarbose to therapy with metformin since acarbose acts principally during a meal to delay carbohydrate absorption. Limited data suggest that combined therapy with metformin and a sulfonylurea is as effective or more effective in reducing fasting blood glucose and HbA1c concentrations than combined therapy with acarbose and a sulfonylurea; however, acarbose may provide better control of postprandial blood glucose concentrations.

Conflicting data regarding the long-term benefit of metformin as part of an intensive antidiabetic regimen have been reported in UKPDS, which consisted of middle-aged, newly diagnosed, overweight (exceeding 120% of ideal body weight) or non-overweight patients with type 2 diabetes mellitus who received long-term therapy (over 10 years) with intensive or conventional treatment.(See Glycemic Control and Microvascular Complications, under Uses: Diabetes Mellitus.) In a UKPDS substudy, overweight patients receiving metformin as initial therapy in a stepwise intensive regimen had a 32% lower risk of developing any diabetes-related endpoint (including macrovascular and microvascular complications) compared with those managed by dietary modification alone; the reduction in any diabetes-related end point was greater in those receiving metformin than in those receiving initial intensive therapy with a sulfonylurea or insulin. The risk for diabetes-related death or myocardial infarction (39% lower) was also lower with intensive therapy with metformin or sulfonylureas or insulin compared with conventional therapy; no differences between the effects of intensive therapies were noted. In contrast, a second UKPDS substudy in which metformin was added to sulfonylurea therapy to improve glycemic control resulted in an increase in the risk of diabetes-related death or death from any cause compared with continuing therapy with a sulfonylurea alone. A pooled analysis of both trials and epidemiologic analysis of other data from UKPDS in patients who received stepwise therapy with metformin and sulfonylurea therapy because of progressive hyperglycemia showed a small reduction in diabetes-related death, all-cause mortality, myocardial infarction, and stroke. Reasons for disparate results of these trials are unclear but may be related to trial design, the relatively smaller number of patients receiving metformin, analytical methods, or differences in response between overweight and non-overweight patients. Pending the results of additional studies, the American Diabetes Association (ADA) and other clinicians do not recommend changing current guidelines regarding the use of metformin as monotherapy or in combination with sulfonylureas.

When lifestyle interventions, metformin, and a second oral antidiabetic agent are not effective in maintaining the target glycemic goal in patients with type 2 diabetes mellitus, ADA and other clinicians generally recommend the addition of insulin therapy. In patients whose HbA1c is close to the target level (less than 8%) on metformin and a second oral antidiabetic agent, addition of a third oral antidiabetic agent instead of insulin may be considered. However, ADA states that triple combination oral antidiabetic therapy is more costly and potentially not as effective as adding insulin therapy to dual combination oral antidiabetic therapy.

Combination Therapy with Insulin

Metformin is used in combination with insulin in patients in whom adequate glycemic control cannot be achieved by monotherapy with an oral antidiabetic agent, diet, and exercise. ADA and other clinicians state that combined therapy with insulin and metformin with or without other oral antidiabetic agents is one of several options for the management of hyperglycemia in patients not responding adequately to oral monotherapy with metformin, the preferred agent for initiation of oral antidiabetic therapy. In patients with a HbA1c exceeding 8.5% or symptoms secondary to hyperglycemia) despite metformin monotherapy, consideration should be given to adding insulin. When glycemia is not controlled with metformin with or without other oral antidiabetic agents and basal insulin (e.g., given as intermediate- or long-acting insulin at bedtime or in the morning), therapy with insulin should be intensified by adding additional short-acting or rapid-acting insulin injections at mealtimes. Therapy with insulin secretagogues (i.e., sulfonylureas, meglitinides) should be tapered and discontinued when intensive insulin therapy is initiated, as insulin secretagogues do not appear to be synergistic with such insulin therapy.

Combined therapy with insulin and one or more oral antidiabetic agents appears to increase glycemic control with lower doses of insulin than would be required with insulin alone and with a decreased potential for body weight gain associated with insulin therapy. Data from a small, placebo-controlled, 24-week trial indicate that addition of metformin improved glycemic control (as measured by a reduction in HbA1c) in patients who failed to achieve adequate glycemic control with insulin therapy; insulin dosage in patients receiving adjunctive metformin therapy was decreased by 16%. In another small, placebo-controlled study in patients adequately controlled with insulin therapy, insulin dosage requirements were reduced by 19% after addition of metformin.

Metformin has been used as an adjunct to insulin to reduce insulin requirements in a limited number of patients with type 1 diabetes mellitus, but the potential benefits and risks require further evaluation before such combined therapy can be recommended.

Polycystic Ovary Syndrome

Metformin has been used in the management of metabolic and reproductive abnormalities associated with polycystic ovary syndrome. However, adequate and well-controlled clinical trials evaluating metformin therapy for polycystic ovary syndrome remain limited, particularly regarding long-term efficacy, and available data are conflicting regarding the benefits of the drug in ameliorating various manifestations of the condition.

While metformin has beneficial effects on cardiovascular risk factors such as insulin resistance and obesity, evidence from pooled analyses of data suggest that the drug has limited overall benefits on reproductive outcomes (e.g., live birth rates) in women with polycystic ovary syndrome. As with diabetes mellitus, lifestyle changes (e.g., diet, exercise, weight loss in obese patients) are strongly recommended for the initial management of polycystic ovary syndrome; however, long-term success with such measures alone is difficult to achieve and drug therapy, including metformin, often is used for symptomatic management of this condition.

Polycystic ovary syndrome is characterized by chronic anovulation (generally manifested as oligomenorrhea or amenorrhea) and hyperandrogenism (excessive production of male hormones in women) with clinical manifestations of irregular menstrual cycles, infertility, hirsutism, acne, and dyslipidemia. While the principal etiology is unknown, insulin resistance with compensatory hyperinsulinemia is a prominent manifestation of polycystic ovary syndrome. Hyperinsulinemia stimulates ovarian and adrenal androgen secretion, leading to hyperandrogenism and its associated clinical manifestations. In addition, cardiovascular risk factors such as obesity and impaired glucose tolerance, including metabolic syndrome and type 2 diabetes mellitus, are present in a substantial proportion of women with polycystic ovary syndrome, making the use of insulin-sensitizing drugs such as metformin reasonable in the treatment of this condition.

Metformin and other insulin-sensitizing agents (e.g., thiazolidinedione antidiabetic agents) improve insulin resistance, which leads to a reduction in androgen production in ovarian theca cells and potential beneficial effects on metabolic and hormonal abnormalities associated with polycystic ovary syndrome. Although metformin therapy has not been shown specifically to reduce cardiovascular events in women with polycystic ovary syndrome, the drug's pharmacologic and clinical effects support its use as maintenance therapy to ameliorate insulin resistance and hyperinsulinemia in such women.

Estrogen-progestin oral contraceptives with or without an antiandrogen (e.g., spironolactone) traditionally have been used in the long-term management of polycystic ovary syndrome; however, such therapy may worsen preexisting insulin resistance and glucose tolerance and potentially increase cardiovascular risk. In a meta-analysis based on a small number of randomized, controlled trials in patients with polycystic ovary syndrome, oral contraceptive therapy (ethinyl estradiol with cyproterone acetate [not commercially available in the US] or norgestimate) for up to 12 months was associated with improvement in menstrual pattern and serum androgen concentrations compared with metformin, while metformin was more effective than oral contraceptives in reducing fasting insulin and triglyceride concentrations. However, a preference for either drug as maintenance therapy for polycystic ovary syndrome could not be determined because of a lack of adequate trial data. Another meta-analysis was unable to determine clinically important effects of metformin or thiazolidinedione therapy on metabolic or hyperandrogenism parameters such as fasting insulin or glucose concentrations, hirsutism, or hormone levels. Because of a lack of adequate long-term clinical trials, the effects of therapy with oral contraceptives or metformin on long-term outcomes such as diabetes, cardiovascular disease, or endometrial cancer in women with polycystic ovary syndrome have not been established.

Variable effects have been reported with metformin therapy used alone or in combination with fertility-enhancing drugs (e.g., clomiphene) for the treatment of infertility in women with polycystic ovary syndrome. Currently available evidence suggests that metformin hydrochloride dosages of 1.5-2.5 g daily in women with polycystic ovary syndrome increase the frequency of spontaneous ovulation, menstrual cyclicity, and ovulatory response after ovarian stimulation (e.g., with clomiphene, recombinant follicle-stimulating hormone). However, improvement in the rate of live births with metformin therapy generally has not been comparable to that associated with clomiphene therapy in such women. Results of a meta-analysis also indicated improvement in ovulation and clinical pregnancy rates with combined metformin and clomiphene treatment compared with clomiphene alone in women with polycystic ovary syndrome. However, another meta-analysis found only minimal improvement in ovulation rate and no improvement in pregnancy rate with metformin therapy. Some clinicians suggest that metformin therapy may be useful for inducing ovulation in women with polycystic ovary syndrome who desire pregnancy at a more distant time (e.g., more than 6 months away), and that clomiphene therapy may be preferable in those who desire to become pregnant much sooner. A potential advantage of metformin therapy over clomiphene for infertility is a reduced chance of twin or triplet pregnancy with metformin. Additional large, randomized, well-controlled studies are needed to establish the efficacy of metformin alone or in combination with other therapies for treatment of infertility associated with polycystic ovary syndrome.

Dosage and Administration

Administration

Metformin is administered orally. In patients receiving metformin hydrochloride conventional tablets at a dosage of 2 g or less daily, the drug usually can be given as 2 divided doses daily; however, in patients who require more than 2 g daily, the drug usually should be administered as 3 divided doses daily. Metformin hydrochloride in fixed combination with pioglitazone, rosiglitazone, repaglinide, or sitagliptin is administered in divided doses daily with meals to reduce the GI effects of the metformin hydrochloride component. Although food decreases the extent and slightly delays absorption of metformin conventional tablets, the manufacturer states that the clinical importance of these effects is not known and recommends that the drug be taken with meals to decrease adverse GI effects.

Dosage of the fixed combination of metformin and repaglinide should be administered within approximately 15 minutes prior to meals; timing may vary from immediately before meals to 30 minutes before meals. Patients who skip a meal should omit the dose of the fixed combination of metformin and repaglinide for that meal.

Metformin hydrochloride extended-release tablets should be taken with the evening meal. The manufacturer of Fortamet extended-release tablets states that each dose of the drug should be taken with a full glass of water. The matrix core of some extended-release tablet preparations (e.g., GlucophageXR, Glumetza) usually is broken up in the GI tract, but patients should be advised that occasionally the biologically inert components of the tablet may remain intact and be passed in the stool as a soft, hydrated mass. Occasionally, Glumetza may be eliminated in the feces as a soft, hydrated mass or an insoluble shell. The membrane coating surrounding the core of another extended-release tablet (Fortamet) remains intact through the GI tract and is excreted in feces as a soft mass that may resemble the original tablet.(See Chemistry and Stability: Stability.)

Extended-release metformin hydrochloride tablets and fixed-combination preparations containing the extended-release form of the drug must be swallowed whole and not chewed, cut, or crushed; inactive ingredients occasionally may be eliminated in feces as a soft mass that may resemble the original tablet.

Dosage

Diabetes Mellitus

Dosage of metformin hydrochloride must be individualized carefully based on patient response and tolerance. The goal of therapy should be to reduce both fasting glucose and glycosylated hemoglobin (hemoglobin A1c [HbA1c]) values to normal or near normal using the lowest effective dosage of metformin hydrochloride, either when used as monotherapy or combined with another antidiabetic agent. Patients should be monitored with regular laboratory evaluations, including fasting blood (or plasma) glucose determinations, to assess therapeutic response and the minimum effective dosage of metformin hydrochloride. (Glucose concentrations in plasma generally are 10-15% higher than those in whole blood; glucose concentrations also may vary according to the method and laboratory used for these determinations.) Glucose determinations also should be monitored to detect primary failure (inadequate lowering of glucose concentration at the maximum recommended dosage) or secondary failure (loss of glycemic control following an initial period of effectiveness) to the drug. If inadequate glycemic control and/or secondary failure occurs during maintenance therapy with metformin or an oral sulfonylurea alone, combined therapy may result in an adequate response. If secondary failure occurs with combined metformin and oral sulfonylurea therapy, most clinicians currently recommend discontinuance of oral antidiabetic agents and initiation of insulin therapy.

Following initiation of metformin therapy and dosage titration, determination of HbA1c concentrations at intervals of approximately 3 months is useful for assessing the patient's continued response to therapy. HbA1c is a better indicator of long-term glycemic control than fasting plasma glucose concentrations alone. In patients usually well controlled by dietary management alone, short-term therapy with metformin may be sufficient during periods of transient loss of diabetic control.

Since adverse GI effects with metformin appear to be dose related, it is recommended that dosage of the drug be increased gradually and that the drug be taken with meals.(See Cautions: GI Effects.)

Initial Dosage

For the management of type 2 diabetes mellitus in adults, the manufacturer states that the usual initial dosage of metformin hydrochloride as conventional tablets is 500 mg twice daily or 850 mg once daily with meals. Alternatively, an initial metformin hydrochloride dosage of 500 mg once daily has been suggested by some experts. When metformin hydrochloride oral solution is used, the usual initial dosage is 500 mg twice daily or 850 mg once daily with meals. The manufacturers state that in general, clinically important responses are not observed at metformin hydrochloride dosages of less than 1.5 g daily.

When metformin hydrochloride is administered as certain extended-release tablet preparations (e.g., Glucophage XR), the usual initial dosage in adults is 500 mg once daily with the evening meal. With another extended-release tablet preparation (Fortamet), the usual initial dosage is 1 g once daily with the evening meal, although the manufacturer states that 500 mg once daily may be used when clinically appropriate. The recommended initial dosage of another extended-release preparation of metformin hydrochloride (Glumetza) is 1 g once daily with the evening meal. Subsequent dosage of metformin hydrochloride should be adjusted according to the patient's therapeutic response, using the lowest possible effective dosage.(See Dosage: Maintenance Dosage, under Dosage and Administration.)

Although satisfactory control of blood glucose concentrations may be achieved within a few days after dosage adjustment, the full effects of the drug may not be observed for up to 2 weeks.

Metformin should be used with caution in geriatric patients since aging is associated with reduced renal function, and accumulation of the drug resulting in lactic acidosis may occur in patients with renal impairment. In addition, renal function should be monitored regularly in geriatric patients to determine the appropriate dosage of metformin hydrochloride. Metformin should not be initiated in geriatric patients 80 years of age or older unless determinations of creatinine clearance indicate normal renal function. Initial dosages of metformin hydrochloride should be conservative and should be titrated carefully; dosage generally should not be titrated to the maximum level recommended for younger adults. It has been suggested, based on limited data, that initial dosages of metformin hydrochloride in geriatric patients be reduced by approximately 33% compared with such dosages in other patients with type 2 diabetes mellitus.

For the management of type 2 diabetes mellitus in children or adolescents 10-16 years of age, the usual initial dosage of metformin hydrochloride as conventional tablets or the oral solution is 500 mg twice daily given in the morning and evening with meals. Safety and efficacy of certain extended-release tablet preparations of metformin hydrochloride (Glucophage XR, Fortamet) have not been established in children or adolescents younger than 17 years of age. Safety and efficacy of another extended-release tablet preparation (Glumetza) have not been established in children and adolescents younger than 18 years of age.

Transferring from Therapy with Other Antidiabetic Agents

When transferring from most sulfonylurea antidiabetic agents to metformin, a transition period generally is not required, and administration of the sulfonylurea antidiabetic agent may be abruptly discontinued. Because an exaggerated hypoglycemic response may occur in some patients during the transition from a sulfonylurea antidiabetic agent with a prolonged half-life (e.g., chlorpropamide) to metformin, patients being transferred from such agents should be monitored closely for the occurrence of hypoglycemia during the initial 2 weeks of the transition period.

Dosage Titration

In adults receiving an initial metformin hydrochloride dosage of 500 mg twice daily as conventional tablets or the oral solution, daily dosage may be increased by 500 mg at weekly intervals until the desired fasting blood glucose concentration (e.g., less than 140 mg/dL) is achieved or a dosage of 2 g daily is reached. Alternatively, in adults receiving 500 mg of metformin hydrochloride twice daily as conventional tablets or the oral solution, dosage may be increased to 850 mg twice daily after 2 weeks. In adults receiving an initial dosage of 500 mg of metformin hydrochloride once or twice daily (with breakfast and/or dinner), some experts recommend increasing the dosage to 850 mg or 1 g twice daily after 5-7 days if additional glycemic control is needed and the drug is well tolerated (e.g., no adverse GI effects). If adverse GI effects appear during dosage titration of metformin hydrochloride, dosage should be decreased to the previous lower dosage, and further dosage increments attempted at a later time. In adults receiving an initial metformin hydrochloride dosage of 850 mg daily as conventional tablets or the oral solution, daily dosage may be increased by 850 mg every other week (i.e., every 2 weeks) until the desired fasting blood glucose concentration (e.g., less than 140 mg/dL) is achieved or a total dosage of 2 g daily is reached. For patients requiring additional glycemic control with metformin hydrochloride, a maximum daily dosage of 2.55 g as conventional tablets or the oral solution may be used.

In adults (17-18 years of age or older) receiving certain metformin hydrochloride extended-release tablets (e.g., Glucophage XR, Glumetza), daily dosage may be increased by 500 mg at weekly intervals until the desired glycemic response is achieved or a maximum dosage of 2 g daily is reached. If glycemic control is not achieved with metformin hydrochloride extended-release tablets (e.g., Glucophage XR, Glumetza) at a dosage of 2 g once daily, a dosage of 1 g twice daily should be considered. If a dosage exceeding 2 g daily is needed in patients receiving certain metformin hydrochloride extended-release tablet preparations (e.g., Glucophage XR), the manufacturers suggest that therapy be switched to conventional metformin hydrochloride tablets and dosage titrated up to a maximum dosage of 2.55 g daily in divided doses. Conversely, therapy with extended-release tablets may be substituted for conventional tablets at the same total daily dosage of conventional tablets; dosage subsequently should be adjusted according to glycemic response.

With another extended-release metformin hydrochloride tablet preparation (Fortamet), daily dosage may be increased by 500 mg at weekly intervals up to a maximum of 2.5 g once daily with the evening meal. In patients transferring from conventional tablets to an extended-release tablet preparation, glycemic control should be closely monitored and dosage adjustments made accordingly.

Dosage in adults generally should not exceed 2.55 g daily when given as metformin hydrochloride tablets or oral solution, 2.5 g daily when given as certain extended-release tablets (Fortamet), or 2 g daily when given as certain other extended-release tablet preparations (GlucophageXR). Metformin hydrochloride dosages of up to 3 g daily have been associated with modestly greater effectiveness than 1.7 g daily. However, adverse GI effects may limit the maximum dosage that can be tolerated. (Consult the manufacturer's labeling for product-specific details.) Dosages exceeding 2 g of metformin hydrochloride daily as conventional tablets or the oral solution may be better tolerated if given in 3 divided doses daily with meals. Maintenance dosage of metformin hydrochloride should be conservative in debilitated, malnourished, or geriatric patients because of an increased risk of hypoglycemia in these patients. Dosage of metformin hydrochloride in fixed combination with pioglitazone in such patients should not be titrated to the maximum recommended dosage.(See Cautions: Precautions and Contraindications.)

Metformin should be used with caution in geriatric patients since aging is associated with reduced renal function, and accumulation of the drug resulting in lactic acidosis may occur in patients with renal impairment. In addition, renal function should be monitored periodically in geriatric patients to determine the appropriate dosage of metformin hydrochloride. Any dosage adjustment in geriatric patients should be based on a careful assessment of renal function. Maintenance dosage of metformin hydrochloride in geriatric, debilitated, or malnourished patients generally should not be titrated to the maximum level recommended for other patients. It has been suggested, based on limited data, that maximum dosages in geriatric patients be reduced by approximately 33% compared with such dosages in other patients with type 2 diabetes mellitus.

In children or adolescents 10-16 years of age receiving metformin hydrochloride 500 mg twice daily as conventional tablets or the oral solution, daily dosage may be increased by 500 mg at weekly intervals until the desired glycemic response is achieved or up to a maximum dosage of 2 g daily given in divided doses.

Concomitant Therapy with Metformin and Sulfonylurea Antidiabetic Agents

In patients who do not respond to a 4-week trial of metformin hydrochloride therapy at the maximum recommended dosage, gradual addition of a sulfonylurea antidiabetic agent may be considered even if prior primary or secondary failure to a sulfonylurea antidiabetic agent has occurred. The manufacturer of glipizide states that other oral antidiabetic agents may be added to glipizide therapy if glycemic control is inadequate with glipizide. The manufacturers of glimepiride or glyburide state that combination therapy with metformin may be used in patients who no longer respond adequately to either antidiabetic agent alone, despite appropriate antidiabetic monotherapy, diet, and exercise. ADA states that a second antidiabetic agent may be added as soon as monotherapy with metformin at the maximum tolerated dosage no longer provides adequate glycemic control (i.e., when the target glycemic goal is not achieved within 2-3 months of initiation of therapy with metformin or at any other time when the HbA1c goal is not achieved). With concomitant metformin hydrochloride and sulfonylurea therapy, dosage of each drug should be adjusted to obtain adequate glycemic control with the minimum effective dosage of each drug. In patients who do not respond to 1-3 months of concomitant therapy at the maximum dosage of each oral antidiabetic agent, therapeutic alternatives include use of insulin with or without concomitant metformin hydrochloride therapy.

The commercially available preparation containing metformin hydrochloride in fixed combination with glyburide (e.g., Glucovance) may be used as initial therapy in patients with type 2 diabetes mellitus whose blood glucose is not adequately controlled with diet and exercise alone, or as second-line therapy in those in whom glycemic control with glyburide or metformin monotherapy is not adequate. If the fixed combination of metformin and glyburide is used as initial therapy, the recommended initial dosage is 250 mg of metformin hydrochloride and 1.25 mg of glyburide daily with a meal. Patients with more severe hyperglycemia (as determined by HbA1c exceeding 9% or fasting plasma glucose concentrations exceeding 200 mg/dL) may receive an initial dosage of 250 mg of metformin hydrochloride and 1.25 mg of glyburide twice daily with the morning and evening meals. Daily dosage may be increased in increments of 1.25 mg of glyburide and 250 mg of metformin hydrochloride at 2-week intervals until the minimum effective dosage required to achieve adequate blood glucose control is reached. A total daily dosage exceeding 10 mg of glyburide and 2 g of metformin hydrochloride has not been evaluated in clinical trials in patients receiving the fixed-combination preparation as initial therapy. The manufacturer states that the fixed-combination preparation containing 5 mg of glyburide and 500 mg of metformin hydrochloride should not be used as initial therapy in treatment-naive patients because of the increased risk for hypoglycemia.

If the fixed combination of metformin and glipizide (e.g., Metaglip) is used as initial therapy in patients who have inadequate glycemic control with diet and exercise alone, the recommended initial dosage is 250 mg of metformin hydrochloride and 2.5 mg of glipizide once daily with a meal. Patients with more severe hyperglycemia (as determined by fasting plasma glucose concentrations of 280-320 mg/dL) may receive an initial dosage of 500 mg of metformin hydrochloride and 2.5 mg of glipizide twice daily. The efficacy of metformin in fixed combination with glipizide has not been established in patients whose fasting plasma glucose concentrations exceed 320 mg/dL. Daily dosage may be increased in increments of one tablet (using the tablet strength at which therapy was initiated, either 2.5 mg of glipizide and 250 mg of metformin hydrochloride or 2.5 mg of glipizide and 500 mg of metformin in hydrochloride) at 2-week intervals until the minimum effective dosage required to achieve adequate blood glucose control is reached; there is no experience with total daily dosages exceeding 2 g of metformin hydrochloride and 10 mg of glipizide in clinical trials in patients receiving the fixed combination for initial therapy. A total daily dosage exceeding 2 g of metformin hydrochloride and 10 mg of glipizide has not been evaluated in clinical trials in patients receiving the fixed-combination preparation as initial therapy.

The commercially available preparations containing metformin hydrochloride in fixed combination with glyburide or glipizide also may be used as second-line therapy in patients with type 2 diabetes mellitus whose blood glucose is not adequately controlled with either glyburide or glipizide (or another sulfonylurea antidiabetic agent) or metformin alone. Dosage of the fixed combinations is based on the patient's current dosages of metformin hydrochloride and glyburide or glipizide, effectiveness, and tolerability. The recommended initial dosage of the commercially available fixed-combination tablets in previously treated patients is 500 mg of metformin hydrochloride and 2.5 or 5 mg of glyburide or glipizide twice daily with the morning and evening meals. In order to minimize the risk of hypoglycemia, the initial dosage of glyburide and metformin hydrochloride in fixed combination should not exceed the daily dosage of metformin hydrochloride, glyburide, or glipizide (or the equivalent dosage of another sulfonylurea) previously received. The daily dosage of the fixed combination of metformin hydrochloride and glyburide or glipizide should be titrated upward in increments not exceeding 500 mg of metformin hydrochloride and 5 mg of glyburide or glipizide until adequate control of blood glucose is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glyburide or glipizide is reached.

For patients being switched from combined therapy with separate preparations, the initial dosage of the fixed-combination preparation of metformin hydrochloride and glyburide or glipizide should not exceed the daily dosage of glyburide, glipizide (or equivalent dosage of another sulfonylurea antidiabetic agent), and metformin hydrochloride currently being taken. Such patients should be monitored for signs and symptoms of hypoglycemia following the switch. In the transfer from previous antidiabetic therapy to the fixed combination, the decision to switch to the nearest equivalent dosage or to titrate dosage should be based on clinical judgment. Hypoglycemia and hyperglycemia are possible in such patients, and any change in the therapy of type 2 diabetic patients should be undertaken with caution and appropriate monitoring. If blood glucose concentrations are not adequately controlled following initial administration of the fixed-combination preparations, the daily dosage may be titrated in increments of no more than 5 mg of glyburide and 500 mg of metformin hydrochloride daily until adequate glycemic control is achieved or a maximum daily dosage of 20 mg of glyburide or glipizide and 2 g of metformin hydrochloride is reached. The safety and efficacy of switching from another combined therapy with separate preparations of glyburide (or another sulfonylurea antidiabetic agent) and metformin in the fixed-combination preparation have not been established in clinical studies.

Therapy with metformin in fixed combination with glyburide should be used with caution in geriatric patients, since aging is associated with reduced renal function. The initial and maintenance dosages of metformin hydrochloride in fixed combination with glyburide should be conservative and should be titrated carefully in such patients. Renal function should be assessed with initial dosage selection and with each dosage adjustment, particularly in geriatric patients, to aid in prevention of lactic acidosis. To minimize the risk of hypoglycemia, maintenance dosage of the fixed combination of metformin hydrochloride and glyburide in geriatric, debilitated, or malnourished patients should not be titrated to the maximum dosage recommended for other patients.

For patients whose hyperglycemia is not adequately controlled on therapy with metformin in fixed combination with glyburide, a thiazolidinedione (e.g., pioglitazone, rosiglitazone) may be added at its recommended initial dosage and the dosage of the fixed combination may be continued unchanged. In patients requiring further glycemic control, the dosage of the thiazolidinedione may be titrated upward, based on the dosage regimen recommended by the manufacturer. Such triple therapy with glyburide, metformin, and a thiazolidinedione may increase the potential for hypoglycemia at any time of day. If hypoglycemia develops during such triple therapy, consideration should be given to reducing the dosage of the glyburide component; adjustment of the dosage of the other components of the antidiabetic regimen also should be considered as clinically indicated.

Combination Therapy with Metformin and a Thiazolidinedione

The commercially available fixed-combination preparation containing metformin hydrochloride and rosiglitazone (Avandamet) may be used in patients with type 2 diabetes mellitus when treatment with both metformin and rosiglitazone is appropriate.

The commercially available fixed-combination preparations containing metformin hydrochloride (immediate- or extended-release) and pioglitazone (Actoplus Met, Actoplus Met XR) are used as second-line therapy in patients with type 2 diabetes mellitus who have inadequate glycemic control with pioglitazone or metformin monotherapy or in those who are already receiving each drug component separately.

When the commercially available fixed-combination preparations containing metformin hydrochloride and pioglitazone are used as second-line therapy in patients inadequately controlled on monotherapy with the individual drugs or to replace concurrent therapy with the drugs given as separate tablets, dosage of the fixed combinations should be based on the patient's current dosages of metformin hydrochloride and/or pioglitazone, effectiveness, and tolerability. If the fixed combination containing metformin hydrochloride and pioglitazone (Actoplus Met) is used, the usual initial dosage is metformin hydrochloride 500 or 850 mg and pioglitazone 15 mg given once or twice daily. If the fixed combination containing extended-release metformin hydrochloride and immediate-release pioglitazone (Actoplus Met XR) is used, the usual initial dosage is metformin hydrochloride 1 g and pioglitazone 15 or 30 mg given once daily with the evening meal. Dosage should be titrated gradually, based on assessment of therapeutic response, to a maximum daily dosage of 2.55 g of metformin hydrochloride and 45 mg of pioglitazone (as Actoplus Met) or 2 g of extended-release metformin hydrochloride and 45 mg of immediate-release pioglitazone (as Actoplus Met XR).

The safety and efficacy of transferring from therapy with other oral antidiabetic agents to the fixed combination of pioglitazone and metformin hydrochloride have not been specifically established in clinical studies. Any change in the therapy of patients with type 2 diabetes mellitus should be undertaken with caution and appropriate monitoring, as changes in glycemic control can occur. Ideally, long-term glycemic control should be evaluated using HbA1c (HbA1c) at 8-12 weeks following transfer of therapy unless there is evidence of deterioration of glycemic control as measured by fasting plasma glucose concentrations.

When the commercially available preparation containing metformin hydrochloride in fixed combination with rosiglitazone (Avandamet) is used in patients with type 2 diabetes mellitus, selection of the fixed-combination dosage should be based on the patient's current dosages of the individual drugs. In patients currently receiving rosiglitazone monotherapy, the usual initial dosage of metformin hydrochloride (in fixed combination with rosiglitazone) is 1 g daily plus the patient's existing dosage of rosiglitazone, given in 2 divided doses. In patients currently receiving metformin hydrochloride monotherapy, the usual initial dosage of rosiglitazone (in fixed combination with metformin hydrochloride) is 4 mg daily plus the patient's existing dosage of metformin hydrochloride, given in 2 divided doses. (See Table 1.)

Table 1. Initial Dosage of the Fixed Combination of Rosiglitazone and Metformin Hydrochloride (Avandamet®) as Second-Line Therapy
Prior Therapy Usual Initial Dosage of Avandamet® Total Daily Dosage Tablet Strength Number of Tablets
Metformin Hydrochloride
1 g 2 mg/500 mg 1 tablet twice daily
2 g 2 mg/1 g 1 tablet twice daily
Rosiglitazone
4 mg 2 mg/500 mg 1 tablet twice daily
8 mg 4 mg/500 mg 1 tablet twice daily

Therapy should be individualized in patients already receiving metformin hydrochloride at dosages not available in the fixed combination (i.e., dosages other than 1 or 2 g).

For patients switching from combined therapy with separate preparations of metformin hydrochloride and rosiglitazone, the initial dosage of the fixed-combination preparation of metformin hydrochloride and rosiglitazone should be the same as the daily dosage of metformin hydrochloride and rosiglitazone currently being taken.

If additional glycemic control is needed following initial therapy or transfer, the dosage of the fixed combination of metformin hydrochloride and rosiglitazone may be titrated upward in increments not exceeding 500 mg of metformin hydrochloride and/or 4 mg of rosiglitazone until adequate glycemic control is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 8 mg of rosiglitazone is reached.

Therapy with metformin in fixed combination with rosiglitazone should be used with caution in geriatric patients, since aging is associated with reduced renal function. The initial and maintenance dosages of metformin hydrochloride in fixed combination with rosiglitazone should be conservative and should be titrated carefully in such patients. Renal function should be assessed with initial dosage selection and with each dosage adjustment, particularly in geriatric patients, to aid in prevention of lactic acidosis. To minimize the risk of hypoglycemia, maintenance dosage of the fixed combination of metformin hydrochloride and glyburide in geriatric, debilitated, or malnourished patients should not be titrated to the maximum dosage recommended for other patients.

Combination Therapy with Metformin and Repaglinide

When the fixed combination of metformin hydrochloride and repaglinide (PrandiMet) is used as second-line therapy in patients inadequately controlled on monotherapy with one of the drugs or to replace concurrent therapy with the drugs given as separate tablets, dosage of the fixed combination should be individualized based on the patient's current dosage regimen, effectiveness, and tolerability. In patients inadequately controlled on metformin hydrochloride monotherapy, the usual initial dosage of the fixed combination is metformin hydrochloride 500 mg and repaglinide 1 mg twice daily with meals, with gradual dosage escalation as needed to reduce the risk of hypoglycemia with repaglinide. In patients inadequately controlled on repaglinide monotherapy, the usual initial dosage of the metformin hydrochloride component (in fixed combination with repaglinide) is 500 mg twice daily with meals, with gradual dosage escalation as needed to reduce GI adverse effects with metformin.

For patients being switched from concurrent therapy with metformin hydrochloride and repaglinide given as separate tablets, the initial dosage of the fixed combination should be the one that most closely provides (but does not exceed) the patient's existing dosage of these drugs.

Dosage of the fixed combination should be titrated gradually, based on assessment of therapeutic response, to a maximum daily dosage of 2.5 g of metformin hydrochloride and 10 mg of repaglinide given in 2 or 3 divided doses. Dosages of metformin and repaglinide given in fixed combination should not exceed 1 g or 4 mg, respectively, per meal. Safety and efficacy of transferring from therapy with other oral antidiabetic agents to the fixed combination of repaglinide and metformin hydrochloride have not been specifically established in clinical studies. Any change in the therapy of patients with type 2 diabetes mellitus should be undertaken with caution and appropriate monitoring, as changes in glycemic control can occur.

Dosage of metformin hydrochloride in fixed combination with repaglinide should be titrated with caution in patients of advanced age, since aging is associated with reduced renal function. In geriatric patients, particularly those 80 years of age or older, dosage adjustment should be based on careful assessment of renal function.

Combination Therapy with Metformin and Sitagliptin

Dosage of the commercially available fixed-combination preparation containing metformin hydrochloride and sitagliptin (Janumet) should be individualized based on the patient's current dosage regimen, effectiveness, and tolerability while not exceeding the maximum recommended daily dosage of 2 g of metformin hydrochloride and 100 mg of sitagliptin. When the fixed-combination preparation containing metformin hydrochloride and sitagliptin is used in patients with type 2 diabetes mellitus who are not currently receiving metformin, the usual initial dosage is metformin hydrochloride 500 mg and sitagliptin 50 mg twice daily with meals. Dosage of the fixed combination should be gradually titrated to reduce adverse GI effects associated with metformin.

When the fixed-combination preparation containing metformin hydrochloride and sitagliptin is used in patients with type 2 diabetes mellitus who are currently receiving metformin, the initial dosage of the fixed combination should provide 50 mg of sitagliptin twice daily and the dosage of metformin hydrochloride currently being taken. Patients currently receiving metformin hydrochloride 850 mg twice daily as monotherapy should initially receive 50 mg of sitagliptin and 1 g of metformin hydrochloride as the fixed combination twice daily with meals. In patients who have inadequate glycemic control with sitagliptin monotherapy, the usual initial dosage of the fixed combination is metformin hydrochloride 500 mg and sitagliptin 50 mg twice daily with meals. Dosage of the fixed combination should be gradually titrated to reduce adverse GI effects associated with metformin.

The safety and efficacy of transferring from therapy with other oral antidiabetic agents to the fixed combination of sitagliptin and metformin hydrochloride have not been specifically established in clinical studies. Any change in the therapy of patients with type 2 diabetes mellitus should be undertaken with caution and appropriate monitoring, as changes in glycemic control can occur.

Concomitant administration of the fixed combination of metformin hydrochloride and sitagliptin with a sulfonylurea or insulin may require reduced dosages of the sulfonylurea or insulin to reduce the risk of hypoglycemia.

Dosage of metformin hydrochloride in fixed combination with sitagliptin should be selected carefully in patients of advanced age, since aging is associated with reduced renal function. In geriatric patients, dosage adjustment should be based on careful and regular assessment of renal function.

Concomitant Therapy with Metformin and Insulin

Combination therapy with metformin and insulin may be used in patients who no longer respond adequately to therapy with oral antidiabetic agents. In such patients, an initial metformin hydrochloride dosage of 500 mg once daily is recommended. The daily dosage may be increased by 500 mg at weekly intervals up to a maximum of 2.5 g daily with conventional tablets, the oral solution, or an extended-release tablet preparation (Fortamet); a maximum of 2 g daily with other extended-release tablet preparations (e.g., GlucophageXR, Glumetza); or until the desired fasting blood glucose concentration is achieved. Dosages up to 2 g may be given in 2 divided doses daily (e.g., 2 g daily given as 1 g with the morning and evening meals); dosages exceeding 2 g of metformin hydrochloride daily may be better tolerated if given in 3 divided doses daily with meals. Concurrent insulin dosage should initially remain unchanged. Patients should be monitored closely (e.g., with determination of fasting glucose concentrations) during the dosage titration. When fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving combined metformin and insulin therapy, the insulin dosage may be decreased by 10-25%. Further dosage adjustments should be individualized based on glycemic response. Periodic adjustments in dosage may be necessary during continued combination therapy, as guided by monitoring of fasting glucose and/or HbA1c concentrations.

Polycystic Ovary Syndrome

In women with polycystic ovary syndrome, metformin hydrochloride dosages of 1.5-2.25 g daily in divided doses generally have been used to ameliorate symptoms of insulin resistance and hyperinsulinemia and to increase the frequency of spontaneous ovulation, menstrual cyclicity, and ovulatory response after ovarian stimulation.

Dosage in Renal and Hepatic Impairment

Because of the risk of lactic acidosis, which occurs rarely but may be fatal in approximately 50% of cases, metformin should not be used in patients with severe renal disease or dysfunction and should be avoided in those with clinical or laboratory evidence of hepatic disease. In patients with moderate renal disease, the benefits and risks of continuing metformin therapy should be assessed.(See Cautions: Lactic Acidosis.)

While metformin has been contraindicated in patients with renal impairment (e.g., men or women with serum creatinine concentrations equal to or exceeding 1.5 or 1.4 mg/dL, respectively), an FDA review of clinical studies evaluating the safety of metformin in patients with reduced kidney function suggests that metformin can be used safely in patients with mild impairment in kidney function and in some patients with moderate impairment in kidney function.

FDA states that renal function (estimated glomerular filtration rate [eGFR]) should be assessed prior to initiation of metformin and at least annually; more frequent monitoring has been recommended in patients with an increased risk of developing renal impairment (e.g., geriatric patients). FDA states that metformin therapy should not be initiated in patients with an eGFR between 30-45 mL/minute per 1.73 m and that the benefits and risks of continuing the drug should be assessed in those with an eGFR in this range who are already receiving metformin. FDA states that metformin should not be used in patients with an eGFR of less than 30 mL/minute per 1.73 m. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) states that the exact GFR cutoff for metformin use to avoid lactic acidosis is controversial. The NKF-KDOQI and other clinicians suggest that metformin therapy be avoided in patients with a GFR less than 30 mL/minute per 1.73 m but that the risk-benefit of such therapy should be considered if GFR is stable. In addition, the NKF-KDOQI states that metformin therapy is probably safe when GFR is at least 45 mL/minute per 1.73 m but that use of the drug should be reviewed when GFR falls below 45 mL/minute per 1.73 m.(See Cautions: Precautions and Contraindications.)

Cautions

Adverse effects, principally GI effects, reportedly occur in about 5-50% of patients receiving metformin therapy as conventional tablets in clinical trials and generally required discontinuance of the drug in 6% or less of patients. When metformin hydrochloride in used in fixed combination with other drugs (e.g., sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, meglitinides), the cautions, precautions, and contraindications associated with these concomitant agents must be considered in addition to those associated with metformin.

Lactic Acidosis

Accumulation of metformin may occur in patients with renal impairment, and such accumulation rarely can result in lactic acidosis, a serious, potentially fatal metabolic disease. The risk of developing lactic acidosis is much lower (e.g., 10-fold lower) with metformin than with phenformin (no longer commercially available in the US); the reported overall incidence of lactic acidosis in patients receiving metformin therapy is approximately 0.03 cases per 1000 patient-years of metformin therapy. (See Cautions: Precautions and Contraindications and also see Chemistry and Stability: Chemistry.) However, lactic acidosis constitutes a medical emergency requiring immediate hospitalization and treatment; in such cases, metformin should be discontinued and general supportive therapy (e.g., volume expansion, diuresis) should be initiated immediately. Prompt hemodialysis also is recommended.(See Acute Toxicity.)

Lactic acidosis is characterized by elevated blood lactate concentrations (exceeding 45 mg/dL), decreased blood pH (less than 7.35), electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. Lactic acidosis also may occur in association with a variety of pathophysiologic conditions, including diabetes mellitus, and whenever substantial tissue hypoperfusion and hypoxemia exist. Approximately 50% of cases of metformin-associated lactic acidosis have been reported to be fatal. However, it has been suggested that in such cases of lactic acidosis not accompanied by conditions predisposing to tissue anoxia (e.g., heart failure, renal or pulmonary disease), techniques for the elimination of metformin from the body may allow recovery rates exceeding 80%.

The manufacturer states that when metformin has been implicated as the cause of lactic acidosis, plasma metformin concentrations exceeding 5 mcg/mL generally have been observed. However, plasma metformin concentrations may not be an accurate indication of tissue accumulation of the drug in patients with metformin-induced lactic acidosis, and increased plasma concentrations of lactic acid or lactic acidosis have been demonstrated during metformin therapy despite normal plasma concentrations of the drug. Patients with lactic acidosis and normal plasma metformin concentrations also may have other conditions contributing to the development of lactic acidosis (e.g., hypoxia, dehydration).

Fasting venous plasma lactate concentrations that exceed the upper limit of normal but are less than 45 mg/dL do not necessarily indicate impending lactic acidosis in patients receiving metformin. Such concentrations may be related to poorly controlled diabetes, obesity, vigorous physical activity, or technical problems in handling samples for plasma lactate determinations. Some observational data suggest that neither plasma metformin concentrations nor plasma lactate concentrations are related to mortality in patients with lactic acidosis receiving metformin.

Lactic acidosis often has a subtle onset and may be accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis also may occur. Patients and clinicians should be aware of the possible importance of such symptoms, and patients should be instructed to notify their clinician immediately if these symptoms occur; metformin should be discontinued until the patient is hospitalized and a clinician has evaluated the patient's condition. Once a patient is stabilized at any dosage of metformin hydrochloride, GI symptoms, which are common during initiation of therapy, are unlikely to be drug related; later occurrence of GI symptoms could be manifestations of lactic acidosis or other serious disease.

Lactic acidosis associated with metformin therapy generally has occurred in diabetic patients with severe renal insufficiency, including those with both intrinsic renal impairment and renal hypoperfusion; most cases of lactic acidosis have been reported in patients with concomitant medical and/or surgical problems who were receiving multiple drugs. Lactic acidosis may be manifested as metabolic acidosis without ketoacidosis (ketonuria and ketonemia) in patients with diabetes mellitus.

Some observational studies and meta-analyses suggest that the incidence of lactic acidosis in patients with type 2 diabetes mellitus who are receiving metformin therapy is similar to that in patients not receiving the drug. Analyses of pooled data that included all known prospective comparative trials and observational cohort studies of metformin therapy of at least 1 month's duration (up to 70,490 patient-years of metformin treatment) revealed no cases of fatal or nonfatal metformin-induced lactic acidosis; therefore, an incidence rate for metformin-associated lactic acidosis could not be calculated. While these analyses allowed for the inclusion of patients with at least one contraindication to metformin (e.g., renal insufficiency), information on the safety of metformin in the presence of such contraindications could not be evaluated because of the lack of information on the number of included patients with such conditions. In these analyses, all cases of lactic acidosis reportedly occurred in patients with comorbidities predisposing to lactic acidosis, suggesting that association of the condition with metformin use may be coincidental rather than causal.

The risk of lactic acidosis appears to increase with the degree of renal impairment and the patient's age; therefore, the risk of this condition can be minimized by periodic monitoring of renal function and use of the minimum effective dosage of metformin hydrochloride. Metformin therapy should be withheld promptly in patients with any condition associated with hypoxemia, sepsis, or dehydration, or in any patient who becomes acutely unwell. Therapy with the drug alone or in fixed combinations also should be avoided in patients with clinical or laboratory evidence of hepatic impairment since elimination of lactate may be reduced substantially in such patients. Patients should be advised not to consume excessive amounts of alcohol, either acutely or chronically, since alcohol may potentiate the effects of metformin on lactate metabolism by decreasing hepatic gluconeogenesis.

FDA and other clinicians state that metformin therapy should be discontinued before or at the time of an iodinated contrast imaging procedure in patients with an estimated glomerular filtration rate (eGFR) of 30-60 mL/minute per 1.73 m and in patients with a history of liver disease, alcoholism, or heart failure. Therapy with metformin-containing preparations also should be withheld temporarily in patients undergoing surgery or receiving intra-arterial iodinated contrast agents. Renal function should be evaluated 48 hours after the imaging procedure and metformin therapy may be reinstituted if renal function is stable.(See Cautions: Precautions and Contraindications.)

GI Effects

Adverse GI effects such as diarrhea, nausea, vomiting, flatulence, indigestion, and abdominal discomfort (e.g., bloating, abdominal cramping or pain) are the most common adverse effects associated with metformin-containing therapy as conventional tablets; diarrhea and nausea/vomiting are among the most common drug-related adverse effects reported in clinical trials with the extended-release tablets. Because substantial diarrhea and/or vomiting may cause dehydration and prerenal azotemia, metformin should be discontinued in patients who develop such potentially serious GI effects; persistent diarrhea resolves promptly upon discontinuance of the drug. Unpleasant or metallic taste (taste disorder/disturbance), which usually resolves spontaneously, has been reported in approximately 1-5% of patients receiving metformin conventional or extended-release tablets. Other adverse GI effects reported in 1-5% of patients receiving conventional or an extended-release metformin tablet preparation (GlucophageXR) include abnormal stools, distended abdomen, constipation, or dyspepsia/heartburn. Other adverse GI effects reported in 1-5% of patients receiving another metformin extended-release tablet (Fortamet) include dyspepsia, flatulence, and abdominal pain. Anorexia also has been reported with metformin therapy.

Metformin-induced adverse GI effects appear to be dose related, generally occur at initiation of therapy, and usually subside spontaneously during continued metformin therapy; in some cases, a reduction in metformin hydrochloride dosage may be useful in hastening resolution of these effects. Diarrhea severe enough to require discontinuance of metformin occurred in about 6% of patients receiving the conventional tablets and in about 0.6% of those receiving the extended-release tablets in controlled clinical trials. Since adverse GI effects occurring during initiation of metformin therapy appear to be dose related, they may be reduced by gradual dosage escalation and administration of the drug with meals.

Diarrhea was reported in up to 7.5% of patients receiving combined therapy with metformin hydrochloride and sitagliptin in clinical trials.

Hypoglycemia

Hypoglycemia is uncommon in patients receiving metformin as monotherapy; however, it may occur when metformin is used concomitantly with an oral sulfonylurea antidiabetic agent, a thiazolidinedione, or insulin, when caloric intake is deficient, or when strenuous exercise is not accompanied by food intake. Symptoms of hypoglycemia (such as dizziness, shakiness, sweating, hunger) have occurred in 21.3, 11.4, or 37.7% of patients receiving glyburide (5.3 mg), glyburide in fixed combination with metformin hydrochloride (2.78 mg of glyburide, 557 mg of metformin hydrochloride), or glyburide in fixed combination with metformin hydrochloride at a final mean titrated dosage of 824 mg of metformin hydrochloride and 4.1 mg of glyburide in controlled clinical trials. In a controlled initial therapy trial of metformin hydrochloride in fixed combination with glipizide, symptomatic hypoglycemia and blood glucose concentrations 50 mg/dL or less occurred in 2.9, 0, 7.6, or 9.3% of patients receiving glipizide monotherapy (final mean dosage of 16.7 mg), metformin hydrochloride monotherapy (final mean dosage of 1.749 g of metformin hydrochloride), the fixed combination with glipizide (final mean dosage of 791 mg of metformin hydrochloride and 7.9 mg of glipizide), and the fixed combination with a higher dosage of the metformin hydrochloride component (final mean dosage of 1.477 g of metformin hydrochloride and 7.4 mg of glipizide). In a controlled trial in patients inadequately controlled by monotherapy with metformin hydrochloride or a sulfonylurea agent, documented hypoglycemia (as determined by blood glucose concentrations of 50 mg/dL or less) occurred in 0, 1.3, or 12.6% of patients receiving glipizide monotherapy (mean final dosage of 30 mg), metformin hydrochloride monotherapy (mean final dosage of 1.927 g), or metformin hydrochloride in fixed combination with glipizide at a final mean dosage of 1.747 g of metformin hydrochloride and 5 mg of glipizide. When rosiglitazone was added to fixed combination therapy of glyburide and metformin hydrochloride, documented hypoglycemia occurred in 22% of such patients compared to 3.3% of patients receiving glyburide in fixed combination with metformin hydrochloride. (See Cautions: Precautions and Contraindications.)

Hypoglycemia was reported in 16.4% of patients when sitagliptin was added to combined metformin hydrochloride and glimepiride therapy, compared with 0.9% of those receiving placebo in conjunction with metformin hydrochloride and glimepiride therapy.

Hematologic Effects

Asymptomatic decreases in serum vitamin B12 concentration were reported in about 7-9% of patients receiving metformin alone, and in about 6% of those receiving metformin concomitantly with a sulfonylurea antidiabetic agent, during 29-week controlled clinical trials. Such decreases may be related to interference with absorption of vitamin B12 from B12-intrinsic factor complex; however, they rarely are associated with anemia and are rapidly reversible following discontinuation of metformin or supplementation with vitamin B12. Serum folic acid concentrations do not appear to decrease substantially in patients receiving metformin therapy. Megaloblastic anemia has been reported rarely (e.g., approximately 5 case reports outside the US to date) in patients receiving metformin, and no increased incidence of neuropathy has been observed in patients receiving the drug. Hematologic parameters (e.g., hemoglobin, serum vitamin B12 concentrations) should be monitored annually in patients receiving metformin, and any apparent abnormalities appropriately investigated and managed. In certain individuals who appear to be at risk for developing subnormal vitamin B12 levels (e.g., those who have inadequate vitamin B12 or calcium intake or absorption), routine serum vitamin B12 measurements every 2-3 years may be useful. Some clinicians have suggested that periodic supplementation with parenteral vitamin B12 be considered in such patients and in alcoholics.(See Cautions: Precautions and Contraindications.)

Dermatologic Reactions

The manufacturer states that incidence of rash or dermatitis in patients receiving metformin monotherapy is similar to that with placebo, and that the incidence of these dermatologic effects in patients receiving metformin concomitantly with a sulfonylurea antidiabetic agent is similar to that in individuals receiving a sulfonylurea antidiabetic agent alone.

Nervous System Effects

Headache, agitation, dizziness, and tiredness were reported in a small comparative study in geriatric diabetic patients receiving metformin. Headache was reported in 4.7 or 5.1% of patients receiving metformin as an extended-release tablet preparation (Fortamet) or as conventional tablets, respectively. Headache has been reported in 9.3 or 8.9% of patients receiving metformin or metformin in fixed combination with glyburide, respectively. Headache has been reported in 5.3 or 12.6% of patients receiving metformin or metformin in fixed combination with glipizide, respectively. Headache has been reported in 5.9% of patients receiving combined therapy with metformin and sitagliptin and 6.9% of patients receiving combined therapy with metformin, sitagliptin, and glimepiride in clinical trials. Dizziness has been reported in 3.8 or 5.5% of patients receiving metformin or metformin in fixed combination with glyburide, respectively. Dizziness has been reported in 3.8 or 5.5% of patients receiving metformin or metformin in fixed combination with glyburide, respectively.

Respiratory Effects

Pneumonitis with vasculitis has been reported rarely with concomitant metformin and oral sulfonylurea (e.g., glyburide) therapy. Upper respiratory tract infection was reported in 16.3 or 17.3% of patients receiving metformin or metformin in fixed combination with glyburide, respectively. Upper respiratory tract infection was reported in 8.5 or 8.1-9.9% of patients receiving metformin or metformin in fixed combination with glipizide, respectively, as initial therapy for type 2 diabetes mellitus. Upper respiratory tract infection was reported in 10.7 or 10.3% of patients receiving metformin or metformin in fixed combination with glipizide, respectively, as second-line therapy for type 2 diabetes mellitus. Upper respiratory tract infection was reported in 5.2 or 6.2% of patients receiving metformin or metformin combined with sitagliptin, respectively, in clinical trials. Rhinitis was reported in 4.2 or 5.6% of patients receiving metformin as an extended-release tablet preparation (Fortamet) or as conventional tablets, respectively. Infection was reported in 20.5 or 20.9% of patients receiving an extended-release tablet preparation (Fortamet) or conventional tablets, respectively.

Other Adverse Effects

Urinary tract infection has been reported in 8 or 1.1% of patients receiving metformin alone or in fixed combination with glipizide, respectively. Hypertension has been reported in 5.6 or 2.9-3.5% of patients receiving metformin alone or in fixed combination with glipizide, respectively. Musculoskeletal pain has been reported in 6.7 or 8% of patients receiving metformin alone or in fixed combination with glipizide, respectively. Severe acute hepatitis associated with marked elevations in serum hepatic aminotransferase values and cholestasis has been reported following initiation of metformin therapy in a patient receiving glipizide and enalapril. Accidental injury was reported in 7.3 or 5.6% of patients receiving metformin as an extended-release tablet preparation (Fortamet) or as conventional tablets, respectively.

Precautions and Contraindications

When metformin hydrochloride is used in fixed combination with other drugs (e.g., sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, meglitinides), the cautions, precautions, and contraindications associated with these concomitant agents must be considered in addition to those associated with metformin.

The diagnostic and therapeutic measures for managing diabetes mellitus that are necessary to ensure optimum control of the disease with insulin are generally necessary with metformin. Clinicians who prescribe metformin should be familiar with the indications, limitations, and patient-selection criteria for therapy with oral antidiabetic agents to ensure appropriate patient management. Patients receiving metformin should be monitored with regular laboratory evaluations, including blood glucose determinations, to determine the minimum effective dosage of metformin hydrochloride when used either as monotherapy or in combination with a sulfonylurea or thiazolidinedione antidiabetic agent. Glycosylated hemoglobin (hemoglobin A1c [HbA1c]) measurements also are useful, particularly for monitoring long-term control of blood glucose concentration. Blood glucose determinations are important to detect primary failure (inadequate lowering of blood glucose concentration at the maximum recommended dosage) or secondary failure (loss of control of blood glucose concentration following an initial period of effectiveness) to the drug.

Patients should be informed of the risks of lactic acidosis and conditions that predispose to its development.(See Cautions: Lactic Acidosis.) Since metformin is excreted substantially by the kidneys, accumulation of the drug resulting in lactic acidosis may occur in patients with renal impairment; the risk of lactic acidosis increases with degree of renal impairment. Hemodialysis has been used in patients with lactic acidosis to accelerate the clearance of metformin. (See Acute Toxicity.) The manufacturer states that renal function should be evaluated prior to initiation of therapy with metformin preparations and at least annually thereafter.

Metformin therapy is contraindicated in patients with an eGFR of less than 30 mL/minute per 1.73 m. In patients in whom development of impaired renal function is anticipated (e.g., those with blood glucose concentrations exceeding 300 mg/dL, who may develop renal dysfunction as a result of polyuria and volume depletion; geriatric patients), renal function should be monitored more frequently. In addition, drugs that may affect renal function, produce substantial hemodynamic changes, or interfere with metformin elimination (e.g., cimetidine) should be used with caution in patients receiving metformin. The National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (KDOQI) recommends temporary discontinuance of potentially nephrotoxic and renally excreted drugs (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, aldosterone inhibitors, direct renin inhibitors, diuretics, nonsteroidal anti-inflammatory agents [NSAIAs], metformin, lithium, digoxin) in patients with a GFR less than 60 mL/minute per 1.73 m.

Extended-release metformin hydrochloride tablets or fixed-combination preparations containing the extended-release form of the drug should not be chewed, cut, or crushed; these dosage forms must be swallowed whole. Patients should be aware that the biologically inert components of the tablet may occasionally be eliminated in the feces as a soft, hydrated mass.

Some clinicians state that metformin should not be used in patients with heart failure requiring drug therapy (e.g., digoxin, furosemide), such as those with unstable or acute heart failure. These patients are at risk for hypoperfusion and hypoxemia, which may lead to lactic acidosis. It has been suggested that metformin may be reinstituted once acute heart failure has resolved and renal function is normal (as measured by creatinine clearance); the decision to continue metformin therapy in such patients should be individualized.

Iodinated contrast agents are a potential concern for furthering renal damage in patients with acute kidney injury, and in patients with severe chronic kidney disease (stage IV or stage V). Since administration of iodinated contrast media may lead to acute alteration of renal function and has been associated with lactic acidosis in patients receiving metformin, metformin should be discontinued before or at the time of the procedure in patients with an eGFR between 30-60 mL/minute per 1.73 m; in patients with a history of liver disease, alcoholism, or heart failure; and in those receiving intra-arterial iodinated contrast agents. Renal function should be evaluated 48 hours after the imaging procedure and metformin therapy may be reinstituted if renal function is stable. However, the American College of Radiology states that in patients with no evidence of acute kidney injury and an eGFR of at least 30 mL/minute per 1.73 m, there is no need to discontinue metformin either prior to or following the administration of iodinated contrast media, nor is there a need to reassess the patient's renal function following the test or procedure.

The manufacturers state that metformin also should be discontinued temporarily in patients undergoing surgery, except minor surgery that is not associated with restricted food or fluid intake; the drug should be reinitiated only when the patient's oral intake has resumed and renal function has been shown to be normal. In addition, any diabetic patient previously well controlled with metformin therapy who develops a clinical illness (especially one that is vague and poorly defined) or whose laboratory test results deviate from normal should be evaluated promptly for evidence of ketoacidosis or lactic acidosis.(See Cautions: Lactic Acidosis.) Such evaluation should include determinations of serum electrolytes and ketones, blood glucose, and if indicated, blood pH, lactate, pyruvate, and metformin concentrations. Since cardiovascular collapse (shock), heart failure, ischemic heart disease (e.g., acute myocardial infarction), peripheral vascular disease (e.g., claudication), obstructive airways disease, or other conditions that are likely to cause central hypoxemia or reduced peripheral perfusion have been associated with lactic acidosis and prerenal azotemia, metformin should be discontinued in patients developing such conditions.

The cardiovascular risks associated with use of oral antidiabetic agents have not been fully determined. In 1970, the University Group Diabetes Program (UGDP) reported that administration of oral antidiabetic agents (i.e., tolbutamide or phenformin) was associated with increased cardiovascular mortality compared with treatment with dietary regulation alone or with dietary regulation and insulin. The UGDP reported that type 2 diabetic patients who were treated for 5-8 years with dietary regulation and a fixed dose (1.5 g daily) of tolbutamide or dietary regulation and a fixed dose (100 mg daily) of phenformin (currently not commercially available in the US) had a cardiovascular mortality rate approximately 2.5 times that of patients treated with dietary regulation alone. Although a substantial increase in total mortality was observed only with phenformin, both tolbutamide and phenformin were discontinued because of the increases in cardiovascular mortality. The results of the UGDP study have been analyzed exhaustively, and there has been general disagreement in the scientific and medical communities regarding the study's validity and clinical importance. The management of patients with type 2 diabetes mellitus has changed substantially since the UGDP was initiated in 1961. Dietary management, weight reduction, better control of blood glucose concentration, and regular physical activity have received greater emphasis in the management of diabetes in these patients. In addition, reduction of existing cardiovascular risk factors (e.g., management of hypertension, discontinuance of smoking) has been emphasized. The American Diabetes Association (ADA) currently recommends that clinician judgment in the management of type 2 diabetes mellitus be based on assessment of all available therapeutic information, including data on cardiovascular risk factors, the positive effect of metabolic control of diabetes on cardiovascular disease, the importance of dietary management and weight reduction in obese diabetic patients, the importance of regular physical activity, and objective reports in the scientific literature that pertain to the UGDP study and to the long-term use of sulfonylureas.

Results of several long-term studies by the UKPDS group indicate that effects of metformin on mortality and macrovascular outcomes vary considerably depending on the patient population evaluated. In one study, intensive therapy (target fasting plasma glucose of less than 108 mg/dL) initiated with metformin or other antidiabetic agents (chlorpropamide, glyburide, or insulin) was compared with conventional therapy (target fasting plasma glucose of less than 270 mg/dL) consisting of diet and supplemental therapy with the same antidiabetic agents for marked hyperglycemia in overweight (exceeding 120% of ideal body weight) patients. In this study, cardiovascular disease accounted for 62% of the total mortality observed in patients receiving conventional therapy. Intensive therapy initiated with metformin in these overweight patients was associated with a 36% reduction in all-cause mortality and a 30% lower risk of developing macrovascular disease (myocardial infarction, sudden death, angina, stroke, peripheral vascular disease) compared with conventional therapy; the reduction in macrovascular disease was similar among intensive therapies employing other antidiabetic agents.

In another study, metformin was given as supplemental therapy in overweight and non-overweight patients who were poorly controlled on existing sulfonylurea therapy, or sulfonylurea therapy alone was continued. In this study, intensive metformin and sulfonylurea therapy was associated with an increase in the risk of diabetes-related death or death from any cause compared with that in patients continuing to receive sulfonylurea therapy alone. Similarly, another study by the UKPDS group found no decrease in mortality when metformin was added to sulfonylurea therapy (i.e., chlorpropamide or glyburide) or insulin alone in an intensive regimen (target fasting plasma glucose concentration of 108 mg/dL) in obese and non-obese patients. A pooled analysis of both UKPDS trials and epidemiologic analysis of other non-overweight and overweight patients from UKPDS who received metformin and sulfonylurea therapy because of progressive hyperglycemia showed a small reduction in diabetes-related death, all-cause mortality, myocardial infarction, and stroke.

Patients should be advised fully and completely about the nature of diabetes mellitus, what they must do to prevent and detect complications, and how to control their condition.Patients should be informed of the potential risks and advantages of metformin therapy and of alternative forms of treatment. Patients should be instructed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular assessment of blood glucose, HbA1c, renal function, and hematologic parameters. The possibility of primary and secondary failure to metformin therapy also should be explained to patients.

Patients and responsible family members should be informed of the risks of hypoglycemia, symptoms and treatment of hypoglycemic reactions, and conditions that predispose to the development of such reactions, since these reactions occasionally may occur during therapy with metformin. Hypoglycemia occurs infrequently in patients receiving metformin therapy under usual conditions of use; the incidence of hypoglycemia with metformin is much lower than that in patients receiving sulfonylureas, meglitinides (e.g., repaglinide), or insulin. However, hypoglycemia may occur when the drug is used concomitantly with a sulfonylurea antidiabetic agent and/or insulin. In addition, certain other factors (e.g., deficient caloric intake, strenuous exercise not compensated by caloric supplementation, alcohol ingestion, adrenal or pituitary insufficiency) may predispose patients to the development of hypoglycemia. Debilitated, malnourished, or geriatric patients also may be particularly susceptible to hypoglycemia; this condition may be difficult to recognize in geriatric patients or in those receiving β-adrenergic blocking agents or other sympatholytic agents.(See Drug Interactions: β-Adrenergic Blocking Agents.)

To maintain control of diabetes during periods of stress (e.g., fever of any cause, trauma, infection, surgery), temporary discontinuance of metformin and administration of insulin may be required. Metformin therapy may be reinstituted after the acute episode is resolved. Patients should contact a clinician promptly concerning changes in dosage requirements during periods of stress.

Since decreases in serum vitamin B12 concentrations have been reported in some patients receiving metformin, hematologic parameters (e.g., hemoglobin, hematocrit, erythrocyte indices) should be evaluated prior to initiation of metformin therapy and at least annually during treatment and any abnormality properly investigated. Some patients (i.e., those with an inadequate absorption or intake of vitamin B12 or calcium) appear to be predisposed to developing decreased vitamin B12 concentrations; vitamin B12 concentrations should be monitored every 2-3 years while these patients are receiving metformin therapy.

Metformin alone or in fixed combination with other drugs is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/minute per 1.73 m) , which may result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, or septicemia. Initiation of therapy with metformin in fixed combination with pioglitazone or rosiglitazone is contraindicated in patients with New York Heart Association (NYHA) class III or IV heart failure. Patients with NYHA class III or IV heart failure were not studied in clinical trials of metformin in fixed combination with pioglitazone or rosiglitazone, and these fixed combinations are not recommended in these patients or in patients with symptomatic heart failure. Metformin-containing therapy also is contraindicated as sole therapy in patients with type 1 diabetes mellitus and in patients with diabetes complicated by acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma. Insulin is required for the treatment of diabetic ketoacidosis. Metformin-containing therapy also is contraindicated in patients with known hypersensitivity to any ingredient in the respective formulations.

No studies have been performed evaluating the safety or efficacy of metformin and rosiglitazone in combination with insulin, and the manufacturer of Avandamet states that use of such combination therapy is not indicated. An increased incidence of adverse cardiovascular events (e.g., edema, CHF) has occurred with rosiglitazone in combination with insulin. If metformin is used concomitantly with rosiglitazone and insulin, patients treated with this combination should be monitored for adverse cardiovascular events. Combination therapy with rosiglitazone, metformin, and insulin should be discontinued in patients who do not respond to such therapy (as determined by a reduction in HbA1c values or insulin dosage within 4-5 months) or in those who develop clinically important adverse effects.

Pediatric Precautions

Safety and efficacy of metformin conventional or certain extended-release tablets (Glucophage XR, Fortamet) in pediatric patients younger than 10 or younger than 17 years of age, respectively, have not been established. Safety and efficacy of another extended-release preparation (Glumetza) have not been established in pediatric patients younger than 18 years of age. Safety and efficacy of metformin oral solution in children younger than 10 years of age have not been established. Data from a placebo-controlled clinical trial indicated a similar glycemic response and adverse effect profile for metformin in pediatric patients (10-16 years of age) as in adults. (See Diabetes Mellitus: Metformin Monotherapy, in Uses.) The safety and efficacy of metformin in fixed combination with glipizide, pioglitazone, rosiglitazone, repaglinide, or sitagliptin in pediatric patients have not been established. Data from a comparative trial evaluating the safety and efficacy of metformin in fixed combination with glyburide compared with monotherapy with each agent in pediatric patients (9-16 years of age) with type 2 diabetes mellitus indicate no unexpected safety concerns with such combination therapy. The American Diabetes Association (ADA) states that most pediatric diabetologists use oral antidiabetic agents in children with type 2 diabetes mellitus because of greater patient compliance and convenience for the patient's family and a lack of evidence demonstrating better efficacy of insulin as initial therapy for type 2 diabetes mellitus.

Geriatric Precautions

Controlled clinical trials evaluating metformin hydrochloride conventional, and extended-release tablets (GlucophageXR, Glumetza) did not include sufficient numbers of geriatric patients to determine whether geriatric patients respond differently to metformin than younger patients, although other reported clinical experience has not identified any differences in response between geriatric and younger patients. Data from controlled clinical trials evaluating another metformin hydrochloride extended-release preparation (Fortamet) indicate no overall differences in safety or efficacy in geriatric patients compared with younger adults. Data from controlled clinical trials with metformin in fixed combination with glyburide or glipizide have not revealed age-related differences in safety and efficacy of the combination, but greater sensitivity of geriatric patients to these fixed combinations cannot be ruled out. Since metformin is excreted principally by the kidneys and renal function declines with age, the drug should be used with caution in geriatric patients. As geriatric patients are at risk for the development of lactic acidosis, metformin therapy should not be initiated in geriatric patients 80 years of age and older without confirmation of adequate renal function as measured by creatinine clearance. In addition, renal function should be monitored periodically and care should be taken in dosage selection for geriatric patients; such patients generally should not receive the maximum recommended dosage of metformin hydrochloride.(See Dosage: Maintenance Dosage in Dosage and Administration.)

Mutagenicity and Carcinogenicity

No evidence of mutagenicity or chromosomal damage was observed in vivo in a micronucleus test in mice or in in vitro test systems, including microbial (Ames test) and mammalian (mouse lymphoma and human lymphocytes) assays.

No evidence of carcinogenic potential was seen in a 104-week study in male and female rats receiving metformin hydrochloride dosages up to and including 900 mg/kg daily or in a 91-week study in male and female mice receiving metformin hydrochloride at dosages up to and including 1500 mg/kg daily; these dosages are about 3 times the maximum recommended human daily dosage based on body surface area. However, an increased incidence of benign stromal uterine polyps was observed in female rats treated with 900 mg/kg of metformin hydrochloride daily.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats and rabbits given metformin hydrochloride dosages of 600 mg/kg daily (about twice the maximum recommended human daily dosage based on body surface area or about 2 and 6 times the maximum recommended human daily dosage of extended-release tablets [2 g] based on body surface area comparisons with rats and rabbits, respectively) have not revealed evidence of harm (e.g., teratogenicity) to the fetus. Determination of fetal concentrations of metformin 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.

There are no adequate and controlled studies to date using metformin in pregnant women. Limited data from uncontrolled or retrospective studies are conflicting with regard to the effects of long-term maternal therapy with metformin hydrochloride (1.5-3 g daily) on neonatal morbidity (e.g., congenital malformations) and mortality. Metformin should be used during pregnancy only when clearly needed. Metformin in fixed combination with pioglitazone should not be used in pregnancy unless the potential benefit justifies the potential risk to the fetus. Metformin in fixed combination with rosiglitazone is not recommended for use in pregnant women.

Fertility

No evidence of impaired fertility was observed in rats following administration of metformin hydrochloride dosages of 600 mg/kg daily (about twice the maximum recommended human dosage based on body surface area).

Lactation

Metformin is distributed into milk in lactating rats and reaches concentrations comparable to those in plasma. Limited data indicate that small amounts of metformin also are distributed into breast milk in humans. In a study in 7 nursing women who received metformin hydrochloride (median dosage 1500 mg daily), the mean milk-to-plasma ratio for metformin was 0.35 and the overall average concentration in milk over the dosing interval was 0.27 mg/L. Metformin was present in low or undetectable amounts in the plasma of 4 breast-fed infants, and no adverse effects were noted in 6 infants that were evaluated. In another study, mean peak and trough metformin concentrations in 4 nursing women receiving metformin hydrochloride 500 mg twice daily were 1.06 and 0.42 mcg/mL, respectively, in serum and 0.42 and 0.39 mcg/mL, respectively, in breast milk. The mean milk-to-serum ratio was 0.63 and the mean estimated infant dose as a percentage of the mother's weight-adjusted dose was 0.65%. Blood glucose concentrations obtained in 3 infants 4 hours after breastfeeding were within normal limits (47-77 mg/dL). However, the manufacturer states that because of the potential for hypoglycemia in infants, 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 alone or in fixed combination with pioglitazone is discontinued in a nursing mother and dietary therapy is inadequate for glycemic control, insulin therapy should be considered.

Drug Interactions

Antidiabetic Agents

Although hypoglycemia occurs infrequently in patients receiving metformin therapy alone, hypoglycemia may occur when the drug is used concomitantly with a sulfonylurea antidiabetic agent (e.g., glyburide), a meglitinide (e.g., repaglinide), and/or insulin.(See Cautions: Precautions and Contraindications.)

In a single-dose study in patients with type 2 diabetes mellitus, concomitant administration of glyburide with metformin did not alter the pharmacokinetics or pharmacodynamics of metformin. Although variable decreases in the area under the blood concentration-time curve (AUC) and peak blood concentration of glyburide were observed, the single-dose nature of this study and the lack of a relationship between glyburide blood concentrations and pharmacodynamic effects preclude evaluation of the clinical importance of these effects.

In a single-dose study, administration of metformin concomitantly with an α-glucosidase inhibitor (acarbose) resulted in an acute decrease in the bioavailability of metformin. Coadministration of guar gum (10 g) and metformin hydrochloride (1.7 g) with a standard meal in healthy individuals reduced and delayed the absorption of metformin from the GI tract.

Diuretics

Thiazide diuretics can exacerbate diabetes mellitus, resulting in increased requirements of oral antidiabetic agents, temporary loss of diabetic control, or secondary failure to the antidiabetic agent. If control of diabetes is impaired by a thiazide diuretic, clinicians may consider substituting a less diabetogenic diuretic (e.g., potassium-sparing diuretic), reducing the dosage of or discontinuing the diuretic, or increasing the dosage of the oral antidiabetic agent.

In a single-dose study in healthy individuals, administration of furosemide concomitantly with metformin increased peak plasma and blood concentrations of metformin by approximately 22% and AUC of metformin by approximately 15%. Administration of metformin concomitantly with furosemide decreased peak plasma furosemide concentrations by approximately 31% and AUC by approximately 12%. The renal clearance of both drugs remained unchanged during such concomitant use, but the half-life of furosemide was decreased by 32%. The manufacturer states that no information is available on potential interactions between metformin and furosemide during long-term administration.

Nifedipine

Concomitant administration of single doses of metformin and nifedipine in healthy individuals resulted in enhanced absorption of metformin, as indicated by increases of 20 and 9% in the peak plasma concentration and AUC, respectively, of metformin. Nifedipine also increased the urinary excretion of metformin; half-life and time to peak plasma concentration of metformin remained unchanged. Metformin appears to have minimal effects on the pharmacokinetics of nifedipine.

Cationic Agents

Cimetidine may reduce the urinary excretion of metformin by competing for renal tubular organic cationic transport systems. In single- and multiple-dose studies in healthy individuals, concomitant administration of cimetidine and metformin increased the peak plasma and whole blood concentrations of metformin by approximately 60-81% and the area under the plasma or whole blood concentration-time curve (AUC) of metformin by approximately 40-50%. Metformin has negligible effects on cimetidine pharmacokinetics, possibly because cimetidine has a higher affinity for renal tubular transport sites. The manufacturer states that the possibility of other cationic drugs that undergo substantial tubular secretion (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, vancomycin) decreasing the urinary excretion of metformin should be considered. Patients receiving metformin concomitantly with a cationic drug that is excreted by the proximal renal tubules should be monitored carefully and the need for possible dosage adjustment of either agent considered.

β-Adrenergic Blocking Agents

In single-dose studies in healthy individuals, concomitant administration of metformin and propranolol did not alter the pharmacokinetics of either drug. However, several potential interactions between β-adrenergic blocking agents and oral antidiabetic agents (e.g., sulfonylureas, metformin) exist. β-Adrenergic blocking agents may impair glucose tolerance; increase the frequency or severity of hypoglycemia; block hypoglycemia-induced tachycardia but not hypoglycemic sweating, which may actually be increased; delay the rate of recovery of blood glucose concentration following drug-induced hypoglycemia; alter the hemodynamic response to hypoglycemia, possibly resulting in an exaggerated hypertensive response; and possibly impair peripheral circulation. Nonselective β- adrenergic blocking agents (e.g., propranolol, nadolol) without intrinsic sympathomimetic activity are more likely to affect glucose metabolism than more selective β-adrenergic blocking agents (e.g., metoprolol, atenolol) or those with intrinsic sympathomimetic activity (e.g., acebutolol, pindolol). Signs of hypoglycemia (e.g., tachycardia, blood pressure changes, tremor, feelings of anxiety) mediated by catecholamines may be masked by either nonselective or selective β-adrenergic blocking agents. These drugs should be used with caution in patients with type 2 diabetes mellitus who are receiving antidiabetic agents, especially in those with labile disease or in those prone to hypoglycemia. Use of low-dose, selective β1-adrenergic blockers (e.g., metoprolol) or β-adrenergic blocking agents with intrinsic sympathomimetic activity in patients receiving oral antidiabetic agents may theoretically decrease the risk of affecting glycemic control. When an oral antidiabetic agent and a β-adrenergic blocking agent are used concomitantly, the patient should be advised about and monitored closely for altered antidiabetic response.

Alcohol

Combined use of alcohol and metformin can increase the risk of hypoglycemia and lactic acidosis, since alcohol decreases lactate clearance and hepatic gluconeogenesis and may increase insulin secretion.(See Cautions: Lactic Acidosis.) Excessive alcohol intake, on an acute or chronic basis, should be avoided in patients receiving metformin therapy.

Protein-Bound Drugs

Binding of metformin to plasma proteins is negligible; therefore, metformin is less likely to interact with drugs that are highly protein bound compared with sulfonylurea antidiabetic agents, which are extensively bound to plasma proteins.

Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril, enalapril) may reduce fasting blood glucose concentrations in nondiabetic individuals and have been associated with unexplained hypoglycemia in patients whose diabetes had been controlled with insulin or oral antidiabetic agents, including combined therapy with glyburide and metformin. Testing in some of these patients indicated that the ACE inhibitor (e.g., captopril) apparently increased insulin sensitivity; the mechanism of this effect is not known. Other investigators have reported no alterations in glycemic control with concomitant use of an ACE inhibitor and oral antidiabetic agents or insulin in diabetic patients. The potential risk of precipitating hypoglycemia or hyperglycemia appears to be low but should be considered when therapy with an ACE inhibitor is initiated or withdrawn in diabetic patients; blood glucose concentrations should be monitored during dosage adjustments with either agent.

Clomiphene

In premenopausal patients with polycystic ovary syndrome, therapy with certain oral antidiabetic agents, including metformin, may result in the resumption of ovulation in a modest number of women. Ovulatory response is further increased in patients pretreated with metformin hydrochloride (500 mg 3 times daily for 35 days) receiving additional low-dose clomiphene (50 mg daily for 5 days); ovulation was associated with decreased insulin secretion and increased serum progesterone concentrations.

Other Drugs

Drugs that cause hyperglycemia and may exacerbate loss of glycemic control in patients with diabetes mellitus include corticosteroids, oral contraceptives, thiazide diuretics, sympathomimetics, phenothiazines, niacin, calcium-channel blocking agents, and isoniazid. When such drugs are added to or withdrawn from therapy in patients receiving oral antidiabetic agents, patients should be observed closely for evidence of altered glycemic control.

Pharmacokinetics

The pharmacokinetics of metformin in patients with normal renal function do not appear to be affected by gender, race, or the presence of diabetes mellitus. Following administration of a single 500-mg dose of metformin hydrochloride as conventional tablets with food in pediatric patients (12-16 years of age) with type 2 diabetes mellitus, mean peak plasma concentrations and area under the concentration-time curve (AUC) differed less than 5% compared with those values in healthy adults; all patients had normal renal function. In pediatric patients 11-16 years of age receiving a single dose of metformin in fixed combination with glyburide, mean dose-normalized glyburide peak plasma concentration and AUC differed less than 6% from historical values in healthy adults.

Bioequivalence has been demonstrated between the fixed combination of rosiglitazone and metformin and each agent given concurrently and also between the fixed combination of sitagliptin and metformin and each agent given concurrently. Bioequivalence also has been demonstrated between the fixed combination of pioglitazone and metformin and each agent (pioglitazone and extended-release metformin [Fortamet]) given concurrently. In healthy individuals who received the extended-release metformin hydrochloride preparation (Glumetza) in a single-dose crossover study, a 1-g tablet has been shown to be bioequivalent to two 500-mg tablets based on peak plasma concentrations and AUC.

Absorption

Metformin is slowly and incompletely absorbed from the GI tract, mainly from the small intestine; absorption is complete within 6 hours. The absolute oral bioavailability of the drug under fasting conditions is reported to be approximately 50-60% with metformin hydrochloride doses of 0.5-1.5 g; binding of the drug to the intestinal wall may explain the difference between the amount of drug absorbed (as determined by the urinary and fecal excretion of unchanged drug) and the amount bioavailable in some studies. In single-dose studies with metformin hydrochloride conventional tablets doses of 0.5-1.5 g or 0.85-2.55 g, plasma metformin concentrations did not increase in proportion to increasing doses, suggesting an active saturable absorption process. Similarly, in single-dose studies with an extended-release tablet preparation (Glumetza) at doses of 0.5-2.5 g, plasma metformin concentrations did not increase in proportion to increasing doses. At steady state after administration of a metformin hydrochloride extended-release tablet preparation (Glucophage XR), the AUC and peak plasma concentrations were not dose proportional within the range of 0.5-2 g. However, limited data from studies in animals and in human intestinal cell cultures suggest that transepithelial transfer of metformin in the intestine may occur through a passive, nonsaturable mechanism, possibly involving a paracellular route. In several studies with another metformin hydrochloride extended-release tablet preparation (Fortamet) using doses of 1-2.5 g, metformin exposure was dose-related.

Food decreases and slightly delays the absorption of metformin conventional tablets; the clinical importance of these effects is unknown.(See Dosage and Administration: Administration.) Administration of metformin hydrochloride conventional tablets with food reportedly has decreased peak plasma concentrations of the drug by 35-40%, reduced area under the plasma concentration-time curve (AUC) by 20-25%, and delayed time to peak plasma drug concentration by 35-40 minutes compared with these parameters in fasting individuals receiving this metformin preparation. However, in one study, concomitant administration of the drug as conventional tablets with food had a less pronounced effect (average reduction in bioavailability of 10%) on absorption.

Following oral administration of metformin hydrochloride as an extended-release tablet preparation (Glucophage XR) with food, the extent of absorption (as measured by AUC) increased by approximately 50%, but peak plasma concentrations and time to achieve peak plasma concentrations were not altered. Following administration of another metformin hydrochloride extended-release tablet formulation (Fortamet) with food, the extent of absorption (as measured by AUC) increased by approximately 60%, peak plasma concentrations were increased by approximately 30%, and time to achieve peak plasma concentrations was prolonged (6.1 hours versus 4 hours) compared with those in the fasting state. The pharmacokinetics of a certain metformin extended-release tablet preparation (Glucophage XR) were not affected by the fat content of meals. However, following administration of another metformin hydrochloride extended-release preparation (Glumetza) with low-fat and high-fat meals, the AUCs increased by 38 and 73%, respectively, compared with those in the fasting state. Following administration of the fixed combination of extended-release metformin hydrochloride 1 g and immediate-release pioglitazone 30 mg (Actoplus Met XR) with food, there was no change in the extent of absorption (as measured by AUC) of pioglitazone but there was a decrease of approximately 18% in peak concentration. Peak concentrations of the extended-release metformin hydrochloride component were increased by approximately 98% and AUC exposure by approximately 85% when Actoplus Met XR was given with food. Time to peak concentration was prolonged by approximately 3 hours for pioglitazone and 2 hours for extended-release metformin hydrochloride under fed conditions.

Following oral administration of metformin hydrochloride as an oral solution with food, the extent of absorption (as measured by AUC) increased by approximately 17-21% compared with administration in the fasted state. Food delayed the time to achieve peak plasma concentrations by 1.4 hours compared with administration in the fasted state. The pharmacokinetics of metformin oral solution were not appreciably affected by the fat content of meals.

Following oral administration of 0.5-1.5 g of metformin hydrochloride as conventional tablets in healthy individuals or in patients with type 2 diabetes mellitus, peak plasma drug concentrations of approximately 0.4-3 mcg/mL usually are attained within 2-4 hours. Following oral administration of a single dose (0.5-2 g) of metformin hydrochloride as extended-release tablets (Glucophage XR), peak plasma drug concentrations of 0.6-1.8 mcg/mL usually are attained within a median of 7 hours (range: 4-8 hours). Following administration of a single dose (0.5-2.5 g) of another extended-release preparation (Glumetza), peak plasma drug concentrations of 0.47-1.6 mcg/mL usually are attained within 7-8 hours. Peak plasma drug concentrations following administration of metformin extended-release tablets (Glucophage XR) are approximately 20% lower than those following administration of the same dose as conventional tablets. The extent of absorption of metformin hydrochloride 2 g once daily as extended-release tablets is similar to that following administration of 1 g of the drug twice daily as conventional tablets. Steady-state plasma concentrations with usual dosages of metformin hydrochloride as conventional tablets (e.g., 1.5-2.55 g daily in 1 to 3 divided doses) are attained within 24-48 hours and generally average about 1 mcg/mL or less.

A precise correlation between plasma metformin concentrations and the drug's antihyperglycemic effect has not been established. In addition, plasma metformin concentrations generally have shown no correlation with plasma lactate concentrations during metformin therapy in patients with type 2 diabetes mellitus. Although metformin-associated lactic acidosis generally has been associated with plasma metformin concentrations exceeding 5 mcg/mL(see Cautions: Lactic Acidosis), such high concentrations reportedly were not observed during controlled clinical trials with the drug, even at maximum dosage (2.5-2.55 g daily).

Satisfactory control of blood or plasma glucose concentration may occur within a few days to 1 week following initiation of metformin therapy in patients with type 2 diabetes mellitus, but the maximum antihyperglycemic effect may be delayed for up to 2 weeks. Following discontinuance of metformin therapy, blood glucose concentration increases within 2 weeks.

Distribution

Metformin is distributed rapidly in animals and humans into peripheral body tissues and fluids, particularly the GI tract; the drug also appears to distribute slowly into erythrocytes and into a deep tissue compartment (probably GI tissues). The highest tissue concentrations of metformin (at least 10 times the plasma concentration) occur in the GI tract (e.g., esophagus, stomach, duodenum, jejunum, ileum), with lower concentrations (twice the plasma concentration) occurring in kidney, liver, and salivary gland tissue. The drug distributes into salivary glands with a half-life of about 9 hours. Metformin concentrations in saliva are tenfold lower than those in plasma and may be responsible for the metallic taste reported in some patients receiving the drug. Any local effect of metformin on glucose absorption in the GI tract may be associated with the relatively high GI concentrations of the drug compared with those in other tissues. It is not known whether metformin crosses the blood-brain barrier or the placenta in humans or if the drug is distributed into human milk; however, in lactating rats, metformin is distributed into breast milk at levels comparable to those in plasma.

Following oral administration of single 850-mg doses of metformin hydrochloride as conventional tablets, the apparent volume of distribution has been reported to average 654 L. Volume of distribution reported after IV administration of the drug generally has been smaller (e.g., 63-276 L) than that with oral administration, perhaps because of less drug binding in the GI tract and/or different methods of determining volume of distribution in various studies. Unlike oral sulfonylurea antidiabetic agents, which are more than 90% bound to plasma proteins, metformin is negligibly bound to plasma proteins. Metformin equilibrates freely between erythrocytes and plasma, most likely as a function of time; drug bound to erythrocytes is approximately 5% of total blood concentration.

Elimination

Following oral administration of metformin hydrochloride (0.5-1.5 g) as conventional tablets in healthy individuals or in patients with type 2 diabetes mellitus, plasma concentrations decline in a triphasic manner. Following multiple-dose administration of metformin hydrochloride (500 mg twice daily for 7-14 days) as conventional tablets in a limited number of patients with type 2 diabetes mellitus, peak plasma concentrations remained unchanged, but trough drug concentrations were higher than with single-dose administration, suggesting some drug accumulation in a peripheral tissue compartment.(See Pharmacokinetics: Distribution.) No accumulation of metformin appears to occur following repeated oral doses of the drug as extended-release tablets. The principal plasma elimination half-life of metformin averages approximately 6.2 hours; 90% of the drug is cleared within 24 hours in patients with normal renal function. The decline in plasma metformin concentrations is slower after oral than after IV administration of the drug, indicating that elimination is absorption rate-limited. Urinary excretion data and data from whole blood indicate a slower terminal-elimination phase half-life of 8-20 hours (e.g., 17.6 hours) suggesting that the erythrocyte mass may be a compartment of distribution.

Metformin is not metabolized in the liver or GI tract and is not excreted in bile; no metabolites of the drug have been identified in humans. Renal elimination of metformin involves glomerular filtration and secretion by the proximal convoluted tubules as unchanged drug. Following single-dose oral administration of metformin hydrochloride (0.5-1.5 g) as conventional tablets, urinary recovery ranges from 35-52% of the total dose. Following administration of a single dose of metformin hydrochloride as an extended-release tablet (Fortamet) in healthy individuals, urinary recovery was 40.9% over 24 hours. Approximately 20-33% of the total oral dose as conventional tablets is excreted in feces within 4-7 days. Total plasma clearance of metformin hydrochloride following single-dose oral administration (0.5-1.5 g) has ranged from 718-1552 mL/minute. Metformin is removed by hemodialysis with a clearance of up to 170 mL/minute under good hemodynamic conditions.

Renal clearance is approximately 3.5 times greater than creatinine clearance, indicating that tubular secretion is the principal route of metformin elimination. Following a single 850-mg oral dose of metformin hydrochloride, renal clearance averaged 552, 491, or 412 mL/minute in nondiabetic adults, diabetic adults, or healthy geriatric individuals, respectively. Renal impairment results in increased peak plasma concentrations of metformin, a prolonged time to peak plasma concentration, and a decreased volume of distribution. Renal clearance is decreased in patients with renal impairment (as measured by decreases in creatinine clearance) and, apparently because of reduced renal function with age, in geriatric individuals. In geriatric individuals, decreased renal and plasma clearance of metformin also results in increased plasma concentrations of the drug; volume of distribution remains unaffected.(See Cautions: Precautions and Contraindications.)

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