Get your patient on Synjardy (Empagliflozin And Metformin Hydrochloride)

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Synjardy prescribing information

Boxed Warning

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/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL
[see
5.1 Lactic Acidosis

There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension, and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of SYNJARDY or SYNJARDY XR. In SYNJARDY or SYNJARDY XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery

.

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue SYNJARDY or SYNJARDY XR and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

Renal Impairment:
The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include:

  • Before initiating SYNJARDY or SYNJARDY XR, obtain an estimated glomerular filtration rate (eGFR).
  • SYNJARDY and SYNJARDY XR are contraindicated in patients with an eGFR below 30 mL/min/1.73 m2
  • Obtain an eGFR at least annually in all patients taking SYNJARDY or SYNJARDY XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

Drug Interactions:
The concomitant use of SYNJARDY or SYNJARDY XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation. Therefore, consider more frequent monitoring of patients.

Age 65 or Greater:
The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.

Radiological Studies with Contrast:
Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop SYNJARDY or SYNJARDY XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart SYNJARDY or SYNJARDY XR if renal function is stable.

Surgery and Other Procedures:
Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. SYNJARDY or SYNJARDY XR should be temporarily discontinued while patients have restricted food and fluid intake.

Hypoxic States:
Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue SYNJARDY or SYNJARDY XR.

Excessive Alcohol Intake:
Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving SYNJARDY or SYNJARDY XR.

Hepatic Impairment:
Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of SYNJARDY or SYNJARDY XR in patients with clinical or laboratory evidence of hepatic disease.

]
.

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., 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
[see
2.1 Testing Prior to Initiation of SYNJARDY or SYNJARDY XR
,
4 CONTRAINDICATIONS

SYNJARDY and SYNJARDY XR are contraindicated in patients with:

  • Severe renal impairment (eGFR below 30 mL/min/1.73 m2) (4)
  • Metabolic acidosis, including diabetic ketoacidosis (4)
  • Hypersensitivity to empagliflozin, metformin HCl or any of the excipients in SYNJARDY or SYNJARDY XR (4)
,
5.1 Lactic Acidosis

There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension, and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of SYNJARDY or SYNJARDY XR. In SYNJARDY or SYNJARDY XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery

.

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue SYNJARDY or SYNJARDY XR and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

Renal Impairment:
The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include:

  • Before initiating SYNJARDY or SYNJARDY XR, obtain an estimated glomerular filtration rate (eGFR).
  • SYNJARDY and SYNJARDY XR are contraindicated in patients with an eGFR below 30 mL/min/1.73 m2
  • Obtain an eGFR at least annually in all patients taking SYNJARDY or SYNJARDY XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

Drug Interactions:
The concomitant use of SYNJARDY or SYNJARDY XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation. Therefore, consider more frequent monitoring of patients.

Age 65 or Greater:
The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.

Radiological Studies with Contrast:
Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop SYNJARDY or SYNJARDY XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart SYNJARDY or SYNJARDY XR if renal function is stable.

Surgery and Other Procedures:
Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. SYNJARDY or SYNJARDY XR should be temporarily discontinued while patients have restricted food and fluid intake.

Hypoxic States:
Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue SYNJARDY or SYNJARDY XR.

Excessive Alcohol Intake:
Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving SYNJARDY or SYNJARDY XR.

Hepatic Impairment:
Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of SYNJARDY or SYNJARDY XR in patients with clinical or laboratory evidence of hepatic disease.

,
7 DRUG INTERACTIONS

SeeTable 4for clinically relevant interactions with SYNJARDY or SYNJARDY XR.

Table 4 Clinically Relevant Interactions with SYNJARDY or SYNJARDY XR
Carbonic Anhydrase Inhibitors
Clinical Impact
Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with SYNJARDY or SYNJARDY XR may increase the risk of lactic acidosis.
Intervention
Consider more frequent monitoring of these patients.
Drugs that Reduce Metformin Clearance
Clinical Impact
Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis.
Intervention
Consider the benefits and risks of concomitant use.
Alcohol
Clinical Impact
Alcohol is known to potentiate the effect of metformin on lactate metabolism.
Intervention
Warn patients against excessive alcohol intake while receiving SYNJARDY or SYNJARDY XR.
Diuretics
Clinical Impact
Coadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids, which might enhance the potential for volume depletion.
Intervention
Before initiating SYNJARDY or SYNJARDY XR, assess volume status and renal function. In patients with volume depletion, correct this condition before initiating SYNJARDY or SYNJARDY XR. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.
Insulin or Insulin Secretagogues
Clinical Impact
The risk of hypoglycemia is increased when SYNJARDY or SYNJARDY XR is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin.
Intervention
Coadministration of SYNJARDY or SYNJARDY XR with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.
Drugs Affecting Glycemic Control
Clinical Impact
Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid.
Intervention
When such drugs are administered to a patient receiving SYNJARDY or SYNJARDY XR, the patient should be closely observed to maintain adequate glycemic control. When such drugs are withdrawn from a patient receiving SYNJARDY or SYNJARDY XR, the patient should be observed closely for hypoglycemia.
Lithium
Clinical Impact
Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations.
Intervention
Monitor serum lithium concentration more frequently during SYNJARDY or SYNJARDY XR initiation and dosage changes.
Positive Urine Glucose Test
Clinical Impact
SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests.
Intervention
Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.
Interference with 1,5-anhydroglucitol (1,5-AG) Assay
Clinical Impact
Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors.
Intervention
Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control.
  • Carbonic Anhydrase Inhibitors:
    May increase risk of lactic acidosis. Consider more frequent monitoring. (7)
  • Drugs that Reduce Metformin Clearance:
    May increase risk of lactic acidosis. Consider benefits and risks of concomitant use. (7)
  • See full prescribing information for additional drug interactions and information on interference of SYNJARDY or SYNJARDY XR with laboratory tests. (7)
, and
8.6 Renal Impairment

SYNJARDY or SYNJARDY XR should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m2due to the metformin HCl component and is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2).

Empagliflozin

The glucose lowering benefit of empagliflozin 25 mg decreased in adult patients with worsening renal function. The risks of renal impairment, volume depletion adverse reactions and urinary tract infection-related adverse reactions increased with worsening renal function

. In the trial of pediatric patients aged 10 to 17 years with type 2 diabetes mellitus, patients with an eGFR less than 60 mL/min/1.73 m2were not enrolled.

Metformin HCl

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment

.

,
8.7 Hepatic Impairment

Use of metformin HCl in patients with hepatic impairment has been associated with some cases of lactic acidosis. SYNJARDY and SYNJARDY XR are not recommended in patients with hepatic impairment

].

If metformin-associated lactic acidosis is suspected, immediately discontinue SYNJARDY or SYNJARDY XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended
[see
5.1 Lactic Acidosis

There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension, and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of SYNJARDY or SYNJARDY XR. In SYNJARDY or SYNJARDY XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery

.

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue SYNJARDY or SYNJARDY XR and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

Renal Impairment:
The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include:

  • Before initiating SYNJARDY or SYNJARDY XR, obtain an estimated glomerular filtration rate (eGFR).
  • SYNJARDY and SYNJARDY XR are contraindicated in patients with an eGFR below 30 mL/min/1.73 m2
  • Obtain an eGFR at least annually in all patients taking SYNJARDY or SYNJARDY XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

Drug Interactions:
The concomitant use of SYNJARDY or SYNJARDY XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation. Therefore, consider more frequent monitoring of patients.

Age 65 or Greater:
The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.

Radiological Studies with Contrast:
Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop SYNJARDY or SYNJARDY XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart SYNJARDY or SYNJARDY XR if renal function is stable.

Surgery and Other Procedures:
Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. SYNJARDY or SYNJARDY XR should be temporarily discontinued while patients have restricted food and fluid intake.

Hypoxic States:
Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue SYNJARDY or SYNJARDY XR.

Excessive Alcohol Intake:
Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving SYNJARDY or SYNJARDY XR.

Hepatic Impairment:
Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of SYNJARDY or SYNJARDY XR in patients with clinical or laboratory evidence of hepatic disease.

].

Recent Major Changes
Indications and Usage (
1 INDICATIONS AND USAGE

SYNJARDY

SYNJARDY is a combination of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor and metformin hydrochloride (HCl) immediate-release, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus.

SYNJARDY XR

SYNJARDY XR is a combination of empagliflozin, a SGLT2 inhibitor and metformin HCl extended-release, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

.

Empagliflozin

Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of:

  • Cardiovascular (CV) death in adults with established CV disease. (1)
  • CV death and hospitalization for heart failure in adults with heart failure. (1)
  • Sustained decline in eGFR, end-stage kidney disease, CV death, and hospitalization in adults with chronic kidney disease at risk of progression. (1)

Limitations of Use
:

  • Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients. (1)
  • Because of the metformin HCl component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications. (1)
  • Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of intravenous immunosuppressive therapy or greater than 45 mg of prednisone or equivalent for kidney disease. Empagliflozin is not expected to be effective in these populations. (1)

SYNJARDY

SYNJARDY is a combination of empagliflozin and metformin hydrochloride (HCl) immediate-release indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus

.

SYNJARDY XR

SYNJARDY XR is a combination of empagliflozin and metformin HCl extended-release indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

.

Empagliflozin

Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of:

  • Cardiovascular (CV) death in adults with established CV disease.
  • CV death and hospitalization for heart failure in adults with heart failure.
  • Sustained decline in eGFR, end-stage kidney disease, CV death, and hospitalization in adults with chronic kidney disease at risk of progression.

Limitations of Use

  • SYNJARDY and SYNJARDY XR are not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients.
  • Because of the metformin HCl component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications.
  • Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of intravenous immunosuppressive therapy or greater than 45 mg of prednisone or equivalent for kidney disease. Empagliflozin is not expected to be effective in these populations.
)		3/2025
Warnings and Precautions, Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections (
5.4 Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections

Empagliflozin increases urinary glucose excretionand increases the risk of genitourinary infections including urinary tract infections and genital mycotic infections in both male and female patients.

Serious genitourinary infections, including urosepsis, pyelonephritis, and necrotizing fasciitis of the perineum (Fournier's gangrene, a rare life-threatening infection requiring urgent surgical intervention), have occurred in patients with and without diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin. Cases have required hospitalization
.
In patients with Fournier's gangrene, serious outcomes have included multiple surgeries and death. SYNJARDY and SYNJARDY XR are only indicated for use in patients with type 2 diabetes mellitus.

Patients with a history of chronic or recurrent genitourinary infections are more likely to develop genitourinary infections when using SYNJARDY or SYNJARDY XR. Monitor patients for signs and symptoms of genitourinary infections and treat promptly, if indicated.

Immediately evaluate patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, for necrotizing fasciitis. If suspected, discontinue SYNJARDY or SYNJARDY XR and promptly institute appropriate medical and/or surgical intervention.

)		10/2025
Warnings and Precautions, Lower Limb Amputation (
5.6 Lower Limb Amputation

In some clinical studies with SGLT2 inhibitors an imbalance in the incidence of lower limb amputation has been observed. Across four empagliflozin outcome trials, lower limb amputation event rates were 4.3 and 5.0 events per 1,000 patient-years in the placebo group and the empagliflozin 10 mg or 25 mg dose group, respectively, with a HR of 1.05 (95% CI) (0.81, 1.36).

In a long-term cardio-renal outcome trial with empagliflozin, in patients with chronic kidney disease, the occurrence of lower limb amputations was reported with event rates of 2.9, and 4.3 events per 1,000 patient-years in the placebo, and empagliflozin 10 mg treatment arms, respectively. Amputation of the toe and mid-foot were most frequent (21 out of 28 empagliflozin 10 mg treated patients with lower limb amputations), and some involving above and below the knee. Some patients had multiple amputations.

Peripheral artery disease, and diabetic foot infection (including osteomyelitis), were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of diabetic foot, peripheral artery disease (including previous amputation) or diabetes.

Counsel patients about the importance of routine preventative foot care. Monitor patients receiving SYNJARDY or SYNJARDY XR for signs and symptoms of diabetic foot infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and institute appropriate treatment.

)		3/2025
Indications & Usage

SYNJARDY

SYNJARDY is a combination of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor and metformin hydrochloride (HCl) immediate-release, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus.

SYNJARDY XR

SYNJARDY XR is a combination of empagliflozin, a SGLT2 inhibitor and metformin HCl extended-release, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

.

Empagliflozin

Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of:

  • Cardiovascular (CV) death in adults with established CV disease. (
    1 INDICATIONS AND USAGE

    SYNJARDY

    SYNJARDY is a combination of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor and metformin hydrochloride (HCl) immediate-release, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus.

    SYNJARDY XR

    SYNJARDY XR is a combination of empagliflozin, a SGLT2 inhibitor and metformin HCl extended-release, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

    .

    Empagliflozin

    Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of:

    • Cardiovascular (CV) death in adults with established CV disease. (1)
    • CV death and hospitalization for heart failure in adults with heart failure. (1)
    • Sustained decline in eGFR, end-stage kidney disease, CV death, and hospitalization in adults with chronic kidney disease at risk of progression. (1)

    Limitations of Use
    :

    • Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients. (1)
    • Because of the metformin HCl component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications. (1)
    • Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of intravenous immunosuppressive therapy or greater than 45 mg of prednisone or equivalent for kidney disease. Empagliflozin is not expected to be effective in these populations. (1)

    SYNJARDY

    SYNJARDY is a combination of empagliflozin and metformin hydrochloride (HCl) immediate-release indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus

    .

    SYNJARDY XR

    SYNJARDY XR is a combination of empagliflozin and metformin HCl extended-release indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

    .

    Empagliflozin

    Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of:

    • Cardiovascular (CV) death in adults with established CV disease.
    • CV death and hospitalization for heart failure in adults with heart failure.
    • Sustained decline in eGFR, end-stage kidney disease, CV death, and hospitalization in adults with chronic kidney disease at risk of progression.

    Limitations of Use

    • SYNJARDY and SYNJARDY XR are not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients.
    • Because of the metformin HCl component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications.
    • Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of intravenous immunosuppressive therapy or greater than 45 mg of prednisone or equivalent for kidney disease. Empagliflozin is not expected to be effective in these populations.
    )
  • CV death and hospitalization for heart failure in adults with heart failure. (
    1 INDICATIONS AND USAGE

    SYNJARDY

    SYNJARDY is a combination of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor and metformin hydrochloride (HCl) immediate-release, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus.

    SYNJARDY XR

    SYNJARDY XR is a combination of empagliflozin, a SGLT2 inhibitor and metformin HCl extended-release, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

    .

    Empagliflozin

    Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of:

    • Cardiovascular (CV) death in adults with established CV disease. (1)
    • CV death and hospitalization for heart failure in adults with heart failure. (1)
    • Sustained decline in eGFR, end-stage kidney disease, CV death, and hospitalization in adults with chronic kidney disease at risk of progression. (1)

    Limitations of Use
    :

    • Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients. (1)
    • Because of the metformin HCl component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications. (1)
    • Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of intravenous immunosuppressive therapy or greater than 45 mg of prednisone or equivalent for kidney disease. Empagliflozin is not expected to be effective in these populations. (1)

    SYNJARDY

    SYNJARDY is a combination of empagliflozin and metformin hydrochloride (HCl) immediate-release indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus

    .

    SYNJARDY XR

    SYNJARDY XR is a combination of empagliflozin and metformin HCl extended-release indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

    .

    Empagliflozin

    Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of:

    • Cardiovascular (CV) death in adults with established CV disease.
    • CV death and hospitalization for heart failure in adults with heart failure.
    • Sustained decline in eGFR, end-stage kidney disease, CV death, and hospitalization in adults with chronic kidney disease at risk of progression.

    Limitations of Use

    • SYNJARDY and SYNJARDY XR are not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients.
    • Because of the metformin HCl component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications.
    • Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of intravenous immunosuppressive therapy or greater than 45 mg of prednisone or equivalent for kidney disease. Empagliflozin is not expected to be effective in these populations.
    )
  • Sustained decline in eGFR, end-stage kidney disease, CV death, and hospitalization in adults with chronic kidney disease at risk of progression. (
    1 INDICATIONS AND USAGE

    SYNJARDY

    SYNJARDY is a combination of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor and metformin hydrochloride (HCl) immediate-release, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus.

    SYNJARDY XR

    SYNJARDY XR is a combination of empagliflozin, a SGLT2 inhibitor and metformin HCl extended-release, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

    .

    Empagliflozin

    Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of:

    • Cardiovascular (CV) death in adults with established CV disease. (1)
    • CV death and hospitalization for heart failure in adults with heart failure. (1)
    • Sustained decline in eGFR, end-stage kidney disease, CV death, and hospitalization in adults with chronic kidney disease at risk of progression. (1)

    Limitations of Use
    :

    • Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients. (1)
    • Because of the metformin HCl component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications. (1)
    • Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of intravenous immunosuppressive therapy or greater than 45 mg of prednisone or equivalent for kidney disease. Empagliflozin is not expected to be effective in these populations. (1)

    SYNJARDY

    SYNJARDY is a combination of empagliflozin and metformin hydrochloride (HCl) immediate-release indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus

    .

    SYNJARDY XR

    SYNJARDY XR is a combination of empagliflozin and metformin HCl extended-release indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

    .

    Empagliflozin

    Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of:

    • Cardiovascular (CV) death in adults with established CV disease.
    • CV death and hospitalization for heart failure in adults with heart failure.
    • Sustained decline in eGFR, end-stage kidney disease, CV death, and hospitalization in adults with chronic kidney disease at risk of progression.

    Limitations of Use

    • SYNJARDY and SYNJARDY XR are not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients.
    • Because of the metformin HCl component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications.
    • Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of intravenous immunosuppressive therapy or greater than 45 mg of prednisone or equivalent for kidney disease. Empagliflozin is not expected to be effective in these populations.
    )

Limitations of Use
:

  • Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients. (
    1 INDICATIONS AND USAGE

    SYNJARDY

    SYNJARDY is a combination of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor and metformin hydrochloride (HCl) immediate-release, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus.

    SYNJARDY XR

    SYNJARDY XR is a combination of empagliflozin, a SGLT2 inhibitor and metformin HCl extended-release, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

    .

    Empagliflozin

    Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of:

    • Cardiovascular (CV) death in adults with established CV disease. (1)
    • CV death and hospitalization for heart failure in adults with heart failure. (1)
    • Sustained decline in eGFR, end-stage kidney disease, CV death, and hospitalization in adults with chronic kidney disease at risk of progression. (1)

    Limitations of Use
    :

    • Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients. (1)
    • Because of the metformin HCl component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications. (1)
    • Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of intravenous immunosuppressive therapy or greater than 45 mg of prednisone or equivalent for kidney disease. Empagliflozin is not expected to be effective in these populations. (1)

    SYNJARDY

    SYNJARDY is a combination of empagliflozin and metformin hydrochloride (HCl) immediate-release indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus

    .

    SYNJARDY XR

    SYNJARDY XR is a combination of empagliflozin and metformin HCl extended-release indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

    .

    Empagliflozin

    Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of:

    • Cardiovascular (CV) death in adults with established CV disease.
    • CV death and hospitalization for heart failure in adults with heart failure.
    • Sustained decline in eGFR, end-stage kidney disease, CV death, and hospitalization in adults with chronic kidney disease at risk of progression.

    Limitations of Use

    • SYNJARDY and SYNJARDY XR are not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients.
    • Because of the metformin HCl component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications.
    • Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of intravenous immunosuppressive therapy or greater than 45 mg of prednisone or equivalent for kidney disease. Empagliflozin is not expected to be effective in these populations.
    )
  • Because of the metformin HCl component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications. (
    1 INDICATIONS AND USAGE

    SYNJARDY

    SYNJARDY is a combination of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor and metformin hydrochloride (HCl) immediate-release, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus.

    SYNJARDY XR

    SYNJARDY XR is a combination of empagliflozin, a SGLT2 inhibitor and metformin HCl extended-release, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

    .

    Empagliflozin

    Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of:

    • Cardiovascular (CV) death in adults with established CV disease. (1)
    • CV death and hospitalization for heart failure in adults with heart failure. (1)
    • Sustained decline in eGFR, end-stage kidney disease, CV death, and hospitalization in adults with chronic kidney disease at risk of progression. (1)

    Limitations of Use
    :

    • Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients. (1)
    • Because of the metformin HCl component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications. (1)
    • Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of intravenous immunosuppressive therapy or greater than 45 mg of prednisone or equivalent for kidney disease. Empagliflozin is not expected to be effective in these populations. (1)

    SYNJARDY

    SYNJARDY is a combination of empagliflozin and metformin hydrochloride (HCl) immediate-release indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus

    .

    SYNJARDY XR

    SYNJARDY XR is a combination of empagliflozin and metformin HCl extended-release indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

    .

    Empagliflozin

    Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of:

    • Cardiovascular (CV) death in adults with established CV disease.
    • CV death and hospitalization for heart failure in adults with heart failure.
    • Sustained decline in eGFR, end-stage kidney disease, CV death, and hospitalization in adults with chronic kidney disease at risk of progression.

    Limitations of Use

    • SYNJARDY and SYNJARDY XR are not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients.
    • Because of the metformin HCl component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications.
    • Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of intravenous immunosuppressive therapy or greater than 45 mg of prednisone or equivalent for kidney disease. Empagliflozin is not expected to be effective in these populations.
    )
  • Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of intravenous immunosuppressive therapy or greater than 45 mg of prednisone or equivalent for kidney disease. Empagliflozin is not expected to be effective in these populations. (
    1 INDICATIONS AND USAGE

    SYNJARDY

    SYNJARDY is a combination of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor and metformin hydrochloride (HCl) immediate-release, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus.

    SYNJARDY XR

    SYNJARDY XR is a combination of empagliflozin, a SGLT2 inhibitor and metformin HCl extended-release, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

    .

    Empagliflozin

    Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of:

    • Cardiovascular (CV) death in adults with established CV disease. (1)
    • CV death and hospitalization for heart failure in adults with heart failure. (1)
    • Sustained decline in eGFR, end-stage kidney disease, CV death, and hospitalization in adults with chronic kidney disease at risk of progression. (1)

    Limitations of Use
    :

    • Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients. (1)
    • Because of the metformin HCl component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications. (1)
    • Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of intravenous immunosuppressive therapy or greater than 45 mg of prednisone or equivalent for kidney disease. Empagliflozin is not expected to be effective in these populations. (1)

    SYNJARDY

    SYNJARDY is a combination of empagliflozin and metformin hydrochloride (HCl) immediate-release indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus

    .

    SYNJARDY XR

    SYNJARDY XR is a combination of empagliflozin and metformin HCl extended-release indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

    .

    Empagliflozin

    Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of:

    • Cardiovascular (CV) death in adults with established CV disease.
    • CV death and hospitalization for heart failure in adults with heart failure.
    • Sustained decline in eGFR, end-stage kidney disease, CV death, and hospitalization in adults with chronic kidney disease at risk of progression.

    Limitations of Use

    • SYNJARDY and SYNJARDY XR are not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients.
    • Because of the metformin HCl component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications.
    • Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of intravenous immunosuppressive therapy or greater than 45 mg of prednisone or equivalent for kidney disease. Empagliflozin is not expected to be effective in these populations.
    )
Dosage & Administration
  • Assess renal function before initiating and as clinically indicated. Assess volume status and correct volume depletion before initiating. (
    2.1 Testing Prior to Initiation of SYNJARDY or SYNJARDY XR
    )
  • Individualize the starting dosage based on the patient's current regimen and renal function. (
    2.2 Recommended Dosage and Administration of SYNJARDY or SYNJARDY XR in Adults
    • When switching to SYNJARDY or SYNJARDY XR from:
      • Metformin HCl: initiate SYNJARDY or SYNJARDY XR at a similar total daily dosage of metformin HCl and a total daily empagliflozin dosage of 10 mg.
      • Empagliflozin: initiate SYNJARDY or SYNJARDY XR at the same total daily dosage of empagliflozin and a total daily metformin HCl dosage of 1,000 mg.
      • Empagliflozin and metformin HCl: initiate SYNJARDY or SYNJARDY XR at the same total daily dosages of each component.
    • Recommended dosage of SYNJARDY or SYNJARDY XR:
      • The recommended total daily dosage of empagliflozin is 10 mg.
      • For additional glycemic control, empagliflozin may be increased to a maximum total daily dosage of 25 mg in patients tolerating 10 mg daily and metformin HCl may be increased to a maximum total daily dosage of 2,000 mg, with gradual escalation to reduce gastrointestinal adverse reactions with metformin HCl
    • Take SYNJARDY orally twice daily with meals.
    • Take SYNJARDY XR orally once daily with a meal in the morning. Swallow each tablet whole. Do not split, crush, dissolve, or chew.
    ,
    2.3 Recommended Dosage and Administration of SYNJARDY in Pediatric Patients Aged 10 Years and Older
    • Individualize the dosage of SYNJARDY based on the patient's current regimen.
    • Monitor effectiveness and tolerability, and adjust dosage as appropriate, not to exceed the maximum total daily dosage of empagliflozin 25 mg and metformin HCl 2,000 mg
      .
    • Take SYNJARDY orally twice daily with meals; with gradual dose escalation to reduce gastrointestinal adverse reactions with metformin HCl
    ,
    2.4 Dosage Recommendations in Patients with Renal Impairment
    )
  • The maximum recommended dosage is 25 mg/day of empagliflozin and 2,000 mg/day of metformin HCl. (
    2.2 Recommended Dosage and Administration of SYNJARDY or SYNJARDY XR in Adults
    • When switching to SYNJARDY or SYNJARDY XR from:
      • Metformin HCl: initiate SYNJARDY or SYNJARDY XR at a similar total daily dosage of metformin HCl and a total daily empagliflozin dosage of 10 mg.
      • Empagliflozin: initiate SYNJARDY or SYNJARDY XR at the same total daily dosage of empagliflozin and a total daily metformin HCl dosage of 1,000 mg.
      • Empagliflozin and metformin HCl: initiate SYNJARDY or SYNJARDY XR at the same total daily dosages of each component.
    • Recommended dosage of SYNJARDY or SYNJARDY XR:
      • The recommended total daily dosage of empagliflozin is 10 mg.
      • For additional glycemic control, empagliflozin may be increased to a maximum total daily dosage of 25 mg in patients tolerating 10 mg daily and metformin HCl may be increased to a maximum total daily dosage of 2,000 mg, with gradual escalation to reduce gastrointestinal adverse reactions with metformin HCl
    • Take SYNJARDY orally twice daily with meals.
    • Take SYNJARDY XR orally once daily with a meal in the morning. Swallow each tablet whole. Do not split, crush, dissolve, or chew.
    ,
    2.3 Recommended Dosage and Administration of SYNJARDY in Pediatric Patients Aged 10 Years and Older
    • Individualize the dosage of SYNJARDY based on the patient's current regimen.
    • Monitor effectiveness and tolerability, and adjust dosage as appropriate, not to exceed the maximum total daily dosage of empagliflozin 25 mg and metformin HCl 2,000 mg
      .
    • Take SYNJARDY orally twice daily with meals; with gradual dose escalation to reduce gastrointestinal adverse reactions with metformin HCl
    )
  • Initiation of SYNJARDY or SYNJARDY XR is not recommended in patients with an eGFR less than 45 mL/min/1.73 m2, due to the metformin HCl component. (
    2.4 Dosage Recommendations in Patients with Renal Impairment
    )
  • SYNJARDY: take orally twice daily with meals, with gradual dosage escalation to reduce the gastrointestinal adverse reactions due to metformin HCl. (
    2.2 Recommended Dosage and Administration of SYNJARDY or SYNJARDY XR in Adults
    • When switching to SYNJARDY or SYNJARDY XR from:
      • Metformin HCl: initiate SYNJARDY or SYNJARDY XR at a similar total daily dosage of metformin HCl and a total daily empagliflozin dosage of 10 mg.
      • Empagliflozin: initiate SYNJARDY or SYNJARDY XR at the same total daily dosage of empagliflozin and a total daily metformin HCl dosage of 1,000 mg.
      • Empagliflozin and metformin HCl: initiate SYNJARDY or SYNJARDY XR at the same total daily dosages of each component.
    • Recommended dosage of SYNJARDY or SYNJARDY XR:
      • The recommended total daily dosage of empagliflozin is 10 mg.
      • For additional glycemic control, empagliflozin may be increased to a maximum total daily dosage of 25 mg in patients tolerating 10 mg daily and metformin HCl may be increased to a maximum total daily dosage of 2,000 mg, with gradual escalation to reduce gastrointestinal adverse reactions with metformin HCl
    • Take SYNJARDY orally twice daily with meals.
    • Take SYNJARDY XR orally once daily with a meal in the morning. Swallow each tablet whole. Do not split, crush, dissolve, or chew.
    ,
    2.3 Recommended Dosage and Administration of SYNJARDY in Pediatric Patients Aged 10 Years and Older
    • Individualize the dosage of SYNJARDY based on the patient's current regimen.
    • Monitor effectiveness and tolerability, and adjust dosage as appropriate, not to exceed the maximum total daily dosage of empagliflozin 25 mg and metformin HCl 2,000 mg
      .
    • Take SYNJARDY orally twice daily with meals; with gradual dose escalation to reduce gastrointestinal adverse reactions with metformin HCl
    )
  • SYNJARDY XR: take orally once daily with a meal in the morning, with gradual dosage escalation to reduce the gastrointestinal adverse reactions due to metformin HCl. Swallow whole; do not split, crush, dissolve, or chew. (
    2.2 Recommended Dosage and Administration of SYNJARDY or SYNJARDY XR in Adults
    • When switching to SYNJARDY or SYNJARDY XR from:
      • Metformin HCl: initiate SYNJARDY or SYNJARDY XR at a similar total daily dosage of metformin HCl and a total daily empagliflozin dosage of 10 mg.
      • Empagliflozin: initiate SYNJARDY or SYNJARDY XR at the same total daily dosage of empagliflozin and a total daily metformin HCl dosage of 1,000 mg.
      • Empagliflozin and metformin HCl: initiate SYNJARDY or SYNJARDY XR at the same total daily dosages of each component.
    • Recommended dosage of SYNJARDY or SYNJARDY XR:
      • The recommended total daily dosage of empagliflozin is 10 mg.
      • For additional glycemic control, empagliflozin may be increased to a maximum total daily dosage of 25 mg in patients tolerating 10 mg daily and metformin HCl may be increased to a maximum total daily dosage of 2,000 mg, with gradual escalation to reduce gastrointestinal adverse reactions with metformin HCl
    • Take SYNJARDY orally twice daily with meals.
    • Take SYNJARDY XR orally once daily with a meal in the morning. Swallow each tablet whole. Do not split, crush, dissolve, or chew.
    )
  • SYNJARDY or SYNJARDY XR may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. (
    2.5 Discontinuation for Iodinated Contrast Imaging Procedures

    Discontinue SYNJARDY or SYNJARDY XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart SYNJARDY or SYNJARDY XR if renal function is stable

    .

    )
  • Withhold SYNJARDY or SYNJARDY XR at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. (
    2.6 Temporary Interruption for Surgery

    Withhold SYNJARDY or SYNJARDY XR for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume SYNJARDY or SYNJARDY XR when the patient is clinically stable and has resumed oral intake

    .

    )
Dosage Forms & Strengths

SYNJARDY Tablets:

  • 5 mg empagliflozin/500 mg metformin HCl (
    3 DOSAGE FORMS AND STRENGTHS

    SYNJARDY Tablets:

    • 5 mg empagliflozin/500 mg metformin HCl (3)
    • 5 mg empagliflozin/1,000 mg metformin HCl (3)
    • 12.5 mg empagliflozin/500 mg metformin HCl (3)
    • 12.5 mg empagliflozin/1,000 mg metformin HCl (3)

    SYNJARDY XR Tablets:

    • 5 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
    • 10 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
    • 12.5 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
    • 25 mg empagliflozin/1,000 mg metformin HCl extended-release (3)

    SYNJARDY Tablets:

    Empagliflozin StrengthMetformin HCl StrengthColor/ShapeTablet Markings
    5 mg500 mgorange yellow, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "500".
    5 mg1,000 mgbrownish yellow, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "1000".
    12.5 mg500 mgpale brownish purple, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "500".
    12.5 mg1,000 mgdark brownish purple, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "1000".

    SYNJARDY XR Tablets:

    Empagliflozin StrengthMetformin HCl Extended - Release StrengthColor/ShapeTablet Markings
    5 mg1,000 mgolive green, oval, biconvex, film-coated tabletPrinted on one side in black ink with the Boehringer Ingelheim company symbol and "S5" on the top line and "1000 M" on the bottom line.
    10 mg1,000 mgorange, oval, biconvex,

    film-coated tablet    		Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S10" on the top line and "1000 M" on the bottom line.
    12.5 mg1,000 mgblue, oval, biconvex,

    film-coated tablet    		Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S12" on the top line and "1000 M" on the bottom line.
    25 mg1,000 mglight green, oval, biconvex,

    film-coated tablet    		Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S25" on the top line and "1000 M" on the bottom line.
    )
  • 5 mg empagliflozin/1,000 mg metformin HCl (
    3 DOSAGE FORMS AND STRENGTHS

    SYNJARDY Tablets:

    • 5 mg empagliflozin/500 mg metformin HCl (3)
    • 5 mg empagliflozin/1,000 mg metformin HCl (3)
    • 12.5 mg empagliflozin/500 mg metformin HCl (3)
    • 12.5 mg empagliflozin/1,000 mg metformin HCl (3)

    SYNJARDY XR Tablets:

    • 5 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
    • 10 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
    • 12.5 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
    • 25 mg empagliflozin/1,000 mg metformin HCl extended-release (3)

    SYNJARDY Tablets:

    Empagliflozin StrengthMetformin HCl StrengthColor/ShapeTablet Markings
    5 mg500 mgorange yellow, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "500".
    5 mg1,000 mgbrownish yellow, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "1000".
    12.5 mg500 mgpale brownish purple, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "500".
    12.5 mg1,000 mgdark brownish purple, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "1000".

    SYNJARDY XR Tablets:

    Empagliflozin StrengthMetformin HCl Extended - Release StrengthColor/ShapeTablet Markings
    5 mg1,000 mgolive green, oval, biconvex, film-coated tabletPrinted on one side in black ink with the Boehringer Ingelheim company symbol and "S5" on the top line and "1000 M" on the bottom line.
    10 mg1,000 mgorange, oval, biconvex,

    film-coated tablet    		Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S10" on the top line and "1000 M" on the bottom line.
    12.5 mg1,000 mgblue, oval, biconvex,

    film-coated tablet    		Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S12" on the top line and "1000 M" on the bottom line.
    25 mg1,000 mglight green, oval, biconvex,

    film-coated tablet    		Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S25" on the top line and "1000 M" on the bottom line.
    )
  • 12.5 mg empagliflozin/500 mg metformin HCl (
    3 DOSAGE FORMS AND STRENGTHS

    SYNJARDY Tablets:

    • 5 mg empagliflozin/500 mg metformin HCl (3)
    • 5 mg empagliflozin/1,000 mg metformin HCl (3)
    • 12.5 mg empagliflozin/500 mg metformin HCl (3)
    • 12.5 mg empagliflozin/1,000 mg metformin HCl (3)

    SYNJARDY XR Tablets:

    • 5 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
    • 10 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
    • 12.5 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
    • 25 mg empagliflozin/1,000 mg metformin HCl extended-release (3)

    SYNJARDY Tablets:

    Empagliflozin StrengthMetformin HCl StrengthColor/ShapeTablet Markings
    5 mg500 mgorange yellow, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "500".
    5 mg1,000 mgbrownish yellow, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "1000".
    12.5 mg500 mgpale brownish purple, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "500".
    12.5 mg1,000 mgdark brownish purple, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "1000".

    SYNJARDY XR Tablets:

    Empagliflozin StrengthMetformin HCl Extended - Release StrengthColor/ShapeTablet Markings
    5 mg1,000 mgolive green, oval, biconvex, film-coated tabletPrinted on one side in black ink with the Boehringer Ingelheim company symbol and "S5" on the top line and "1000 M" on the bottom line.
    10 mg1,000 mgorange, oval, biconvex,

    film-coated tablet    		Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S10" on the top line and "1000 M" on the bottom line.
    12.5 mg1,000 mgblue, oval, biconvex,

    film-coated tablet    		Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S12" on the top line and "1000 M" on the bottom line.
    25 mg1,000 mglight green, oval, biconvex,

    film-coated tablet    		Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S25" on the top line and "1000 M" on the bottom line.
    )
  • 12.5 mg empagliflozin/1,000 mg metformin HCl (
    3 DOSAGE FORMS AND STRENGTHS

    SYNJARDY Tablets:

    • 5 mg empagliflozin/500 mg metformin HCl (3)
    • 5 mg empagliflozin/1,000 mg metformin HCl (3)
    • 12.5 mg empagliflozin/500 mg metformin HCl (3)
    • 12.5 mg empagliflozin/1,000 mg metformin HCl (3)

    SYNJARDY XR Tablets:

    • 5 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
    • 10 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
    • 12.5 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
    • 25 mg empagliflozin/1,000 mg metformin HCl extended-release (3)

    SYNJARDY Tablets:

    Empagliflozin StrengthMetformin HCl StrengthColor/ShapeTablet Markings
    5 mg500 mgorange yellow, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "500".
    5 mg1,000 mgbrownish yellow, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "1000".
    12.5 mg500 mgpale brownish purple, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "500".
    12.5 mg1,000 mgdark brownish purple, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "1000".

    SYNJARDY XR Tablets:

    Empagliflozin StrengthMetformin HCl Extended - Release StrengthColor/ShapeTablet Markings
    5 mg1,000 mgolive green, oval, biconvex, film-coated tabletPrinted on one side in black ink with the Boehringer Ingelheim company symbol and "S5" on the top line and "1000 M" on the bottom line.
    10 mg1,000 mgorange, oval, biconvex,

    film-coated tablet    		Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S10" on the top line and "1000 M" on the bottom line.
    12.5 mg1,000 mgblue, oval, biconvex,

    film-coated tablet    		Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S12" on the top line and "1000 M" on the bottom line.
    25 mg1,000 mglight green, oval, biconvex,

    film-coated tablet    		Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S25" on the top line and "1000 M" on the bottom line.
    )

SYNJARDY XR Tablets:

  • 5 mg empagliflozin/1,000 mg metformin HCl extended-release (
    3 DOSAGE FORMS AND STRENGTHS

    SYNJARDY Tablets:

    • 5 mg empagliflozin/500 mg metformin HCl (3)
    • 5 mg empagliflozin/1,000 mg metformin HCl (3)
    • 12.5 mg empagliflozin/500 mg metformin HCl (3)
    • 12.5 mg empagliflozin/1,000 mg metformin HCl (3)

    SYNJARDY XR Tablets:

    • 5 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
    • 10 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
    • 12.5 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
    • 25 mg empagliflozin/1,000 mg metformin HCl extended-release (3)

    SYNJARDY Tablets:

    Empagliflozin StrengthMetformin HCl StrengthColor/ShapeTablet Markings
    5 mg500 mgorange yellow, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "500".
    5 mg1,000 mgbrownish yellow, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "1000".
    12.5 mg500 mgpale brownish purple, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "500".
    12.5 mg1,000 mgdark brownish purple, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "1000".

    SYNJARDY XR Tablets:

    Empagliflozin StrengthMetformin HCl Extended - Release StrengthColor/ShapeTablet Markings
    5 mg1,000 mgolive green, oval, biconvex, film-coated tabletPrinted on one side in black ink with the Boehringer Ingelheim company symbol and "S5" on the top line and "1000 M" on the bottom line.
    10 mg1,000 mgorange, oval, biconvex,

    film-coated tablet    		Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S10" on the top line and "1000 M" on the bottom line.
    12.5 mg1,000 mgblue, oval, biconvex,

    film-coated tablet    		Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S12" on the top line and "1000 M" on the bottom line.
    25 mg1,000 mglight green, oval, biconvex,

    film-coated tablet    		Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S25" on the top line and "1000 M" on the bottom line.
    )
  • 10 mg empagliflozin/1,000 mg metformin HCl extended-release (
    3 DOSAGE FORMS AND STRENGTHS

    SYNJARDY Tablets:

    • 5 mg empagliflozin/500 mg metformin HCl (3)
    • 5 mg empagliflozin/1,000 mg metformin HCl (3)
    • 12.5 mg empagliflozin/500 mg metformin HCl (3)
    • 12.5 mg empagliflozin/1,000 mg metformin HCl (3)

    SYNJARDY XR Tablets:

    • 5 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
    • 10 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
    • 12.5 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
    • 25 mg empagliflozin/1,000 mg metformin HCl extended-release (3)

    SYNJARDY Tablets:

    Empagliflozin StrengthMetformin HCl StrengthColor/ShapeTablet Markings
    5 mg500 mgorange yellow, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "500".
    5 mg1,000 mgbrownish yellow, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "1000".
    12.5 mg500 mgpale brownish purple, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "500".
    12.5 mg1,000 mgdark brownish purple, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "1000".

    SYNJARDY XR Tablets:

    Empagliflozin StrengthMetformin HCl Extended - Release StrengthColor/ShapeTablet Markings
    5 mg1,000 mgolive green, oval, biconvex, film-coated tabletPrinted on one side in black ink with the Boehringer Ingelheim company symbol and "S5" on the top line and "1000 M" on the bottom line.
    10 mg1,000 mgorange, oval, biconvex,

    film-coated tablet    		Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S10" on the top line and "1000 M" on the bottom line.
    12.5 mg1,000 mgblue, oval, biconvex,

    film-coated tablet    		Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S12" on the top line and "1000 M" on the bottom line.
    25 mg1,000 mglight green, oval, biconvex,

    film-coated tablet    		Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S25" on the top line and "1000 M" on the bottom line.
    )
  • 12.5 mg empagliflozin/1,000 mg metformin HCl extended-release (
    3 DOSAGE FORMS AND STRENGTHS

    SYNJARDY Tablets:

    • 5 mg empagliflozin/500 mg metformin HCl (3)
    • 5 mg empagliflozin/1,000 mg metformin HCl (3)
    • 12.5 mg empagliflozin/500 mg metformin HCl (3)
    • 12.5 mg empagliflozin/1,000 mg metformin HCl (3)

    SYNJARDY XR Tablets:

    • 5 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
    • 10 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
    • 12.5 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
    • 25 mg empagliflozin/1,000 mg metformin HCl extended-release (3)

    SYNJARDY Tablets:

    Empagliflozin StrengthMetformin HCl StrengthColor/ShapeTablet Markings
    5 mg500 mgorange yellow, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "500".
    5 mg1,000 mgbrownish yellow, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "1000".
    12.5 mg500 mgpale brownish purple, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "500".
    12.5 mg1,000 mgdark brownish purple, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "1000".

    SYNJARDY XR Tablets:

    Empagliflozin StrengthMetformin HCl Extended - Release StrengthColor/ShapeTablet Markings
    5 mg1,000 mgolive green, oval, biconvex, film-coated tabletPrinted on one side in black ink with the Boehringer Ingelheim company symbol and "S5" on the top line and "1000 M" on the bottom line.
    10 mg1,000 mgorange, oval, biconvex,

    film-coated tablet    		Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S10" on the top line and "1000 M" on the bottom line.
    12.5 mg1,000 mgblue, oval, biconvex,

    film-coated tablet    		Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S12" on the top line and "1000 M" on the bottom line.
    25 mg1,000 mglight green, oval, biconvex,

    film-coated tablet    		Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S25" on the top line and "1000 M" on the bottom line.
    )
  • 25 mg empagliflozin/1,000 mg metformin HCl extended-release (
    3 DOSAGE FORMS AND STRENGTHS

    SYNJARDY Tablets:

    • 5 mg empagliflozin/500 mg metformin HCl (3)
    • 5 mg empagliflozin/1,000 mg metformin HCl (3)
    • 12.5 mg empagliflozin/500 mg metformin HCl (3)
    • 12.5 mg empagliflozin/1,000 mg metformin HCl (3)

    SYNJARDY XR Tablets:

    • 5 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
    • 10 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
    • 12.5 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
    • 25 mg empagliflozin/1,000 mg metformin HCl extended-release (3)

    SYNJARDY Tablets:

    Empagliflozin StrengthMetformin HCl StrengthColor/ShapeTablet Markings
    5 mg500 mgorange yellow, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "500".
    5 mg1,000 mgbrownish yellow, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "1000".
    12.5 mg500 mgpale brownish purple, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "500".
    12.5 mg1,000 mgdark brownish purple, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "1000".

    SYNJARDY XR Tablets:

    Empagliflozin StrengthMetformin HCl Extended - Release StrengthColor/ShapeTablet Markings
    5 mg1,000 mgolive green, oval, biconvex, film-coated tabletPrinted on one side in black ink with the Boehringer Ingelheim company symbol and "S5" on the top line and "1000 M" on the bottom line.
    10 mg1,000 mgorange, oval, biconvex,

    film-coated tablet    		Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S10" on the top line and "1000 M" on the bottom line.
    12.5 mg1,000 mgblue, oval, biconvex,

    film-coated tablet    		Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S12" on the top line and "1000 M" on the bottom line.
    25 mg1,000 mglight green, oval, biconvex,

    film-coated tablet    		Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S25" on the top line and "1000 M" on the bottom line.
    )
Pregnancy & Lactation
  • Pregnancy:
    Advise females of the potential risk to a fetus especially during the second and third trimesters. (
    8.1 Pregnancy

    Risk Summary

    Based on animal data showing adverse renal effects from empagliflozin, SYNJARDY and SYNJARDY XR are not recommended during the second and third trimesters of pregnancy.

    The limited available data with SYNJARDY, SYNJARDY XR, or empagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage. Published studies with metformin HCl use during pregnancy have not reported a clear association with metformin HCl and major birth defect or miscarriage risk

    (seeData)
    . There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.

    In animal studies, empagliflozin, a component of SYNJARDY and SYNJARDY XR, resulted in adverse renal changes in rats when administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy. Doses approximately 13-times the maximum clinical dose caused renal pelvic and tubule dilatations that were reversible. No adverse developmental effects were observed when metformin HCl was administered to pregnant rats or rabbits

    (seeData)
    .

    The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20% to 25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

    Clinical Considerations

    Disease-associated maternal and/or embryo/fetal risk

    Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

    Data

    Human Data

    Published data from postmarketing studies have not reported a clear association with metformin HCl and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin HCl was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups.

    Animal Data

    Empagliflozin:
    Empagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 10, 30, and 100 mg/kg/day caused increased kidney weights and renal tubular and pelvic dilatation at 100 mg/kg/day, which approximates 13-times the maximum clinical dose of 25 mg, based on AUC. These findings were not observed after a 13-week, drug-free recovery period. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development.

    In embryo-fetal development studies in rats and rabbits, empagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. Doses up to 300 mg/kg/day, which approximates 48-times (rats) and 128-times (rabbits) the maximum clinical dose of 25 mg (based on AUC), did not result in adverse developmental effects. In rats, at higher doses of empagliflozin causing maternal toxicity, malformations of limb bones increased in fetuses at 700 mg/kg/day or 154-times the 25 mg maximum clinical dose. Empagliflozin crosses the placenta and reaches fetal tissues in rats. In the rabbit, higher doses of empagliflozin resulted in maternal and fetal toxicity at 700 mg/kg/day, or 139-times the 25 mg maximum clinical dose.

    In pre- and postnatal development studies in pregnant rats, empagliflozin was administered from gestation day 6 through to lactation day 20 (weaning) at up to 100 mg/kg/day (approximately 16-times the 25 mg maximum clinical dose) without maternal toxicity. Reduced body weight was observed in the offspring at greater than or equal to 30 mg/kg/day (approximately 4-times the 25 mg maximum clinical dose).

    Metformin HCl:
    Metformin HCl did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits at doses up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of approximately 2- and 6-times a clinical dose of 2,000 mg, based on body surface area (mg/m2) for rats and rabbits, respectively.

    Empagliflozin and Metformin HCl:
    No adverse developmental effects were observed when empagliflozin and metformin HCl were coadministered to pregnant rats during the period of organogenesis at exposures of approximately 35- and 14-times the clinical AUC exposure of empagliflozin associated with the 10 mg and 25 mg doses, respectively, and 4-times the clinical AUC exposure of metformin HCl associated with the 2,000 mg dose.

    )
  • Lactation:
    Not recommended when breastfeeding. (
    8.2 Lactation

    Risk Summary

    There is limited information regarding the presence of SYNJARDY, SYNJARDY XR, or its components (empagliflozin or metformin HCl) in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk

    (seeData)
    . Empagliflozin is present in the milk of lactating rats
    (seeData)
    . Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney.

    Because of the potential for serious adverse reactions in a breastfed infant, including the potential for empagliflozin to affect postnatal renal development, advise patients that use of SYNJARDY or SYNJARDY XR is not recommended while breastfeeding.

    Data

    Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin HCl during lactation because of small sample size and limited adverse event data collected in infants.

    Empagliflozin was present at a low level in rat fetal tissues after a single oral dose to the dams at gestation day 18. In rat milk, the mean milk to plasma ratio ranged from 0.634 to 5, and was greater than one from 2 to 24 hours post-dose. The mean maximal milk to plasma ratio of 5 occurred at 8 hours post-dose, suggesting accumulation of empagliflozin in the milk. Juvenile rats directly exposed to empagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.

    )
  • Females and Males of Reproductive Potential:
    Advise premenopausal females of the potential for an unintended pregnancy. (
    8.3 Females and Males of Reproductive Potential

    Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin HCl may result in ovulation in some anovulatory women.

    )
  • Geriatric Patients:
    Higher incidence of adverse reactions related to volume depletion and reduced renal function. (
    8.5 Geriatric Use

    Assess renal function more frequently in SYNJARDY or SYNJARDY XR-treated geriatric patients because there is a greater risk of empagliflozin-associated intravascular volume contraction and symptomatic hypotension in geriatric patients and there is a greater risk of metformin-associated lactic acidosis in geriatric patients

    The recommended dosage for the metformin HCl component of SYNJARDY or SYNJARDY XR in geriatric patients should usually start at the lower end of the dosage range.

    Empagliflozin

    In empagliflozin type 2 diabetes mellitus trials, 2,721 empagliflozin-treated patients were 65 years of age and older and 491 patients were 75 years of age and older. In these trials, volume depletion-related adverse reactions occurred in 2.1%, 2.3%, and 4.4% of patients 75 years of age and older in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg once daily groups, respectively; and urinary tract infections occurred in 10.5%, 15.7%, and 15.1% of patients 75 years of age and older in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg once daily groups, respectively.

    In the EMPEROR-Reduced, EMPEROR-Preserved, and EMPA-KIDNEY trials, no overall differences in safety and effectiveness have been observed between patients 65 years of age and older and younger adult patients. EMPEROR-Reduced included 1,188 (64%) patients treated with empagliflozin 65 years of age and older, and 503 (27%) patients 75 years of age and older. EMPEROR-Preserved included 2,403 (80%) patients treated with empagliflozin 65 years of age and older, and 1,281 (43%) patients 75 years of age and older. EMPA-KIDNEY included 1,803 (55%) patients treated with empagliflozin 65 years of age and older, and 758 (23%) patients 75 years of age and older.

    Metformin HCl

    Clinical studies of metformin HCl did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients

    .

    )
  • Renal Impairment:
    Higher incidence of adverse reactions related to reduced renal function. (
    8.6 Renal Impairment

    SYNJARDY or SYNJARDY XR should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m2due to the metformin HCl component and is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2).

    Empagliflozin

    The glucose lowering benefit of empagliflozin 25 mg decreased in adult patients with worsening renal function. The risks of renal impairment, volume depletion adverse reactions and urinary tract infection-related adverse reactions increased with worsening renal function

    . In the trial of pediatric patients aged 10 to 17 years with type 2 diabetes mellitus, patients with an eGFR less than 60 mL/min/1.73 m2were not enrolled.

    Metformin HCl

    Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment

    .

    )
  • Hepatic Impairment:
    Avoid use in patients with hepatic impairment. (
    8.7 Hepatic Impairment

    Use of metformin HCl in patients with hepatic impairment has been associated with some cases of lactic acidosis. SYNJARDY and SYNJARDY XR are not recommended in patients with hepatic impairment

    )
Contraindications

SYNJARDY and SYNJARDY XR are contraindicated in patients with:

  • severe renal impairment (eGFR less than 30 mL/min/1.73 m2)
    [see
    5.1 Lactic Acidosis

    There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension, and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

    If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of SYNJARDY or SYNJARDY XR. In SYNJARDY or SYNJARDY XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery

    .

    Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue SYNJARDY or SYNJARDY XR and report these symptoms to their healthcare provider.

    For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

    Renal Impairment:
    The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include:

    • Before initiating SYNJARDY or SYNJARDY XR, obtain an estimated glomerular filtration rate (eGFR).
    • SYNJARDY and SYNJARDY XR are contraindicated in patients with an eGFR below 30 mL/min/1.73 m2
    • Obtain an eGFR at least annually in all patients taking SYNJARDY or SYNJARDY XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

    Drug Interactions:
    The concomitant use of SYNJARDY or SYNJARDY XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation. Therefore, consider more frequent monitoring of patients.

    Age 65 or Greater:
    The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.

    Radiological Studies with Contrast:
    Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop SYNJARDY or SYNJARDY XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart SYNJARDY or SYNJARDY XR if renal function is stable.

    Surgery and Other Procedures:
    Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. SYNJARDY or SYNJARDY XR should be temporarily discontinued while patients have restricted food and fluid intake.

    Hypoxic States:
    Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue SYNJARDY or SYNJARDY XR.

    Excessive Alcohol Intake:
    Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving SYNJARDY or SYNJARDY XR.

    Hepatic Impairment:
    Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of SYNJARDY or SYNJARDY XR in patients with clinical or laboratory evidence of hepatic disease.

    and
    8.6 Renal Impairment

    SYNJARDY or SYNJARDY XR should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m2due to the metformin HCl component and is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2).

    Empagliflozin

    The glucose lowering benefit of empagliflozin 25 mg decreased in adult patients with worsening renal function. The risks of renal impairment, volume depletion adverse reactions and urinary tract infection-related adverse reactions increased with worsening renal function

    . In the trial of pediatric patients aged 10 to 17 years with type 2 diabetes mellitus, patients with an eGFR less than 60 mL/min/1.73 m2were not enrolled.

    Metformin HCl

    Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment

    .

    ].
  • acute or chronic metabolic acidosis, including diabetic ketoacidosis
    [see
    5.1 Lactic Acidosis

    There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension, and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

    If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of SYNJARDY or SYNJARDY XR. In SYNJARDY or SYNJARDY XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery

    .

    Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue SYNJARDY or SYNJARDY XR and report these symptoms to their healthcare provider.

    For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

    Renal Impairment:
    The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include:

    • Before initiating SYNJARDY or SYNJARDY XR, obtain an estimated glomerular filtration rate (eGFR).
    • SYNJARDY and SYNJARDY XR are contraindicated in patients with an eGFR below 30 mL/min/1.73 m2
    • Obtain an eGFR at least annually in all patients taking SYNJARDY or SYNJARDY XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

    Drug Interactions:
    The concomitant use of SYNJARDY or SYNJARDY XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation. Therefore, consider more frequent monitoring of patients.

    Age 65 or Greater:
    The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.

    Radiological Studies with Contrast:
    Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop SYNJARDY or SYNJARDY XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart SYNJARDY or SYNJARDY XR if renal function is stable.

    Surgery and Other Procedures:
    Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. SYNJARDY or SYNJARDY XR should be temporarily discontinued while patients have restricted food and fluid intake.

    Hypoxic States:
    Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue SYNJARDY or SYNJARDY XR.

    Excessive Alcohol Intake:
    Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving SYNJARDY or SYNJARDY XR.

    Hepatic Impairment:
    Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of SYNJARDY or SYNJARDY XR in patients with clinical or laboratory evidence of hepatic disease.

    ].
  • hypersensitivity to empagliflozin, metformin HCl or any of the excipients in SYNJARDY or SYNJARDY XR, reactions such as angioedema have occurred
    [see
    5.7 Hypersensitivity Reactions

    There have been postmarketing reports of serious hypersensitivity reactions (e.g., angioedema) in patients treated with empagliflozin. If a hypersensitivity reaction occurs, discontinue SYNJARDY or SYNJARDY XR; treat promptly per standard of care, and monitor until signs and symptoms resolve. SYNJARDY and SYNJARDY XR are contraindicated in patients with hypersensitivity to empagliflozin or any of the excipients in SYNJARDY or SYNJARDY XR

    .

    ]
    .
Warnings & Precautions
  • Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis:
    Consider ketone monitoring in patients at risk of ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue SYNJARDY or SYNJARDY XR if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting. (
    5.2 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis

    In patients with type 1 diabetes mellitus, empagliflozin, a component of SYNJARDY or SYNJARDY XR, significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium glucose co-transporter 2 (SGLT2) inhibitors compared to patients who received placebo and fatal ketoacidosis has occurred with empagliflozin. SYNJARDY and SYNJARDY XR are not indicated for glycemic control in patients with type 1 diabetes mellitus.

    Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including SYNJARDY or SYNJARDY XR.

    Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse.

    Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing SYNJARDY or SYNJARDY XR

    ; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors.

    Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue SYNJARDY or SYNJARDY XR, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting SYNJARDY or SYNJARDY XR.

    Withhold SYNJARDY or SYNJARDY XR, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume SYNJARDY or SYNJARDY XR when the patient is clinically stable and has resumed oral intake

    .

    Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue SYNJARDY or SYNJARDY XR and seek medical attention immediately if signs and symptoms occur.

    )
  • Volume Depletion:
    Before initiating SYNJARDY or SYNJARDY XR, assess volume status and renal function in patients with impaired renal function, elderly patients, or patients on loop diuretics. Monitor for signs and symptoms during therapy. (
    5.3 Volume Depletion

    Empagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine

    . There have been post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating SYNJARDY or SYNJARDY XR in patients with one or more of these characteristics, assess volume status and renal function. In patients with volume depletion, correct this condition before initiating SYNJARDY or SYNJARDY XR. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.

    )
  • Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections:
    Monitor patients for signs and symptoms of genitourinary infections and treat promptly, if indicated. Immediately evaluate patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, for necrotizing fasciitis and if suspected, discontinue SYNJARDY or SYNJARDY XR, and promptly institute appropriate medical and/or surgical intervention. (
    5.4 Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections

    Empagliflozin increases urinary glucose excretionand increases the risk of genitourinary infections including urinary tract infections and genital mycotic infections in both male and female patients.

    Serious genitourinary infections, including urosepsis, pyelonephritis, and necrotizing fasciitis of the perineum (Fournier's gangrene, a rare life-threatening infection requiring urgent surgical intervention), have occurred in patients with and without diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin. Cases have required hospitalization
    .
    In patients with Fournier's gangrene, serious outcomes have included multiple surgeries and death. SYNJARDY and SYNJARDY XR are only indicated for use in patients with type 2 diabetes mellitus.

    Patients with a history of chronic or recurrent genitourinary infections are more likely to develop genitourinary infections when using SYNJARDY or SYNJARDY XR. Monitor patients for signs and symptoms of genitourinary infections and treat promptly, if indicated.

    Immediately evaluate patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, for necrotizing fasciitis. If suspected, discontinue SYNJARDY or SYNJARDY XR and promptly institute appropriate medical and/or surgical intervention.

    )
  • Hypoglycemia:
    Adult patients taking an insulin secretagogue or insulin may have an increased risk of hypoglycemia. In pediatric patients 10 years of age and older, the risk of hypoglycemia was higher regardless of insulin use. Consider lowering the dosage of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating SYNJARDY or SYNJARDY XR. (
    5.5 Hypoglycemia

    Insulin and insulin secretagogues are known to cause hypoglycemia. In adult patients, the risk of hypoglycemia may be increased when SYNJARDY or SYNJARDY XR is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin. In pediatric patients aged 10 years and older, the risk of hypoglycemia was higher with empagliflozin regardless of insulin use

    .

    The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin. Inform patients using these concomitant medications and pediatric patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

    )
  • Lower Limb Amputation:
    Monitor patients for infections or ulcers of lower limbs, and institute appropriate treatment. (
    5.6 Lower Limb Amputation

    In some clinical studies with SGLT2 inhibitors an imbalance in the incidence of lower limb amputation has been observed. Across four empagliflozin outcome trials, lower limb amputation event rates were 4.3 and 5.0 events per 1,000 patient-years in the placebo group and the empagliflozin 10 mg or 25 mg dose group, respectively, with a HR of 1.05 (95% CI) (0.81, 1.36).

    In a long-term cardio-renal outcome trial with empagliflozin, in patients with chronic kidney disease, the occurrence of lower limb amputations was reported with event rates of 2.9, and 4.3 events per 1,000 patient-years in the placebo, and empagliflozin 10 mg treatment arms, respectively. Amputation of the toe and mid-foot were most frequent (21 out of 28 empagliflozin 10 mg treated patients with lower limb amputations), and some involving above and below the knee. Some patients had multiple amputations.

    Peripheral artery disease, and diabetic foot infection (including osteomyelitis), were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of diabetic foot, peripheral artery disease (including previous amputation) or diabetes.

    Counsel patients about the importance of routine preventative foot care. Monitor patients receiving SYNJARDY or SYNJARDY XR for signs and symptoms of diabetic foot infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and institute appropriate treatment.

    )
  • Hypersensitivity Reactions:
    Serious hypersensitivity reactions (e.g., angioedema) have occurred with empagliflozin. If hypersensitivity reactions occur, discontinue SYNJARDY or SYNJARDY XR, treat promptly, and monitor until signs and symptoms resolve. (
    5.7 Hypersensitivity Reactions

    There have been postmarketing reports of serious hypersensitivity reactions (e.g., angioedema) in patients treated with empagliflozin. If a hypersensitivity reaction occurs, discontinue SYNJARDY or SYNJARDY XR; treat promptly per standard of care, and monitor until signs and symptoms resolve. SYNJARDY and SYNJARDY XR are contraindicated in patients with hypersensitivity to empagliflozin or any of the excipients in SYNJARDY or SYNJARDY XR

    .

    )
  • Vitamin B12 Deficiency:
    Metformin may lower vitamin B12 levels. Measure hematologic parameters annually and vitamin B12 at 2 to 3 year intervals and manage any abnormalities. (
    5.8 Vitamin B12Deficiency

    In metformin HCl clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12levels was observed in approximately 7% of metformin-treated patients. Such decrease, possibly due to interference with B12absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B12supplementation. Certain individuals (those with inadequate vitamin B12or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12levels. Measure hematologic parameters on an annual basis and vitamin B12at 2 to 3 year intervals in patients on SYNJARDY or SYNJARDY XR and manage any abnormalities

    )
Adverse Reactions

The following important adverse reactions are described below and elsewhere in the labeling:

  • Lactic Acidosis
    [see
    WARNING: LACTIC ACIDOSIS

    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/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an 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 (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., 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 SYNJARDY or SYNJARDY XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended

    WARNING: LACTIC ACIDOSIS

    See full prescribing information for complete boxed warning.

    • Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL. (5.1)
    • Risk factors include renal impairment, concomitant use of certain drugs, age ≥65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, 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. (5.1)
    • If lactic acidosis is suspected, discontinue SYNJARDY or SYNJARDY XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. (5.1)
    and
    5.1 Lactic Acidosis

    There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension, and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

    If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of SYNJARDY or SYNJARDY XR. In SYNJARDY or SYNJARDY XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery

    .

    Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue SYNJARDY or SYNJARDY XR and report these symptoms to their healthcare provider.

    For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

    Renal Impairment:
    The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include:

    • Before initiating SYNJARDY or SYNJARDY XR, obtain an estimated glomerular filtration rate (eGFR).
    • SYNJARDY and SYNJARDY XR are contraindicated in patients with an eGFR below 30 mL/min/1.73 m2
    • Obtain an eGFR at least annually in all patients taking SYNJARDY or SYNJARDY XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

    Drug Interactions:
    The concomitant use of SYNJARDY or SYNJARDY XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation. Therefore, consider more frequent monitoring of patients.

    Age 65 or Greater:
    The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.

    Radiological Studies with Contrast:
    Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop SYNJARDY or SYNJARDY XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart SYNJARDY or SYNJARDY XR if renal function is stable.

    Surgery and Other Procedures:
    Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. SYNJARDY or SYNJARDY XR should be temporarily discontinued while patients have restricted food and fluid intake.

    Hypoxic States:
    Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue SYNJARDY or SYNJARDY XR.

    Excessive Alcohol Intake:
    Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving SYNJARDY or SYNJARDY XR.

    Hepatic Impairment:
    Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of SYNJARDY or SYNJARDY XR in patients with clinical or laboratory evidence of hepatic disease.

    ]
  • Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis
    [see
    5.2 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis

    In patients with type 1 diabetes mellitus, empagliflozin, a component of SYNJARDY or SYNJARDY XR, significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium glucose co-transporter 2 (SGLT2) inhibitors compared to patients who received placebo and fatal ketoacidosis has occurred with empagliflozin. SYNJARDY and SYNJARDY XR are not indicated for glycemic control in patients with type 1 diabetes mellitus.

    Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including SYNJARDY or SYNJARDY XR.

    Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse.

    Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing SYNJARDY or SYNJARDY XR

    ; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors.

    Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue SYNJARDY or SYNJARDY XR, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting SYNJARDY or SYNJARDY XR.

    Withhold SYNJARDY or SYNJARDY XR, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume SYNJARDY or SYNJARDY XR when the patient is clinically stable and has resumed oral intake

    .

    Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue SYNJARDY or SYNJARDY XR and seek medical attention immediately if signs and symptoms occur.

    ]
  • Volume Depletion
    [see
    5.3 Volume Depletion

    Empagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine

    . There have been post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating SYNJARDY or SYNJARDY XR in patients with one or more of these characteristics, assess volume status and renal function. In patients with volume depletion, correct this condition before initiating SYNJARDY or SYNJARDY XR. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.

    ]
  • Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections
    [see
    5.4 Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections

    Empagliflozin increases urinary glucose excretionand increases the risk of genitourinary infections including urinary tract infections and genital mycotic infections in both male and female patients.

    Serious genitourinary infections, including urosepsis, pyelonephritis, and necrotizing fasciitis of the perineum (Fournier's gangrene, a rare life-threatening infection requiring urgent surgical intervention), have occurred in patients with and without diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin. Cases have required hospitalization
    .
    In patients with Fournier's gangrene, serious outcomes have included multiple surgeries and death. SYNJARDY and SYNJARDY XR are only indicated for use in patients with type 2 diabetes mellitus.

    Patients with a history of chronic or recurrent genitourinary infections are more likely to develop genitourinary infections when using SYNJARDY or SYNJARDY XR. Monitor patients for signs and symptoms of genitourinary infections and treat promptly, if indicated.

    Immediately evaluate patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, for necrotizing fasciitis. If suspected, discontinue SYNJARDY or SYNJARDY XR and promptly institute appropriate medical and/or surgical intervention.

    ]
  • Hypoglycemia
    [see
    5.5 Hypoglycemia

    Insulin and insulin secretagogues are known to cause hypoglycemia. In adult patients, the risk of hypoglycemia may be increased when SYNJARDY or SYNJARDY XR is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin. In pediatric patients aged 10 years and older, the risk of hypoglycemia was higher with empagliflozin regardless of insulin use

    .

    The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin. Inform patients using these concomitant medications and pediatric patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

    ]
  • Lower Limb Amputation
    [see
    5.6 Lower Limb Amputation

    In some clinical studies with SGLT2 inhibitors an imbalance in the incidence of lower limb amputation has been observed. Across four empagliflozin outcome trials, lower limb amputation event rates were 4.3 and 5.0 events per 1,000 patient-years in the placebo group and the empagliflozin 10 mg or 25 mg dose group, respectively, with a HR of 1.05 (95% CI) (0.81, 1.36).

    In a long-term cardio-renal outcome trial with empagliflozin, in patients with chronic kidney disease, the occurrence of lower limb amputations was reported with event rates of 2.9, and 4.3 events per 1,000 patient-years in the placebo, and empagliflozin 10 mg treatment arms, respectively. Amputation of the toe and mid-foot were most frequent (21 out of 28 empagliflozin 10 mg treated patients with lower limb amputations), and some involving above and below the knee. Some patients had multiple amputations.

    Peripheral artery disease, and diabetic foot infection (including osteomyelitis), were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of diabetic foot, peripheral artery disease (including previous amputation) or diabetes.

    Counsel patients about the importance of routine preventative foot care. Monitor patients receiving SYNJARDY or SYNJARDY XR for signs and symptoms of diabetic foot infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and institute appropriate treatment.

    ]
  • Hypersensitivity Reactions
    [see
    5.7 Hypersensitivity Reactions

    There have been postmarketing reports of serious hypersensitivity reactions (e.g., angioedema) in patients treated with empagliflozin. If a hypersensitivity reaction occurs, discontinue SYNJARDY or SYNJARDY XR; treat promptly per standard of care, and monitor until signs and symptoms resolve. SYNJARDY and SYNJARDY XR are contraindicated in patients with hypersensitivity to empagliflozin or any of the excipients in SYNJARDY or SYNJARDY XR

    .

    ]
  • Vitamin B12 Deficiency
    [see
    5.8 Vitamin B12Deficiency

    In metformin HCl clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12levels was observed in approximately 7% of metformin-treated patients. Such decrease, possibly due to interference with B12absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B12supplementation. Certain individuals (those with inadequate vitamin B12or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12levels. Measure hematologic parameters on an annual basis and vitamin B12at 2 to 3 year intervals in patients on SYNJARDY or SYNJARDY XR and manage any abnormalities

    ]
Drug Interactions

See

Table 4 Clinically Relevant Interactions with SYNJARDY or SYNJARDY XR
Carbonic Anhydrase Inhibitors
Clinical Impact
Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with SYNJARDY or SYNJARDY XR may increase the risk of lactic acidosis.
Intervention
Consider more frequent monitoring of these patients.
Drugs that Reduce Metformin Clearance
Clinical Impact
Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis.
Intervention
Consider the benefits and risks of concomitant use.
Alcohol
Clinical Impact
Alcohol is known to potentiate the effect of metformin on lactate metabolism.
Intervention
Warn patients against excessive alcohol intake while receiving SYNJARDY or SYNJARDY XR.
Diuretics
Clinical Impact
Coadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids, which might enhance the potential for volume depletion.
Intervention
Before initiating SYNJARDY or SYNJARDY XR, assess volume status and renal function. In patients with volume depletion, correct this condition before initiating SYNJARDY or SYNJARDY XR. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.
Insulin or Insulin Secretagogues
Clinical Impact
The risk of hypoglycemia is increased when SYNJARDY or SYNJARDY XR is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin.
Intervention
Coadministration of SYNJARDY or SYNJARDY XR with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.
Drugs Affecting Glycemic Control
Clinical Impact
Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid.
Intervention
When such drugs are administered to a patient receiving SYNJARDY or SYNJARDY XR, the patient should be closely observed to maintain adequate glycemic control. When such drugs are withdrawn from a patient receiving SYNJARDY or SYNJARDY XR, the patient should be observed closely for hypoglycemia.
Lithium
Clinical Impact
Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations.
Intervention
Monitor serum lithium concentration more frequently during SYNJARDY or SYNJARDY XR initiation and dosage changes.
Positive Urine Glucose Test
Clinical Impact
SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests.
Intervention
Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.
Interference with 1,5-anhydroglucitol (1,5-AG) Assay
Clinical Impact
Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors.
Intervention
Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control.
for clinically relevant interactions with SYNJARDY or SYNJARDY XR.

Table 4 Clinically Relevant Interactions with SYNJARDY or SYNJARDY XR
Carbonic Anhydrase Inhibitors
Clinical Impact
Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with SYNJARDY or SYNJARDY XR may increase the risk of lactic acidosis.
Intervention
Consider more frequent monitoring of these patients.
Drugs that Reduce Metformin Clearance
Clinical Impact
Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis
[see
12.3 Pharmacokinetics

SYNJARDY

Administration of 12.5 mg empagliflozin/1,000 mg metformin HCl under fed conditions resulted in a 9% decrease in AUC and a 28% decrease in Cmaxfor empagliflozin, when compared to fasted conditions. For metformin, AUC decreased by 12% and Cmaxdecreased by 26% compared to fasting conditions. The observed effect of food on empagliflozin and metformin is not considered to be clinically relevant.

SYNJARDY XR

Administration of SYNJARDY XR with food resulted in no change in overall exposure of empagliflozin. For metformin HCl extended-release high-fat meals increased systemic exposure to metformin (as measured by area-under-the-curve [AUC]) by approximately 70% relative to fasting, while Cmaxis not affected. Meals prolonged Tmaxby approximately 3 hours.

Empagliflozin

The pharmacokinetics of empagliflozin has been characterized in healthy volunteers and patients with type 2 diabetes mellitus and no clinically relevant differences were noted between the two populations. The steady-state mean plasma AUC and Cmaxwere 1,870 nmol∙h/L and 259 nmol/L, respectively, with 10 mg empagliflozin once daily treatment, and 4,740 nmol∙h/L and 687 nmol/L, respectively, with 25 mg empagliflozin once daily treatment. Systemic exposure of empagliflozin increased in a dose-proportional manner in the therapeutic dose range. Empagliflozin does not appear to have time-dependent pharmacokinetic characteristics. Following once-daily dosing, up to 22% accumulation, with respect to plasma AUC, was observed at steady-state.

Absorption

After oral administration, peak plasma concentrations of empagliflozin were reached at 1.5 hours post-dose. Administration of 25 mg empagliflozin after intake of a high-fat and high-calorie meal resulted in slightly lower exposure; AUC decreased by approximately 16% and Cmaxdecreased by approximately 37%, compared to fasted condition. The observed effect of food on empagliflozin pharmacokinetics was not considered clinically relevant and empagliflozin may be administered with or without food.

Distribution

The apparent steady-state volume of distribution was estimated to be 73.8 L based on a population pharmacokinetic analysis. Following administration of an oral [14C]-empagliflozin solution to healthy subjects, the red blood cell partitioning was approximately 36.8% and plasma protein binding was 86.2%.

Elimination

The apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 h and apparent oral clearance was 10.6 L/h based on the population pharmacokinetic analysis.

Metabolism

No major metabolites of empagliflozin were detected in human plasma and the most abundant metabolites were three glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide). Systemic exposure of each metabolite was less than 10% of total drug-related material.

In vitro
studies suggested that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9.

Excretion

Following administration of an oral [14C]-empagliflozin solution to healthy subjects, approximately 95.6% of the drug-related radioactivity was eliminated in feces (41.2%) or urine (54.4%). The majority of drug-related radioactivity recovered in feces was unchanged parent drug and approximately half of drug-related radioactivity excreted in urine was unchanged parent drug.

Metformin HCl

Absorption

The absolute bioavailability of a metformin HCl 500 mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin HCl tablets 500 mg to 1,500 mg, and 850 mg to 2,550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination.

Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower Cmax, a 25% lower AUC, and a 35 minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.

Metformin HCl extended-release

Following a single oral dose of 1,000 mg (2 × 500 mg tablets) metformin HCl extended-release after a meal, the time to reach maximum plasma metformin concentration (Tmax) is achieved at approximately 7 to 8 hours. In both single- and multiple-dose studies in healthy subjects, once daily 1,000 mg (2 × 500 mg tablets) dosing provides equivalent systemic exposure, as measured by AUC, and up to 35% higher Cmaxof metformin relative to the immediate-release given as 500 mg twice daily.

Single oral doses of metformin HCl extended-release from 500 mg to 2,500 mg resulted in less than proportional increase in both AUC and Cmax. Low-fat and high-fat meals increased the systemic exposure (as measured by AUC) from metformin extended-release tablets by about 38% and 73%, respectively, relative to fasting. Both meals prolonged metformin Tmaxby approximately 3 hours but Cmaxwas not affected.

Distribution

The apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin HCl tablets 850 mg averaged 654±358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time.

Elimination

Metformin has a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Metabolism

Intravenous single-dose studies in normal subjects demonstrate that metformin does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion.

Excretion

Following oral administration, approximately 90% of the absorbed drug is excreted via the renal route within the first 24 hours. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination.

Specific Populations

Geriatric Patients

SYNJARDY or SYNJARDY XR:
Studies characterizing the pharmacokinetics of empagliflozin and metformin after administration of SYNJARDY or SYNJARDY XR in geriatric patients have not been performed

Empagliflozin:
Age did not have a clinically meaningful impact on the pharmacokinetics of empagliflozin based on a population pharmacokinetic analysis

Metformin HCl:
Limited data from controlled pharmacokinetic studies of metformin HCl in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmaxis increased, compared with healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.

Pediatric Patients

Empagliflozin:
The pharmacokinetics and pharmacodynamics of empagliflozin were investigated in pediatric patients aged 10 to 17 years with type 2 diabetes mellitus. Oral administration of empagliflozin at 10 mg and 25 mg resulted in exposure within the range observed in adult patients.

Metformin:
After administration of a single oral metformin HCl 500 mg immediate-release tablet with food, geometric mean metformin Cmaxand AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal renal function.

Effects of Age, Body Mass Index, Gender, and Race

Empagliflozin:
Age, body mass index (BMI), gender and race (Asians versus primarily Whites) do not have a clinically meaningful effect on pharmacokinetics of empagliflozin.

Metformin HCl:
No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin HCl in patients with type 2 diabetes mellitus, the antihyperglycemic effect was comparable in Whites (n=249), Blacks or African Americans (n=51), and Hispanics or Latinos (n=24).

Patients with Renal Impairment

SYNJARDY or SYNJARDY XR:
Studies characterizing the pharmacokinetics of empagliflozin and metformin HCl after administration of SYNJARDY or SYNJARDY XR in renally impaired patients have not been performed.

Empagliflozin:
In adult patients with type 2 diabetes mellitus with mild (eGFR: 60 to less than 90 mL/min/1.73 m2), moderate (eGFR: 30 to less than 60 mL/min/1.73 m2), and severe (eGFR: less than 30 mL/min/1.73 m2) renal impairment and patients on dialysis due to kidney failure, AUC of empagliflozin increased by approximately 18%, 20%, 66%, and 48%, respectively, compared to subjects with normal renal function. Peak plasma levels of empagliflozin were similar in patients with moderate renal impairment and patients on dialysis due to kidney failure, compared to subjects with normal renal function. Peak plasma levels of empagliflozin were roughly 20% higher in patients with mild and severe renal impairment as compared to patients with normal renal function. Population pharmacokinetic analysis showed that the apparent oral clearance of empagliflozin decreased with a decrease in eGFR leading to an increase in drug exposure. However, the fraction of empagliflozin that was excreted unchanged in urine, and urinary glucose excretion, declined with decrease in eGFR.

Metformin HCl:
In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased.

Patients with Hepatic Impairment

SYNJARDY or SYNJARDY XR:
Studies characterizing the pharmacokinetics of empagliflozin and metformin after administration of SYNJARDY or SYNJARDY XR in hepatically impaired patients have not been performed.

Empagliflozin:
In adult patients with mild, moderate, and severe hepatic impairment according to the Child-Pugh classification, AUC of empagliflozin increased by approximately 23%, 47%, and 75%, and Cmaxincreased by approximately 4%, 23%, and 48%, respectively, compared to subjects with normal hepatic function.

Metformin HCl:
No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment.

Drug Interaction Studies

Pharmacokinetic drug interaction studies with SYNJARDY or SYNJARDY XR have not been performed; however, such studies have been conducted with the individual components empagliflozin and metformin HCl.

Empagliflozin

In vitro Assessment of Drug Interactions:
Empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms.
In vitro
data suggest that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT1A3, UGT1A8, UGT1A9, and UGT2B7. Empagliflozin does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. Therefore, no effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of the major CYP450 isoforms or UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. The effect of UGT induction (e.g., induction by rifampicin or any other UGT enzyme inducer) on empagliflozin exposure has not been evaluated.

Empagliflozin is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but it does not inhibit these efflux transporters at therapeutic doses. Based on

in vitro
studies, empagliflozin is considered unlikely to cause interactions with drugs that are P-gp substrates. Empagliflozin is a substrate of the human uptake transporters OAT3, OATP1B1, and OATP1B3, but not OAT1 and OCT2. Empagliflozin does not inhibit any of these human uptake transporters at clinically relevant plasma concentrations and, therefore, no effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of these uptake transporters.

In vivo Assessment of Drug Interactions:
Empagliflozin pharmacokinetics were similar with and without coadministration of metformin HCl, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, and simvastatin in healthy volunteers and with or without coadministration of hydrochlorothiazide and torsemide in patients with type 2 diabetes mellitus (seeFigure 1). In subjects with normal renal function, coadministration of empagliflozin with probenecid resulted in a 30% decrease in the fraction of empagliflozin excreted in urine without any effect on 24-hour urinary glucose excretion. The relevance of this observation to patients with renal impairment is unknown.

Figure 1 Effect of Various Medications on the Pharmacokinetics of Empagliflozin as Displayed as 90% Confidence Interval of Geometric Mean AUC and CmaxRatios [reference lines indicate 100% (80% - 125%)]

Referenced Image

aempagliflozin, 50 mg, once daily;bempagliflozin, 25 mg, single dose;cempagliflozin, 25 mg, once daily;dempagliflozin, 10 mg, single dose

Empagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, digoxin, ramipril, simvastatin, hydrochlorothiazide, torsemide, and oral contraceptives when coadministered in healthy volunteers (seeFigure 2).

Figure 2 Effect of Empagliflozin on the Pharmacokinetics of Various Medications as Displayed as 90% Confidence Interval of Geometric Mean AUC and CmaxRatios [reference lines indicate 100% (80% - 125%)]

Referenced Image

aempagliflozin, 50 mg, once daily;bempagliflozin, 25 mg, once daily;cempagliflozin, 25 mg, single dose;dadministered as simvastatin;eadministered as warfarin racemic mixture;fadministered as Microgynon®;gadministered as ramipril

Figure 1
Figure 1
Figure 2
Figure 2

Metformin HCl

Table 5 Effect of Coadministered Drug on Plasma Metformin Systemic Exposure
Coadministered DrugDose of Coadministered Drug*Dose of Metformin HCl*Geometric Mean Ratio

(ratio with/without coadministered drug)

No effect=1.0
AUC†Cmax
* All metformin and coadministered drugs were given as single doses
† AUC = AUC (INF)
≠ Metformin HCl extended-release tablets 500 mg
‡ Ratio of arithmetic means
**At steady-state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC (0-12 hours)
Glyburide5 mg500 mg≠metformin0.98‡0.99‡
Furosemide40 mg850 mgmetformin1.09‡1.22‡
Nifedipine10 mg850 mgmetformin1.161.21
Propranolol40 mg850 mgmetformin0.900.94
Ibuprofen400 mg850 mgmetformin1.05‡1.07‡
Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination
Cimetidine400 mg850 mgmetformin1.401.61
Carbonic anhydrase inhibitors may cause metabolic acidosis.
Topiramate**100 mg500 mgmetformin1.251.17
Table 6 Effect of Metformin on Coadministered Drug Systemic Exposure
Coadministered DrugDose of Coadministered Drug*Dose of Metformin HCl*Geometric Mean Ratio

(ratio with/without metformin)

No effect=1.0
AUC†Cmax
* All metformin and coadministered drugs were given as single doses
† AUC = AUC (INF) unless otherwise noted
‡ Ratio of arithmetic means, p-value of difference <0.05
§ AUC (0-24 hours) reported
¶ Ratio of arithmetic means
Glyburide5 mg500 mg§glyburide0.78‡0.63‡
Furosemide40 mg850 mgfurosemide0.87‡0.69‡
Nifedipine10 mg850 mgnifedipine1.10§1.08
Propranolol40 mg850 mgpropranolol1.01§0.94
Ibuprofen400 mg850 mgibuprofen0.97¶1.01¶
Cimetidine400 mg850 mgcimetidine0.95§1.01
]
.
Intervention
Consider the benefits and risks of concomitant use.
Alcohol
Clinical Impact
Alcohol is known to potentiate the effect of metformin on lactate metabolism.
Intervention
Warn patients against excessive alcohol intake while receiving SYNJARDY or SYNJARDY XR.
Diuretics
Clinical Impact
Coadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids, which might enhance the potential for volume depletion.
Intervention
Before initiating SYNJARDY or SYNJARDY XR, assess volume status and renal function. In patients with volume depletion, correct this condition before initiating SYNJARDY or SYNJARDY XR. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.
Insulin or Insulin Secretagogues
Clinical Impact
The risk of hypoglycemia is increased when SYNJARDY or SYNJARDY XR is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin.
Intervention
Coadministration of SYNJARDY or SYNJARDY XR with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.
Drugs Affecting Glycemic Control
Clinical Impact
Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid.
Intervention
When such drugs are administered to a patient receiving SYNJARDY or SYNJARDY XR, the patient should be closely observed to maintain adequate glycemic control. When such drugs are withdrawn from a patient receiving SYNJARDY or SYNJARDY XR, the patient should be observed closely for hypoglycemia.
Lithium
Clinical Impact
Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations.
Intervention
Monitor serum lithium concentration more frequently during SYNJARDY or SYNJARDY XR initiation and dosage changes.
Positive Urine Glucose Test
Clinical Impact
SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests.
Intervention
Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.
Interference with 1,5-anhydroglucitol (1,5-AG) Assay
Clinical Impact
Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors.
Intervention
Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control.
Description

SYNJARDY and SYNJARDY XR tablets for oral use contain: empagliflozin and metformin HCl.

Pharmacology

SYNJARDY or SYNJARDY XR

SYNJARDY and SYNJARDY XR contain: empagliflozin, a SGLT2 inhibitor, and metformin HCl, a biguanide.

Nonclinical Toxicology

SYNJARDY or SYNJARDY XR

No carcinogenicity, mutagenicity, or impairment of fertility studies have been conducted with the combination of empagliflozin and metformin HCl. General toxicity studies in rats up to 13 weeks were performed with the combined components. These studies indicated that no additive toxicity is caused by the combination of empagliflozin and metformin HCl.

Clinical Studies

In adult patients with type 2 diabetes mellitus, treatment with empagliflozin and metformin HCl produced clinically and statistically significant improvements in HbA1c compared to placebo and metformin HCl. Reductions in HbA1c were observed across subgroups including age, sex, race, and baseline BMI.

How Supplied/Storage & Handling

SYNJARDY tablets are available as follows:

Tablet StrengthColor/ShapeTablet MarkingsPackage SizeNDC Number
5 mg Empagliflozin

500 mg Metformin HCl		orange yellow, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "500".Bottles of 60

Bottles of 180		0597-0159-60

0597-0159-18
5 mg Empagliflozin 1,000 mg Metformin HClbrownish yellow, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "1000".Bottles of 60

Bottles of 180		0597-0175-60

0597-0175-18
12.5 mg Empagliflozin 500 mg Metformin HClpale brownish purple, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "500".Bottles of 60

Bottles of 180		0597-0180-60

0597-0180-18
12.5 mg Empagliflozin 1,000 mg Metformin HCldark brownish purple, oval, biconvex, film-coated tabletBoehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "1000".Bottles of 60

Bottles of 180		0597-0168-60

0597-0168-18

SYNJARDY XR extended-release tablets are available as follows:

Tablet StrengthColor/ShapeTablet MarkingsPackage SizeNDC Number
5 mg Empagliflozin

1,000 mg Metformin HCl		olive green, oval, biconvex, film-coated tabletPrinted on one side in black ink with the Boehringer Ingelheim company symbol and "S5" on the top line and "1000 M" on the bottom line.Bottles of 60

Bottles of 180		0597-0290-74

0597-0290-59
10 mg Empagliflozin

1,000 mg Metformin HCl		orange, oval, biconvex, film-coated tabletPrinted on one side in black ink with the Boehringer Ingelheim company symbol and "S10" on the top line and "1000 M" on the bottom line.Bottles of 30

Bottles of 90		0597-0280-73

0597-0280-90
12.5 mg Empagliflozin 1,000 mg Metformin HClblue, oval, biconvex, film-coated tabletPrinted on one side in black ink with the Boehringer Ingelheim company symbol and "S12" on the top line and "1000 M" on the bottom line.Bottles of 60

Bottles of 180		0597-0300-45

0597-0300-93
25 mg Empagliflozin 1,000 mg Metformin HCllight green, oval, biconvex, film-coated tabletPrinted on one side in black ink with the Boehringer Ingelheim company symbol and "S25" on the top line and "1000 M" on the bottom line.Bottles of 30

Bottles of 90		0597-0295-88

0597-0295-78
Mechanism of Action

SYNJARDY or SYNJARDY XR

SYNJARDY and SYNJARDY XR contain: empagliflozin, a SGLT2 inhibitor, and metformin HCl, a biguanide.

Data SourceWe receive information directly from the FDA and PrescriberPoint is updated as frequently as changes are made available
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