Brand name: Glumetza
Drug class: Biguanides

Medically reviewed by Drugs.com on Sep 10, 2025. Written by ASHP.

Introduction

Antidiabetic agent; a biguanide, chemically and pharmacologically unrelated to sulfonylurea antidiabetic agents.^{1 18 20 22 23 27 29 33 72 146 234 254}

Uses for metFORMIN

Type 2 Diabetes Mellitus

Used as an adjunct to diet and exercise for the management of type 2 diabetes mellitus.^{1 6 8 15 16 17 18 19 20 27 29 95 166 234 254} Immediate-release tablets and oral solution used in adult and pediatric patients ≥10 years of age; extended-release tablets used in adult patients.^{1 257 258 261}

May be used in combination with a glucagon-like peptide-1 (GLP-1) agonist, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, a dipeptidyl peptidase-4 (DPP-4) inhibitor, a thiazolidinedione antidiabetic agent, a sulfonylurea, or a meglitinide (repaglinide, nateglinide) for the management of type 2 diabetes mellitus in patients who do not achieve adequate glycemic control on monotherapy with metformin or any of these medications.^{1 6 15 18 20 22 27 29 48 59 78 95 97 99 112 166 191 234 237 238 239 241 242 248 249 254 260 352 355 362 368 370 372 374 376 378 610 711 712}

May be used with insulin to improve glycemic control and/or decrease the required dosage of insulin.^{1 6 90 94 95 146 711 712}

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}

Commercially available in fixed combination with pioglitazone for use as an adjunct to diet and exercise in adult 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.^{260 710}

Commercially available in fixed combination with the DPP-4 inhibitors alogliptin, linagliptin, saxagliptin, or sitagliptin for use in adult patients as an adjunct to diet and exercise when treatment with both medication components is appropriate.^{314 352 368 376 378 610}

Commercially available in fixed combinations with the SGLT2 inhibitors canagliflozin, dapagliflozin, and empagliflozin in adult and pediatric patients ≥10 years of age and with ertugliflozin for use in adults when treatment with both medication components is appropriate.^{355 362 370 372 374}

Guidelines from the American Diabetes Association (ADA) and other experts recommend metformin for those patients that require initiation or intensification of glucose-lowering therapy to meet glycemic goals and do not have additional needs beyond glucose lowering and for add-on therapy to maintain HbA_1c goals.^{711 712} When selecting a treatment regimen, consider factors such as cardiovascular and renal comorbidities, drug efficacy and adverse effects, hypoglycemic risk, presence of overweight or obesity, cost, access, and patient preferences.^{711 712} Weight management should be included as a distinct treatment goal and other healthy lifestyle behaviors should also be considered.^{711 712}

Polycystic Ovary Syndrome

Has been used in the management of metabolic and reproductive abnormalities associated with polycystic ovary syndrome^{† [off-label]}.^{289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 713}

metFORMIN Dosage and Administration

General

Pretreatment Monitoring

• Assess renal function.^{1 257 258 261}

• Assess hematologic parameters and vitamin B₁₂ concentration.^{1 257 258 261}

Patient Monitoring

• Monitor hematologic parameters on an annual basis and vitamin B₁₂ at 2- to 3-year intervals.^{1 257 258 261} Replete vitamin B₁₂as appropriate.^{1 257 258 261}

• Assess renal function (i.e., estimated glomerular filtration rate [eGFR]) at least annually; assess more frequently in patients at risk for development of renal impairment (e.g., geriatric patients).^{1 257 258 261}

• Monitor with regular laboratory evaluations, including blood glucose determinations, to assess therapeutic response and to determine minimum effective dosage.^{1 85 179 257 258 261} Glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) measurements are also useful, particularly for long-term control of blood glucose concentrations.^{711 712}

• Following initiation and dosage titration, determination of HbA_1c concentrations at intervals of approximately 3 months is useful for assessing patient's continued response to therapy.²³⁴

Dispensing and Administration Precautions

• The Institute for Safe Medication Practices (ISMP) includes metFORMIN and metroNIDAZOLE on the ISMP List of Confused Drug Names, and recommends special safeguards to ensure the accuracy of prescriptions for these medications.⁷¹⁴

Other General Considerations

• Discontinue at the time of, or prior to, an iodinated procedure in patients with an eGFR 30—60 mL/minute per 1.73 m²; in patients with a history of liver disease, alcohol use disorder, or heart failure; or in patients who will be administered intraarterial contrast.^{1 257 258 261} Assess eGFR 48 hours after the imaging procedure and restart if renal function is stable.^{1 257 258 261}

• Discontinue temporarily in patients who require restricted food and fluid intake during surgical or other procedures, as this may increase the risk for volume depletion, hypotension, and renal impairment.^{1 257 258 261}

Administration

Oral Administration

Administer orally with meals to reduce adverse GI effects.^{1 18 53 85}

Administer immediate-release tablets in 2 divided doses daily if total dosage ≤2 g daily or in 3 divided doses daily if total dosage is >2 g daily.¹

Administer oral solution either once or twice daily with meals.²⁵⁷ Dosages >2 g daily may be better tolerated if administered in 3 divided doses daily.²⁵⁷ Measure each dose using a specific dosing cup.²⁵⁷

Administer extended-release tablets once daily with the evening meal; swallow whole and do not chew, cut, or crush.^{258 261}

Administer immediate-release metformin hydrochloride in fixed combination with canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, glipizide, glyburide, pioglitazone, alogliptin, linagliptin, or sitagliptin in divided doses daily with meals to reduce the GI effects of the metformin hydrochloride component.^{234 254 260 314 355 362 370 372 376 610} See full prescribing information for additional administration instructions for combination products.^{234 254 260 314 355 370 372 376 610}

Administer extended-release metformin hydrochloride in fixed combination with canagliflozin, dapagliflozin, or empagliflozin once daily with the morning meal.^{362 370 374} See full prescribing information for additional administration instructions for combination products.^{362 370 374}

Administer the fixed combination of extended-release metformin hydrochloride and linagliptin once daily with a meal.³⁷⁸ Administer the fixed combination of extended-release metformin hydrochloride and sitagliptin once daily with a meal, preferably the evening meal.³⁵² Administer extended-release metformin hydrochloride in fixed combination with saxagliptin once daily with the evening meal.³⁶⁸ See full prescribing information for additional administration instructions for combination products.^{352 368 378}

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

Pediatric Patients

Type 2 Diabetes Mellitus

Metformin Hydrochloride Monotherapy

Oral

Immediate-release tablets or immediate-release oral solution in children or adolescents ≥10 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 2 divided doses.^{1 257}

Immediate-release Metformin Hydrochloride in Fixed Combination with Canagliflozin (Invokamet)

Oral

Individualize dosage based on patient's current antidiabetic regimen.³⁷⁰ May increase dosage gradually based on effectiveness and tolerability.³⁷⁰

Children or adolescents ≥10 years of age not currently receiving either metformin hydrochloride or canagliflozin: Initially, 500 mg of metformin hydrochloride and 50 mg of canagliflozin twice daily.³⁷⁰

Children or adolescents ≥10 years of age currently receiving metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to the patient's existing dosage and 100 mg of canagliflozin, administered in 2 divided doses.³⁷⁰ In patients currently receiving an evening dose of extended-release metformin hydrochloride, skip last dose of extended-release metformin hydrochloride prior to initiating therapy with the fixed combination of metformin hydrochloride and canagliflozin the following morning.³⁷⁰

Children or adolescents ≥10 years of age currently receiving canagliflozin: Initially, 1 g of metformin hydrochloride and same daily dosage of canagliflozin administered in 2 divided doses.³⁷⁰

Children or adolescents ≥10 years of age currently receiving metformin hydrochloride and canagliflozin: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and same daily dosage of canagliflozin, administered in 2 divided doses.³⁷⁰

Extended-release Metformin Hydrochloride in Fixed Combination with Canagliflozin (Invokamet XR)

Oral

Individualize dosage based on patient's current antidiabetic regimen.³⁷⁰ May increase dosage gradually based on effectiveness and tolerability.³⁷⁰

Children or adolescents ≥10 years of age not currently receiving either metformin hydrochloride or canagliflozin: Initially, 1 g of metformin hydrochloride and 100 mg of canagliflozin once daily.³⁷⁰

Children or adolescents ≥10 years of age currently receiving metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to the patient's existing dosage and 100 mg of canagliflozin, administered once daily.³⁷⁰ In patients currently receiving an evening dose of extended-release metformin hydrochloride, skip last dose of extended-release metformin hydrochloride prior to initiating therapy with the fixed combination of metformin hydrochloride and canagliflozin the following morning.³⁷⁰

Children or adolescents ≥10 years of age currently receiving canagliflozin: Initially, 1 g of metformin hydrochloride and same daily dosage of canagliflozin administered once daily.³⁷⁰

Children or adolescents ≥10 years of age currently receiving metformin hydrochloride and canagliflozin: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and same daily dosage of canagliflozin, administered once daily.³⁷⁰

Extended-release Metformin Hydrochloride in Fixed Combination with Dapagliflozin (Xigduo XR)

Oral

Initial dosage based on patient's current regimen with metformin hydrochloride and/or dapagliflozin.³⁶² May increase dosage gradually based on effectiveness and tolerability.³⁶²

Children or adolescents ≥10 years of age not currently receiving metformin and/or dapagliflozin: Initially, 500 mg of the extended-release metformin component and 5 mg of the dapagliflozin component once daily.³⁶² Titrate gradually based on effectiveness and tolerability, up to a maximum daily dosage of 2 g of extended-release metformin and 10 mg of dapagliflozin.³⁶²

Children or adolescents ≥10 years of age already receiving extended-release metformin hydrochloride in the evening who are switching to the fixed combination of metformin hydrochloride and dapagliflozin: Skip last dose of metformin hydrochloride before initiating therapy with the fixed combination the following morning.³⁶²

Immediate-release Metformin Hydrochloride in Fixed Combination with Empagliflozin (Synjardy)

Oral

Individualize dosage based on the patient's current antidiabetic regimen.³⁷² May increase dosage gradually based on effectiveness and tolerability.³⁷²

Children or adolescents ≥10 years of age currently receiving metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and 10 mg of empagliflozin, administered in 2 divided doses.³⁷²

Children or adolescents ≥10 years of age currently receiving empagliflozin: Initially, 1 g of metformin hydrochloride and same daily dosage of empagliflozin administered in 2 divided doses.³⁷²

Children or adolescents ≥10 years of age currently receiving metformin hydrochloride and empagliflozin: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and same daily dosage of empagliflozin, administered in 2 divided doses.³⁷²

Extended-release Metformin Hydrochloride in Fixed Combination with Empagliflozin (Synjardy)

Oral

Individualize dosage based on the patient's current antidiabetic regimen.³⁷⁴ May increase dosage gradually based on effectiveness and tolerability.³⁷⁴

Children or adolescents ≥10 years of age currently receiving metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and 10 mg of empagliflozin, administered once daily.³⁷⁴

Children or adolescents ≥10 years of age currently receiving empagliflozin: Initially, 1 g of metformin hydrochloride and same daily dosage of empagliflozin administered once daily.³⁷⁴

Children or adolescents ≥10 years of age currently receiving metformin hydrochloride and empagliflozin: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and same daily dosage of empagliflozin, administered once daily.³⁷⁴

Adults

Type 2 Diabetes Mellitus

Metformin Hydrochloride Monotherapy

Oral

Immediate-release tablets or immediate-release 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 2.55 g daily given in divided doses.^{1 257}

Clinically important responses generally not observed at dosages <1.5 g daily.^{1 257}

Extended-release tablets: Initially, 500 mg once daily with the evening meal.^{258 261} Increase daily dosage by 500 mg at weekly intervals²⁵⁸ or every 1 to 2 weeks²⁶¹ based on glycemic control and tolerability up to a maximum of 2 g daily. If glycemic control is not achieved with 2 g once daily, consider administering 1 g twice daily.²⁵⁸ If >2 g daily is required, switch to immediate-release 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

May switch from immediate-release to extended-release metformin hydrochloride tablets at the same total daily dosage, up to 2 g once daily.^{1 258 261} Following a switch from immediate-release to extended-release metformin, closely monitor glycemic control and adjust dosage accordingly.^{1 258 261}

Immediate-release Metformin Hydrochloride in Fixed Combination with Glipizide

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), consider 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 1 or 2 g of metformin hydrochloride and 10 mg of glipizide in divided doses is reached.²⁵⁴

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 daily dosages exceeding 2 g of metformin hydrochloride and 10 mg of glipizide as initial therapy.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 500 mg of metformin hydrochloride and 5 mg of glipizide until adequate glycemic control is achieved or maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glipizide is reached.²⁵⁴

Immediate-release Metformin Hydrochloride in Fixed Combination with Glyburide

Oral

Patients not already receiving either metformin hydrochloride or glyburide (or another sulfonylurea): Initially, 250 mg of metformin hydrochloride and 1.25 mg of glyburide once or twice daily with meals.²³⁴ Titrate daily dosage gradually based on glycemic control and tolerability up to a maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glyburide.²³⁴

Patients with inadequate glycemic control on either glyburide (or another sulfonylurea) or metformin hydrochloride monotherapy: Initially, 500 mg of metformin hydrochloride and 2.5 mg of glyburide or 500 mg of metformin hydrochloride and 5 mg of glyburide twice daily with meals.²³⁴ Increase daily dosage gradually based on glycemic control and tolerability up to a maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glyburide.²³⁴

Patients with inadequate glycemic control on the combination of metformin and a sulfonylurea: Initial dosage of the fixed combination should not exceed the patient's current daily dosage of metformin hydrochloride and glyburide (or equivalent dosage of another sulfonylurea antidiabetic agent).²³⁴ Increase daily dosage gradually based on glycemic control and tolerability up to a maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glyburide.²³⁴

Immediate-release Metformin Hydrochloride in Fixed Combination with Pioglitazone (Actoplus Met)

Oral

Individualize dosage based on the patient’s current dosage regimen, effectiveness, and tolerability.^{260 710}

Patients in whom combination therapy with metformin and pioglitazone considered appropriate: Initially, 850 mg of metformin hydrochloride and 15 mg of pioglitazone once daily.^{260 710}

Patients inadequately controlled on metformin monotherapy: Initially, 850 mg of metformin hydrochloride and 15 mg of pioglitazone once or twice daily (depending on metformin hydrochloride dosage already being taken).^{260 710}

Patients inadequately controlled on pioglitazone monotherapy: Initially, 850 mg of metformin hydrochloride and 15 mg of pioglitazone once daily.^{260 710}

Patients switching from combination therapy with metformin hydrochloride and pioglitazone given as separate tablets: Use dosage of the fixed combination as close as possible to dosages of metformin hydrochloride and pioglitazone already being taken.^{260 710}

Patients with NYHA class I or II congestive heart failure: Initially, 850 mg of metformin hydrochloride and 15 mg of pioglitazone once daily.^{260 710} Initiation of the fixed combination in patients with NYHA class III or IV congestive heart failure contraindicated.^{260 710}

Gradually titrate dosage as needed based on therapeutic response and tolerability to maximum daily dosage of 2.55 g of metformin hydrochloride and 45 mg of pioglitazone.^{260 710} Metformin hydrochloride dosages >2 g daily may be better tolerated if given in 3 divided doses daily.^{260 710}

Immediate-release Metformin Hydrochloride in Fixed Combination with Alogliptin (Kazano)

Oral

Individualize dosage based on current antidiabetic regimen, effectiveness, and patient tolerability.⁶¹⁰ Increase dosage gradually to minimize adverse GI effects, up to a maximum daily dosage of 2 g of metformin hydrochloride and 25 mg of alogliptin.⁶¹⁰

Immediate-release Metformin Hydrochloride in Fixed Combination with Linagliptin (Jentadueto)

Oral

Individualize dosage based on effectiveness and patient tolerability.³⁷⁶ May increase dosage up to a maximum daily dosage of 2 g of metformin hydrochloride and 5 mg of linagliptin.³⁷⁶

Patients not currently receiving metformin hydrochloride: Initially, 1 g of metformin hydrochloride and 5 mg of linagliptin administered in 2 divided doses.³⁷⁶

Patients currently receiving metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and 5 mg of linagliptin, administered in 2 divided doses.³⁷⁶

Patients currently receiving metformin hydrochloride and linagliptin: Initially, same total daily dosage of each component administered in 2 divided doses daily.³⁷⁶

Extended-release Metformin Hydrochloride in Fixed Combination with Linagliptin (Jentadueto XR)

Oral

Individualize dosage based on effectiveness and patient tolerability.³⁷⁸ May increase dosage up to a maximum daily dosage of 2 g of metformin hydrochloride and 5 mg of linagliptin.³⁷⁸

Patients not currently receiving metformin hydrochloride: Initially, 1 g of metformin hydrochloride and 5 mg of linagliptin once daily.³⁷⁸

Patients currently receiving metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and 5 mg of linagliptin, administered once daily.³⁷⁸

Patients currently receiving metformin hydrochloride and linagliptin: Initially, same total daily dosage of each component, administered once daily.³⁷⁸

Extended-release Metformin Hydrochloride in Fixed Combination with Saxagliptin (Kombiglyze XR)

Oral

Individualize dosage based on current antidiabetic regimen, clinical response, and tolerability.³⁶⁸

Patients who need 5 mg of saxagliptin and who are not currently treated with metformin: Initially, 500 mg of extended-release metformin hydrochloride and 5 mg of saxagliptin once daily; gradually increase dosage to reduce adverse GI effects of metformin.³⁶⁸

Patients treated with metformin, the recommended starting dosage of the fixed-combination preparation should provide metformin at the dose already being taken, or the nearest therapeutically appropriate dose.³⁶⁸ Following a switch from immediate-release to extended-release metformin, monitor glycemic control closely and make dosage adjustments accordingly.³⁶⁸

Patients who need saxagliptin 2.5 mg daily in combination with metformin extended-release: 1 g of extended-release metformin hydrochloride and 2.5 mg of saxagliptin daily.³⁶⁸ Patients who require 2.5 mg of saxagliptin who are either metformin naïve or require a dose of metformin hydrochloride exceeding 1 g should use the individual components.³⁶⁸

Maximum recommended dosages of extended-release metformin hydrochloride and saxagliptin in fixed combination are 2 g of extended-release metformin hydrochloride and 5 mg of saxagliptin daily.³⁶⁸

When the fixed-combination preparation containing extended-release metformin hydrochloride and saxagliptin is used concomitantly with a potent cytochrome P-450 isoenzyme 3A4/5 (CYP3A4/5) inhibitor, limit dosage of saxagliptin to 2.5 mg once daily.³⁶⁸

Immediate-release Metformin Hydrochloride in Fixed Combination with Sitagliptin (Janumet)

Oral

Patients not currently receiving metformin hydrochloride: Initially, 500 mg of metformin hydrochloride and 50 mg of sitagliptin twice daily.³¹⁴

Patients currently receiving metformin hydrochloride: Initially, 500 mg of metformin hydrochloride and 50 mg of sitagliptin twice daily or 1 g of metformin hydrochloride and 50 mg of sitagliptin twice daily, depending on the patient's existing dosage of metformin hydrochloride.³¹⁴

Patients currently receiving immediate-release metformin hydrochloride 850 or 1000 mg twice daily: 1 g of metformin hydrochloride and 50 mg of sitagliptin twice daily.³¹⁴

Maintain the same total daily dosage of sitagliptin and metformin hydrochloride when transitioning between the fixed combination of sitagliptin and immediate-release metformin hydrochloride (Janumet) and the fixed combination of sitagliptin and extended-release metformin hydrochloride (Janumet XR).³⁵²

Efficacy and safety of switching therapy from oral antidiabetic agents other than metformin hydrochloride or sitagliptin to the fixed combination of sitagliptin and metformin hydrochloride not established.³¹⁴

Extended-release Metformin Hydrochloride in Fixed Combination with Sitagliptin (Janumet XR)

Oral

Patients not currently receiving metformin hydrochloride: Initially, 1 g of metformin hydrochloride and 100 mg of sitagliptin once daily.³⁵²

Patients currently receiving metformin hydrochloride: Initially, 1 g of metformin hydrochloride and 100 mg of sitagliptin once daily or 2 g of metformin hydrochloride and 100 mg of sitagliptin once daily, depending on the patient's existing dosage of metformin hydrochloride.³⁵²

Patients currently receiving immediate-release metformin hydrochloride 850 or 1000 mg twice daily: 2 g of metformin hydrochloride and 100 mg of sitagliptin once daily.^{314 352}

Maintain the same total daily dosage of metformin hydrochloride and sitagliptin when transitioning between the fixed combination of sitagliptin and immediate-release metformin hydrochloride and sitagliptin (Janumet) and the fixed combination of extended-release metformin hydrochloride and sitagliptin (Janumet XR).³⁵²

Efficacy and safety of switching therapy from oral antidiabetic agents other than metformin hydrochloride or sitagliptin to the fixed combination of metformin hydrochloride and sitagliptin not established.³⁵²

Immediate-release Metformin Hydrochloride in Fixed Combination with Canagliflozin (Invokamet)

Oral

Individualize dosage based on patient's current antidiabetic regimen.³⁷⁰ May increase dosage gradually based on effectiveness and tolerability.³⁷⁰

Patients not currently receiving either metformin hydrochloride or canagliflozin: Initially, 500 mg of metformin hydrochloride and 50 mg of canagliflozin twice daily.³⁷⁰

Patients currently receiving metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to the patient's existing dosage and 100 mg of canagliflozin, administered in 2 divided doses.³⁷⁰ In patients currently receiving an evening dose of extended-release metformin hydrochloride, skip last dose of extended-release metformin hydrochloride prior to initiating therapy with the fixed combination of metformin hydrochloride and canagliflozin the following morning.³⁷⁰

Patients currently receiving canagliflozin: Initially, 1 g of metformin hydrochloride and same daily dosage of canagliflozin administered in 2 divided doses.³⁷⁰

Patients currently receiving metformin hydrochloride and canagliflozin: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and same daily dosage of canagliflozin, administered in 2 divided doses.³⁷⁰

Extended-release Metformin Hydrochloride in Fixed Combination with Canagliflozin (Invokamet XR)

Oral

Individualize dosage based on patient's current antidiabetic regimen.³⁷⁰ May increase dosage gradually based on effectiveness and tolerability.³⁷⁰

Patients not currently receiving either metformin hydrochloride or canagliflozin: Initially, 1 g of metformin hydrochloride and 100 mg of canagliflozin once daily.³⁷⁰

Patients currently receiving metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to the patient's existing dosage and 100 mg of canagliflozin, administered once daily.³⁷⁰ In patients currently receiving an evening dose of extended-release metformin hydrochloride, skip last dose of extended-release metformin hydrochloride prior to initiating therapy with the fixed combination of metformin hydrochloride and canagliflozin the following morning.³⁷⁰

Patients currently receiving canagliflozin: Initially, 1 g of metformin hydrochloride and same daily dosage of canagliflozin administered once daily.³⁷⁰

Patients currently receiving metformin hydrochloride and canagliflozin: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and same daily dosage of canagliflozin, administered once daily.³⁷⁰

Extended-release Metformin Hydrochloride in Fixed Combination with Dapagliflozin (Xigduo XR)

Oral

Initial dosage based on patient's current regimen with metformin hydrochloride and/or dapagliflozin.³⁶² May increase dosage gradually based on effectiveness and tolerability.³⁶²

Patients not currently receiving metformin and/or dapagliflozin: Initially, 500 mg of the extended-release metformin component and 5 mg of the dapagliflozin component once daily.³⁶² Titrate gradually based on effectiveness and tolerability, up to a maximum daily dosage of 2 g of extended-release metformin and 10 mg of dapagliflozin.³⁶²

Patients already receiving extended-release metformin hydrochloride in the evening who are switching to the fixed combination of metformin hydrochloride and dapagliflozin: Skip last dose of metformin hydrochloride before initiating therapy with the fixed combination the following morning.³⁶²

Immediate-release Metformin Hydrochloride in Fixed Combination with Empagliflozin (Synjardy)

Oral

Individualize dosage based on the patient's current antidiabetic regimen.³⁷² May increase dosage gradually based on effectiveness and tolerability.³⁷²

Patients currently receiving metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and 10 mg of empagliflozin, administered in 2 divided doses.³⁷²

Patients currently receiving empagliflozin: Initially, 1 g of metformin hydrochloride and same daily dosage of empagliflozin administered in 2 divided doses.³⁷²

Patients currently receiving metformin hydrochloride and empagliflozin: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and same daily dosage of empagliflozin, administered in 2 divided doses.³⁷²

Extended-release Metformin Hydrochloride in Fixed Combination with Empagliflozin (Synjardy XR)

Oral

Individualize dosage based on the patient's current antidiabetic regimen.³⁷⁴ May increase dosage gradually based on effectiveness and tolerability.³⁷⁴

Patients currently receiving metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and 10 mg of empagliflozin, administered once daily.³⁷⁴

Patients currently receiving empagliflozin: Initially, 1 g of metformin hydrochloride and same daily dosage of empagliflozin administered once daily.³⁷⁴

Patients currently receiving metformin hydrochloride and empagliflozin: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and same daily dosage of empagliflozin, administered once daily.³⁷⁴

Immediate-release Metformin Hydrochloride in Fixed Combination with Ertugliflozin (Segluromet)

Oral

Initial dosage based on patient's current regimen with metformin hydrochloride and/or ertugliflozin.³⁵⁵ May increase dosage gradually based on effectiveness and tolerability.³⁵⁵

Patients currently receiving metformin hydrochloride: Initially, total daily metformin hydrochloride dosage similar to patient's existing dosage and total daily dosage of 5 mg of ertugliflozin (administered as fixed combination with 2.5 mg of ertugliflozin), given in 2 divided doses daily.³⁵⁵

Patients currently receiving ertugliflozin: Initially, total daily dosage of 1 g of metformin hydrochloride (administered as fixed combination with 500 mg of metformin hydrochloride) and the same daily dosage of ertugliflozin , given in 2 divided doses daily.³⁵⁵

Patients currently receiving metformin hydrochloride and ertugliflozin (administered as separate tablets): Initially, give fixed combination containing a total daily metformin hydrochloride dosage similar to patient's existing dosage and same total daily dose of ertugliflozin, in 2 divided doses daily.³⁵⁵

Polycystic Ovary Syndrome† [off-label]

Oral

In general, 1.5–2.25 g daily in divided doses.^{291 292 294 296 299 300 301 302 303 305 306 307 713}

Special Populations

Renal Impairment

Metformin Hydrochloride Monotherapy

eGFR 30–45 mL/minute per 1.73 m²: Initiation of therapy not recommended; assess benefits and risks of continued treatment if eGFR falls below 45 mL/minute per 1.73 m² in patients already receiving metformin.^{1 257 258 261 330 336}

eGFR <30 mL/minute per 1.73 m²: Contraindicated; discontinue in patients already receiving metformin.^{1 165 257 258 261 330 336}

Metformin Hydrochloride in Fixed Combination with Glipizide

eGFR 30–45 mL/minute per 1.73 m²: Initiation of therapy not recommended; assess benefits and risks of continued treatment if eGFR falls below 45 mL/minute per 1.73 m².²⁵⁴

eGFR <30 mL/minute per 1.73 m²: Contraindicated; discontinue use in patients already receiving.²⁵⁴

Metformin Hydrochloride in Fixed Combination with Glyburide

eGFR 30–45 mL/minute per 1.73 m²: Initiation of therapy not recommended; assess benefits and risks of continued treatment if eGFR falls below 45 mL/minute per 1.73 m².²³⁴

eGFR <30 mL/minute per 1.73 m²: Contraindicated; discontinue use in patients already receiving.²³⁴

Metformin Hydrochloride in Fixed Combination with Pioglitazone

eGFR 30–45 mL/minute per 1.73 m²: Initiation of therapy not recommended; assess benefits and risks of continued treatment if eGFR falls below 45 mL/minute per 1.73 m².^{260 710}

eGFR <30 mL/minute per 1.73 m²: Contraindicated; discontinue use in patients already receiving.^{260 710}

Metformin Hydrochloride in Fixed Combination with Alogliptin

eGFR ≥60 mL/minute per 1.73 m²: No dosage adjustment necessary.⁶¹⁰

eGFR 30—59 mL/minute per 1.73 m²: Use not recommended.⁶¹⁰

eGFR <30 mL/minute per 1.73 m²: Contraindicated.⁶¹⁰

Metformin Hydrochloride in Fixed Combination with Linagliptin

eGFR 30–45 mL/minute per 1.73 m²: Initiation of therapy not recommended; assess benefits and risks of continued treatment if eGFR falls below 45 mL/minute per 1.73 m².^{376 378}

eGFR <30 mL/minute per 1.73 m²: Contraindicated; discontinue use in patients already receiving.^{376 378}

Metformin Hydrochloride in Fixed Combination with Saxagliptin

eGFR ≥45 mL/minute per 1.73 m²: No dosage adjustment necessary.³⁶⁸

eGFR 30— <45 mL/minute per 1.73 m²: Initiation of therapy not recommended.³⁶⁸ Assess benefits and risks of continued treatment if eGFR falls below 45 mL/minute per 1.73 m².³⁶⁸

eGFR <30 mL/minute per 1.73 m²: Contraindicated; discontinue use in patients already receiving.³⁶⁸

Metformin Hydrochloride in Fixed Combination with Sitagliptin

eGFR 30—45 mL/minute per 1.73 m², immediate-releasemetformin hydrochloride: Use not recommended.³¹⁴

eGFR 30—45 mL/minute per 1.73 m², extended-release metformin hydrochloride: Initiation of therapy not recommended.³⁵² Assess benefits and risks of continued treatment if eGFR falls below 45 mL/minute per 1.73 m².³⁵²

eGFR <30 mL/minute per 1.73 m², immediate-release metformin hydrochloride: Contraindicated.³¹⁴

eGFR <30 mL/minute per 1.73 m², extended-release metformin hydrochloride: Contraindicated; discontinue use in patients already receiving.³⁵²

Metformin Hydrochloride in Fixed Combination with Canagliflozin

eGFR 45 to <60 mL/minute per 1.73 m²: Maximum daily dosage of 100 mg of canagliflozin component.³⁷⁰

eGFR <45 mL/minute per 1.73 m²: Initiation of therapy not recommended.³⁷⁰ Assess benefits and risks of continued treatment if eGFR falls below 45 mL/minute per 1.73 m² and do not exceed a maximum daily dosage of 100 mg of canagliflozin component.³⁷⁰

eGFR <30 mL/minute per 1.73 m²: Contraindicated; discontinue use in patients already receiving.³⁷⁰

Metformin Hydrochloride in Fixed Combination with Dapagliflozin

eGFR >45 mL/minute per 1.73 m²: No dosage adjustment necessary.³⁶²

eGFR 30—45 mL/minute per 1.73 m²: Initiation of therapy not recommended.³⁶² Assess benefits and risks of continued treatment if eGFR falls below 45 mL/minute per 1.73 m².³⁶²

eGFR <30 mL/minute per 1.73 m²: Contraindicated; discontinue use in patients already receiving.³⁶²

Metformin Hydrochloride in Fixed Combination with Empagliflozin

eGFR <45 mL/minute per 1.73 m²: Initiation of therapy not recommended.^{372 374}

eGFR <30 mL/minute per 1.73 m²: Contraindicated.^{372 374}

Metformin Hydrochloride in Fixed Combination with Ertugliflozin

eGFR <45 mL/minute per 1.73 m²: Use not recommended.³⁵⁵

eGFR <30 mL/minute per 1.73 m², end stage-renal disease, dialysis: Contraindicated.³⁵⁵

Hepatic Impairment

Avoid use in those with clinical or laboratory evidence of hepatic disease.^{1 165 260 287 314 330 336}

Geriatric Patients

In general, initiate therapy on the lower end of the dosing range and do not titrate to the maximum dosage recommended for younger adults;^{1 165 254 257 258 261 314} limited data suggest reducing initial dosage by approximately 33% in geriatric patients.¹⁷⁴

Monitor renal function more frequently to determine appropriate dosage.^{1 164 165 257 258 260 261 314}

Cautions for metFORMIN

Contraindications

• Acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma.^{1 257 258 261}

• Severe renal impairment (eGFR <30 mL/minute per 1.73 m²).^{1 257 258 261}

• Hypersensitivity to metformin hydrochloride.^{1 257 258 261 254}

Warnings/Precautions

Warnings

Lactic Acidosis

Lactic acidosis resulting in death, hypothermia, hypotension, and resistant bradyarrhythmias reported (see Boxed Warning).^{1 234 254 257 258 261} Onset often subtle and may be accompanied by only nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific and unexplained abdominal distress with nausea and vomiting or diarrhea.^{1 33 62 119 234 257 258 260 261 314} Characterized by elevated blood lactate concentrations (exceeding 45 mg/dL), anion gap acidosis (without evidence of ketonuria or ketonemia), and increased lactate/pyruvate ratio.^{1 257 258 261} Risk appears to increase with degree of renal impairment and patient's age; risk can be minimized by periodic monitoring of renal function and cautious dosage selection.^{1 32 62 63 65 76 85 91 93 96 119 123 124 158 164 165 234 238 287} Other risk factors include concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age ≥65 years, undergoing radiological procedures with intravascular contrast agents, surgery and other procedures, hypoxic states, excessive alcohol consumption, and hepatic impairment.^{234 254 260}

Lactic acidosis constitutes a medical emergency requiring immediate clinician evaluation;^{1 314 352 355} in such cases, metformin should be discontinued and general supportive therapy (e.g., volume expansion, diuresis) initiated immediately.^{1 32 62 119 260 314 352 355 361} Hemodialysis also recommended.^{1 23 32 62 117 119 257 258 260 261 314 352 355}

Withhold therapy promptly in patients with any condition associated with hypoxemia, sepsis, or dehydration, or in any patient who becomes acutely unwell.^{1 62 63 93 234 254 257 258} Avoid use in patients with clinical or laboratory evidence of hepatic impairment.^{1 63 65 85 91 93 156 158 234 254 257 258 260 261 314 352 355 362 368 370 372 374 376 378 610} Discontinue before or at the time of intravascular iodinated contrast imaging procedures in patients with an eGFR 30—60 mL/minute per 1.73 m² history of liver disease, alcohol use disorder, or heart failure.^{1 62 63 93 158 234 254 257 258 260 261 314 330 336 352 355 610} Evaluate renal function 48 hours after imaging procedure and reinstitute therapy if renal function stable.^{1 257 258 260 261 314 330 352 355 610} Withhold temporarily in patients undergoing surgery.^{1 62 63 93 158 234 254 257 258 260 261 314 330 336 352 355 610}

Educate patients of the importance of lactic acid symptoms (e.g., malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific and unexplained abdominal distress with nausea and vomiting or diarrhea) and instruct patients to notify their clinician immediately if these symptoms occur.^{1 257 258 261} Advise patients to avoid excessive alcohol intake.^{1 63 76 91 93 158 234 254 257 258 260 261 314 352 355}

Other Warnings and Precautions

Vitamin B12 Deficiency

Decreased serum vitamin B₁₂ concentrations, ^{1 18} with or without clinical manifestations (e.g., anemia).¹ Some patients (i.e., those with an inadequate absorption or intake of vitamin B₁₂ or calcium) appear to be predisposed.^{1 148 168 257 258 260 261}

Symptoms rapidly reversible following discontinuation of metformin or supplementation with vitamin B₁₂.^{1 6 20 70 77 82} Monitor hematologic parameters (e.g., hemoglobin, serum vitamin B₁₂ concentrations)^{1 82 114 148} prior to initiation of therapy and at least annually during treatment..^{1 257 258 261}

Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Metformin may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogues.^{1 257 258 261} A lower dosage of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia.^{1 257 258 261}

Macrovascular Outcomes

No conclusive evidence of macrovascular risk reduction with metformin.^{1 257 258 261}

Use of Fixed Combinations

When used in fixed combination with other medications consider the cautions, precautions, contraindications, and drug interactions associated with the concomitant agent(s) in addition to metformin.^{234 237 254 260 314 352 355 362 368 370 372 374 376 378 610}

Specific Populations

Pregnancy

Insufficient evidence to determine a medication-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes; available studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes.^{1 257 258 261} Limited data from uncontrolled or retrospective studies are conflicting regarding long-term maternal therapy on neonatal morbidity (e.g., congenital malformations) and mortality.^{92 115}

Poorly controlled diabetes in pregnancy increases maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications and increases fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.^{1 234 254 257 258 261}

Most clinicians recommend use of insulin during pregnancy in diabetic patients to maintain optimum control of blood glucose concentrations.^{1 18 92}

Lactation

Distributed into milk in rats; distributed into human milk.^{1 257 258 260 261 285 286} Insufficient information to determine effects on breast-fed infant and no available information on effects on milk production.^{1 257 258 261}

Consider developmental and health benefits of breastfeeding along with mother's clinical need for the medication and potential adverse effects on breast-fed child (e.g., hypoglycemia).^{234 254} Monitor breastfed infants for signs of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, seizures).^{234 254}

Females and Males of Reproductive Potential

Potential for unplanned pregnancy should be discussed with premenopausal females since metformin-containing therapy may result in ovulation in some anovulatory females.^{1 257 258 261}

Pediatric Use

Safety and efficacy of metformin as immediate-release tablets or immediate-release oral solution established in pediatric patients 10—16 years of age; not established in children <10 years of age.^{1 257}

Safety and efficacy of metformin as extended-release tablets in children <17 years of age have not been established.^{1 258 261}

Geriatric Use

Insufficient number of geriatric patients in controlled clinical trials of metformin hydrochloride immediate-release and extended-release tablets to determine if such patients respond differently than younger adults.^{1 257 258 261}

Start at the low end of the dosage range in geriatric patients, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other medication therapy and higher risk of lactic acidosis.^{1 257 258 261} Such patients generally should not receive the maximum recommended dosage.^{1 85 174 234 254 257 258 261 314}

Monitor renal function more frequently.^{1 164 165 314}

Hepatic Impairment

Generally avoid use in patients with clinical or laboratory evidence of hepatic disease.^{1 165 257 258 260 261 314 330 336} Elimination of lactate may be substantially reduced.^{1 257 258 261}

Renal Impairment

Substantially excreted renally; risk of accumulation and lactic acidosis increases with degree of renal impairment.^{1 257 258 261} Half-life prolonged and renal clearance decreased in patients with decreased renal function.^{1 257 258 261}

Evaluate renal function prior to initiation of therapy and at least annually thereafter.^{1 77 85 234 254 260 330}

Monitor more frequently if development of impaired renal function is anticipated (e.g., geriatric patients, those with blood glucose concentrations >300 mg/dL, those who may develop renal dysfunction as a result of polyuria and volume depletion).^{1 156 234 254 260 330}

Discontinue metformin if patient's eGFR drops below 30 mL/minute per 1.73 m² while on metformin therapy; contraindicated in such patients.^{1 234 254 257 260 330 336}

Common Adverse Effects

Immediate-release metformin hydrochloride tablets (>5%): diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.¹

Immediate-release metformin hydrochloride oral solution: diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.²⁵⁷

Extended-release metformin hydrochloride tablets (>5%): diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.²⁵⁸

Extended-release metformin hydrochloride tablets (Glumetza) (>5%): hypoglycemia, diarrhea, and nausea.²⁶¹

Drug Interactions

Drugs Affecting or Affected by Transport Systems

Concomitant use of medications (e.g., ranolazine, vandetanib, dolutegravir, cimetidine) that interfere with common renal tubular transport systems involved in renal elimination of metformin hydrochloride (e.g., organic cationic transporter [OCT] 2/multidrug and toxic extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis.^{1 257 258 261} Consider benefits and risk of concomitant use of such medications with metformin.^{1 257 258 261}

Drugs That May Antagonize Hypoglycemic Effects

Calcium-channel blocking agents, corticosteroids, thiazide diuretics, estrogens and progestins (e.g., oral contraceptives), isoniazid, niacin, phenothiazines, phenytoin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), thyroid preparations; observe patient closely for evidence of altered glycemic control when such medications are added to or withdrawn from therapy.^{1 80 85 91 120 121 139 143 151 152 153 154 159 160 257 258 261}

Specific Drugs or Foods

metFORMIN Pharmacokinetics

Absorption

Bioavailability

Approximately 50–60% (absolute) with dosages of 0.5–1.5 g.^{1 18 33 43 50 65 85 89}

Onset

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

Duration

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

Food

Food decreases and slightly delays absorption of immediate-release tablets.^{1 18 208 314}

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

Food increases the extent of absorption of extended-release tablets.²⁶¹ Peak plasma concentrations and time to achieve peak plasma concentrations not altered by administration of one extended-release preparation with food.²⁵⁸

Distribution

Extent

Rapidly distributed into peripheral body tissues and fluids, particularly GI tract.^{50 65 89 162 167}

Slowly distributed into erythrocytes and a deep tissue compartment (probably GI tissue).^{50 65 89 162 167}

Distributed into human breast milk.^{1 257 258 261}

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 89} Eliminated as unchanged drug.^{1 6 33 50 63 65 75 85 89 314}

Half-life

Approximately 6.2 hours.^{1 6 18 33 38 50 51 65 85 89 125 314}

Special Populations

Renal impairment may reduce clearance, including in geriatric patients with age-related decline in renal function.^{1 33 51 174 257 258 261} Renal impairment results in increased peak plasma concentrations, prolonged time to peak plasma concentration and half-life, and decreased volume of distribution.^{1 51 174 257 258 261}

Stability

Storage

Oral

Tablets

Immediate-release 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).^{258 261}

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

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

Metformin/pioglitazone fixed combination: Tight containers at 25°C.²⁶⁰

Metformin/alogliptin fixed combination: Tight containers at 25°C (may be exposed to 15—30°C).⁶¹⁰

Metformin/linagliptin fixed combination: 20—25°C (may be exposed to 15–30°C); protect from exposure to high humidity.^{376 378}

Metformin/saxagliptin fixed combination: 20–25°C (may be exposed to 15–30°C).³⁶⁸

Metformin/sitagliptin fixed combination: 20–25°C (may be exposed to 15–30°C).^{314 352}

Metformin/canagliflozin fixed combination: 20–25°C (may be exposed to 15–30°C).³⁷⁰ Store and dispense in original container.³⁷⁰ May store in pillbox for ≤30 days.³⁷⁰

Metformin/dapagliflozin: 20–25°C (may be exposed to 15–30°C).³⁶²

Metformin/empagliflozin: 25°C (may be exposed to 15–30°C).^{372 374}

Metformin/ertugliflozin: 20–25°C (may be exposed to 15–30°C); protect from moisture and store in a dry place.³⁵⁵

Solution

15–30°C.²⁵⁷

Actions

• Lowers blood glucose concentrations in patients with type 2 diabetes mellitus without increasing insulin secretion from pancreatic β cells.^{1 18 20 27 31 40 60 234 254} 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 18 20 27 29 102 103 111}

• Lowers both basal (fasting) and postprandial glucose concentrations in patients with type 2 diabetes mellitus.^{1 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 18 20 42 60 68 102 166 254}

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Patient Information).^{1 257 258 261}

• When metformin hydrochloride is used in fixed combination with other medications, inform patients of other precautionary information about the concomitant agent(s).^{234 254 257 258 261 314 355 362 363 368 369 370 371 372 373 374 375 376 377 378 379 610}

• Advise patients to take with meals and to swallow the tablet whole and do not crush, cut, or chew the tablet.^{1 257 258 261}

• Advise patients taking extended-release tablet preparations of metformin hydrochloride that occasionally the biologically inert components of the tablet may remain intact and be passed in the stool as a soft, hydrated mass.^{258 261}

• Advise patients or caregivers to use the supplied dosing cup to measure the prescribed amount of metformin hydrochloride oral solution.²⁵⁷ Inform patients that additional dosing cups or oral dosing syringes may be obtained from their pharmacy.²⁵⁷

• Advise patients that if a dose is missed, they should take the next dose at the prescribed time and not to take an extra dose the next day.^{1 257 258 261}

• Advise patients to inform their clinician that they are taking metformin hydrochloride prior to any surgical or radiological procedure, as temporary discontinuation may be required.^{1 257 258 261}

• Advise patients to inform their clinician of times of stress, such as fever, trauma, or infection, as the dosage of metformin hydrochloride may require adjustment.^{1 257 258 261}

• Inform patients of the risks of lactic acidosis, its symptoms, and conditions that predispose to its development. Advise patients to discontinue metformin hydrochloride immediately and to promptly notify their clinician if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur.^{1 257 258 261}

• Inform patients of the need for regular testing of renal function and hematological parameters.^{1 257 258 261}

• Inform patients that hypoglycemia may occur.^{1 257 258 261} Inform patients receiving concomitant therapy of the risk of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development.^{1 257 258 261}

• Advise patients to avoid excessive alcohol intake.^{1 257 258 261}

• Inform patients of the importance of adherence to dietary instructions, regular physical activity, period blood glucose monitoring and glycosylated hemoglobin (hemoglobin A_1c; HbA_1c) testing, and assessment of diabetes mellitus complications.^{1 257 258 261}

• Advise females of reproductive potential that treatment with metformin hydrochloride may result in ovulation in some premenopausal anovulatory women, which may lead to unintended pregnancy.^{1 257 258 261}

• Advise patient to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.^{1 257 258 261}

• Advise patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed.^{1 257 258 261}

• Inform patients of other important precautionary information.^{1 257 258 261}

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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Frequently asked questions

• How long does metformin take to work?
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