metFORMIN

Class: Biguanides
ATC Class: A10BA02
VA Class: HS502
Chemical Name: 1,1-Dimethylbiguanide monohydrochloride
Molecular Formula: C₄H₁₁N₅ • HCl
CAS Number: 1115-70-4
Brands: Fortamet, Glumetza, Riomet

Medically reviewed by Drugs.com on Jun 21, 2021. Written by ASHP.

Warning

Lactic acidosis rare but potentially fatal. Increased risk of lactic acidosis in patients with renal impairment and advanced age.
Generally has occurred in diabetic patients with severe renal insufficiency and concomitant medical and/or surgical problems who were receiving multiple drugs; metformin plasma concentrations >5 mcg/mL often found in patients with lactic acidosis.
Periodically monitor renal function and use the minimum effective dosage. Withhold metformin promptly in patients with any condition associated with hypoxemia, sepsis, or dehydration. Avoid use in patients with clinical or laboratory evidence of hepatic impairment. Manufacturers state to temporarily discontinue metformin therapy before or at the time of an intravascular (e.g., IV, intra-arterial) iodinated contrast imaging procedure in patients with eGFR of 30–60 mL/minute per 1.73 m² and in patients with a history of liver disease, alcoholism, or heart failure. Withhold metformin temporarily in patients undergoing surgery. Concomitant drugs that may affect renal function, produce substantial hemodynamic changes, or alter metformin elimination should be used with caution.

However, the American College of Radiology states that in patients with no evidence of acute kidney injury and eGFR ≥30 mL/minute per 1.73 m², no need to discontinue metformin either before or following the administration of iodinated contrast media, nor is there a need to reassess the patient's renal function after the test or procedure.
Advise patients not to consume excessive amounts of alcohol, acutely or chronically.
If lactic acidosis occurs, discontinue metformin and institute general supportive therapy immediately. Treat as medical emergency, with immediate hospitalization and treatment required; prompt hemodialysis recommended.

Introduction

Antidiabetic agent; a biguanide, chemically and pharmacologically unrelated to sulfonylurea antidiabetic agents.

Uses for metFORMIN

Type 2 Diabetes Mellitus

Used as an adjunct to diet and exercise for the management of type 2 diabetes mellitus.

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 drugs.

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

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

Commercially available in fixed combination with pioglitazone 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.

Commercially available in fixed combination with the DPP-4 inhibitors alogliptin, linagliptin, saxagliptin, or sitagliptin for use as an adjunct to diet and exercise when treatment with both drug components is appropriate.

Commercially available in fixed combinations with the SGLT2 inhibitors canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin for use when treatment with both drug components is appropriate.

Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications in patients with recent-onset type 2 diabetes mellitus or mild hyperglycemia because of its well-established safety and efficacy (i.e., beneficial effects on glycosylated hemoglobin [hemoglobin A_1c; HbA_1c], weight, and cardiovascular mortality). 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.

In patients with metformin contraindications or intolerance (e.g., risk of lactic acidosis, GI intolerance) or in selected other patients, some experts suggest that initial therapy with a drug from another class of antidiabetic agents (e.g., a GLP-1 receptor agonist, SGLT2 inhibitor, DPP-4 inhibitor, sulfonylurea, thiazolidinedione, basal insulin) may be acceptable based on patient factors.

May need to initiate therapy with 2 agents (e.g., metformin plus another drug) in patients with high initial HbA_1c (>7.5% or ≥1.5% above target). In such patients with metformin intolerance, some experts suggest initiation of therapy with 2 drugs from other antidiabetic drug classes with complementary mechanisms of action.

Consider early initiation of combination therapy for the treatment of type 2 diabetes mellitus to extend the time to treatment failure and more rapidly attain glycemic goals.

For patients with inadequate glycemic control on metformin monotherapy, consider patient comorbidities (e.g., atherosclerotic cardiovascular disease [ASCVD], established kidney disease, heart failure), hypoglycemia risk, impact on weight, cost, risk of adverse effects, and patient preferences when selecting additional antidiabetic agents for combination therapy.

Consider early introduction of insulin for severe hyperglycemia (e.g., blood glucose ≥300 mg/dL or HbA_1c >9–10%), especially if accompanied by catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.

Experts recommend that patients with type 2 diabetes mellitus who have established (or are at a high risk for) ASCVD, established kidney disease, or heart failure receive a GLP-1 receptor agonist or SGLT2 inhibitor with demonstrated cardiovascular disease benefit. In patients with these comorbidities, consider GLP-1 receptor agonist or SGLT2 inhibitor therapy independently of patient's HbA_1c.

In patients with type 2 diabetes mellitus and CKD, consider a GLP-1 receptor agonist or SGLT2 inhibitor shown to reduce the risk of CKD progression, cardiovascular events, or both, in addition to metformin therapy or in those in whom metformin cannot be used.

In patients on metformin monotherapy without established ASCVD or indicators of high ASCVD risk, heart failure, or CKD, base decision regarding addition of other antidiabetic agents on avoidance of adverse effects, cost, and individual patient factors.

Not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

Polycystic Ovary Syndrome

Has been used in the management of metabolic and reproductive abnormalities associated with polycystic ovary syndrome†.

metFORMIN Dosage and Administration

General

When therapy is transferred from most sulfonylurea antidiabetic agents to metformin, sulfonylurea agent may be abruptly discontinued (no transition period generally required).
Close monitoring for hypoglycemia has been advised during the initial 2 weeks following transfer of therapy from chlorpropamide (no longer commercially available in the US) to metformin.
Goal of therapy should be to reduce both fasting glucose and HbA_1c values to normal or near normal using the lowest effective dosage of metformin hydrochloride, either when used as monotherapy or combined with another antidiabetic agent.

Administration

Oral Administration

Administer orally with meals to reduce adverse GI effects.

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.

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

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.

Administer extended-release metformin hydrochloride in fixed combination with canagliflozin, dapagliflozin, or empagliflozin once daily with the morning meal.

Administer the fixed combination of extended-release metformin hydrochloride and linagliptin once daily with a meal. Administer the fixed combination of extended-release metformin hydrochloride and sitagliptin once daily with a meal, preferably the evening meal. Administer extended-release metformin hydrochloride in fixed combination with saxagliptin once daily with the evening meal.

Dosage

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

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

Pediatric Patients

Type 2 Diabetes Mellitus

Oral

Immediate-release tablets or immediate-release oral solution in children or adolescents 10–16 years of age: Initially, 500 mg twice daily with meals.

Increase daily dosage in increments of 500 mg at weekly intervals to a maximum of 2 g daily given in 2 divided doses.

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

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. May increase dosage from 500 mg twice daily to 850 mg twice daily after 2 weeks.

Clinically important responses generally not observed at dosages <1.5 g daily.

Certain extended-release tablets: Initially, 500 mg once daily with the evening meal. Increase daily dosage by 500 mg at weekly intervals 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. 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). May switch from immediate-release to extended-release metformin hydrochloride tablets at the same total daily dosage, up to 2 g once daily.

Extended-release tablets (Glumetza) in patients ≥18 years of age: Initially, 1 g once daily with the evening meal. Increase daily dosage by 500 mg at weekly intervals to a maximum of 2 g once daily with the evening meal. If glycemic control not achieved with 2 g once daily, consider administering 1 g twice daily.

Manufacturer states that based on a clinical trial, therapy with immediate-release metformin may be switched to extended-release metformin (Glumetza) once daily at the same total daily dosage, up to 2 g once daily. Following a switch from immediate-release metformin to extended-release metformin hydrochloride (Glumetza), closely monitor glycemic control and adjust dosage accordingly.

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. Increase daily dosage by 500 mg at weekly intervals to a maximum of 2.5 g once daily with the evening meal.

Manufacturer states that based on a clinical trial, therapy with immediate-release metformin may be switched to extended-release metformin (Fortamet) once daily at the same total daily dosage, up to 2.5 g once daily. Following a switch from immediate-release metformin to extended-release metformin hydrochloride (Fortamet), closely monitor glycemic control and adjust dosage accordingly.

Combined Metformin Hydrochloride and Oral Sulfonylurea Therapy

Oral

Certain extended-release metformin hydrochloride tablets (Fortamet, Glumetza): Manufacturers suggest gradual addition of an oral sulfonylurea antidiabetic agent in patients not responding to 4 weeks of monotherapy with maximum dosages of metformin hydrochloride; continue metformin hydrochloride at the maximum dosage even if prior primary or secondary failure to a sulfonylurea has occurred. Adjust dosage of metformin hydrochloride (e.g., Fortamet, Glumetza) and the sulfonylurea to obtain the desired level of glycemic control with the minimum effective dosage. Concomitant metformin and sulfonylurea therapy may increase risk of hypoglycemia; take appropriate precautions. If patient has not responded satisfactorily to 1–3 months of concomitant therapy with maximum dosages of metformin hydrochloride (e.g., Fortamet, Glumetza) and an oral sulfonylurea, consider therapeutic alternatives, including switching to insulin with or without metformin.

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. 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. 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.

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

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. 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). 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.

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). Use clinical judgment regarding whether to switch to the nearest equivalent dosage or to titrate dosage. 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.

Immediate-release Metformin Hydrochloride in Fixed Combination with Glyburide

Oral

Patients not already receiving either glyburide (or another sulfonylurea) or metformin hydrochloride: Initially, 250 mg of metformin hydrochloride and 1.25 mg of glyburide once or twice daily with meals. 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.

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. 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.

Patients with inadequate glycemic control on the combination of a sulfonylurea and metformin: 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. 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.

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.

Patients in whom combination therapy with metformin and pioglitazone considered appropriate: Initially, 500 mg of metformin hydrochloride and 15 mg of pioglitazone twice daily or 850 mg of metformin hydrochloride and 15 mg of pioglitazone once daily.

Patients inadequately controlled on metformin monotherapy: Initially, 500 mg of metformin hydrochloride and 15 mg of pioglitazone twice daily or 850 mg of metformin hydrochloride and 15 mg of pioglitazone once or twice daily (depending on metformin hydrochloride dosage already being taken).

Patients inadequately controlled on pioglitazone monotherapy: Initially, 500 mg of metformin hydrochloride and 15 mg of pioglitazone twice daily or 850 mg of metformin hydrochloride and 15 mg of pioglitazone once daily.

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.

Patients with NYHA class I or II congestive heart failure: Initially, 500 mg of metformin hydrochloride and 15 mg of pioglitazone or 850 mg of metformin hydrochloride and 15 mg of pioglitazone once daily. Initiation of the fixed combination in patients with NYHA class III or IV congestive heart failure contraindicated.

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. Metformin hydrochloride dosages >2 g daily may be better tolerated if given in 3 divided doses daily.

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

Oral

Individualize dosage based on current antidiabetic regimen, effectiveness, and patient tolerability. 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.

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

Oral

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

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

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.

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

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

Oral

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

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

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.

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

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

Oral

Patients inadequately controlled on monotherapy with saxagliptin 5 mg daily: Initially, 500 mg of metformin hydrochloride and 5 mg of saxagliptin once daily; increase dosage gradually to minimize adverse GI effects of metformin.

Patients inadequately controlled on monotherapy with extended-release metformin hydrochloride: Dosage of the fixed combination should provide metformin hydrochloride at the current dosage or the nearest therapeutically appropriate dosage.

Following a switch from immediate-release to extended-release metformin hydrochloride, closely monitor glycemic control and adjust dosage accordingly.

Patients inadequately controlled on monotherapy with saxagliptin 2.5 mg daily: Initially, 1 g of metformin hydrochloride and 2.5 mg of saxagliptin daily. Use the individual components in patients who require 2.5 mg of saxagliptin and are either metformin naive or require a metformin hydrochloride dose >1 g.

If used with a potent CYP3A4/5 inhibitor, limit dosage of saxagliptin to 2.5 mg once daily.

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.

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.

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.

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).

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

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.

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.

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.

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

Oral

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

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

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. 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.

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

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.

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

Oral

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

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

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. 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.

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

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. May increase dosage gradually based on effectiveness and tolerability.

Patients not currently receiving dapagliflozin: Initially, 5 mg of the dapagliflozin component once daily. 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.

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.

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

Oral

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

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.

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

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

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

Oral

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

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.

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

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. May increase dosage gradually based on effectiveness and tolerability.

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.

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 a total daily ertugliflozin dosage similar to the patient's existing dosage, given in 2 divided doses daily.

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.

Metformin Hydrochloride Dosage in Patients Receiving Insulin

Oral

Certain extended-release tablets (Fortamet, Glumetza): Initially, 500 mg once daily; concurrent insulin dosage initially remains unchanged. Increase metformin hydrochloride dosage by 500 mg daily at weekly intervals until adequate glycemic control is achieved or a maximum daily dosage of 2.5 g (Fortamet) or 2 g (Glumetza) is reached. When fasting plasma glucose concentration decreases to <120 mg/dL, decrease insulin dosage by 10–25%. Individualize further dosage adjustments according to glycemic response.

Polycystic Ovary Syndrome†

Oral

In general, 1.5–2.25 g daily in divided doses.

Prescribing Limits

Pediatric Patients

Type 2 Diabetes Mellitus

Oral

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

Adults

Type 2 Diabetes Mellitus

Metformin Hydrochloride Monotherapy

Oral

Maximum 2.55 g daily as immediate-release tablets or immediate-release oral solution, 2.5 g daily as Fortamet extended-release tablets, or 2 g daily as certain other extended-release tablets. Switch to immediate-release tablets for further dosage titration if required dosage exceeds 2 g daily.

Metformin Hydrochloride in Fixed Combination with Glyburide

Oral

Maximum daily dosage is 2 g of metformin hydrochloride and 20 mg of glyburide.

Metformin Hydrochloride in Fixed Combination with Glipizide

Oral

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

Metformin Hydrochloride in Fixed Combination with Linagliptin (Jentadueto, Jentadueto XR)

Oral

Maximum daily dosage is 2 g of metformin hydrochloride and 5 mg of linagliptin.

Metformin Hydrochloride in Fixed Combination with Saxagliptin (Kombiglyze XR)

Oral

Maximum daily dosage is 2 g of metformin hydrochloride and 5 mg of saxagliptin.

Metformin Hydrochloride in Fixed Combination with Sitagliptin (Janumet, Janumet XR)

Oral

Maximum daily dosage is 2 g of metformin hydrochloride and 100 mg of sitagliptin.

Metformin Hydrochloride in Fixed Combination with Canagliflozin (Invokamet, Invokamet XR)

Oral

Patients with eGFR ≥60 mL/minute per 1.73 m²: Maximum daily dosage is 2 g of metformin hydrochloride and 300 mg of canagliflozin.

Patients with eGFR 45 to <60 mL/minute per 1.73 m²: Maximum daily dosage is 2 g of metformin hydrochloride and 100 mg of canagliflozin.

Metformin Hydrochloride in Fixed Combination with Dapagliflozin (Xigduo XR)

Oral

Maximum daily dosage is 2 g of metformin hydrochloride and 10 mg of dapagliflozin.

Metformin Hydrochloride in Fixed Combination with Empagliflozin (Synjardy, Synjardy XR)

Oral

Maximum daily dosage is 2 g of metformin hydrochloride and 25 mg of empagliflozin.

Metformin Hydrochloride in Fixed Combination with Ertugliflozin (Segluromet)

Oral

Maximum daily dosage is 2 g of metformin hydrochloride and 15 mg of ertugliflozin.

Special Populations

Renal Impairment

eGFR 30–45 mL/minute per 1.73 m²: Initiation of metformin 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.

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

Hepatic Impairment

Avoid use in those with clinical or laboratory evidence of hepatic disease.

Geriatric Patients

In general, do not titrate to the maximum dosage recommended for younger adults; limited data suggest reducing initial dosage by approximately 33% in geriatric patients.

Monitor renal function regularly to determine appropriate dosage.

Cautions for metFORMIN

Contraindications

Acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma.
Severe renal impairment (eGFR <30 mL/minute per 1.73 m²), which may result from conditions such as cardiovascular collapse (shock), acute MI, or septicemia.
Known hypersensitivity to metformin hydrochloride or any ingredient in the formulations.

Warnings/Precautions

Warnings

Lactic Acidosis

See Boxed Warning.

Other Warnings and Precautions

Hypoglycemia

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

Hematologic Effects

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

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

In patients who develop neuropathy while on metformin, monitor vitamin B₁₂ levels and administer supplementation if needed; 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).

Macrovascular Outcomes

The manufacturer states that there have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin.

Concurrent Illness

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

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

Use of Fixed Combinations

When used in fixed combination with other drugs, consider the cautions, precautions, contraindications, and interactions associated with the concomitant agent(s).

Specific Populations

Pregnancy

Category B.

Available studies suggest no clear association between metformin use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. Use metformin during pregnancy only when clearly needed.

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

Lactation

Distributed into milk in rats; small amounts distributed into human milk. Consider developmental and health benefits of breastfeeding along with mother's clinical need for the drug and potential adverse effects on breastfed child (e.g., hypoglycemia). Monitor breastfed infants for signs of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, seizures).

Pediatric Use

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

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

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

Geriatric Use

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

Use with caution, since renal function declines with age.

Monitor renal function periodically.

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

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

Renal Impairment

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

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

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

Discontinue metformin if patient's eGFR <30 mL/minute per 1.73 m² or drops below 30 mL/minute per 1.73 m² while on metformin therapy; contraindicated in such patients.

Hepatic Impairment

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

Common Adverse Effects

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

Interactions for metFORMIN

Cationic Agents Secreted by Proximal Renal Tubules

Pharmacokinetic interaction with cimetidine (decreased excretion of metformin).

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

Monitor carefully; consider dosage adjustment of either agent.

Protein-bound Drugs

Pharmacokinetic interaction unlikely.

Drugs That May Antagonize Hypoglycemic Effects

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

Specific Drugs or Foods

Drug	Interaction	Comments
Acarbose	Acute decrease in metformin bioavailability in single-dose study
ACE inhibitors	Potential risk of hypoglycemia/hyperglycemia when ACE inhibitor therapy is initiated/withdrawn	Monitor blood glucose concentrations during dosage adjustments with either agent
Alcohol	Increased risk of hypoglycemia and lactic acidosis	Avoid excessive alcohol intake
Antidiabetic agents (e.g., sulfonylureas, meglitinides, insulin)	Possible hypoglycemia	May need to reduce dosage of concomitant antidiabetic agent
β-Adrenergic blocking agents	May impair glucose tolerance; may increase frequency or severity of hypoglycemia and hypoglycemia-induced complications	If concomitant therapy necessary, a β₁-selective adrenergic blocking agent or β-adrenergic blocking agents with intrinsic sympathomimetic activity preferred
Carbonic anhydrase inhibitors	May reduce serum bicarbonate concentrations and induce non-anion gap, hyperchloremic metabolic acidosis; may increase risk for lactic acidosis	Consider more frequent monitoring of patients receiving such concomitant therapy
Cimetidine	Possible decreased excretion of metformin Increased peak concentrations and AUC of metformin; negligible effects on cimetidine pharmacokinetics	Carefully monitor patient; consider need for dosage adjustment
Clomiphene	Possible resumption of ovulation in premenopausal patients with polycystic ovary syndrome
Furosemide	Increased peak concentrations of metformin and decreased peak concentrations and terminal half-life of furosemide in single-dose study
Glyburide	Pharmacokinetics and pharmacodynamics of metformin not altered in single-dose study
Guar gum	Reduced and delayed GI absorption of metformin
Nifedipine	Enhanced absorption and increased urinary excretion of metformin; minimal effects on nifedipine pharmacokinetics
Thiazide diuretics	May exacerbate diabetes mellitus	Consider using less diabetogenic diuretic (e.g., potassium-sparing diuretic), reducing dosage of or discontinuing diuretic, or increasing dosage of oral antidiabetic agent

metFORMIN Pharmacokinetics

Absorption

Bioavailability

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

Onset

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

Duration

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

Food

Food decreases and slightly delays absorption of immediate-release tablets.

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

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

Distribution

Extent

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

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

Plasma Protein Binding

Negligible.

Elimination

Metabolism

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

Elimination Route

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

Half-life

Approximately 6.2 hours.

Special Populations

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

Stability

Storage

Oral

Tablets

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

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

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

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

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

Metformin/linagliptin fixed combination: 25°C (may be exposed to 15–30°C); protect from exposure to high humidity.

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

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

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

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

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

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

Solution

15–30°C.

Actions

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

Advice to Patients

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

Preparations

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

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

* 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*	metFORMIN Hydrochloride Solution
			Riomet	Ranbaxy
	Tablets, extended-release	500 mg*	Fortamet	Shionogi Pharma
			Glumetza	Depomed
			metFORMIN Hydrochloride Extended-Release Tablets
		750 mg*	metFORMIN Hydrochloride Extended-Release Tablets
		1 g*	Fortamet	Shionogi Pharma
			Glumetza	Depomed
			metFORMIN Hydrochloride Extended-Release Tablets
	Tablets, film-coated	500 mg*	metFORMIN Hydrochloride Tablets
		625 mg*	metFORMIN Hydrochloride Tablets
		750 mg*	metFORMIN Hydrochloride Tablets
		850 mg*	metFORMIN Hydrochloride Tablets
		1 g*	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	500 mg with Immediate-release Canagliflozin (anhydrous) 50 mg	Invokamet XR	Janssen
		500 mg with Immediate-release Canagliflozin (anhydrous) 150 mg	Invokamet XR	Janssen
		500 mg with Immediate-release Dapagliflozin Propanediol 5 mg (of dapagliflozin)	Xigduo XR	AstraZeneca
		500 mg with Immediate-release Dapagliflozin Propanediol 10 mg (of dapagliflozin)	Xigduo XR	AstraZeneca
		500 mg with Immediate-release Saxagliptin 5 mg	Kombiglyze XR	AstraZeneca
		500 mg with Immediate-release Sitagliptin 50 mg	Janumet XR	Merck
		1 g with Immediate-release Canagliflozin (anhydrous) 50 mg	Invokamet XR	Janssen
		1 g with Immediate-release Canagliflozin (anhydrous) 150 mg	Invokamet XR	Janssen
		1 g with Immediate-release Dapagliflozin Propanediol 2.5 mg (of dapagliflozin)	Xigduo XR	AstraZeneca
		1 g with Immediate-release Dapagliflozin Propanediol 5 mg (of dapagliflozin)	Xigduo XR	AstraZeneca
		1 g with Immediate-release Dapagliflozin Propanediol 10 mg (of dapagliflozin)	Xigduo XR	AstraZeneca
		1 g with Immediate-release Empagliflozin 5 mg	Synjardy XR	Boehringer Ingelheim
		1 g with Immediate-release Empagliflozin 10 mg	Synjardy XR	Boehringer Ingelheim
		1 g with Immediate-release Empagliflozin 12.5 mg	Synjardy XR	Boehringer Ingelheim
		1 g with Immediate-release Empagliflozin 25 mg	Synjardy XR	Boehringer Ingelheim
		1 g with Immediate-release Linagliptin 2.5 mg	Jentadueto XR	Boehringer Ingelheim
		1 g with Immediate-release Linagliptin 5 mg	Jentadueto XR	Boehringer Ingelheim
		1 g with Immediate-release Saxagliptin 2.5 mg	Kombiglyze XR	AstraZeneca
		1 g with Immediate-release Saxagliptin 5 mg	Kombiglyze XR	AstraZeneca
		1 g with Immediate-release Sitagliptin 50 mg	Janumet XR	Merck
		1 g with Immediate-release Sitagliptin 100 mg	Janumet XR	Merck
	Tablets, film-coated	250 mg with Glipizide 2.5 mg*	metFORMIN Hydrochloride and Glipizide Tablets
		250 mg with Glyburide 1.25 mg*	metFORMIN Hydrochloride and Glyburide Tablets
		500 mg with Alogliptin Benzoate 12.5 mg (of alogliptin)	Kazano	Takeda
		500 mg with Canagliflozin (anhydrous) 50 mg	Invokamet	Janssen
		500 mg with Canagliflozin (anhydrous) 150 mg	Invokamet	Janssen
		500 mg with Empagliflozin 5 mg	Synjardy	Boehringer Ingelheim
		500 mg with Empagliflozin 12.5 mg	Synjardy	Boehringer Ingelheim
		500 mg with Ertugliflozin L-pyroglutamic Acid 2.5 mg (of ertugliflozin)	Segluromet	Merck
		500 mg with Ertugliflozin L-pyroglutamic Acid 7.5 mg (of ertugliflozin)	Segluromet	Merck
		500 mg with Glipizide 2.5 mg*	metFORMIN Hydrochloride and Glipizide Tablets
		500 mg with Glipizide 5 mg*	metFORMIN Hydrochloride and Glipizide Tablets
		500 mg with Glyburide 2.5 mg*	metFORMIN Hydrochloride and Glyburide Tablets
		500 mg with Glyburide 5 mg*	MetFORMIN Hydrochloride and Glyburide Tablets
		500 mg with Linagliptin 2.5 mg	Jentadueto	Boehringer Ingelheim
		500 mg with Pioglitazone Hydrochloride 15 mg (of pioglitazone)	Actoplus Met	Takeda
		500 mg with Sitagliptin Phosphate 50 mg (of sitagliptin)	Janumet	Merck
		850 mg with Linagliptin 2.5 mg	Jentadueto	Boehringer Ingelheim
		850 mg with Pioglitazone Hydrochloride 15 mg (of pioglitazone)	Actoplus Met	Takeda
		1 g with Alogliptin Benzoate 12.5 mg (of alogliptin)	Kazano	Takeda
		1 g with Canagliflozin (anhydrous) 50 mg	Invokamet	Janssen
		1 g with Canagliflozin (anhydrous) 150 mg	Invokamet	Janssen
		1 g with Empagliflozin 5 mg	Synjardy	Boehringer Ingelheim
		1 g with Empagliflozin 12.5 mg	Synjardy	Boehringer Ingelheim
		1 g with Ertugliflozin L-pyroglutamic Acid 2.5 mg (of ertugliflozin)	Segluromet	Merck
		1 g with Ertugliflozin L-pyroglutamic Acid 7.5 mg (of ertugliflozin)	Segluromet	Merck
		1 g with Linagliptin 2.5 mg	Jentadueto	Boehringer Ingelheim
		1 g with Sitagliptin Phosphate 50 mg (of sitagliptin)	Janumet	Merck