Metformin + Empagliflozin

Pharmacologic Category

Antidiabetic Agent, Biguanide; Antidiabetic Agent, Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor; Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor

Dosing: Adult

Note: If present, correct volume depletion prior to initiation.

Diabetes mellitus, type 2: Oral:

Initial: Individualize initial dose based on patient's current antidiabetic regimen. May gradually increase dose based on effectiveness and tolerability.

Patients on metformin: 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: Metformin 1,000 mg/day plus similar total daily dose of empagliflozin, administered in 2 divided doses (immediate release) or once daily (extended release)

Maximum: Empagliflozin 25 mg/metformin 2,000 mg per day, administered in 2 divided doses (immediate release) or once daily (extended release).

Concomitant use with insulin and/or insulin secretagogues (eg, sulfonylureas): Reduced dose of insulin and/or insulin secretagogues may be needed.

Dosing: Geriatric

Refer to adult dosing. The initial and maintenance dosing should be conservative, due to the potential for decreased renal function (monitor).

Dosing: Renal Impairment: Adult

eGFR ≥45 mL/minute/1.73 m²: No dosage adjustment necessary. Monitor renal function at least annually.

eGFR <45 mL/minute/1.73 m²: Use is contraindicated by the manufacturer; refer also to individual agents.

End-stage renal disease (ESRD): Use is contraindicated.

Dialysis: Use is contraindicated.

Dosing: Hepatic Impairment: Adult

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, continued use of metformin in patients with diabetes with liver dysfunction, including cirrhosis, has been used successfully and 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) (Brackett 2010; Crowley 2017; Zhang 2014).

Use: Labeled Indications

Diabetes mellitus, type 2: Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both empagliflozin and metformin is appropriate. Note: Empagliflozin is also indicated for risk reduction of cardiovascular mortality in adults with type 2 diabetes mellitus and established cardiovascular disease.

Clinical Practice Guidelines

Refer to individual monographs.

Administration: 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.

Storage/Stability

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to lower blood sugar in patients with high blood sugar (diabetes).

• It is used to lower the chance of death from heart disease in certain people.

Frequently reported side effects of this drug

• Passing gas

• Loss of strength or energy

• Headache

• Stuffy nose

• Sore throat

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, fast heartbeat, increased thirst, seizures, loss of strength and energy, lack of appetite, unable to pass urine or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting.

• Acidosis like confusion, fast breathing, fast heartbeat, abnormal heartbeat, severe abdominal pain, nausea, vomiting, fatigue, shortness of breath, or loss of strength and energy.

• Lactic acidosis like fast breathing, fast heartbeat, abnormal heartbeat, vomiting, fatigue, shortness of breath, severe loss of strength and energy, severe dizziness, feeling cold, or muscle pain or cramps.

• Low blood sugar like dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating

• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.

• Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain.

• Pain, swelling, or signs of infection in the genitals or rectum

• Vaginal yeast infection

• Penile yeast infection

• Severe abdominal pain

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Synjardy: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206111s018lbl.pdf#page=39

Synjardy XR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208658s004lbl.pdf#page=39

Contraindications

History of serious hypersensitivity to empagliflozin, metformin, or any component of the formulation; moderate to severe renal impairment (eGFR <45 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, serum creatinine levels above the upper limit of normal range, or renal dysfunction (serum creatinine ≥136 micromol/L in males or ≥124 micromol/L in females or abnormal creatinine clearance <60 mL/minute) which may result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia; 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

Warnings/Precautions

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 are at greater risk.

• Hypersensitivity: Hypersensitivity reactions (eg, angioedema, skin rash, urticaria) have been observed with empagliflozin; discontinue promptly if hypersensitivity occurs and treat as indicated. Use is contraindicated in patients with a previous serious hypersensitivity reaction to empagliflozin.

• Hypotension: 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, 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; monitor for signs and symptoms of hypotension after initiation.

• 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; discontinue therapy and treat promptly if ketoacidosis is suspected.

• Lactic acidosis: [US Boxed Warning]: Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset is often subtle, accompanied by nonspecific symptoms (eg, malaise, myalgias, respiratory distress, somnolence, abdominal pain); elevated blood lactate levels (>5 mmol/L); anion gap acidosis (without evidence of ketonuria or ketonemia); increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Risk factors for lactic acidosis include patients with renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), ≥65 years of age, having a radiologic study with contrast, surgery and other procedures, hypoxic states (eg, acute heart failure), excessive alcohol intake, and hepatic impairment. Discontinue immediately if lactic acidosis is suspected; prompt hemodialysis is recommended. Lactic acidosis should be suspected in any patient with diabetes receiving metformin with evidence of acidosis but without evidence of ketoacidosis. Discontinue use in patients with conditions associated with dehydration, hypoperfusion, sepsis, or hypoxemia. Temporarily discontinue therapy in patients with restricted food and fluid intake. The risk of accumulation and lactic acidosis increases with the degree of impairment of renal function.

• 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. Discontinue in patients who develop necrotizing fasciitis and initiate treatment immediately.

• 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, angiotensin receptor blockers, or NSAIDs]). 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. In the EMPA-REG OUTCOME study, administration of empagliflozin caused early decline in eGFR which tended to stabilize after ~4 weeks (Wanner 2016). Assess renal function prior to initiation and periodically during treatment.

• Urinary tract infection: Serious urinary infections including urosepsis and pyelonephritis requiring hospitalization have been reported; treatment with SGLT2 inhibitors, including empagliflozin, increases the risk for UTIs; monitor for signs and symptoms of UTI and treat as needed.

• Vitamin B₁₂ concentrations: Long-term metformin use is associated with vitamin B₁₂ deficiency; monitor vitamin B₁₂ serum concentrations periodically with long-term therapy. Monitoring of B₁₂ serum concentrations should be considered in all patients receiving metformin and in particular those with peripheral neuropathy or anemia (ADA 2019).

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 2013; Melissas 2013). After gastric bypass (Roux-en-Y gastric bypass [RYGB]), administration of IR tablets led to increased absorption (AUC_0-∞ 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 2013).

– 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 (HF); avoid use in unstable or hospitalized patients with heart failure (ADA 2019). Risk of lactic acidosis may be increased secondary to hypoperfusion. In a scientific statement from the American Heart Association, metformin has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: major) (AHA [Page 2016]). Use of metformin in patients with HF may be associated with reduced mortality and reduction in hospital readmission for HF (Crowley 2017; Eurich 2013).

• Hepatic impairment: The manufacturer recommends to generally avoid use in patients with hepatic impairment due to potential for lactic acidosis. However, continued use of metformin in patients with diabetes with liver dysfunction, including cirrhosis, may be associated with a survival benefit in carefully selected patients (Brackett 2010; Crowley 2017; Zhang 2014).

• Renal impairment: Metformin is substantially excreted by the kidney; assess renal function prior to initiation of therapy and periodically thereafter using eGFR; the risk of metformin accumulation and lactic acidosis increase with degree of renal impairment. According to the manufacturer, use of the combination product is contraindicated in patients with an eGFR <45 mL/minute/1.73 m², ESRD, or maintained on dialysis. 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. Glycemic efficacy of empagliflozin may be decreased in renal impairment. In the EMPA-REG OUTCOME trial, empagliflozin reduced the occurrence of incident or worsening nephropathy (a secondary end-point) in diabetic patients with an eGFR ≥30 mL/minute/1.73 m² and high cardiovascular risk receiving standard care. Post-hoc analysis suggested that the renal benefits may persist in the subset of patients with baseline renal impairment (eGFR 30 to <60 mL/minute/1.73 m²) (Wanner 2016). An additional post-hoc analysis showed consistent cardiovascular mortality benefits across subgroups with eGFR 30 to <45, 45 to <60, and ≥60 mL/minute/1.73 m² (Wanner 2018). However, additional trials may be necessary to definitively establish whether empagliflozin improves these outcomes in patients with renal impairment.

• Stress-related states: It may be necessary to discontinue and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use with caution; risk of metformin associated lactic acidosis increases with age.

Other warnings/precautions:

• Appropriate use: Not for use in patients with diabetic ketoacidosis (DKA) or 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: According to the manufacturer, it is recommended to temporarily discontinue metformin at the time of or before iodinated contrast imaging procedures in patients with an eGFR 45 to 60 mL/minute/1.73 m²; or with a history of hepatic disease, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. Reevaluate eGFR 48 hours after imaging procedure; restart if renal function is stable. Alternatively, the American College of Radiology (ACR) guidelines recommend that metformin may be used prior to or following administration of iodinated contrast media in patients with no evidence of acute kidney injury (AKI) and with an eGFR ≥30 mL/minute/1.73 m²; ACR guidelines recommend temporary discontinuation of metformin in patients with known AKI or severe chronic kidney disease (stage IV or V [ie, eGFR <30 mL/minute/1.73 m²]) or who are undergoing arterial catheter studies (ACR 2017).

• Patient education: Diabetes self-management education is essential to maximize the effectiveness of therapy.

• 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.

Geriatric Considerations

Limited data suggest that metformin's total body clearance may be decreased and AUC and half-life increased in elderly patients; presumably due to decreased renal clearance. Metformin has been well tolerated by the elderly but lower doses and frequent monitoring are recommended. In one study of elderly subjects, its effects could not be distinguished from tolbutamide, except for weight loss. The initial and maintenance dosing should be conservative, due to the potential for decreased renal function. Generally, elderly patients should not be titrated to the maximum dose of metformin. However, recent studies suggest that metformin may be safely continued in patients with GFR ≥30 mL/minute/1.73 m² (ADA 2017b); see Dosing: Renal Impairment for specific recommendations for patients whose eGFR is ≥30 mL/minute/1.73 m² and <60 mL/minute/1.73 m². Use is contraindicated in eGFR <30 mL/minute/1.73 m².^. Older adults with diabetes are at a higher risk of cognitive decline and institutionalization (ADA 2017b).

Clinical trials for empagliflozin included 32% and 6% of participants ages >65 and >75 years old, respectively (per the manufacturer). Elderly patients may be more prone to adverse events due to volume depletion (eg, hypotension) and should be assessed for depleted volume prior to starting empagliflozin. Patients >75 years are at greater risk for volume depletion and urinary tract infections.

Intensive glucose control (HbA1c <6.5%) has been linked to increased all-cause and cardiovascular mortality, hypoglycemia requiring assistance, and weight gain in adult type 2 diabetes. How "tightly" to control a geriatric patient's blood glucose needs to be individualized. Such a decision should be based on several factors, including the patient's functional and cognitive status, how well he/she recognizes hypoglycemic or hyperglycemic symptoms, and how to respond to them and other disease states. An HbA1c <7.5% is an acceptable endpoint for a healthy older adult, while <8% is acceptable for frail elderly patients, those with a duration of illness >10 years, or those with comorbid conditions and requiring combination diabetes medications. In patients with advanced microvascular complications and/or a life expectancy <5 years, a target HbA1c of 8% to 9% is reasonable. For elderly patients with diabetes who are relatively healthy, attaining target goals for aspirin use, blood pressure, lipids, smoking cessation, and diet and exercise may be more important than normalized glycemic control.

Pregnancy Considerations

Metformin crosses the placenta (ADA 2020). Use of empagliflozin/metformin combination product is not recommended during the second and third trimesters. Refer to individual monographs.

Breast-Feeding Considerations

Metformin is excreted into breast milk; excretion of empagliflozin is not known. Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer does not recommend use of empagliflozin/metformin in women who are breastfeeding. Refer to individual monographs.

Lexicomp Pregnancy & Lactation, In-Depth

• Empagliflozin
• MetFORMIN

Briggs' Drugs in Pregnancy & Lactation

• Empagliflozin
• Metformin

Adverse Reactions

See individual agents.

Allergy and Idiosyncratic Reactions

• Biguanide Allergy

Metabolism/Transport Effects

Refer to individual components.

Drug Interactions Open Interactions

Abemaciclib: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy

Alcohol (Ethyl): May enhance the adverse/toxic effect of MetFORMIN. Specifically, alcohol 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. Exceptions: Danazol. Risk C: Monitor therapy

Bictegravir: May increase the serum concentration of MetFORMIN. 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. Exceptions: Brinzolamide; Dorzolamide. 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

Dalfampridine: MetFORMIN may increase the serum concentration of Dalfampridine. Dalfampridine may increase the serum concentration of MetFORMIN. Risk C: Monitor therapy

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 the risks and benefits of this combination. If combined, limit the daily metformin dose to 1,000 mg when used with dolutegravir. Monitor for increased metformin effects/toxicities (including lactic acidosis) during concomitant use. Risk D: Consider therapy modification

Erdafitinib: May increase the serum concentration of OCT2 Substrates. 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

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. Exceptions: Diatrizoate Meglumine; Diatrizoate Sodium; Ethiodized Oil. Risk D: Consider therapy modification

Isavuconazonium Sulfate: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy

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

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

Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Nitisinone: May increase the serum concentration of OAT1/3 Substrates. 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

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

Pretomanid: May increase the serum concentration of OAT1/3 Substrates. 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

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 inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modification

Tafenoquine: May increase the serum concentration of MATE1 Substrates. 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. 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

Teriflunomide: May increase the serum concentration of OAT1/3 Substrates. Risk C: Monitor therapy

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Tolvaptan: May increase the serum concentration of OAT1/3 Substrates. Management: Avoid concomitant use of OAT1/3 substrates in patients receiving the Jynarque brand of tolvaptan. Concentrations and effects of the OAT1/3 substrate would be expected to increase with combined use. Risk D: Consider therapy modification

Topiramate: May enhance the adverse/toxic effect of MetFORMIN. Risk C: Monitor therapy

Trimethoprim: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy

Trospium: MetFORMIN may decrease the serum concentration of Trospium. Risk C: Monitor therapy

Vandetanib: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy

Verapamil: May diminish the therapeutic effect of MetFORMIN. Risk C: Monitor therapy

Monitoring Parameters

Blood glucose, HbA1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change (ADA 2019); renal function (baseline and annually thereafter or when clinically indicated); volume status (eg, blood pressure, hematocrit, electrolytes); hematologic parameters (annually); blood pressure; genital mycotic infections, urinary tract infections, and vitamin B₁₂ (periodically with long term therapy); folate (if megaloblastic anemia is suspected); 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])

Reference Range

Recommendations for glycemic control in nonpregnant adults with diabetes (ADA 2019):

HbA_1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA_1c goal may be targeted based on patient-specific characteristics)

Preprandial capillary blood glucose: 80 to 130 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics)

Peak postprandial capillary blood glucose: <180 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics)

Recommendations for glycemic control in older adults (≥65 years) with diabetes (ADA 2019):

HbA_1c: <7.5% (healthy); <8% (complex/intermediate health); <8.5% (very complex/poor health) (individualization may be appropriate based on patient and caregiver preferences)

Preprandial capillary blood glucose: 90 to 130 mg/dL (healthy); 90 to150 mg/dL (complex/intermediate health); 100 to 180 mg/dL (very complex/poor health)

Bedtime capillary blood glucose: 90 to 150 mg/dL (healthy); 100 to 180 mg/dL (complex/intermediate health); 110 to 200 mg/dL (very complex/poor health)

Advanced Practitioners Physical Assessment/Monitoring

Assess renal function; dosage adjustments may be needed. Obtain blood glucose, HbA_1c, CBC, and LDL-C. Monitor blood pressure. Observe for signs of UTI or genital infection. Assess for signs and symptoms of vitamin B₁₂ and/or folic acid deficiency during therapy; supplementation may be required. Assess for signs and symptoms of metabolic acidosis. Refer patient to diabetes educator for instruction if needed.

Nursing Physical Assessment/Monitoring

Check ordered labs and report abnormalities. Monitor blood pressure. Watch for signs of hypoglycemia. Refer patient to diabetes educator for instruction if needed. Educate patient about increased risk of urinary tract or genital infection and to report any signs or symptoms.

Dosage Forms: US

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 aluminum lake]

Dosage Forms: Canada

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]

Anatomic Therapeutic Chemical (ATC) Classification

• A10BD20

Generic Available (US)

No

Pricing: US

Tablet, 24-hour (Synjardy XR Oral)

5-1000 mg (per each): $10.45

10-1000 mg (per each): $20.90

12.5-1000 mg (per each): $10.45

25-1000 mg (per each): $20.90

Tablets (Synjardy Oral)

5-500 mg (per each): $10.45

5-1000 mg (per each): $10.45

12.5-500 mg (per each): $10.45

12.5-1000 mg (per each): $10.45

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.

Mechanism of Action

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.

Metformin: Decreases hepatic glucose production, decreases intestinal absorption of glucose, improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

Pharmacodynamics/Kinetics

See individual agents

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Dizziness and syncope have been reported; patients may experience orthostatic hypotension as they stand up after treatment; especially if lying in dental chair for extended periods of time. Use caution with sudden changes in position during and after dental treatment.

Empagliflozin-dependent patients with diabetes (noninsulin dependent, type 2) should be questioned by the dental professional at each dental visit to assess their risk for stress-induced hypoglycemia. The dental professional should inquire about the patient’s routine (ie, work, sleep schedule, eating patterns), history of hypoglycemia, time of last medication dose, last meal, and most recent blood sugar assessment. Keep a supply of glucose tablets and other carbohydrates in the office to prepare for a hypoglycemic event. Seek medical attention when necessary (American Diabetes Association 2016).

Effects on Bleeding

No information available to require special precautions

Related Information

• Empagliflozin
• MetFORMIN
• Oral Antidiabetic Agents Comparison Table
• Oral Medications That Should Not Be Crushed or Altered

Index Terms

Empagliflozin/Metformin HCl; Metformin and Empagliflozin

FDA Approval Date

August 27, 2015

References

American College of Radiology Committee on Drugs and Contrast Media. ACR Manual on Contrast Media. Version 10.3. https://www.acr.org/Clinical-Resources/Contrast-Manual. Published 2017. Accessed January 3, 2018.

American Diabetes Association (ADA). Diabetes Care. 2019;42(suppl 1):S1-S193. http://care.diabetesjournals.org/content/42/Supplement_1. Accessed January 10, 2019.

American Diabetes Association (ADA). Standards of medical care in diabetes–2020. Diabetes Care. 2020;43(suppl 1):S1-S212. https://care.diabetesjournals.org/content/43/Supplement_1. Accessed January 22, 2020.

Bobart SA, Gleason B, Martinez N, Norris K, Williams SF. Euglycemic ketoacidosis caused by sodium-glucose cotransporter 2 inhibitors: a case report. Ann Intern Med. 2016;165(7):530-532. doi: 10.7326/L15-0535.[PubMed 27699391]

Brackett CC. Clarifying metformin’s role and risks in liver dysfunction. J Am Pharm Assoc (2003). 2010;50(3):407-410.[PubMed 20452916]

Crowley MJ, Diamantidis CJ, McDuffie JR, et al. Clinical outcomes of metformin use in populations with chronic kidney disease, congestive heart failure, or chronic liver disease: A systematic review. Ann Intern Med. 2017;166(3):191-200. doi: 10.7326/M16-1901.[PubMed 28055049]

Deden LN, Aarts EO, Aelfers SCW, et al. Risk of metformin-associated lactic acidosis (MALA) in patients after gastric bypass surgery. Obes Surg. 2018;28(4):1080-1085. doi: 10.1007/s11695-017-2974-1.[PubMed 29058235]

Eurich DT, Weir DL, Majumdar SR, et al. Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34,000 patients. Circ Heart Fail. 2013;6(3):395-402. doi: 10.1161/CIRCHEARTFAILURE.112.000162.[PubMed 23508758]

FDA Drug Safety Communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. Food and Drug Administration website. http://www.fda.gov/Drugs/DrugSafety/ucm475463.htm. Published December 4, 2015. Accessed October 2016.

Handelsman Y, Henry RR, Bloomgarden ZT, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Position Statement on the Association of SGLT-2 Inhibitors and Diabetic Ketoacidosis. Endocr Pract. 2016;22(6):753-762.[PubMed 27082665]

Mechanick JI, Youdim A, Jones DB, et al. Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient--2013 update: cosponsored by American Association of Clinical Endocrinologists, the Obesity Society, and American Society for Metabolic & Bariatric Surgery. Surg Obes Relat Dis. 2013;9(2):159-191. doi: 10.1016/j.soard.2012.12.010.[PubMed 23537696]

Melissas J, Leventi A, Klinaki I, et al. Alterations of global gastrointestinal motility after sleeve gastrectomy: a prospective study. Ann Surg. 2013;258(6):976-982. doi: 10.1097/SLA.0b013e3182774522.[PubMed 23160151]

Padwal RS, Gabr RQ, Sharma AM, et al. Effect of gastric bypass surgery on the absorption and bioavailability of metformin. Diabetes Care. 2011;34(6):1295-1300. doi: 10.2337/dc10-2140.[PubMed 21478461]

Page RL 2nd, O'Bryant CL, Cheng D, et al; American Heart Association Clinical Pharmacology and Heart Failure and Transplantation Committees of the Council on Clinical Cardiology; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular and Stroke Nursing; and Council on Quality of Care and Outcomes Research. Drugs that may cause or exacerbate heart failure: a scientific statement from the American Heart Association [published correction appears in Circulation. 2016;134(12):e261]. Circulation. 2016;134(6):e32-e69.[PubMed 27400984]

Ruanpeng D, Ungprasert P, Sangtian J, et al. Sodium-glucose cotransporter 2 (SGLT2) inhibitors and fracture risk in patients with type 2 diabetes mellitus: A meta-analysis. Diabetes Metab Res Rev. 2017;33(6). doi: 10.1002/dmrr.2903.[PubMed 28440590]

Synjardy (empagliflozin/metformin) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; October 2018.

Synjardy (empagliflozin/metformin) [product monograph]. Burlington, Ontario, Canada: Boehringer Ingelheim (Canada) Ltd; January 2019.

Synjardy XR (empagliflozin/metformin) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; January 2020.

Tang HL, Li DD, Zhang JJ, et al. Lack of evidence for a harmful effect of sodium-glucose co-transporter 2 (SGLT2) inhibitors on fracture risk among type 2 diabetes patients: a network and cumulative metaanalysis of randomized controlled trials. Diabetes Obes Metab. 2016;18(12):1199-1206. doi: 10.1111/dom.12742.[PubMed 27407013]

van Niekerk C, Wallace J, Takata M, Yu R. Euglycaemic diabetic ketoacidosis in bariatric surgery patients with type 2 diabetes taking canagliflozin [published online August 20, 2018]. BMJ Case Rep. doi: 10.1136/bcr-2017-221527.[PubMed 30131409]

Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323-334.[PubMed 27299675]

Wanner C, Lachin JM, Inzucchi SE, et al; EMPA-REG OUTCOME Investigators. Empagliflozin and clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease. Circulation. 2018;137(2):119-129. doi: 10.1161/CIRCULATIONAHA.117.028268.[PubMed 28904068]

Zhang X, Harmsen WS, Mettler TA, et al. Continuation of metformin use after a diagnosis of cirrhosis significantly improves survival of patients with diabetes. Hepatology. 2014;60(6):2008-2016.[PubMed 24798175]

Brand Names: International

Jardiamet (AU); Jardiance Duo (HK, IL, MY, PH, SG, TH, VN); Jardianz Duo (CR, DO, GT, HN, NI, PA, SV); Synjardy (AT, BE, CZ, DE, DK, EE, EG, ES, GB, HR, HU, IE, IS, LB, LT, LV, NL, NO, PL, PT, SE, SI, SK)

Last Updated 3/4/20