Version May 2024
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 (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and increased lactate/pyruvate ratio; and metformin plasma levels generally >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, 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 empagliflozin/metformin and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
Dosage guidance:
Clinical considerations: Correct hypovolemia, if present, prior to initiating treatment. May require a gradual dose reduction of insulin and/or insulin secretagogues (eg, sulfonylureas) to avoid hypoglycemia.
Diabetes mellitus, type 2; adjunct to diet and exercise: Note: Synjardy is available as multiple fixed-dose combinations of empagliflozin and metformin; use precaution when prescribing and dispensing. The combination empagliflozin/metformin should only be initiated in pediatric patients on already established daily doses of each component.
Children ≥10 years and Adolescents: Immediate-release empagliflozin/metformin tablet (eg, Synjardy): Oral: Dose should be based on patient's existing total daily doses of empagliflozin and metformin administered in divided doses twice daily. Maximum daily dose: Empagliflozin 25 mg/day and metformin 2,000 mg/day.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Altered kidney function:
Children ≥10 years and Adolescents: Oral:
eGFR >60 mL/minute/1.73 m2: No dosage adjustment necessary.
eGFR 45 to <60 mL/minute/1.73 m2: No dosage adjustment necessary based on the metformin component; however, in pediatric trials with empagliflozin, patients with eGFR <60 mL/minute/1.73 m2 were excluded.
eGFR 30 to 45 mL/minute/1.73 m2: Based on the metformin component (Note: In pediatric trials with empagliflozin, patients with eGFR <60 mL/minute/1.73 m2 were excluded):
Preexisting kidney impairment: Initiation of therapy is not recommended.
During therapy:
If eGFR falls between 30 and <45 mL/minute/1.73 m 2: Consider risk/benefit ratio for continuing therapy.
If eGFR falls to <30 mL/minute/1.73 m 2 : Discontinue therapy.
eGFR <30 mL/minute/1.73 m2: Use is contraindicated.
End-stage kidney disease: Use is contraindicated.
Dialysis: Use is contraindicated.
Empagliflozin may be used in patients with hepatic impairment. The manufacturer recommends avoiding metformin because liver disease is considered a risk factor for the development of lactic acidosis during metformin therapy; however, metformin may be used depending on severity of hepatic impairment. Refer to individual agents for additional recommendations.
(For additional information see "Empagliflozin and metformin: Drug information")
Dosage guidance:
Clinical considerations: Correct hypovolemia, if present, prior to initiating treatment. 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.
Initial: Individualize initial dose based on patient's current antidiabetic regimen. May gradually increase dose based on effectiveness and tolerability.
Patients on metformin: Oral: Empagliflozin 10 mg/day plus similar total daily dose of metformin, administered in 2 divided doses (immediate release) or once daily (extended release).
Patients on empagliflozin: Oral: Metformin 1 g/day plus similar total daily dose of empagliflozin, administered in 2 divided doses (immediate release) or once daily (extended release).
Maximum: Oral: Empagliflozin 25 mg/metformin 2 g per day, administered in 2 divided doses (immediate release) or once daily (extended release).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function:
Note: The glycemic efficacy of empagliflozin decreases as kidney function declines.
eGFR ≥45 mL/minute/1.73 m2: No dosage adjustment necessary. Monitor kidney function at least annually.
eGFR 30 to 45 mL/minute/1.73 m2: The US manufacturer does not recommend initiating therapy; refer also to individual agents.
eGFR <30 mL/minute/1.73 m2: Use is contraindicated.
End-stage kidney disease: Use is contraindicated.
Dialysis: Use is contraindicated.
Acute kidney injury during therapy: If acute kidney injury occurs or if risk factors are present (eg, severe vomiting or diarrhea), instruct patient to temporarily hold the medication due to the metformin component (Ref).
Empagliflozin may be used in patients with hepatic impairment. The manufacturer recommends avoiding metformin because liver disease is considered a risk factor for the development of lactic acidosis during metformin therapy; however metformin may be used depending on severity of hepatic impairment. Refer to individual agents for additional recommendations.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Also see individual agents.
1% to 10%: Endocrine & metabolic: Hypoglycemia (1% to 2%)
Frequency not defined: Endocrine & metabolic: Lactic acidosis
Hypersensitivity (eg, angioedema) to empagliflozin, metformin, or any component of the formulation; severe renal impairment (eGFR <30 mL/minute/1.73 m2), end-stage renal disease (ESRD), or patients on dialysis; acute or chronic metabolic acidosis (including diabetic ketoacidosis).
Canadian labeling: Additional contraindications (not in US labeling): Renal function unknown; unstable and/or insulin-dependent (type I) diabetes mellitus; acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma, history of ketoacidosis with or without coma; history of lactic acidosis (regardless of precipitating factors); excessive alcohol intake (acute or chronic); severe hepatic dysfunction or clinical or laboratory evidence of hepatic disease; cardiovascular collapse and disease states associated with hypoxemia including cardiorespiratory insufficiency, which are often associated with hyperlactacidemia; stress conditions (eg, severe infection, trauma, surgery and postoperative recovery phase); dehydration or shock; pregnancy; breast-feeding; period of time around administration of iodinated contrast materials.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• Bone fractures: An increased incidence of bone fractures has been observed with other sodium-glucose cotransporter 2 (SGLT2) inhibitors in some clinical trials. However, meta-analyses of trial data for empagliflozin have not demonstrated increased risk of fracture (Ruanpeng 2017; Tang 2016).
• Genital mycotic infections: Empagliflozin 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: Hypersensitivity reactions (eg, angioedema, skin rash, urticaria) have been observed with empagliflozin.
• Hypotension: Empagliflozin may cause symptomatic hypotension due to intravascular volume depletion, especially in patients with renal impairment (ie, eGFR <60 mL/minute/1.73 m2), elderly, patients on other antihypertensives (eg, diuretics, angiotensin-converting enzyme inhibitors [ACE] inhibitors, or angiotensin receptor blockers [ARBs]), or those with low systolic blood pressure.
• Ketoacidosis: Cases of ketoacidosis (some fatal) have been reported in patients with type 1 and type 2 diabetes mellitus receiving 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 ≥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. Not recommended for use in patients with type 1 diabetes mellitus due to risk of ketoacidosis.
• Lactic acidosis: Lactic acidosis should be suspected in any patient with diabetes receiving metformin with evidence of acidosis but without evidence of ketoacidosis. 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 empagliflozin have not consistently shown an increased risk of lower limb amputation associated with its use (Inzucchi 2018; Khouri 2018). 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.
• 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 empagliflozin. 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 empagliflozin. 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, ARBs, or nonsteroidal anti-inflammatory drugs]). Additional abnormalities in renal function (decreased eGFR, increased serum creatinine) and adverse effects related to renal function may occur. In the EMPA-REG OUTCOME study, administration of empagliflozin caused early decline in eGFR that tended to stabilize after ~4 weeks, but also an overall reduction in adverse kidney outcomes (eg, initiation of renal replacement therapy, doubling of serum creatinine with eGFR ≤45 mL/minute/1.73 m2, progression to macroalbuminuria, death from kidney disease) (Wanner 2016).
• Urinary tract infection: Serious urinary infections including urosepsis and pyelonephritis requiring hospitalization have been reported; treatment with empagliflozin increases the risk for urinary tract infections.
• Vitamin B12 concentrations: Long-term metformin use is associated with vitamin B12 deficiency.
Disease-related concerns:
• Bariatric surgery:
– Altered absorption: Use IR tablets after surgery. Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery. 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).
– 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 (ADA 2023). Use cautiously or avoid in hypoperfusion.
• Hepatic impairment: Use metformin cautiously in patients at risk for lactic acidosis (Brackett 2010; Crowley 2017; Zhang 2014). An increased risk of mortality has been observed with higher metformin doses (eg, >1 g) and more severe liver dysfunction (eg, Child-Turcotte-Pugh C>B>>>A) (Yen 2022). Cases of metformin-induced hepatotoxicity have also been reported (Zheng 2016).
• Renal impairment: Metformin is substantially excreted by the kidney; the risk of metformin accumulation and lactic acidosis increase with degree of 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 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. Risk of intravascular volume contraction and symptomatic hypotension is also increased in older adults treated with empagliflozin, especially if kidney function is compromised.
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.
• Hospitalized patients: Use of SGLT2 inhibitors is not routinely recommended for glycemic control in hospitalized patients (ADA 2023).
• Iodinated contrast: Administration of iodinated contrast agents has been associated with post-contrast acute kidney injury; 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 empagliflozin-containing products ≥3 days prior to surgery; ensure risk factors for ketoacidosis are resolved prior to reinitiating therapy.
Unlike adults, hypoglycemia has been reported in pediatric patients receiving empagliflozin. In trials of pediatric patients ≥10 to <18 years of age, the incidence of hypoglycemia (blood glucose <54 mg/dL) was 19.2% in subjects treated with empagliflozin (regardless of concomitant insulin) compared to 7.5% in the placebo group. No severe hypoglycemia (ie, events requiring interventions) were reported.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Synjardy: Empagliflozin 5 mg and metformin hydrochloride 500 mg, Empagliflozin 5 mg and metformin hydrochloride 1000 mg, Empagliflozin 12.5 mg and metformin hydrochloride 500 mg, Empagliflozin 12.5 mg and metformin hydrochloride 1000 mg [contains corn starch]
Tablet Extended Release 24 Hour, Oral:
Synjardy XR: Empagliflozin 5 mg and metformin hydrochloride 1000 mg, Empagliflozin 10 mg and metformin hydrochloride 1000 mg
Synjardy XR: Empagliflozin 25 mg and metformin hydrochloride 1000 mg, Empagliflozin 12.5 mg and metformin hydrochloride 1000 mg [contains fd&c blue #2 (indigo carm) aluminum lake]
No
Tablet, 24-hour (Synjardy XR Oral)
5-1000 mg (per each): $12.22
10-1000 mg (per each): $24.44
12.5-1000 mg (per each): $12.22
25-1000 mg (per each): $24.44
Tablets (Synjardy Oral)
5-500 mg (per each): $12.22
5-1000 mg (per each): $12.22
12.5-500 mg (per each): $12.22
12.5-1000 mg (per each): $12.22
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:
Synjardy: Empagliflozin 5 mg and metformin hydrochloride 500 mg, Empagliflozin 5 mg and metformin hydrochloride 850 mg, Empagliflozin 5 mg and metformin hydrochloride 1000 mg, Empagliflozin 12.5 mg and metformin hydrochloride 500 mg, Empagliflozin 12.5 mg and metformin hydrochloride 850 mg, Empagliflozin 12.5 mg and metformin hydrochloride 1000 mg [contains corn starch]
Oral: Immediate-release tablets (eg, Synjardy): Administer with meals twice daily.
Surgical procedures: Consider temporary discontinuation of therapy at least 3 days prior to surgery; ensure risk factors for ketoacidosis are resolved prior to reinitiating therapy.
Missed doses: Administer the missed dose as soon as possible; do not double up next dose.
Oral: Administer immediate-release tablets twice daily with meals or extended-release tablets once daily with breakfast. Extended-release tablets should not be split, crushed, chewed, or dissolved.
Bariatric surgery: Tablet, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. Switch to immediate-release separate components. Of note, some patients with unaltered GI tracts have reported incompletely dissolved tablets in stool. GI transit time may be reduced in postbariatric surgery patients rendering incompletely dissolved tablets a possibility postoperatively.
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Synjardy, Synjardy XR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/206111s042,208658s028lbl.pdf#page=44
Adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus (Synjardy: FDA approved in ages ≥10 years and adults; Synjardy XR: FDA approved in adults); reduction of risk of cardiovascular mortality in patients with type 2 diabetes mellitus and established cardiovascular disease (Synjardy, Synjardy XR: FDA approved in adults); reduction of risk of cardiovascular mortality and hospitalization for heart failure in patients with type 2 diabetes mellitus and heart failure (Synjardy, Synjardy XR: FDA approved in adults).
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes that have a heightened risk of causing significant patient harm when used in error.
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 Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Abemaciclib: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Alcohol (Ethyl): May enhance the adverse/toxic effect of MetFORMIN. Specifically, excessive alcohol ingestion (acute or chronic) may potentiate the risk of lactic acidosis. Risk X: Avoid combination
Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Androgens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Beta-Blockers (Beta1 Selective): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Beta-Blockers (Nonselective): May enhance the hypoglycemic effect of Antidiabetic Agents. Beta-Blockers (Nonselective) may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Bortezomib: May enhance the therapeutic effect of Antidiabetic Agents. Bortezomib may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Carbonic Anhydrase Inhibitors: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk of developing lactic acidosis may be increased. Risk C: Monitor therapy
Cephalexin: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Cimetidine: May increase the 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
Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Dofetilide: MetFORMIN may increase the serum concentration of Dofetilide. Risk C: Monitor therapy
Dolutegravir: May increase the 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
Erdafitinib: May increase the serum concentration of OCT2 Substrates (Clinically Relevant with Inhibitors). Management: Consider alternatives to this combination when possible. If combined, monitor for increased effects/toxicities of OCT2 substrates and consider OCT2 substrate dose reductions when appropriate. Risk D: Consider therapy modification
Etilefrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Fexinidazole: May increase the 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 the 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: MetFORMIN may diminish the diagnostic effect of Fludeoxyglucose F 18. 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 the serum concentration of MATE1/2-K Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Gilteritinib: May increase the serum concentration of OCT1 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Glycopyrrolate (Systemic): May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Guar Gum (Partially Hydrolyzed): May decrease the serum concentration of MetFORMIN. Risk C: Monitor therapy
Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Insulins: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may enhance the hypoglycemic effect of Insulins. 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 enhance the adverse/toxic effect 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 the serum concentration of MetFORMIN. Management: The lamotrigine Canadian product monograph states that coadministration of these drugs is not recommended. Risk C: Monitor therapy
Lithium: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may decrease the serum concentration of Lithium. Risk C: Monitor therapy
Loop Diuretics: Empagliflozin may enhance the hypotensive effect of Loop Diuretics. Risk C: Monitor therapy
Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
MATE1/2-K Inhibitors: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Methylol Cephalexin: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of MetFORMIN. Risk C: Monitor therapy
Ombitasvir, Paritaprevir, and Ritonavir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Risk C: Monitor therapy
Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Risk C: Monitor therapy
Ondansetron: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Pacritinib: May increase the serum concentration of OCT1 Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid combination
Patiromer: May decrease the serum concentration of MetFORMIN. Management: Administer metformin at least 3 hours before or 3 hours after patiromer. Risk D: Consider therapy modification
Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Quinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect 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 therapy
Ranolazine: May increase the 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
Risdiplam: May increase the 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 diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Salicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Sulfonylureas: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may enhance the hypoglycemic effect 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 the 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 the 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 diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Topiramate: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. MetFORMIN may increase the serum concentration of Topiramate. Topiramate may increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Verapamil: May diminish the therapeutic effect of MetFORMIN. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): MetFORMIN may diminish the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may enhance the hypoglycemic effect of MetFORMIN. Risk C: Monitor therapy
Individualized medical nutrition therapy based on American Diabetes Association 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).
The manufacturer does not recommend use of empagliflozin/metformin during the second and third trimesters.
Refer to individual monographs for information related to the treatment of diabetes mellitus in pregnancy.
Plasma glucose, HbA1c (every 3 months; if patient is stable and meeting treatment goals, may only need twice-yearly testing [ADA 2022b]); renal function (SCr, BUN) (baseline and periodically during treatment); volume status (eg, BP, hematocrit, electrolytes); monitor for genital mycotic infections and urinary tract infection; assess patients presenting with fever or malaise along with genital or perianal pain, tenderness, erythema, or swelling for necrotizing fasciitis; BP; if signs/symptoms of ketoacidosis (eg, nausea/vomiting, abdominal pain, malaise, shortness of breath), confirm diagnosis by direct measurement of blood ketones and arterial pH (measurement of serum bicarbonate or urinary ketones may not be adequate) (AACE [Handelsman 2016]).
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) (ISPAD [Shah 2022]).
Postprandial glucose: 70 to 140 mg/dL (SI: 3.9 to 7.8 mmol/L) (ISPAD [Shah 2022]).
HbA1c: <7%; target should be individualized; a more stringent goal (<6.5%) may be reasonable if it can be achieved without significant hypoglycemia; lower targets may also be recommended when using insulin pumps and/or continuous glucose monitoring and during the "honeymoon" phase; less aggressive goals (<7.5% or <8%) may be appropriate in patients who cannot articulate symptoms of hypoglycemia, cannot check glucose frequently, have a history of severe hypoglycemia, have extensive comorbid conditions, or lack access to analog insulins, advanced insulin delivery technology, or continuous glucose monitoring (ADA 2022a; ISPAD [de Bock 2022]).
Empagliflozin: By inhibiting sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules, empagliflozin 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. Empagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule, which may lower both pre- and afterload of the heart 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
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