Generic Name: metformin

Brand Names: Metformin Hydrochloride ER, Glumetza, Riomet, Glucophage XR, Glucophage, Fortamet

Uses

Diabetes Mellitus

Used as monotherapy for the management of patients with type 2 diabetes mellitus that cannot be controlled by diet alone.

Used in combination with a sulfonylurea, repaglinide, or thiazolidinedione antidiabetic agent for the management of patients with type 2 diabetes who do not achieve adequate glycemic control on monotherapy with metformin or any of these drugs. Used concomitantly with nateglinide in patients who no longer respond adequately to metformin despite appropriate diet, exercise, and metformin monotherapy.

May be used with insulin to improve glycemic control and/or decrease the required dosage of insulin.

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.

Fixed combinations with glyburide or glipizide used as second-line therapy in patients who do not achieve adequate control of hyperglycemia despite therapy with diet, exercise, and initial treatment with a sulfonylurea antidiabetic agent or metformin.

Add a thiazolidinedione antidiabetic agent to metformin in fixed combination with glyburide in patients who have inadequate glycemic control with the fixed combination.

Commercially available in fixed combination with rosiglitazone for use when treatment with rosiglitazone and metformin is appropriate (i.e., as initial therapy in patients whose hyperglycemia cannot be controlled by diet and exercise alone and as second-line therapy in patients who do not achieve adequate control of hyperglycemia despite therapy with diet, exercise, and treatment with rosiglitazone or metformin).

Metformin is the preferred initial oral antidiabetic agent for patients with type 2 diabetes mellitus.

Not effective as sole therapy in patients with diabetes mellitus complicated by acidosis, ketosis, or coma.

Dosage and Administration

General

• Sulfonylurea agent may be abruptly discontinued (no transition period generally required) when therapy is transferred from most sulfonylurea antidiabetic agents to metformin.
• Patients whose therapy is transferred from chlorpropamide to metformin should be monitored closely for hypoglycemia during the initial 2 weeks following transfer.
• Goal of therapy should be to reduce both fasting glucose and glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) values to normal or near normal using the lowest effective dosage of metformin hydrochloride, either when used as monotherapy or combined with another oral antidiabetic agent (e.g., sulfonylurea, acarbose).

Administration

Oral Administration

Administer orally with meals to reduce adverse GI effects.

Administer conventional tablets 2 or 3 times daily. Administer in 2 divided doses if total dosage ≤2 g daily or in 3 divided doses if total dosage is >2 g daily.

Administer extended-release tablets once daily with the evening meal.

Dosage

Available as metformin hydrochloride; dosage expressed in terms of the salt.

Individualize dosage carefully based on patient’s glycemic response and tolerance.

Pediatric Patients

Diabetes Mellitus

Oral

Conventional tablets or oral solution in children 10–16 years of age: Initially, 500 mg twice daily with meals as monotherapy. Titrate dosage in increments of 500 mg daily at weekly intervals to a maximum of 2 g daily given in divided doses.

Adults

Diabetes Mellitus

Initial Dosage in Previously Untreated Patients

Oral

Conventional tablets or oral solution: Initially, 500 mg twice daily with the morning and evening meal. Titrate dosage by 500 mg daily at weekly intervals to a total of 2 g daily or to 850 mg twice daily after 2 weeks. Clinically important responses generally not observed at dosages <1.5 g daily. Usual maintenance dosage is 850 mg twice daily.

Alternatively, give initial dosage of 500–850 mg once daily in the morning. If initial dosage is 850 mg daily, titrate dosage by 850 mg daily every other week to a total of 2 g daily.

For additional glycemic control, administer up to a maximum daily dosage of 2.55 g given in divided doses.

Extended-release tablets (Glucophage^® XR) in patients ≥17 years of age: Initially, 500 mg once daily with the evening meal. Titrate dosage by 500 mg daily at weekly intervals to a maximum of 2 g daily. If glycemic control is not achieved with 2 g once daily, consider administering 1 g twice daily. If >2 g daily is required, switch to conventional tablet formulation and increase dosage up to 2.55 g daily in divided doses (preferably 3 doses for daily dosages >2 g).

Extended-release tablets (Fortamet^®) in patients ≥17 years of age: Initially, 1 g daily with the evening meal; 500 mg daily may be used when clinically appropriate. Titrate dosage by 500 mg daily at weekly intervals to a maximum of 2.5 g daily with the evening meal.

Initial Dosage of Metformin Hydrochloride in Fixed Combination with Glipizide (Metaglip^®)

Oral

Initially, 250 mg of metformin hydrochloride and 2.5 mg of glipizide once daily with a meal. For more severe hyperglycemia (fasting plasma glucose concentrations of 280–320 mg/dL), 500 mg of metformin hydrochloride and 2.5 mg of glipizide twice daily. Titrate in increments of one tablet (using the tablet strength at which therapy was initiated) daily at 2-week intervals until adequate blood glucose control is achieved or maximum daily dosage of 2 g of metformin hydrochloride and 10 mg of glipizide is reached.

Efficacy of metformin hydrochloride and glipizide in fixed combination not established in patients with fasting plasma glucose concentrations >320 mg/dL. No experience with total initial daily dosages exceeding 2 g of metformin hydrochloride and 10 mg of glipizide.

Initial Dosage of Metformin Hydrochloride in Fixed Combination with Glyburide (Glucovance^®)

Oral

Initially, 250 mg of metformin hydrochloride and 1.25 mg of glyburide once daily with a meal. For more severe hyperglycemia (i.e., fasting plasma glucose concentrations >200 mg/dL or glycosylated hemoglobin >9%), 250 mg of metformin hydrochloride and 1.25 mg of glyburide twice daily with the morning and evening meal. Titrate dosage in increments of 250 mg of metformin hydrochloride and 1.25 mg of glyburide daily at 2-week intervals adequate control of blood glucose is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 10 mg of glyburide.

The fixed combination of metformin hydrochloride 500 mg and glyburide 5 mg should not be used as initial therapy due to an increased risk of hypoglycemia.

Initial Dosage of Metformin Hydrochloride in Fixed Combination with Rosiglitazone (Avandamet^®)

Oral

Initially, 500 mg of metformin hydrochloride and 2 mg of rosiglitazone once or twice daily. For more severe hyperglycemia (i.e., HbA_1c >11% or fasting plasma glucose concentrations >270 mg/dL), consider 500 mg of metformin hydrochloride and 2 mg of rosiglitazone twice daily. If additional glycemic control needed after 4 weeks, titrate dosage upward in increments of 500 mg of metformin hydrochloride and 2 mg of rosiglitazone per day until adequate glycemic control is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 8 mg of rosiglitazone is reached.

Initial Dosage in Patients Transferred to Metformin Hydrochloride in Fixed Combination with Glipizide (Metaglip^®)

Oral

In previously treated patients, 500 mg of metformin hydrochloride and 2.5 or 5 mg of glipizide twice daily with the morning and evening meals. The initial dosage of glipizide and metformin hydrochloride in fixed combination should not exceed the daily dosage of metformin hydrochloride or glipizide (or the equivalent dosage of another sulfonylurea) previously received. Titrate dosage in increments not exceeding 500 mg of metformin hydrochloride and 5 mg of glipizide until adequate control of blood glucose is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glipizide is reached.

For patients switching from combined therapy with separate preparations, the initial dosage of the fixed-combination preparation of glipizide and metformin hydrochloride should not exceed the daily dosages of glipizide (or equivalent dosage of another sulfonylurea antidiabetic agent) and metformin hydrochloride currently being taken. Use clinical judgment regarding whether to switch to the nearest equivalent dosage or to titrate dosage. Titrate dosage in increments of not more than 5 mg of glipizide and 500 mg of metformin hydrochloride until adequate control of blood glucose is achieved or maximum daily dosage of 20 mg of glipizide and 2 g of metformin hydrochloride is reached.

Initial Dosage in Patients Transferred to Metformin Hydrochloride in Fixed Combination with Glyburide (Glucovance^®)

Oral

Initially, 500 mg of metformin hydrochloride and 2.5 or 5 mg of glyburide twice daily with the morning and evening meal. For patients previously receiving metformin hydrochloride or glyburide (or another sulfonylurea agent), the initial dosage of metformin hydrochloride or glyburide should not exceed the dosage (or equivalent dosage) received previously. For patients previously receiving both metformin hydrochloride and glyburide (or another sulfonylurea agent) separately, the initial dosage should not exceed the previous dosage of metformin hydrochloride and glyburide (or the equivalent dosage of the other sulfonylurea) administered separately. Titrate dosage in increments not exceeding 500 mg of metformin hydrochloride and 5 mg of glyburide until adequate control of blood glucose is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glyburide is reached.

For patients whose hyperglycemia is not adequately controlled on therapy with metformin hydrochloride 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, titrate thiazolidinedione dosage upward as recommended.

Initial Dosage in Patients Transferred to Metformin Hydrochloride in Fixed Combination with Rosiglitazone (Avandamet^®)

Oral

In patients not adequately controlled on monotherapy with metformin hydrochloride or rosiglitazone, dosage of the fixed combination is based on the patient’s current dosages of metformin hydrochloride and/or rosiglitazone. (See Table.)

In patients inadequately controlled on metformin monotherapy, the usual initial dosage of rosiglitazone is 4 mg daily given with patient's existing dosage of metformin hydrochloride.

In patients inadequately controlled on rosiglitazone monotherapy, the usual initial dosage of metformin hydrochloride is 1 g daily given with patient's existing dosage of rosiglitazone.

The tablet strength of the fixed combination that is selected should be the one that most closely provides the patient’s existing dosage of metformin hydrochloride or rosiglitazone, respectively. (See Table.)

If additional glycemic control is needed following transfer, titrate dosage upward in increments of 500 mg of metformin hydrochloride and/or 4 mg of rosiglitazone per day until adequate glycemic control is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 8 mg of rosiglitazone is reached. Following increase in dosage of metformin hydrochloride, further dosage adjustment recommended if adequate glycemic control not achieved in 1–2 weeks. Following increase in dosage of rosiglitazone, further dosage adjustment recommended if adequate glycemic control not achieved in 8–12 weeks.

For patients switching from combined therapy with separate preparations, 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.

Initial Metformin Hydrochloride Dosage in Patients Transferred from Insulin

Oral

Initially, 500 mg once daily; increase dosage by 500 mg daily at weekly intervals adequate control of blood glucose is achieved or a maximum daily dosage of 2.5 g (conventional tablets) or 2 g (extended-release tablets) is reached. Concurrent insulin dosage initially remains unchanged. When fasting plasma glucose concentration decreases to <120 mg/dL, decrease insulin dosage by 10–25%.

Prescribing Limits

Pediatric Patients

Oral

Children 10–16 years of age: Maximum 2 g daily as conventional tablets or oral solution.

Adults

Oral

Maximum 2.55 g daily (conventional tablets or oral solution; 2.5 g daily as Fortamet^® extended-release tablets; or 2 g daily as certain other extended-release tablets (e.g., Glucophage^®). Switch to conventional tablets for further dosage titration if required dosage exceeds 2 g daily while on extended-release tablets.

For the fixed combination with glyburide, maximum daily dosage as second-line therapy is 2 g of metformin hydrochloride and 20 mg of glyburide. For the fixed combination with glipizide, maximum daily dosage is 2 g of metformin hydrochloride and 20 mg of glipizide. For the fixed combination with rosiglitazone, maximum daily dosage is 2 g of metformin hydrochloride and 8 mg of rosiglitazone.

Special Populations

Geriatric Patients

Maintenance dosage generally should not be titrated to the maximum recommended for younger adults; limited data suggest reducing initial dosage by approximately 33% in geriatric patients.

Cautions

Contraindications

• Sole therapy in patients with type 1 diabetes and in patients with diabetes complicated by acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma.
• Renal impairment (e.g., ≥1.5 or 1.4 mg/dL in men or women, respectively) or abnormal S_cr. Renal impairment may result from conditions such as cardiovascular collapse (shock), AMI, or septicemia.
• Congestive heart failure requiring drug therapy (e.g., digoxin, furosemide).
• Known hypersensitivity to metformin hydrochloride or any ingredient in the formulations.

Warnings/Precautions

Warnings

Lactic Acidosis

See Boxed Warning.

General Precautions

Hypoglycemia

Uncommon in patients receiving metformin as monotherapy. Debilitated, malnourished, or geriatric patients and patients with renal or hepatic impairment or adrenal or pituitary insufficiency may be particularly susceptible. Strenuous exercise, alcohol ingestion, insufficient caloric intake, or use in combination with other antidiabetic agents may increase risk. Hypoglycemia may be difficult to recognize in geriatric patients or in those receiving β-adrenergic blocking agents. (See Specific Drugs under Interactions.)

Hematologic Effects

Decreased serum vitamin B₁₂ concentrations, with or without clinical manifestations (e.g., anemia).

Symptoms rapidly reversible following discontinuation of metformin or supplementation with vitamin B₁₂. Monitor hematologic parameters (e.g., hemoglobin, serum vitamin B₁₂ concentrations) prior to initiation of therapy and at least annually during treatment and any abnormality properly investigated.

Consider periodic supplementation with parenteral vitamin B₁₂ in patients at high risk for developing subnormal serum vitamin B₁₂ concentrations (e.g., alcoholics, patients with low calcium or vitamin B₁₂ intake or absorption).

Cardiovascular Effects

Possible increased cardiovascular mortality associated with other biguanide antidiabetic agents (i.e., phenformin). 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 pending the results of further studies of metformin alone or in combination with sulfonylureas.

Use of metformin in combination with rosiglitazone and insulin is not indicated; adverse cardiovascular events (e.g., edema, heart failure) have occurred with combined rosiglitazone and insulin therapy.

Concurrent Illness

Evaluate serum electrolytes and ketones, blood glucose, and if indicated, blood pH, lactate, pyruvate, and metformin concentrations for evidence of ketoacidosis or lactic acidosis.

Temporary withdrawal of metformin therapy and administration of insulin may be required to maintain glycemic control during periods of stress.

Use of Fixed Combinations

When used in fixed combination with glipizide, glimepiride, or rosiglitazone, consider the cautions, precautions, and contraindications associated with the concomitant agent.

Specific Populations

Pregnancy

Category B.

Most clinicians recommend use of insulin during pregnancy in diabetic patients to maintain optimum control of blood glucose concentrations.

Lactation

Distributed into milk in rats; not known if distributed into milk in humans. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy of metformin as conventional tablets or oral solution in children <10 years of age have not been established.

Safety and efficacy of metformin as extended-release tablets in children <17 years of age have not been established.

Safety and efficacy of metformin in fixed combination with glipizide or rosiglitazone in children have not been established. Data from a clinical trial in children 9–16 years of age comparing combined therapy with metformin and glyburide (Glucovance^®) with each drug as monotherapy did not reveal unexpected safety findings.

Geriatric Use

Insufficient number of geriatric patients in controlled clinical trials of metformin hydrochloride conventional (Glucophage^®) and extended-release tablets (Glucophage^® XR) to determine if such patients respond differently than younger adults. With another extended-release preparation of metformin hydrochloride (Fortamet^®), no overall differences in safety or efficacy in geriatric patients were observed compared with younger adults.

Use with caution, since renal function declines with age.

Monitor renal function periodically.

Do not initiate in patients ≥80 years of age without confirmation of adequate renal function as measured by Cl_cr.

Geriatric patients particularly susceptible to hypoglycemia, which may be difficult to recognize.

Renal Impairment

Evaluate renal function prior to initiation of therapy and at least annually thereafter.

Monitor more frequently if development of impaired renal function is anticipated (e.g., those with blood glucose concentrations >300 mg/dL, those who may develop renal dysfunction as a result of polyuria and volume depletion).

Discontinue metformin if evidence of renal impairment is present.

Patients whose serum creatinine concentrations exceed the upper limit of normal for their age should not receive metformin.

Hepatic Impairment

Avoid use. Elimination of lactate may be substantially reduced. (See Boxed Warning.)

Common Adverse Effects

Diarrhea, nausea, vomiting, abdominal bloating, abdominal cramping or pain, flatulence, anorexia.

Interactions

Cationic Agents Secreted by Proximal Renal Tubules

Pharmacokinetic interaction with cimetidine (decreased excretion of metformin).

Potential pharmacokinetic interaction with other cationic drugs that undergo substantial tubular secretion (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, vancomycin).

Monitor carefully; consider dosage adjustment of either agent.

Protein-bound Drugs

Pharmacokinetic interaction unlikely.

Drugs That May Antagonize Hypoglycemic Effects

Calcium-channel blocking agents, corticosteroids, thiazide diuretics, estrogens and progestins (e.g., oral contraceptives), isoniazid, niacin, phenothiazines, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline); observe patient closely for evidence of altered glycemic control when such drugs are added to or withdrawn from therapy.

Specific Drugs

Pharmacokinetics

Absorption

Bioavailability

Approximately 50–60% (absolute) with dosages of 0.5–1.5 g.

Fixed-combination preparation containing 500 mg of metformin hydrochloride and 4 mg of rosiglitazone is bioequivalent to mg-equivalent dosages of individual components administered separately under fasted conditions.

Onset

Therapeutic response usually apparent within a few days to 1 week. Maximal glycemic response within 2 weeks.

Duration

Blood glucose concentrations increase within 2 weeks following discontinuance of metformin therapy.

Food

Food decreases and slightly delays absorption of conventional tablets.

Food increases the extent of absorption of extended-release tablets (Glucophage^® XR, Fortamet^®). Peak plasma concentrations and time to achieve peak plasma concentrations not altered by administration of one extended-release preparation (Glucophage^® XR) with food; food increases peak plasma concentrations and prolongs time to peak plasma concentrations of another extended-release tablet preparation (Fortamet^®).

Food increases the extent of absorption and delays the time to peak plasma concentrations of the oral solution. Fat content of meals does not appreciably affect the pharmacokinetics of metformin hydrochloride oral solution.

Distribution

Extent

Rapidly distributed into peripheral body tissues and fluids, particularly GI tract.

Slowly distributed into erythrocytes and a deep tissue compartment (probably GI tissue).

Plasma Protein Binding

Negligible.

Elimination

Metabolism

Not metabolized in the liver or GI tract and not excreted into bile. No metabolites identified in humans.

Elimination Route

Excreted in urine (approximately 35–52%) and feces (20–33%). Eliminated as unchanged drug.

Half-life

3–6 hours.

Special Populations

Renal impairment may reduce clearance, including in geriatric patients with age-related decline in renal function. Renal impairment results in increased peak plasma concentrations, prolonged time to peak plasma concentration and half-life, and decreased volume of distribution.

Stability

Storage

Oral

Tablets

Conventional tablets: tight, light resistant containers at 20–25°C (may be exposed to 15–30°C).

Extended-release tablets: tight, light resistant containers at 20–25° C (may be exposed to 15–30°C).

Fixed-combination preparations with glipizide or rosiglitazone: tight, light resistant containers at 20–25° C (may be exposed to 15–30°C).

Solution

15–30°C.

Actions

• Lowers blood glucose concentrations in patients with type 2 (non-insulin-dependent) diabetes mellitus (NIDDM) without increasing insulin secretion from pancreatic β cells. Ineffective in the absence of some endogenous or exogenous insulin.
• Usually does not lower glucose concentrations below euglycemia, but hypoglycemia occasionally may occur with overdosage.
• Lowers both basal (fasting) and postprandial glucose concentrations in patients with type 2 diabetes mellitus. Improves insulin sensitivity by decreasing hepatic glucose production and enhancing insulin-stimulated uptake and utilization of glucose by peripheral tissues (e.g., skeletal muscle, adipocytes). Insulin secretion usually remains unchanged.

Advice to Patients

• Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs, dietary or herbal supplements, and alcohol consumption, as well as any concomitant illnesses (e.g., renal disease). Importance of avoiding excessive alcohol consumption.
• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
• Importance of adherence to diet and exercise regimens.
• Possibility of primary and secondary failure with metformin therapy.
• Risks of hypoglycemia, symptoms and treatment of hypoglycemic reactions, and conditions that predispose to the development of such reactions.
• Importance of regular laboratory evaluations, including fasting blood (or plasma) glucose determinations.
• Risks of lactic acidosis and conditions that predispose to its development.
• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

AHFS Drug Information. © Copyright, 1959-2009, Selected Revisions July 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.