Version July 2025
Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally greater than 5 mcg/mL.
Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), 65 years and older, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the full prescribing information.
If metformin-associated lactic acidosis is suspected, immediately discontinue therapy and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
Dosage guidance:
Clinical considerations: Correct hypovolemia, if present, prior to initiating therapy. May require a gradual dose reduction of insulin and/or insulin secretagogues (eg, sulfonylureas) to avoid hypoglycemia.
Diabetes mellitus, type 2, treatment: Note: Xigduo XR is available as multiple fixed-dose combinations of dapagliflozin and metformin; use caution when prescribing and dispensing. If converting from a metformin extended-release product that is being taken in the evening, skip the last dose before starting the dapagliflozin/metformin combination product.
Children ≥10 years and Adolescents: Oral: Initial: Individualize based on patient's current antidiabetic regimen. Patients not previously receiving dapagliflozin should initiate dapagliflozin at 5 mg once daily. May gradually increase dose based on effectiveness and tolerability; maximum daily dose: dapagliflozin 10 mg/metformin 2,000 mg once daily.
Note: The glycemic efficacy of dapagliflozin decreases as kidney function declines.
Diabetes mellitus, type 2: Children ≥10 years and Adolescents: Oral:
eGFR ≥45 mL/minute/1.73 m2: No dosage adjustment necessary.
eGFR 30 to <45 mL/minute/1.73 m2:
Preexisting impairment: Initiation not recommended; dapagliflozin unlikely to be effective.
During therapy: If eGFR falls persistently below 30 to <45 mL/minute/1.73 m2, assess risk versus benefit. Dapagliflozin is likely to be ineffective in improving glycemic control in patients with eGFR <45 mL/minute/1.73 m2 and metformin is not recommended in patients with eGFR <45 mL/minute/1.73 m2; refer to individual agents.
eGFR <30 mL/minute/1.73 m2: Use is contraindicated.
End-stage kidney disease: Use is contraindicated.
Dialysis: Use is contraindicated.
Children ≥10 years and Adolescents: Oral: The manufacturer recommends avoiding metformin in patients with hepatic impairment; liver disease is a risk factor for the development of lactic acidosis during metformin therapy. No dosage adjustment is necessary for dapagliflozin in patients with mild to severe hepatic impairment according to the manufacturer's labeling for dapagliflozin.
(For additional information see "Dapagliflozin and metformin: Drug information")
Dosage guidance:
Clinical considerations: Correct volume depletion, if present, prior to initiation. May require a gradual dose reduction of insulin and/or insulin secretagogues (eg, sulfonylureas, meglitinides) to avoid hypoglycemia (Ref).
Diabetes mellitus, type 2, treatment:
Note: Additional therapeutic considerations may apply; refer to individual agents for information. If converting from a metformin ER product that is being taken in the evening, skip the last dose before starting the dapagliflozin/metformin combination product.
ER tablets:
For improvement in glycemic control: Oral: Initial: Individualize based on patient's current antidiabetic regimen. In patients not previously receiving dapagliflozin, initiate at dapagliflozin 5 mg once daily plus appropriate dose of metformin. May gradually increase dose based on effectiveness and tolerability; dosing range: dapagliflozin 5 mg/metformin 500 mg once daily to dapagliflozin 10 mg/metformin 2 g once daily. Maximum: dapagliflozin 10 mg/metformin 2 g once daily.
For indications related to chronic kidney disease and heart failure: Oral: Dapagliflozin 10 mg once daily plus appropriate dose of metformin. Maximum: Dapagliflozin 10 mg/metformin 2 g once daily.
IR tablets (Canadian product):
For improvement in glycemic control: Oral: Initial: Individualize based on patient's current antidiabetic regimen. May gradually increase dose based on effectiveness and tolerability; range: dapagliflozin 5 mg/metformin 850 mg twice daily to dapagliflozin 5 mg/metformin 1 g twice daily. Maximum: dapagliflozin 10 mg/metformin 2 g/day.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
eGFR ≥45 mL/minute/1.73 m2: No dosage adjustment necessary.
eGFR 30 to <45 mL/minute/1.73 m2:
US labeling: The manufacturer does not recommend initiation of therapy; assess risk versus benefit if eGFR falls persistently below this level. Dapagliflozin is likely to be ineffective in improving glycemic control and dose reduction or avoidance of metformin is recommended; refer to individual agents.
Canadian labeling: Maximum metformin dose: 1,000 mg per day; more frequent monitoring is recommended.
eGFR <30 mL/minute/1.73 m2: Use is contraindicated.
Hemodialysis: Use is contraindicated.
The manufacturer recommends avoiding metformin because liver disease is considered a risk factor for the development of lactic acidosis during metformin therapy. However, continued use of metformin in patients with diabetes and chronic liver disease with impaired hepatic function may be associated with a survival benefit in carefully selected patients; use cautiously in patients at risk for lactic acidosis (eg, renal impairment, alcohol use) (Ref). No dosage adjustment is necessary for dapagliflozin in patients with mild to severe hepatic impairment according to the manufacturer's labeling for dapagliflozin.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults. Also see individual agents.
1% to 10%:
Endocrine & metabolic: Dyslipidemia (2% to 3%)
Gastrointestinal: Constipation (3%), nausea (3% to 4%)
Genitourinary: Dysuria (2%), genitourinary fungal infection (female: 9%; including abscess [genital], bacterial vaginosis, female genital tract disease, vaginal infection, vulvovaginal candidiasis, vulvovaginitis; male: 4%; including balanitis, balanitis [candida], balanoposthitis, male genital disease, posthitis), increased urine output (2% to 3%; including pollakiuria, polyuria), urinary tract infection (6%)
Infection: Influenza (3% to 4%)
Nervous system: Dizziness (3%), headache (5%)
Respiratory: Cough (3%), pharyngitis (2% to 3%)
Frequency not defined: Endocrine & metabolic: Lactic acidosis
Postmarketing:
Endocrine & metabolic: Ketoacidosis (FDA 2015)
Genitourinary: Urinary tract infection with sepsis (FDA 2015)
Renal: Pyelonephritis (FDA 2015)
History of serious hypersensitivity (eg, anaphylaxis, angioedema) to dapagliflozin, metformin, or any component of the formulation; severe renal impairment (eGFR <30 mL/minute/1.73 m2), ESRD or patients on dialysis; acute or chronic metabolic acidosis (including diabetic ketoacidosis, with or without coma).
Canadian labeling: Additional contraindications (not in US labeling): Unstable and/or insulin-dependent (type 1) diabetes; history of ketoacidosis with or without coma; history of lactic acidosis, irrespective of precipitating factors; excessive alcohol intake (acute or chronic); clinical or laboratory evidence of hepatic disease; cardiovascular collapse; disease states associated with hypoxemia such as cardiorespiratory insufficiency (which are often associated with hyperlactacidemia); stress conditions (eg, severe infection, trauma or surgery, postoperative recovery); severe dehydration; patients undergoing radiologic studies involving intravascular iodinated contrast media administration; pregnancy; breastfeeding.
Concerns related to adverse effects:
• Bone fractures: An increased incidence of bone fractures has been observed with dapagliflozin in patients with moderate renal impairment (eGFR 30 to 60 mL/minute/1.73 m2) in one randomized, controlled trial (Kohan 2014). However, a second randomized, controlled trial did not confirm a similar increased risk in patients with eGFR 45 to 60 mL/minute/1.73 m2 (Fioretto 2018). In the overall population, dapagliflozin does not appear to increase risk of fractures, though longer-term data may be necessary to clarify risk (Jabbour 2018; Ruanpeng 2017; Tang 2016).
• Genital mycotic infections: Dapagliflozin may increase the risk of genital mycotic infections (eg, vulvovaginal mycotic infection, vulvovaginal candidiasis, vulvovaginitis, candida balanitis, balanoposthitis). Patients with a history of these infections or uncircumcised males are at greater risk.
• Hypersensitivity reactions: Patients may experience hypersensitivity reactions (eg, angioedema, urticaria), with some being severe, due to dapagliflozin.
• Hypotension: Dapagliflozin may cause symptomatic hypotension due to intravascular volume depletion especially in patients with renal impairment (eGFR <60 mL/minute/1.73 m2), elderly, patients on other antihypertensives (eg, diuretics, angiotensin-converting enzyme [ACE] inhibitors, or angiotensin receptor blockers [ARBs]), or those with low systolic blood pressure. Assess volume status prior to initiation in patients at risk of hypotension and correct if depleted.
• Ketoacidosis: Cases of ketoacidosis (some fatal) have been reported in patients with type 1 and type 2 diabetes mellitus receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors; in some cases, patients have presented with normal or only modestly elevated blood glucose (<250 mg/dL). Before initiating treatment, consider risk factors that may predispose to ketoacidosis (eg, pancreatic insulin deficiency, dose decreases of insulin, caloric restriction, alcohol abuse, acute febrile illness, surgery, any other extreme stress event). Consider temporary discontinuation of therapy at least 3 days prior to surgery or any event which may precipitate ketoacidosis; ensure risk factors are resolved prior to reinitiating therapy. Patients presenting with nausea/vomiting, abdominal pain, generalized malaise, and/or shortness of breath should be assessed immediately for ketoacidosis. Ketoacidosis and glucosuria may persist longer than typically expected.
• Lactic acidosis: Lactic acidosis should be suspected in any patient with diabetes receiving metformin with evidence of acidosis but without evidence of ketoacidosis. Discontinue metformin in patients with conditions associated with dehydration, sepsis, or hypoxemia. The risk of accumulation and lactic acidosis increases with the degree of impairment of renal function.
• Lower limb amputation: There is conflicting data involving the risk of lower limb amputations with SGLT2 inhibitor therapy. Canagliflozin was associated with almost a 2-fold increased risk of lower limb amputations compared to placebo in the CANVAS and CANVAS-R trials, which included patients with type 2 diabetes at high cardiovascular risk (Neal 2017). Trials involving dapagliflozin have not consistently shown an increased risk of lower limb amputation associated with its use (Khouri 2018; McMurray 2019; Wiviott 2019). The following FDA guidance (developed specifically for canagliflozin) may reasonably apply to use of other SGLT2 inhibitors: Prior to initiation consider risk factors for amputation including prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Counsel patients about the importance of preventative foot care (FDA Drug Safety Communication 2017).
• Necrotizing fasciitis: Cases of necrotizing fasciitis of the perineum (Fournier gangrene), a rare but serious and potentially fatal infection, have been reported in patients receiving dapagliflozin. Assess patients presenting with fever or malaise along with genital or perianal pain, tenderness, erythema, or swelling for necrotizing fasciitis.
• Renal effects: Acute kidney injury has been reported with dapagliflozin. Prior to initiation, consider risk factors for acute kidney injury (eg, hypovolemia, chronic renal insufficiency, heart failure, use of concomitant medications [eg, diuretics, ACE inhibitors, angiotensin receptor blockers, or nonsteroidal anti-inflammatory drugs]). Temporarily discontinue use with reduced oral intake or fluid losses; discontinue use if acute kidney injury occurs. Additional abnormalities in renal function (decreased eGFR, increased serum creatinine) and adverse effects related to renal function may occur.
• Urinary tract infection: Serious urinary infections, including urosepsis and pyelonephritis requiring hospitalization, have been reported; treatment with SGLT2 inhibitors, including dapagliflozin, increases the risk for urinary tract infection.
• Vitamin B12 concentrations: Long-term metformin use is associated with vitamin B12 deficiency.
Disease-related concerns:
• Bariatric surgery:
– Altered absorption: Use individual components of the formulation as immediate-release (IR) tablets or solution after surgery. Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery. Extended-release (ER) tablets may have a reduced effect after gastric bypass or sleeve gastrectomy due to the direct bypass of the stomach and proximal small bowel with gastric bypass or a more rapid gastric emptying and proximal small bowel transit with sleeve gastrectomy (Mechanick 2020; Melissas 2013). After gastric bypass (Roux-en-Y gastric bypass [RYGB]), administration of IR tablets led to increased absorption (AUC0-∞ increased by 21%) and bioavailability (increased by 50%) (Padwal 2011). Lactate levels decrease after gastric bypass (RYGB)-induced weight loss irrespective of the use of metformin. Routinely lowering metformin dose after gastric bypass is not necessary as long as normal renal function is preserved (Deden 2018).
– Dehydration: Evaluate, correct, and maintain postsurgical fluid requirements and volume status prior to initiating therapy and closely monitor the patient for the duration of therapy; volume depletion and related adverse events (eg, hypotension, orthostatic hypotension, syncope) have occurred. Fluid intake may be more difficult after gastric bypass, sleeve gastrectomy, and gastric band (Mechanick 2020).
– Euglycemic diabetic ketoacidosis: Discontinue therapy 3 to 5 days prior to surgery (Bobart 2016). Postoperatively, assess volume status, caloric intake, and need for diabetes treatment, and withhold antidiabetic medication if type 2 diabetes is in remission. Ketoacidosis has been reported in patients with type 1 and type 2 diabetes on SGLT2 inhibitors. In some cases, normal or only modestly elevated blood glucose was present (<250 mg/dL) (van Niekerk 2018). Risk factors include significant reduction in insulin, caloric restriction, stress of surgery, and infection.
• Heart failure: Metformin may be used in patients with stable heart failure; use cautiously or avoid in hypoperfusion (ADA 2023).
• Hepatic impairment: Use metformin cautiously in patients at risk for lactic acidosis (Brackett 2010; Crowley 2017; Zhang 2014).
• Renal impairment: Metformin is substantially excreted by the kidney; the risk of metformin accumulation and lactic acidosis increases with degree of renal impairment. Glycemic efficacy of dapagliflozin may be decreased in patients with renal impairment. Use of concomitant medications that may affect renal function (ie, affect tubular secretion) may also affect metformin disposition. Metformin should be withheld in patients with dehydration and/or prerenal azotemia.
• Stress-related states: It may be necessary to discontinue metformin and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).
Special populations:
• Older adult: Use with caution; risk of metformin-associated lactic acidosis increases with age.
• Hospitalized patients: Use of SGLT2 inhibitors is not routinely recommended for glycemic control in hospitalized patients (ADA 2023).
Other warnings/precautions:
• Appropriate use: Not for use in patients with diabetic ketoacidosis or for glycemic control in patients with type 1 diabetes mellitus.
• Ethanol use: Instruct patients to avoid excessive acute or chronic ethanol use; ethanol may potentiate metformin's effect on lactate metabolism.
• Iodinated contrast: Administration of iodinated contrast agents has been associated with post-contrast acute kidney injury (AKI); in patients taking metformin, acute decreases in renal function have been associated with an increased risk of lactic acidosis due to reduced metformin excretion (ACR 2021; manufacturer's labeling). Refer to metformin monograph for additional information.
• Surgical procedures: Consider temporary discontinuation of dapagliflozin-containing products at least 3 days prior to surgery; ensure risk factors for ketoacidosis are resolved prior to reinitiating therapy.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet Extended Release 24 Hour, Oral:
Xigduo XR: Dapagliflozin 10 mg [immediate release] and metformin hydrochloride 500 mg [extended release], Dapagliflozin 2.5 mg [immediate release] and metformin hydrochloride 1000 mg [extended release], Dapagliflozin 10 mg [immediate release] and metformin hydrochloride 1000 mg [extended release], Dapagliflozin 5 mg [immediate release] and metformin hydrochloride 1000 mg [extended release]
Xigduo XR: Dapagliflozin 5 mg [immediate release] and metformin hydrochloride 500 mg [extended release] [contains fd&c yellow #6(sunset yellow)alumin lake]
Generic: Dapagliflozin 10 mg [immediate release] and metformin hydrochloride 1000 mg [extended release], Dapagliflozin 5 mg [immediate release] and metformin hydrochloride 1000 mg [extended release]
Yes
Tablet, 24-hour (Dapagliflozin Pro-metFORMIN ER Oral)
5-1000 mg (per each): $11.06
10-1000 mg (per each): $22.13
Tablet, 24-hour (Xigduo XR Oral)
2.5-1000 mg (per each): $11.99
5-500 mg (per each): $23.99
5-1000 mg (per each): $11.99
10-500 mg (per each): $23.99
10-1000 mg (per each): $23.99
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Xigduo: Dapagliflozin 5 mg and metformin hydrochloride 850 mg, Dapagliflozin 5 mg and metformin hydrochloride 1000 mg
Generic: Dapagliflozin 5 mg and metformin hydrochloride 1000 mg, Dapagliflozin 5 mg and metformin hydrochloride 850 mg
Oral: Administer in the morning with food (to reduce GI side effects). Swallow tablets whole; do not crush, cut, or chew.
Surgical procedures: Withhold therapy for at least 3 days, if possible, prior to major surgery or procedures which require prolonged fasting; therapy may resume when patient is stable and has resumed oral intake.
Oral:
Extended-release tablet: Administer in the morning with food (to reduce gastrointestinal side effects). Swallow tablets whole; do not crush, cut, or chew.
Immediate-release tablet (Canadian product): Administer with meals. Swallow tablets whole; do not break or crush.
Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Xigduo XR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/205649s021lbl.pdf#page=59
Adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus (FDA approved in ages ≥10 years and adults); risk reduction of hospitalization for heart failure in patients with type 2 diabetes mellitus and established cardiovascular disease or multiple cardiovascular risk factors (FDA approved in adults); risk reduction of cardiovascular death and hospitalization for heart failure in patients with type 2 diabetes mellitus and heart failure (New York Heart Association class II to IV) with reduced ejection fraction (FDA approved in adults); risk reduction of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in patients with type 2 diabetes mellitus and chronic kidney disease at risk of progression (FDA approved in adults).
Beers Criteria: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are identified in the Beers Criteria as potentially inappropriate medications to be used with caution in patients 65 years and older due to increased risk of urogenital infections, especially in women during the first month of use. In addition, a higher risk of euglycemic diabetic ketoacidosis has been observed in older adults (Beers Criteria [AGS 2023]).
Refer to individual components.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program
Abemaciclib: May increase serum concentration of MetFORMIN. Risk C: Monitor
Alcohol (Ethyl): May increase adverse/toxic effects of MetFORMIN. Specifically, excessive alcohol ingestion (acute or chronic) may potentiate the risk of lactic acidosis. Risk X: Avoid
Alpha-Lipoic Acid: May increase hypoglycemic effects of Antidiabetic Agents. Risk C: Monitor
Androgens: May increase hypoglycemic effects of Agents with Blood Glucose Lowering Effects. Risk C: Monitor
Arimoclomol: May increase serum concentration of OCT2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Beta-Blockers (Beta1 Selective): May increase adverse/toxic effects of Antidiabetic Agents. Specifically, beta-blockers may mask the hypoglycemic symptoms of antidiabetic agents. Risk C: Monitor
Beta-Blockers (Nonselective): May increase hypoglycemic effects of Antidiabetic Agents. Beta-Blockers (Nonselective) may increase adverse/toxic effects of Antidiabetic Agents. Specifically, beta-blockers may mask the hypoglycemic symptoms of antidiabetic agents. Risk C: Monitor
Bictegravir: May increase serum concentration of MetFORMIN. Risk C: Monitor
Bortezomib: May increase therapeutic effects of Antidiabetic Agents. Bortezomib may decrease therapeutic effects of Antidiabetic Agents. Risk C: Monitor
Carbonic Anhydrase Inhibitors: May increase adverse/toxic effects of MetFORMIN. Specifically, the risk of developing lactic acidosis may be increased. Risk C: Monitor
Cephalexin: May increase serum concentration of MetFORMIN. Risk C: Monitor
Cimetidine: May increase serum concentration of MetFORMIN. Management: Consider alternatives to cimetidine in patients receiving metformin due to a potential for increased metformin concentrations and toxicity (including lactic acidosis). Risk D: Consider Therapy Modification
Copanlisib: May decrease therapeutic effects of MetFORMIN. Copanlisib may increase serum concentration of MetFORMIN. Risk C: Monitor
Direct Acting Antiviral Agents (HCV): May increase hypoglycemic effects of Antidiabetic Agents. Risk C: Monitor
Dofetilide: MetFORMIN may increase serum concentration of Dofetilide. Risk C: Monitor
Dolutegravir: May increase serum concentration of MetFORMIN. Management: Consider alternatives to this combination or use of lower metformin doses. Carefully weigh the risk of metformin toxicities (including lactic acidosis) against the benefit of combining dolutegravir with metformin. Risk D: Consider Therapy Modification
Etilefrine: May decrease therapeutic effects of Antidiabetic Agents. Risk C: Monitor
Fedratinib: May increase serum concentration of MATE1/2-K Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Fedratinib: May increase serum concentration of OCT2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Fexinidazole: May increase serum concentration of MATE1/2-K Substrates (Clinically Relevant with Inhibitors). Management: Avoid use of fexinidazole with MATE1/2-K substrates when possible. If combined, monitor for increased MATE1/2-K substrate toxicities. Risk D: Consider Therapy Modification
Fexinidazole: May increase serum concentration of OCT2 Substrates (Clinically Relevant with Inhibitors). Management: Avoid use of fexinidazole with OCT2 substrates when possible. If combined, monitor for increased OCT2 substrate toxicities. Risk D: Consider Therapy Modification
Fludeoxyglucose F 18: Coadministration of MetFORMIN and Fludeoxyglucose F 18 may alter diagnostic results. Management: Consider holding metformin for 48 hours or longer prior to PET scans using fludeoxyglucose F18 (FDG-F18) when imaging of the colon or intestine is required. Consider increased monitoring of blood glucose when metformin is held. Risk D: Consider Therapy Modification
Foslevodopa: May increase serum concentration of MATE1/2-K Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Gilteritinib: May increase serum concentration of OCT1 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Givinostat: May increase serum concentration of OCT2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Glycopyrrolate (Systemic): May increase serum concentration of MetFORMIN. Risk C: Monitor
Guanethidine: May increase hypoglycemic effects of Antidiabetic Agents. Risk C: Monitor
Guar Gum (Partially Hydrolyzed): May decrease serum concentration of MetFORMIN. Risk C: Monitor
Hyperglycemia-Associated Agents: May decrease therapeutic effects of Antidiabetic Agents. Risk C: Monitor
Hypoglycemia-Associated Agents: Antidiabetic Agents may increase hypoglycemic effects of Hypoglycemia-Associated Agents. Risk C: Monitor
Insulin: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may increase hypoglycemic effects of Insulin. Management: Consider a decrease in insulin dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Risk D: Consider Therapy Modification
Iodinated Contrast Agents: May increase adverse/toxic effects of MetFORMIN. Renal dysfunction that may be caused by iodinated contrast agents may lead to metformin-associated lactic acidosis. Management: Management advice varies. Refer to the full drug interaction monograph content for details. Risk D: Consider Therapy Modification
LamoTRIgine: May increase serum concentration of MetFORMIN. Management: The lamotrigine Canadian product monograph states that coadministration of these drugs is not recommended. Risk C: Monitor
Lithium: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may decrease serum concentration of Lithium. Risk C: Monitor
Maitake: May increase hypoglycemic effects of Agents with Blood Glucose Lowering Effects. Risk C: Monitor
MATE1/2-K Inhibitors: May increase serum concentration of MetFORMIN. Risk C: Monitor
Mavorixafor: May decrease serum concentration of MetFORMIN. Risk C: Monitor
Methylol Cephalexin: May increase serum concentration of MetFORMIN. Risk C: Monitor
Monoamine Oxidase Inhibitors: May increase hypoglycemic effects of Agents with Blood Glucose Lowering Effects. Risk C: Monitor
Nonsteroidal Anti-Inflammatory Agents: May increase adverse/toxic effects of MetFORMIN. Risk C: Monitor
Ombitasvir, Paritaprevir, and Ritonavir: May increase adverse/toxic effects of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Risk C: Monitor
Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May increase adverse/toxic effects of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Risk C: Monitor
Ondansetron: May increase serum concentration of MetFORMIN. Risk C: Monitor
Patiromer: May decrease serum concentration of MetFORMIN. Management: Administer metformin at least 3 hours before or 3 hours after patiromer. Risk D: Consider Therapy Modification
Pegvisomant: May increase hypoglycemic effects of Agents with Blood Glucose Lowering Effects. Risk C: Monitor
Prothionamide: May increase hypoglycemic effects of Agents with Blood Glucose Lowering Effects. Risk C: Monitor
Quinolones: May increase hypoglycemic effects of Agents with Blood Glucose Lowering Effects. Quinolones may decrease therapeutic effects of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Risk C: Monitor
Ranolazine: May increase serum concentration of MetFORMIN. Management: Limit the metformin dose to a maximum of 1,700 mg per day when used together with ranolazine 1,000 mg twice daily. Monitor patients for metformin toxicities, including lactic acidosis and carefully weigh the risks and benefits of this combination. Risk D: Consider Therapy Modification
Reproterol: May decrease therapeutic effects of Antidiabetic Agents. Risk C: Monitor
Risdiplam: May increase serum concentration of MATE1/2-K Substrates (Clinically Relevant with Inhibitors). Management: Avoid use of risdiplam with MATE substrates if possible. If the combination cannot be avoided, monitor closely for adverse effects. Consider a reduced dose of the MATE substrate according to that substrate's labeling if appropriate. Risk D: Consider Therapy Modification
Ritodrine: May decrease therapeutic effects of Antidiabetic Agents. Risk C: Monitor
Salicylates: May increase hypoglycemic effects of Agents with Blood Glucose Lowering Effects. Risk C: Monitor
Selective Serotonin Reuptake Inhibitor: May increase hypoglycemic effects of Agents with Blood Glucose Lowering Effects. Risk C: Monitor
Sulfonylureas: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may increase hypoglycemic effects of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and monitor patients for hypoglycemia. Risk D: Consider Therapy Modification
Tafenoquine: May increase serum concentration of MATE1/2-K Substrates (Clinically Relevant with Inhibitors). Management: Avoid use of MATE substrates with tafenoquine, and if the combination cannot be avoided, monitor closely for evidence of toxicity of the MATE substrate and consider a reduced dose of the MATE substrate according to that substrate's labeling. Risk D: Consider Therapy Modification
Tafenoquine: May increase serum concentration of OCT2 Substrates (Clinically Relevant with Inhibitors). Management: Avoid use of OCT2 substrates with tafenoquine, and if the combination cannot be avoided, monitor closely for evidence of toxicity of the OCT2 substrate and consider a reduced dose of the OCT2 substrate according to that substrate's labeling. Risk D: Consider Therapy Modification
Thiazide and Thiazide-Like Diuretics: May decrease therapeutic effects of Antidiabetic Agents. Risk C: Monitor
Topiramate: May increase adverse/toxic effects of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. MetFORMIN may increase serum concentration of Topiramate. Topiramate may increase serum concentration of MetFORMIN. Risk C: Monitor
Verapamil: May decrease therapeutic effects of MetFORMIN. Risk C: Monitor
Vimseltinib: May increase serum concentration of OCT2 Substrates (Clinically Relevant with Inhibitors). Management: Avoid concomitant use of vimseltinib and OCT2 substrates when possible. If combined, monitor for increased effects and toxicities of the OCT2 substrate and consider dose adjustments. Risk D: Consider Therapy Modification
Vitamin K Antagonists: MetFORMIN may decrease anticoagulant effects of Vitamin K Antagonists. Vitamin K Antagonists may increase hypoglycemic effects of MetFORMIN. Risk C: Monitor
Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.
Metformin may increase ovulation in premenopausal anovulatory patients resulting in unintended pregnancies.
Refer to individual monographs for additional information.
Metformin crosses the placenta (ADA 2023).
Refer to individual monographs for information related to the treatment of diabetes mellitus in pregnancy.
Blood glucose; renal function (baseline and periodically during treatment); volume status (eg, weight, BP, hematocrit, electrolytes; baseline and periodically during treatment) and signs/symptoms of hypotension; monitor for genital mycotic infections and urinary tract infection; monitor for signs/symptoms of necrotizing fasciitis (eg, fever and malaise along with genital or perianal pain, tenderness, erythema, swelling), hypersensitivity reactions; monitor for signs/symptoms of ketoacidosis (eg, nausea/vomiting, abdominal pain, malaise, shortness of breath); if present, monitor ketones regardless of blood glucose concentrations. Monitor hematologic parameters (eg, hemoglobin/hematocrit, red blood cell indices) annually and vitamin B12 serum concentrations every 2 to 3 years.
HbA1c: Monitor every 3 months; some recommendations suggest at least twice yearly may be considered in patients who have stable glycemic control and are meeting treatment goals (Ref). Note: In patients prone to glycemic variability (eg, patients with insulin deficiency), or in patients whose HbA1c is discordant with serum glucose levels or symptoms, consider evaluating HbA1c in combination with blood glucose levels and/or a glucose management indicator (Ref).
Plasma blood glucose and HbA1c goals for patients with diabetes: Note: Postprandial blood glucose should be measured when there is a discrepancy between preprandial blood glucose concentrations and HbA1c values and to help assess glycemia for patients who receive basal/bolus or pump regimens. It is usually drawn 1 to 2 hours after starting a meal and is considered to be the "peak."
Children and Adolescents:
Blood glucose:
Type 2 diabetes:
Fasting plasma glucose: 70 to 110 mg/dL (SI: 3.9 to 6.1 mmol/L) (Ref).
Postprandial glucose: 70 to 140 mg/dL (SI: 3.9 to 7.8 mmol/L) (Ref).
HbA1c: <7%; target should be individualized; a more stringent goal (<6.5%) may be reasonable if it can be achieved without significant hypoglycemia and is reasonable in many patients with type 2 diabetes; less aggressive goals (<7.5%) may be appropriate in patients who are at increased risk of hypoglycemia (Ref).
Dapagliflozin: By inhibiting sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules, dapagliflozin reduces reabsorption of filtered glucose from the tubular lumen and lowers the renal threshold for glucose (RTG). SGLT2 is the main site of filtered glucose reabsorption; reduction of filtered glucose reabsorption and lowering of RTG result in increased urinary excretion of glucose, thereby reducing plasma glucose concentrations. Dapagliflozin also reduces sodium reabsorption and increases sodium delivery to the distal tubule, which may decrease cardiac preload/afterload and downregulate sympathetic activity.
Metformin: Decreases hepatic glucose production, decreases intestinal absorption of glucose, improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
See individual agents.
Combination tablets are considered bioequivalent to coadministration of individual dapagliflozin and metformin extended-release tablets.
