What is mechanism of action?

mechanism of action is Sodium-Glucose Transporter 2 Inhibitors [MoA]

Synjardy

(Empagliflozin, Metformin Hydrochloride)

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Synjardy Prescribing Information

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

[see Dosage and Administration (2.4)and Clinical Pharmacology (12.3)]

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
[see Contraindications (4)].
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

[see Drug Interactions (7)]

. 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

[see Use in Specific Populations (8.5)]

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

Assess renal function before initiating SYNJARDY or SYNJARDY XR and as clinically indicated
[see Warnings and Precautions (5.1, 5.3)]
.
Assess volume status. In patients with volume depletion, correct this condition before initiating SYNJARDY or SYNJARDY XR
[see Warnings and Precautions (5.3)and Use in Specific Populations (8.5, 8.6)]
.

4 CONTRAINDICATIONS

SYNJARDY and SYNJARDY XR are contraindicated in patients with:

severe renal impairment (eGFR less than 30 mL/min/1.73 m²)
[see Warnings and Precautions (5.1)and Use in Specific Populations (8.6)].
acute or chronic metabolic acidosis, including diabetic ketoacidosis
[see Warnings and Precautions (5.1)].
hypersensitivity to empagliflozin, metformin HCl or any of the excipients in SYNJARDY or SYNJARDY XR, reactions such as angioedema have occurred
[see Warnings and Precautions (5.9)]
.

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

5.1 Lactic Acidosis

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:

[see Dosage and Administration (2.4)and Clinical Pharmacology (12.3)]

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
[see Contraindications (4)].
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:

[see Drug Interactions (7)]

. Therefore, consider more frequent monitoring of patients.

Age 65 or Greater:

[see Use in Specific Populations (8.5)]

Radiological Studies with Contrast:

Surgery and Other Procedures:

Hypoxic States:

Excessive Alcohol Intake:

Hepatic Impairment:

7 DRUG INTERACTIONS

See Table 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 [see Clinical Pharmacology (12.3)] .
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.
Drugs that Reduce Metformin Clearance:
May increase risk of lactic acidosis. Consider benefits and risks of concomitant use.
See full prescribing information for additional drug interactions and information on interference of SYNJARDY or SYNJARDY XR with laboratory tests.

, 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

[see Warnings and Precautions (5.2)]

. 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

[see Warnings and Precautions (5.1)]

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

[see Warnings and Precautions (5.1)].

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

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:

[see Dosage and Administration (2.4)and Clinical Pharmacology (12.3)]

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
[see Contraindications (4)].
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:

[see Drug Interactions (7)]

. Therefore, consider more frequent monitoring of patients.

Age 65 or Greater:

[see Use in Specific Populations (8.5)]

Radiological Studies with Contrast:

Surgery and Other Procedures:

Hypoxic States:

Excessive Alcohol Intake:

Hepatic Impairment:

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.
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

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.

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
[see Warnings and Precautions (5.2)]
.
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
[see Clinical Studies (14.5)]
. Empagliflozin is not expected to be effective in these populations.

)

3/2025

Warnings and Precautions, Lower Limb Amputation (

5.8 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

SYNJARDY

SYNJARDY XR

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.
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
:
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.
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
[see Warnings and Precautions (5.2)]
.
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
[see Clinical Studies (14.5)]
. 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.
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
:
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.
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
[see Warnings and Precautions (5.2)]
.
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
[see Clinical Studies (14.5)]
. 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.
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
:
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.
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
[see Warnings and Precautions (5.2)]
.
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
[see Clinical Studies (14.5)]
. 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.
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
:
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.
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
[see Warnings and Precautions (5.2)]
.
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
[see Clinical Studies (14.5)]
. 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.
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
:
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.
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
[see Warnings and Precautions (5.2)]
.
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
[see Clinical Studies (14.5)]
. 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.
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
:
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.
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
[see Warnings and Precautions (5.2)]
.
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
[see Clinical Studies (14.5)]
. Empagliflozin is not expected to be effective in these populations.
)

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
- Assess renal function before initiating SYNJARDY or SYNJARDY XR and as clinically indicated
  [see Warnings and Precautions (5.1, 5.3)]
  .
- Assess volume status. In patients with volume depletion, correct this condition before initiating SYNJARDY or SYNJARDY XR
  [see Warnings and Precautions (5.3)and Use in Specific Populations (8.5, 8.6)]
  .
)
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
  [see Adverse Reactions (6.1)].
- 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
  [see Adverse Reactions (6.1)].
,
2.4 Dosage Recommendations in Patients with Renal Impairment
- 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.
- SYNJARDY and SYNJARDY XR are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m²
  [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.6)]
  .
)
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
  [see Adverse Reactions (6.1)].
- 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
  [see Adverse Reactions (6.1)].
)
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
- 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.
- SYNJARDY and SYNJARDY XR are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m²
  [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.6)]
  .
)
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
  [see Adverse Reactions (6.1)].
- 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
  [see Adverse Reactions (6.1)].
)
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
  [see Adverse Reactions (6.1)].
- 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
[see Warnings and Precautions (5.1)]
.
)
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
[see Warnings and Precautions (5.2)and Clinical Pharmacology (12.2)]
.
)

SYNJARDY Tablets:

5 mg empagliflozin/500 mg metformin HCl (

3 DOSAGE FORMS AND STRENGTHS

SYNJARDY Tablets:

5 mg empagliflozin/500 mg metformin HCl
5 mg empagliflozin/1,000 mg metformin HCl
12.5 mg empagliflozin/500 mg metformin HCl
12.5 mg empagliflozin/1,000 mg metformin HCl

SYNJARDY XR Tablets:

5 mg empagliflozin/1,000 mg metformin HCl extended-release
10 mg empagliflozin/1,000 mg metformin HCl extended-release
12.5 mg empagliflozin/1,000 mg metformin HCl extended-release
25 mg empagliflozin/1,000 mg metformin HCl extended-release

SYNJARDY Tablets:

Empagliflozin Strength	Metformin HCl Strength	Color/Shape	Tablet Markings
5 mg	500 mg	orange yellow, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "500".
5 mg	1,000 mg	brownish yellow, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "1000".
12.5 mg	500 mg	pale brownish purple, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "500".
12.5 mg	1,000 mg	dark brownish purple, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "1000".

SYNJARDY XR Tablets:

Empagliflozin Strength	Metformin HCl Extended - Release Strength	Color/Shape	Tablet Markings
5 mg	1,000 mg	olive green, oval, biconvex, film-coated tablet	Printed 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 mg	1,000 mg	orange, 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 mg	1,000 mg	blue, 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 mg	1,000 mg	light 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
5 mg empagliflozin/1,000 mg metformin HCl
12.5 mg empagliflozin/500 mg metformin HCl
12.5 mg empagliflozin/1,000 mg metformin HCl

SYNJARDY XR Tablets:

5 mg empagliflozin/1,000 mg metformin HCl extended-release
10 mg empagliflozin/1,000 mg metformin HCl extended-release
12.5 mg empagliflozin/1,000 mg metformin HCl extended-release
25 mg empagliflozin/1,000 mg metformin HCl extended-release

SYNJARDY Tablets:

Empagliflozin Strength	Metformin HCl Strength	Color/Shape	Tablet Markings
5 mg	500 mg	orange yellow, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "500".
5 mg	1,000 mg	brownish yellow, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "1000".
12.5 mg	500 mg	pale brownish purple, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "500".
12.5 mg	1,000 mg	dark brownish purple, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "1000".

SYNJARDY XR Tablets:

Empagliflozin Strength	Metformin HCl Extended - Release Strength	Color/Shape	Tablet Markings
5 mg	1,000 mg	olive green, oval, biconvex, film-coated tablet	Printed 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 mg	1,000 mg	orange, 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 mg	1,000 mg	blue, 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 mg	1,000 mg	light 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
5 mg empagliflozin/1,000 mg metformin HCl
12.5 mg empagliflozin/500 mg metformin HCl
12.5 mg empagliflozin/1,000 mg metformin HCl

SYNJARDY XR Tablets:

5 mg empagliflozin/1,000 mg metformin HCl extended-release
10 mg empagliflozin/1,000 mg metformin HCl extended-release
12.5 mg empagliflozin/1,000 mg metformin HCl extended-release
25 mg empagliflozin/1,000 mg metformin HCl extended-release

SYNJARDY Tablets:

Empagliflozin Strength	Metformin HCl Strength	Color/Shape	Tablet Markings
5 mg	500 mg	orange yellow, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "500".
5 mg	1,000 mg	brownish yellow, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "1000".
12.5 mg	500 mg	pale brownish purple, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "500".
12.5 mg	1,000 mg	dark brownish purple, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "1000".

SYNJARDY XR Tablets:

Empagliflozin Strength	Metformin HCl Extended - Release Strength	Color/Shape	Tablet Markings
5 mg	1,000 mg	olive green, oval, biconvex, film-coated tablet	Printed 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 mg	1,000 mg	orange, 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 mg	1,000 mg	blue, 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 mg	1,000 mg	light 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
5 mg empagliflozin/1,000 mg metformin HCl
12.5 mg empagliflozin/500 mg metformin HCl
12.5 mg empagliflozin/1,000 mg metformin HCl

SYNJARDY XR Tablets:

5 mg empagliflozin/1,000 mg metformin HCl extended-release
10 mg empagliflozin/1,000 mg metformin HCl extended-release
12.5 mg empagliflozin/1,000 mg metformin HCl extended-release
25 mg empagliflozin/1,000 mg metformin HCl extended-release

SYNJARDY Tablets:

Empagliflozin Strength	Metformin HCl Strength	Color/Shape	Tablet Markings
5 mg	500 mg	orange yellow, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "500".
5 mg	1,000 mg	brownish yellow, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "1000".
12.5 mg	500 mg	pale brownish purple, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "500".
12.5 mg	1,000 mg	dark brownish purple, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "1000".

SYNJARDY XR Tablets:

Empagliflozin Strength	Metformin HCl Extended - Release Strength	Color/Shape	Tablet Markings
5 mg	1,000 mg	olive green, oval, biconvex, film-coated tablet	Printed 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 mg	1,000 mg	orange, 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 mg	1,000 mg	blue, 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 mg	1,000 mg	light 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
5 mg empagliflozin/1,000 mg metformin HCl
12.5 mg empagliflozin/500 mg metformin HCl
12.5 mg empagliflozin/1,000 mg metformin HCl

SYNJARDY XR Tablets:

5 mg empagliflozin/1,000 mg metformin HCl extended-release
10 mg empagliflozin/1,000 mg metformin HCl extended-release
12.5 mg empagliflozin/1,000 mg metformin HCl extended-release
25 mg empagliflozin/1,000 mg metformin HCl extended-release

SYNJARDY Tablets:

Empagliflozin Strength	Metformin HCl Strength	Color/Shape	Tablet Markings
5 mg	500 mg	orange yellow, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "500".
5 mg	1,000 mg	brownish yellow, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "1000".
12.5 mg	500 mg	pale brownish purple, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "500".
12.5 mg	1,000 mg	dark brownish purple, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "1000".

SYNJARDY XR Tablets:

Empagliflozin Strength	Metformin HCl Extended - Release Strength	Color/Shape	Tablet Markings
5 mg	1,000 mg	olive green, oval, biconvex, film-coated tablet	Printed 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 mg	1,000 mg	orange, 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 mg	1,000 mg	blue, 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 mg	1,000 mg	light 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
5 mg empagliflozin/1,000 mg metformin HCl
12.5 mg empagliflozin/500 mg metformin HCl
12.5 mg empagliflozin/1,000 mg metformin HCl

SYNJARDY XR Tablets:

5 mg empagliflozin/1,000 mg metformin HCl extended-release
10 mg empagliflozin/1,000 mg metformin HCl extended-release
12.5 mg empagliflozin/1,000 mg metformin HCl extended-release
25 mg empagliflozin/1,000 mg metformin HCl extended-release

SYNJARDY Tablets:

Empagliflozin Strength	Metformin HCl Strength	Color/Shape	Tablet Markings
5 mg	500 mg	orange yellow, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "500".
5 mg	1,000 mg	brownish yellow, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "1000".
12.5 mg	500 mg	pale brownish purple, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "500".
12.5 mg	1,000 mg	dark brownish purple, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "1000".

SYNJARDY XR Tablets:

Empagliflozin Strength	Metformin HCl Extended - Release Strength	Color/Shape	Tablet Markings
5 mg	1,000 mg	olive green, oval, biconvex, film-coated tablet	Printed 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 mg	1,000 mg	orange, 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 mg	1,000 mg	blue, 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 mg	1,000 mg	light 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
5 mg empagliflozin/1,000 mg metformin HCl
12.5 mg empagliflozin/500 mg metformin HCl
12.5 mg empagliflozin/1,000 mg metformin HCl

SYNJARDY XR Tablets:

5 mg empagliflozin/1,000 mg metformin HCl extended-release
10 mg empagliflozin/1,000 mg metformin HCl extended-release
12.5 mg empagliflozin/1,000 mg metformin HCl extended-release
25 mg empagliflozin/1,000 mg metformin HCl extended-release

SYNJARDY Tablets:

Empagliflozin Strength	Metformin HCl Strength	Color/Shape	Tablet Markings
5 mg	500 mg	orange yellow, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "500".
5 mg	1,000 mg	brownish yellow, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "1000".
12.5 mg	500 mg	pale brownish purple, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "500".
12.5 mg	1,000 mg	dark brownish purple, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "1000".

SYNJARDY XR Tablets:

Empagliflozin Strength	Metformin HCl Extended - Release Strength	Color/Shape	Tablet Markings
5 mg	1,000 mg	olive green, oval, biconvex, film-coated tablet	Printed 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 mg	1,000 mg	orange, 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 mg	1,000 mg	blue, 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 mg	1,000 mg	light 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
5 mg empagliflozin/1,000 mg metformin HCl
12.5 mg empagliflozin/500 mg metformin HCl
12.5 mg empagliflozin/1,000 mg metformin HCl

SYNJARDY XR Tablets:

5 mg empagliflozin/1,000 mg metformin HCl extended-release
10 mg empagliflozin/1,000 mg metformin HCl extended-release
12.5 mg empagliflozin/1,000 mg metformin HCl extended-release
25 mg empagliflozin/1,000 mg metformin HCl extended-release

SYNJARDY Tablets:

Empagliflozin Strength	Metformin HCl Strength	Color/Shape	Tablet Markings
5 mg	500 mg	orange yellow, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "500".
5 mg	1,000 mg	brownish yellow, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "1000".
12.5 mg	500 mg	pale brownish purple, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "500".
12.5 mg	1,000 mg	dark brownish purple, oval, biconvex, film-coated tablet	Boehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "1000".

SYNJARDY XR Tablets:

Empagliflozin Strength	Metformin HCl Extended - Release Strength	Color/Shape	Tablet Markings
5 mg	1,000 mg	olive green, oval, biconvex, film-coated tablet	Printed 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 mg	1,000 mg	orange, 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 mg	1,000 mg	blue, 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 mg	1,000 mg	light 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:
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
(see Data)
. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy
(see Clinical Considerations)
.
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
(see Data)
.
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
(see Data)
. Empagliflozin is present in the milk of lactating rats
(see Data)
. 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
[see Dosage and Administration (2.4)and Warnings and Precautions (5.1, 5.3)].
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
[see Warnings and Precautions (5.2)]
. 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
[see Warnings and Precautions (5.1)]
.
)
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
[see Warnings and Precautions (5.1)].
)

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