Metformin Hydrochloride

Pronunciation

Class: Biguanides
ATC Class: A10BA02
VA Class: HS502
Chemical Name: 1,1-Dimethylbiguanide monohydrochloride
Molecular Formula: C4H11N5 • HCl
CAS Number: 1115-70-4
Brands: Actoplus Met, Actoplus Met XR, Avandamet, Fortamet, Glucophage, Glucophage XR, Glucovance, Glumetza, Janumet, Metaglip, Prandimet, Riomet

Warning(s)

  • Lactic acidosis rare but potentially fatal.1 6 18 20 27 29 30 62 89 96 158 Increased risk of lactic acidosis in patients with renal impairment and advanced age.1 2 62 96 119

  • Generally has occurred in diabetic patients with severe renal insufficiency who frequently had concomitant medical and/or surgical problems and were receiving multiple drugs; metformin plasma concentrations >5 mcg/mL often found in patients with lactic acidosis.1 2 3 20 50 62 64 76 96 123 158 164 165

  • Periodically monitor renal function and use the minimum effective dosage.1 32 62 63 65 76 85 91 93 96 123 124 158 164 165 247 258 313 314 Withhold metformin promptly in patients with any condition associated with hypoxemia, sepsis, or dehydration.1 2 62 63 93 313 Avoid use in patients with clinical or laboratory evidence of hepatic impairment.1 2 63 65 85 91 93 156 158 313 314 Discontinue therapy temporarily in patients undergoing surgery or receiving parenteral iodinated radiographic contrast media.1 2 30 62 63 93 158 313 314 Drugs that may affect renal function or alter metformin elimination should be used with caution.1

  • Advise patients not to consume excessive amounts of alcohol.1 2 63 76 91 93 158

  • If lactic acidosis occurs, discontinue metformin.1 30 313 314 Treat as medical emergency; immediate hospitalization and treatment required; hemodialysis recommended.1 23 32 62 117 119 313 314

Introduction

Antidiabetic agent; a biguanide, chemically and pharmacologically unrelated to sulfonylurea antidiabetic agents.1 2 3 4 18 20 22 23 27 28 29 30 33 72 146 243 245 246

Uses for Metformin Hydrochloride

Diabetes Mellitus

Used as an adjunct to diet and exercise for the management of type 2 diabetes mellitus.1 3 4 6 8 15 16 17 18 19 20 27 29 95 166 243 245 246

May be used in combination with a sulfonylurea, repaglinide, or thiazolidinedione antidiabetic agent for the management of type 2 diabetes mellitusin patients who do not achieve adequate glycemic control on monotherapy with metformin or any of these drugs.1 3 6 15 18 20 22 27 29 30 48 59 78 88 95 97 99 112 134 166 191 234 237 238 239 241 242 243 245 246 249 250 260 Also used concomitantly with nateglinide.248

Slideshow: Can Prescription Drugs Lead to Weight Gain?

May be used with insulin to improve glycemic control and/or decrease the required dosage of insulin.1 3 6 88 90 94 95 146

Commercially available in fixed combination with glyburide or glipizide for use as an adjunct to diet and exercise in adults with type 2 diabetes mellitus.234 254 May add a thiazolidinedione antidiabetic agent if patient has inadequate glycemic control with fixed-combination metformin/glyburide therapy.234

Commercially available in fixed combination with rosiglitazone for use when treatment with both rosiglitazone and metformin is appropriate.247 Use of metformin/rosiglitazone (Avandamet) is restricted to patients who are already being treated successfully with rosiglitazone and to those not already receiving rosiglitazone who are unable to achieve glycemic control with other antidiabetic agents and have decided (in consultation with their healthcare provider) not to take pioglitazone-containing preparations for medical reasons.247 325

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.260

Commercially available in fixed combination with repaglinide for use as an adjunct to diet and exercise 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.313

Commercially available in fixed combination with sitagliptin for use as an adjunct to diet and exercise when treatment with both sitagliptin and metformin is appropriate.314

Metformingenerally is the preferred initial oral antidiabetic agent for patients with type 2 diabetes mellitus.264 Potential advantages of metformin compared with sulfonylureas or insulin include minimal risk of hypoglycemia, more favorable effects on serum lipids, reduction of hyperinsulinemia, and weight loss or lack of weight gain.1 2 3 6 16 17 18 19 20 27 30 42 60 68 102 134 146 166 264

Not effective as sole therapy in patients with diabetes mellitus complicated by acidosis, ketosis, or coma.1 6 30 146 191 192

Polycystic Ovary Syndrome

Has been used in the management of metabolic and reproductive abnormalities associated with polycystic ovary syndrome.289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312

Metformin Hydrochloride 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.1 2

  • Patients whose therapy is transferred from chlorpropamide to metformin should be monitored closely for hypoglycemia during the initial 2 weeks following transfer.1 2 30

  • Goal of therapy should be to reduce both fasting glucose and 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.1 8 13 14 78 85 88 105 134 146 166 234 235 243 245 246

  • Distribution of rosiglitazone and rosiglitazone-containing preparations (e.g., Avandamet) is restricted because of potential increased risk of MI associated with rosiglitazone; can only be obtained through the AVANDIA-Rosiglitazone Medicines Access Program.247 250 325 Contact 800-AVANDIA or visit for specific information.247 250

Administration

Oral Administration

Administer orally with meals to reduce adverse GI effects.1 2 3 18 53 85 243 245 246

Administer conventional tablets 2 or 3 times daily.1 243 245 246 Administer in 2 divided doses if total dosage ≤2 g daily or in 3 divided doses if total dosage is >2 g daily.1

Administer extended-release tablets once daily with the evening meal; swallow whole and do not chew, cut, or crush.1 258 259 260 261 In addition, administer Fortamet extended-release tablets with a full glass of water.258

Administer metformin/pioglitazone, metformin/rosiglitazone, and metformin/sitagliptin fixed-combination preparations with meals and in divided doses to reduce GI effects of the metformin component.247 260 314

Administer metformin/repaglinide fixed-combination tablets within 15 minutes before meals.313 If a meal is skipped, omit dose for that meal.313

Dosage

Available as metformin hydrochloride; dosage expressed in terms of the salt.1

Individualize dosage carefully based on patient’s glycemic response and tolerance.1 4 243 245 246

Pediatric Patients

Diabetes Mellitus
Oral

Conventional tablets or oral solution in children 10–16 years of age: Initially, 500 mg twice daily with meals.1 257 Increase daily dosage in increments of 500 mg at weekly intervals to a maximum of 2 g daily given in divided doses.1 257

Adults

Diabetes Mellitus
Monotherapy
Oral

Conventional tablets or oral solution: Initially, 500 mg twice daily or 850 mg once daily with meals.1 257 Increase daily dosage by 500 mg at weekly intervals or by 850 mg at biweekly (every 2 week) intervals up to a maximum of 2 g daily given in divided doses.1 257 May increase dosage from 500 mg twice daily to 850 mg twice daily after 2 weeks.1 257 Clinically important responses generally not observed at dosages <1.5 g daily.1 257

Initial dosage of 500 mg once daily suggested by some experts.264

For additional glycemic control, increase dosage (as conventional tablets or oral solution) up to a maximum daily dosage of 2.55 g given in divided doses.1 257

Extended-release tablets (Glucophage XR) in patients ≥17 years of age: Initially, 500 mg once daily with the evening meal.1 259 Increase daily dosage by 500 mg at weekly intervals to a maximum of 2 g daily.1 259 If glycemic control is not achieved with 2 g once daily, consider administering 1 g twice daily.1 259 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 per day for daily dosages >2 g).1 259

Extended-release tablets (Fortamet) in patients ≥17 years of age: Initially, 1 g once daily with the evening meal; 500 mg once daily may be used when clinically appropriate.258 Increase daily dosage by 500 mg at weekly intervals to a maximum of 2.5 g daily with the evening meal.258

Metformin Hydrochloride in Fixed Combination with Glipizide (e.g., Metaglip)
Oral

Patients with inadequate glycemic control on diet and exercise alone: Initially, 250 mg of metformin hydrochloride and 2.5 mg of glipizide once daily with a meal.254 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.254 Increase daily dosage in increments of one tablet (using the tablet strength at which therapy was initiated) at 2-week intervals until adequate glycemic control is achieved or maximum daily dosage of 2 g of metformin hydrochloride and 10 mg of glipizide is reached.254 256

Efficacy of metformin hydrochloride and glipizide in fixed combination not established in patients with fasting plasma glucose concentrations >320 mg/dL.254 No experience with total initial daily dosages exceeding 2 g of metformin hydrochloride and 10 mg of glipizide.254

Patients with inadequate glycemic control on either a sulfonylurea or metformin alone: Initially, 500 mg of metformin hydrochloride and 2.5 or 5 mg of glipizide twice daily with the morning and evening meals.254 Initial dosage of the fixed combination should not exceed the patient's current daily dosage of metformin hydrochloride or glipizide (or equivalent dosage of another sulfonylurea).254 Titrate daily dosage in increments not exceeding 500 mg of metformin hydrochloride and 5 mg of glipizide until adequate glycemic control achieved or maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glipizide is reached.254

Patients currently receiving combined therapy with separate metformin and glipizide (or another sulfonylurea) preparations: May switch to 500 mg of metformin hydrochloride and 2.5 or 5 mg of glipizide; initial dosage of the fixed-combination preparation should not exceed the patient's current daily dosage of metformin hydrochloride and glipizide (or equivalent dosage of another sulfonylurea).254 Use clinical judgment regarding whether to switch to the nearest equivalent dosage or to titrate dosage.254 Titrate daily dosage in increments not exceeding until adequate glycemic control is achieved or maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glipizide is reached.254

Metformin Hydrochloride in Fixed Combination with Glyburide (e.g., Glucovance)
Oral

Patients with inadequate glycemic control on diet and exercise alone: Initially, 250 mg of metformin hydrochloride and 1.25 mg of glyburide once daily with a meal.234 For more severe hyperglycemia (i.e., fasting plasma glucose concentrations >200 mg/dL or HbAic >9%), may consider initial dosage of 250 mg of metformin hydrochloride and 1.25 mg of glyburide twice daily with the morning and evening meals.234 Titrate daily dosage in increments of 250 mg of metformin hydrochloride and 1.25 mg of glyburide at 2-week intervals until adequate glycemic control is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 10 mg of glyburide is reached.234

Do not use the fixed combination of metformin hydrochloride 500 mg and glyburide 5 mg as initial therapy due to an increased risk of hypoglycemia.234

Patients with inadequate glycemic control on a sulfonylurea and/or metformin: Initially, 500 mg of metformin hydrochloride and 2.5 or 5 mg of glyburide twice daily.234 Initial dosage of the fixed combination should not exceed the patient's current daily dosage of glyburide (or equivalent dosage of another sulfonylurea antidiabetic agent) and metformin hydrochloride.234 Increase daily dosage in increments not exceeding 500 mg of metformin hydrochloride and 5 mg of glyburide until adequate glycemic control is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glyburide is reached.234

Patients currently receiving combined therapy with separate metformin and glyburide (or another sulfonylurea agent) preparations: Initial dosage of the fixed combination should not exceed the previous dosage of metformin hydrochloride and glyburide (or the equivalent dosage of the other sulfonylurea).234 Titrate daily dosage in increments not exceeding 500 mg of metformin hydrochloride and 5 mg of glyburide until adequate glycemic control is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 20 of mg glyburide is reached.234

For patients whose hyperglycemia is not adequately controlled on the fixed combination, may add a thiazolidinedione (e.g., pioglitazone, rosiglitazone) at its recommended initial dosage and continue same dosage of the fixed combination.234 (See General under Dosage and Administration for information regarding restrictions on use of rosiglitazone.) In patients requiring further glycemic control, increase thiazolidinedione dosage as recommended.234

Metformin Hydrochloride in Fixed Combination with Rosiglitazone (Avandamet)
Oral

Dosage of the fixed combination is based on the patient’s current dosages of metformin hydrochloride and/or rosiglitazone.247 (See Table 1.) In rosiglitazone-naive patients, initiate rosiglitazone component at the lowest recommended dosage.247

In patients currently receiving metformin monotherapy, the usual initial dosage of rosiglitazone is 4 mg daily given in divided doses with patient's existing dosage of metformin hydrochloride.247

In patients currently receiving rosiglitazone monotherapy, the usual initial dosage of metformin hydrochloride is 1 g daily given in divided doses with patient's existing dosage of rosiglitazone.247

Individualize therapy in patients already receiving metformin hydrochloride at doses not available in the fixed combination (i.e., doses other than 1 or 2 g).247

Table 1. Initial Dosage of the Fixed Combination of Metformin Hydrochloride and Rosiglitazone (Avandamet)247

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

For patients switching from combined therapy with separate metforminand rosiglitazone preparations, the usual initial dosage of the fixed combination is the same as the patient's existing dosage of the individual drugs.247

If additional glycemic control is needed following transfer, increase daily dosage in increments of 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.247 Following increase in dosage of metformin hydrochloride, further dosage adjustment recommended if adequate glycemic control not achieved in 1–2 weeks. 247 Following increase in dosage of rosiglitazone, further dosage adjustment recommended if adequate glycemic control not achieved in 8–12 weeks.247

Metformin Hydrochloride in Fixed Combination with Pioglitazone (Actoplus Met, Actoplus Met XR)
Oral

Individualize dosage based on the patient’s current dosage regimen, effectiveness, and tolerability.260

Fixed combination containing metformin and immediate-release pioglitazone (Actoplus Met): Usual initial dosage is 500 or 850 mg of metformin hydrochloride and 15 mg of pioglitazone given once or twice daily with food.260

Fixed combination containing extended-release metforminand immediate-release pioglitazone (Actoplus Met XR): Usual initial dosage is 1 g of metformin hydrochloride and 15 or 30 mg of pioglitazone given once daily with the evening meal.260

Gradually titrate dosage as needed based on therapeutic response.260 Allow sufficient time (e.g., 8–12 weeks) to assess response.260

Safety and efficacy of transferring from therapy with other oral antidiabetic agents to Actoplus Met or Actoplus Met XR not established; undertake any such change with caution and appropriate monitoring.260

Metformin Hydrochloride in Fixed Combination with Repaglinide (PrandiMet)
Oral

Individualize dosage based on the patient’s current dosage regimen, effectiveness, and tolerability.313

Patients with inadequate glycemic control on metformin monotherapy: Initially, 500 mg of metformin hydrochloride and 1 mg of repaglinide twice daily with meals; gradually increase dosage as needed.313

Patients with inadequate glycemic control on repaglinide monotherapy: Initially, 500 mg of the metformin hydrochloride component (given in fixed combination with repaglinide) twice daily; gradually increase dosage as needed.313

Patients switching from combined therapy with separate metformin and repaglinide preparations: Initiate with dosages that are similar to (but do not exceed) patient's existing dosages of the individual drugs.313

Safety and efficacy of transferring to PrandiMet from therapy with other oral antidiabetic agents not established; undertake any such change with caution and appropriate monitoring.313

Metformin Hydrochloride in Fixed Combination with Sitagliptin (Janumet)
Oral

Individualize dosage based on the patient’s current regimen, effectiveness, and tolerability while not exceeding the maximum recommended daily dosage of 2 g of metformin hydrochloride and 100 mg of sitagliptin.314

Patients not currently receiving metformin: Initially, 500 mg of metformin hydrochloride and 50 mg of sitagliptin twice daily; gradually increase dosage as needed.314

Patients currently receiving metformin: Initial dosage should provide 50 mg of sitagliptin twice daily and the dosage of metformin hydrochloride currently being taken.314 Patients currently taking metformin hydrochloride 850 mg twice daily should receive an initial fixed-combination dosage of 50 mg of sitagliptin and 1 g of metformin hydrochloride twice daily.314

Safety and efficacy of transferring to Janumet from therapy with other oral antidiabetic agents not established; undertake any such change with caution and appropriate monitoring.314

Metformin Hydrochloride Dosage in Patients Transferred from Insulin
Oral

Initially, 500 mg once daily; increase dosage by 500 mg daily at weekly intervals until adequate glycemic control is achieved or a maximum daily dosage of 2.5 g (conventional tablets) or 2 g (extended-release tablets) is reached.1 Concurrent insulin dosage initially remains unchanged.1 When fasting plasma glucose concentration decreases to <120 mg/dL, decrease insulin dosage by 10–25%.1

Polycystic Ovary Syndrome
Oral

In general, 1.5–2.25 g daily in divided doses.291 292 294 296 299 300 301 302 303 305 306 307

Prescribing Limits

Pediatric Patients

Diabetes Mellitus
Oral

Children 10–16 years of age: Maximum 2 g daily as conventional tablets or oral solution.1 257

Adults

Diabetes Mellitus
Monotherapy
Oral

Maximum 2.55 g daily as 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 XR).1 2 3 4 14 18 22 85 257 258 259 Switch to conventional tablets for further dosage titration if required dosage exceeds 2 g daily.1 259

Metformin Hydrochloride in Fixed Combination with Glyburide (e.g., Glucovance)
Oral

Maximum daily dosage as second-line therapy is 2 g of metformin hydrochloride and 20 mg of glyburide.234

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 as initial therapy.234

Metformin Hydrochloride in Fixed Combination with Glipizide (e.g., Metaglip)
Oral

Maximum daily dosage is 2 g of metformin hydrochloride and 20 mg of glipizide.254 256

Special Populations

Geriatric Patients

In general, do not titrate to the maximum dosage recommended for younger adults;1 2 3 4 165 243 245 246 314 limited data suggest reducing initial dosage by approximately 33% in geriatric patients.30 174

Monitor renal function regularly to determine appropriate dosage.1 2 3 4 164 165 243 245 246 314

Cautions for Metformin Hydrochloride

Contraindications

  • Acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma.1 2 234 247

  • Renal impairment (e.g., Scr ≥1.5 mg/dL in men or ≥1.4 mg/dL in women) or abnormal Clcr.1 234 247 Renal impairment may result from conditions such as cardiovascular collapse (shock), acute MI, or septicemia.1 234

  • Known hypersensitivity to metformin hydrochloride or any ingredient in the formulations.1 2 234 247 254

Warnings/Precautions

Warnings

Lactic Acidosis

See Boxed Warning.

General Precautions

Hypoglycemia

Uncommon in patients receiving metformin as monotherapy.1 15 30 78 94 99 Debilitated, malnourished, or geriatric patients and patients with renal or hepatic impairment or adrenal or pituitary insufficiency may be particularly susceptible.1 2 Strenuous exercise, alcohol ingestion, insufficient caloric intake, or use in combination with other antidiabetic agents may increase risk.1 2 Hypoglycemia may be difficult to recognize in geriatric patients or in those receiving β-adrenergic blocking agents.1 83 91 128 143 153 159 (See Specific Drugs under Interactions.)

Hematologic Effects

Decreased serum vitamin B12 concentrations, 1 18 with or without clinical manifestations (e.g., anemia).1

Symptoms rapidly reversible following discontinuation of metformin or supplementation with vitamin B12.1 3 6 20 30 70 77 82 134 Monitor hematologic parameters (e.g., hemoglobin, serum vitamin B12 concentrations)1 82 114 122 134 148 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).1 82 114 122 134 148

Cardiovascular Effects

Possible increased cardiovascular mortality associated with other biguanide antidiabetic agents (i.e., phenformin).1 191 192 200 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.220 221 224

Use of metformin in combination with rosiglitazone and insulin is not recommended; adverse cardiovascular events (e.g., edema, heart failure) have occurred with combined rosiglitazone and insulin therapy.247

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.1 88 134 156 169

Temporary withdrawal of metformin therapy and administration of insulin may be required to maintain glycemic control during periods of stress.1

Use of Fixed Combinations

When used in fixed combination with glyburide, glipizide, glimepiride, repaglinide, sitagliptin, pioglitazone, and/or rosiglitazone, consider the cautions, precautions, and contraindications associated with the concomitant agent(s).234 237 247 254 260 313 314

Specific Populations

Pregnancy

Category B.1

Most clinicians recommend use of insulin during pregnancy in diabetic patients to maintain optimum control of blood glucose concentrations.1 3 4 18 72 88 92

Lactation

Distributed into milk in rats; small amounts distributed into human milk.1 284 285 286 Discontinue nursing or the drug.1 3 4

Pediatric Use

Safety and efficacy of metformin as conventional tablets or oral solution in children <10 years of age have not been established.1 257

Safety and efficacy of metformin as extended-release tablets in children <17 years of age have not been established.1 258 259

Safety and efficacy of metformin in fixed combination with glipizide, pioglitazone, repaglinide, rosiglitazone, or sitagliptin in children have not been established.1 3 4 30 134 247 254 260 313 314 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.234

Geriatric Use

Insufficient number of geriatric patients in controlled clinical trials of metformin hydrochloride conventional (Glucophage) and extended-release tablets (Glucophage XR, Glumetza) to determine if such patients respond differently than younger adults.1 261 314 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.258

Use with caution, since renal function declines with age.1 3 4 30 85 174 234 247 254 314

Monitor renal function periodically.1 2 3 4 164 165 314

Do not initiate in patients ≥80 years of age without confirmation of adequate renal function as measured by Clcr.1 209 214 313 314

Geriatric patients particularly susceptible to hypoglycemia,1 2 which may be difficult to recognize.1 83 91 128 143 153 159

Renal Impairment

Do not use in patients with renal disease or dysfunction.1 (See Contraindications.)

Evaluate renal function prior to initiation of therapy and at least annually thereafter.1 2 77 85 234

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).156

Discontinue metformin if evidence of renal impairment is present.1 2 156 164

Patients whose serum creatinine concentrations exceed the upper limit of normal for their age should not receive metformin.1

Hepatic Impairment

Generally avoid use in patients with clinical or laboratory evidence of hepatic disease.1 165 Elimination of lactate may be substantially reduced.1 (See Boxed Warning.)

Common Adverse Effects

Diarrhea,1 31 48 49 53 78 109 118 122 135 nausea,1 31 53 78 109 118 122 vomiting,1 118 122 abdominal bloating, abdominal cramping or pain,1 31 35 42 53 118 122 flatulence,1 anorexia.1 3 6 18

Interactions for Metformin Hydrochloride

Cationic Agents Secreted by Proximal Renal Tubules

Pharmacokinetic interaction with cimetidine (decreased excretion of metformin).1 75

Potential pharmacokinetic interaction with other cationic drugs that undergo substantial tubular secretion (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, vancomycin).1 30

Monitor carefully; consider dosage adjustment of either agent.1

Protein-bound Drugs

Pharmacokinetic interaction unlikely.1

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.1 30 80 85 91 120 121 134 139 143 151 152 153 154 159 160

Specific Drugs or Foods

Drug

Interaction

Comments

Acarbose

Acute decrease in metformin bioavailability in single-dose study138 201

ACE inhibitors

Potential risk of hypoglycemia/hyperglycemia when ACE inhibitor therapy is initiated/withdrawn131 132 134 152 155 160

Monitor blood glucose concentrations during dosage adjustments with either agent130 131 132 134 152 155 160

Alcohol

Increased risk of hypoglycemia and lactic acidosis1 2 18 33 63 72 76 91 93 107 143

Avoid excessive alcohol intake1

Antidiabetic agents (e.g., sulfonylureas, meglitinides, insulin)

Possible hypoglycemia1 15 78 94 99 260 313

May need to reduce dosage of concomitant antidiabetic agent1

β-Adrenergic blocking agents

May impair glucose tolerance; 73 143 152 153 159 may increase frequency or severity of hypoglycemia and hypoglycemia-induced complications91 127 153 159

If concomitant therapy necessary, a β1-selective adrenergic blocking agent or β-adrenergic blocking agents with intrinsic sympathomimetic activity preferred36 143 152 160 173

Cimetidine

Possible decreased excretion of metformin1

Increased peak concentrations and AUC of metformin; negligible effects on cimetidine pharmacokinetics1

Carefully monitor patient; consider need for dosage adjustment1

Clomiphene

Possible resumption of ovulation in premenopausal patients with polycystic ovary syndrome210

Furosemide

Increased peak concentrations of metformin and decreased peak concentrations and terminal half-life of furosemide in single-dose study1

Glyburide

Pharmacokinetics and pharmacodynamics of metformin not altered in single-dose study1 260 261 314

Variable decreases in AUC and peak blood concentration of glyburide1 260 314

Clinical importance uncertain1

Guar gum

Reduced and delayed GI absorption of metformin 18 85 99 106

Nifedipine

Enhanced absorption and increased urinary excretion of metformin; minimal effects on nifedipine pharmacokinetics1

Thiazide diuretics

May exacerbate diabetes mellitus1 91 139 143 151 152 153 154 159 160

Consider using less diabetogenic diuretic (e.g., potassium-sparing diuretic), reducing dosage of or discontinuing diuretic, or increasing dosage of oral antidiabetic agent73 134 152 153 154 159 160

Metformin Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Approximately 50–60% (absolute) with dosages of 0.5–1.5 g.1 2 3 4 18 33 43 50 65 72 85 89

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.247

Onset

Therapeutic response usually apparent within a few days to 1 week.18 53 72 98 134 Maximal glycemic response within 2 weeks.18 53 72 98 134

Duration

Blood glucose concentrations increase within 2 weeks following discontinuance of metformin therapy.53 134

Food

Food decreases and slightly delays absorption of conventional tablets.1 2 3 4 18 208 314

Food increases the extent of absorption of extended-release tablets (Glucophage XR, Fortamet).1 258 Peak plasma concentrations and time to achieve peak plasma concentrations not altered by administration of one extended-release preparation (Glucophage XR) with food; 1 food increases peak plasma concentrations and prolongs time to peak plasma concentrations of another extended-release tablet preparation (Fortamet).258

Peak concentrations and AUC of the extended-release metformin hydrochloride component increased by approximately 98 and 85%, respectively, when Actoplus Met XR was given with food.260 Time to peak concentration prolonged by approximately 3 hours for pioglitazone and 2 hours for extended-release metformin hydrochloride under fed conditions.260

Food increases the extent of absorption and delays the time to peak plasma concentrations of the oral solution.257 Fat content of meals does not appreciably affect the pharmacokinetics of metformin hydrochloride oral solution.257

Distribution

Extent

Rapidly distributed into peripheral body tissues and fluids, particularly GI tract.30 50 65 72 89 134 162 167

Slowly distributed into erythrocytes and a deep tissue compartment (probably GI tissue).30 50 65 72 89 134 162 167

Plasma Protein Binding

Negligible.1 18 50 51 65 85 89

Elimination

Metabolism

Not metabolized in the liver or GI tract and not excreted into bile.1 50 51 89 No metabolites identified in humans.1 50 51 89 314

Elimination Route

Excreted in urine (approximately 35–52%)50 51 89 and feces (20–33%).6 33 43 50 72 89 Eliminated as unchanged drug.1 2 6 33 50 63 65 75 85 89 314

Half-life

Approximately 6.2 hours.1 2 6 18 33 38 50 51 65 85 89 125 134 314

Special Populations

Renal impairment may reduce clearance, including in geriatric patients with age-related decline in renal function.1 33 51 174 Renal impairment results in increased peak plasma concentrations, prolonged time to peak plasma concentration and half-life, and decreased volume of distribution.1 3 51 174

Stability

Storage

Oral

Tablets

Conventional tablets: tight, light-resistant containers at 20–25°C (may be exposed to 15–30°C).1

Extended-release tablets: tight, light resistant containers at 20–25° C (may be exposed to 15–30°C).1 258

Metformin/glyburide fixed combination: Light-resistant containers at 25°C.234

Metformin/glipizide fixed combination: 20–25° C (may be exposed to 15–30°C).254

Metformin/rosiglitazone fixed combination: Tight, light-resistant containers at 25°C (may be exposed to 15–30°C).247

Metformin/pioglitazone fixed combination: Tight (Actoplus Met) or tight, light-resistant (Actoplus Met XR) containers at 25°C (may be exposed to 15–30°C).260

Metformin/repaglinide fixed combination: Tight containers at temperatures not exceeding 25°C.313

Metformin/sitagliptin fixed combination: 20–25°C (may be exposed to 15–30°C).314

Solution

15–30°C.257

Actions

  • Lowers blood glucose concentrations in patients with type 2 (non-insulin-dependent) diabetes mellitus (NIDDM) without increasing insulin secretion from pancreatic β cells.1 2 3 4 18 20 27 31 40 60 134 Ineffective in the absence of some endogenous or exogenous insulin.18 27 40 71 122

  • Usually does not lower glucose concentrations below euglycemia, but hypoglycemia occasionally may occur with overdosage.1 2 18 20 27 28 29 72 102 103 111

  • Lowers both basal (fasting) and postprandial glucose concentrations in patients with type 2 diabetes mellitus.1 2 18 22 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).18 31 40 41 42 44 60 81 146 149 Insulin secretion usually remains unchanged.1 2 3 18 20 42 60 68 102 166

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).1 Importance of avoiding excessive alcohol consumption.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of adherence to diet and exercise regimens.1

  • Possibility of primary and secondary failure with metformin therapy.1

  • Risks of hypoglycemia, symptoms and treatment of hypoglycemic reactions, and conditions that predispose to the development of such reactions.1

  • Importance of regular laboratory evaluations, including fasting blood (or plasma) glucose determinations.1 2 85

  • Risks of lactic acidosis and conditions that predispose to its development.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

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

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Metformin Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

500 mg/5 mL

Riomet

Ranbaxy

Tablets, extended-release

500 mg*

Fortamet

Shionogi Pharma

Glucophage XR

Bristol-Myers Squibb

Glumetza

Depomed

Metformin Hydrochloride Extended-Release Tablets

750 mg*

Glucophage XR

Bristol-Myers Squibb

Metformin Hydrochloride Extended-Release Tablets

1 g*

Fortamet

Shionogi Pharma

Glumetza

Depomed

Tablets, film-coated

500 mg*

Glucophage

Bristol-Myers Squibb

Metformin Hydrochloride Tablets

625 mg*

Metformin Hydrochloride Tablets

750 mg*

Metformin Hydrochloride Tablets

850 mg*

Glucophage

Bristol-Myers Squibb

Metformin Hydrochloride Tablets

1 g*

Glucophage

Bristol-Myers Squibb

Metformin Hydrochloride Tablets

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Metformin Hydrochloride Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, extended-release

1 g with Immediate-release Pioglitazone Hydrochloride 15 mg (of pioglitazone)

Actoplus Met XR

Takeda

1 g with Immediate-release Pioglitazone Hydrochloride 30 mg (of pioglitazone)

Actoplus Met XR

Takeda

Tablets, film-coated

250 mg with Glipizide 2.5 mg*

Metaglip

Bristol-Myers Squibb

Metformin Hydrochloride and Glipizide Tablets

250 mg with Glyburide 1.25 mg*

Glucovance

Bristol-Myers Squibb

Metformin Hydrochloride and Glyburide Tablets

500 mg with Glipizide 2.5 mg*

Metaglip

Bristol-Myers Squibb

Metformin Hydrochloride and Glipizide Tablets

500 mg with Glipizide 5 mg*

Metaglip

Bristol-Myers Squibb

Metformin Hydrochloride and Glipizide Tablets

500 mg with Glyburide 2.5 mg*

Glucovance

Bristol-Myers Squibb

Metformin Hydrochloride and Glyburide Tablets

500 mg with Glyburide 5 mg*

Glucovance

Bristol-Myers Squibb

Metformin Hydrochloride and Glyburide Tablets

500 mg with Pioglitazone Hydrochloride 15 mg (of pioglitazone)

Actoplus Met

Takeda

500 mg with Repaglinide 1 mg

Prandimet

Novo Nordisk

500 mg with Repaglinide 2 mg

Prandimet

Novo Nordisk

500 mg with Rosiglitazone Maleate 2 mg (of rosiglitazone)

Avandamet

GlaxoSmithKline

500 mg with Rosiglitazone Maleate 4 mg (of rosiglitazone)

Avandamet

GlaxoSmithKline

500 mg with Sitagliptin Phosphate 50 mg (of sitagliptin)

Janumet

Merck

850 mg with Pioglitazone Hydrochloride 15 mg (of pioglitazone)

Actoplus Met

Takeda

1 g with Rosiglitazone Maleate 2 mg (of rosiglitazone)

Avandamet

GlaxoSmithKline

1 g with Rosiglitazone Maleate 4 mg (of rosiglitazone)

Avandamet

GlaxoSmithKline

1 g with Sitagliptin Phosphate 50 mg (of sitagliptin)

Janumet

Merck

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Actoplus Met 15-500MG Tablets (TAKEDA PHARMACEUTICALS): 30/$142.99 or 90/$405.97

Actoplus Met 15-850MG Tablets (TAKEDA PHARMACEUTICALS): 30/$142.99 or 90/$409.99

Actoplus met XR 15-1000MG 24-hr Tablets (TAKEDA PHARMACEUTICALS): 30/$158.99 or 90/$456.96

Actoplus met XR 30-1000MG 24-hr Tablets (TAKEDA PHARMACEUTICALS): 30/$309.99 or 90/$906.96

Avandamet 2-1000MG Tablets (GLAXO SMITH KLINE): 60/$161.64 or 180/$455.07

Avandamet 2-500MG Tablets (GLAXO SMITH KLINE): 60/$174.07 or 180/$472.47

Avandamet 4-1000MG Tablets (GLAXO SMITH KLINE): 60/$279.99 or 180/$808.28

Avandamet 4-500MG Tablets (GLAXO SMITH KLINE): 60/$279.99 or 180/$785.93

Fortamet 1000MG 24-hr Tablets (SHIONOGI PHARMA): 60/$683.99 or 180/$2,027.97

Fortamet 500MG 24-hr Tablets (SHIONOGI PHARMA): 60/$338.55 or 180/$980.02

GlipiZIDE-MetFORMIN HCl 2.5-250MG Tablets (HERITAGE PHARMACEUTICALS): 30/$29.99 or 60/$49.97

GlipiZIDE-MetFORMIN HCl 2.5-500MG Tablets (HERITAGE PHARMACEUTICALS): 60/$57.99 or 180/$159.97

GlipiZIDE-MetFORMIN HCl 5-500MG Tablets (HERITAGE PHARMACEUTICALS): 60/$58.99 or 180/$169.99

Glucophage 1000MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 60/$141.08 or 180/$383.29

Glucophage 500MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 60/$69.99 or 180/$179.96

Glucophage 850MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 60/$113.29 or 180/$315.48

Glucophage XR 500MG 24-hr Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 60/$69.99 or 180/$180.97

Glucophage XR 750MG 24-hr Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$53.99 or 90/$139.96

Glucovance 2.5-500MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 60/$85.99 or 180/$249.98

Glucovance 5-500MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 60/$92.00 or 180/$246.06

Glumetza 1000MG 24-hr Tablets (DEPOMED): 100/$859.97 or 300/$2,480.03

Glumetza 500MG 24-hr Tablets (DEPOMED): 100/$389.00 or 300/$1,131.93

GlyBURIDE-MetFORMIN 2.5-500MG Tablets (ACTAVIS MID ATLANTIC): 60/$45.99 or 180/$125.96

GlyBURIDE-MetFORMIN 5-500MG Tablets (TEVA PHARMACEUTICALS USA): 100/$83.99 or 300/$246.97

Janumet 50-1000MG Tablets (MERCK SHARP &amp; DOHME): 60/$224.99 or 180/$645.95

Janumet 50-500MG Tablets (MERCK SHARP &amp; DOHME): 60/$220.99 or 180/$639.96

Kombiglyze XR 2.5-1000MG 24-hr Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$119.99 or 90/$344.98

Kombiglyze XR 5-1000MG 24-hr Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$236.98 or 90/$679.00

Kombiglyze XR 5-500MG 24-hr Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$240.00 or 90/$699.98

Metaglip 2.5-250MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$33.99 or 90/$97.97

Metaglip 5-500MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$42.99 or 90/$109.97

MetFORMIN HCl 1000MG Tablets (ZYDUS PHARMACEUTICALS (USA)): 30/$17.99 or 60/$31.97

MetFORMIN HCl 500MG 24-hr Tablets (AMNEAL PHARMACEUTICALS): 90/$20.99 or 180/$32.98

MetFORMIN HCl 500MG Tablets (ZYDUS PHARMACEUTICALS (USA)): 60/$12.99 or 120/$19.98

MetFORMIN HCl 750MG 24-hr Tablets (WATSON LABS): 30/$32.99 or 90/$89.99

MetFORMIN HCl 850MG Tablets (ZYDUS PHARMACEUTICALS (USA)): 90/$77.99 or 180/$130.99

Riomet 500MG/5ML Solution (RANBAXY LABORATORIES): 473/$201.59 or 1419/$582.36

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 15, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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90. Yki-Jarvinen H, Esko N, Eero H et al. Clinical benefits and mechanisms of a sustained response to intermittent insulin therapy in type 2 diabetic patients with secondary drug failure. Am J Med. 1988; 84:185-192. [IDIS 238481] [PubMed 3044067]

91. Chan JCN, Cockram CS. Drug-induced disturbances of carbohydrate metabolism. Adv Drug React Toxicol Rev. 1991; 10:1-29.

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93. Campbell IW. Metformin and the sulphonylureas: the comparative risk. Horm Metab Res. 1985; 15(Suppl):105-11.

94. Chow CC, Tsang L, Sorensen J et al. Comparison of insulin with or without continuation of oral hypoglycemic agents in the treatment of secondary failure in NIDDM patients. Diabetes Care. 1995; 18:307-14. [IDIS 346283] [PubMed 7555472]

95. Zimmerman B, Espenshade J, Fujimoto W et al. The pharmacological treatment of hyperglycemia in NIDDM. Diabetes Care. 1995; 18:1510-18. [IDIS 355480] [PubMed 8722084]

96. Lalau J, Lacroix C, Compagnon P et al. Role of metformin accumulation in metformin-associated lactic acidosis. Diabetes Care. 1995; 18:779-84. [IDIS 348959] [PubMed 7555503]

97. Gregorio F, Ambrosi F, Marchetti P et al. Low dose metformin in the treatment of type II non-insulin-dependent diabetes: clinical and metabolic evaluations. Acta Diabetol Lat. 1990; 27:139-55. [PubMed 2198745]

98. Lord JM, White SI, Bailey CJ et al. Effect of metformin on insulin receptor binding and glycaemic control in type II diabetes. BMJ. 1983; 286:830-31. [IDIS 168606] [PubMed 6403102]

99. Hermann L. Biguanides and sulfonylureas as combination therapy in NIDDM. Diabetes Care. 1990; 13:37-41. [PubMed 2209342]

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