Empagliflozin and metformin hydrochloride

Empagliflozin and metformin hydrochloride
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shivani Chaparala M.B.B.S [2]

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Black Box Warning

WARNING See full prescribing information for complete Boxed 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 ketonuriaor ketonemia), an increased lactate/pyruvate ratio; and metforminplasma levels generally >5 mcg/mL. Risk factors for metformin-associatedlactic acidosis include renal impairment, concomitant use of certaindrugs (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 congestiveheart failure), excessive alcohol intake, and hepatic impairment. If metformin-associated lactic acidosis is suspected, immediately discontinue SYNJARDY and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

Overview

Empagliflozin and metformin hydrochloride is a combination of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor and metformin hydrochloride, a biguanide that is FDA approved for the treatment of in adults with type 2 diabetes mellitus when treatment with both empagliflozin and metformin hydrochloride is appropriate, as an adjunct to diet and exercise to improve glycemic control. Empagliflozin is indicated to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease. However, the effectiveness of SYNJARDY on reducing the risk of cardiovascular death in adults with type 2 diabetes mellitus and cardiovascular disease has not been established.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include * Most common adverse reactions associated with empagliflozin (5% or greater incidence) were urinary tract infection and female genital mycotic infections.

• Most common adverse reactions associated with metformin (>5%) are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache..

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

• SYNJARDY is a combination of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor and metformin hydrochloride, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both empagliflozin and metformin hydrochloride is appropriate.
• Empagliflozin is indicated to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease.
• However, the effectiveness of SYNJARDY on reducing the risk of cardiovascular death in adults with type 2 diabetes mellitus and cardiovascular disease has not been established.

DOSAGE FORMS AND STRENGTHS

• Tablets:

5 mg empagliflozin/500 mg metformin hydrochloride 5 mg empagliflozin/1000 mg metformin hydrochloride 12.5 mg empagliflozin/500 mg metformin hydrochloride 12.5 mg empagliflozin/1000 mg metformin hydrochloride.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Empagliflozin and metformin hydrochloride in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Empagliflozin and metformin hydrochloride in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Empagliflozin and metformin hydrochloride FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Empagliflozin and metformin hydrochloride in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Empagliflozin and metformin hydrochloride in pediatric patients.

Contraindications

• SYNJARDY is contraindicated in patients with:
  • Moderate to severe renal impairment (eGFR less than 45 mL/min/1.73 m2), end stage renal disease, or dialysis.
  • Acute or chronic metabolic acidosis, including diabetic ketoacidosis.
  • Diabetic ketoacidosis should be treated with insulin.
  • History of serious hypersensitivity reaction to empagliflozin or metformin.

Warnings

WARNING See full prescribing information for complete Boxed 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 ketonuriaor ketonemia), an increased lactate/pyruvate ratio; and metforminplasma levels generally >5 mcg/mL. Risk factors for metformin-associatedlactic acidosis include renal impairment, concomitant use of certaindrugs (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 congestiveheart failure), excessive alcohol intake, and hepatic impairment. If metformin-associated lactic acidosis is suspected, immediately discontinue SYNJARDY and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

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.
• In SYNJARDY-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride 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 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.
  • Before initiating SYNJARDY, obtain an estimated glomerular filtration rate (eGFR).
  • SYNJARDY is contraindicated in patients with an eGFR below 45 mL/min/1.73 m2.
  • Obtain an eGFR at least annually in all patients taking SYNJARDY. 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 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 at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 45 and 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 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 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.

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.

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 in patients with clinical or laboratory evidence of hepatic disease.

Hypotension

• Empagliflozin causes intravascular volume contraction.
• Symptomatic hypotension may occur after initiating empagliflozin particularly in patients with renal impairment, the elderly, in patients with low systolic blood pressure, and in patients on diuretics.
• Before initiating SYNJARDY, assess for volume contraction and correct volume status if indicated.
• Monitor for signs and symptoms of hypotension after initiating therapy and increase monitoring in clinical situations where volume contraction is expected.

Ketoacidosis

• Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors, including empagliflozin.
• Fatal cases of ketoacidosis have been reported in patients taking empagliflozin.
• SYNJARDY is not indicated for the treatment of patients with type 1 diabetes mellitus.
• Patients treated with SYNJARDY who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels, as ketoacidosis associated with SYNJARDY may be present even if blood glucose levels are less than 250 mg/dL.
• If ketoacidosis is suspected, SYNJARDY should be discontinued, patient should be evaluated, and prompt treatment should be instituted.
• Treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement.
• In many of the postmarketing reports, and particularly in patients with type 1 diabetes, the presence of ketoacidosis was not immediately recognized and institution of treatment was delayed because presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL).
• Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath.
• In some but not all cases, factors predisposing to ketoacidosis such as insulin dose reduction, acute febrile illness, reduced caloric intake due to illness or surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified.
• Before initiating SYNJARDY, consider factors in the patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse.
• In patients treated with SYNJARDY consider monitoring for ketoacidosis and temporarily discontinuing SYNJARDY in clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).

Acute Kidney Injury and Impairment in Renal Function

• Empagliflozin causes intravascular volume contraction.
• There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving SGLT2 inhibitors, including empagliflozin; some reports involved patients younger than 65 years of age.
• Before initiating SYNJARDY, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs).
• Consider temporarily discontinuing SYNJARDY in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury.
• If acute kidney injury occurs, discontinue SYNJARDY promptly and institute treatment.
• Empagliflozin increases serum creatinine and decreases eGFR.
• Patients with hypovolemia may be more susceptible to these changes.
• Renal function abnormalities can occur after initiating SYNJARDY.
• Renal function should be evaluated prior to initiation of SYNJARDY and monitored periodically thereafter.
• More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m2.
• Use of SYNJARDY is contraindicated in patients with an eGFR less than 45 mL/min/1.73 m2.

Urosepsis and Pyelonephritis

• There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including empagliflozin.
• Treatment with SGLT2 inhibitors increases the risk for urinary tract infections.
• Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated.

Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Empagliflozin

• Insulin and insulin secretagogues are known to cause hypoglycemia.
• The risk of hypoglycemia is increased when empagliflozin is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin.
• Therefore, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with SYNJARDY.

Metformin

• Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as SUs and insulin) or ethanol.
• Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects.
• Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking β-adrenergic blocking drugs.
• Monitor for a need to lower the dose of SYNJARDY to minimize the risk of hypoglycemia in these patients.

Genital Mycotic Infections

• Empagliflozin increases the risk for genital mycotic infections.
• Patients with a history of chronic or recurrent genital mycotic infections were more likely to develop mycotic genital infections.
• Monitor and treat as appropriate.

Vitamin B12 Levels

• In controlled, 29-week clinical trials of metformin, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of metformin-treated patients.
• Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia or neurologic manifestations due to the short duration (<1 year) of the clinical trials.
• This risk may be more relevant to patients receiving long-term treatment with metformin, and adverse hematologic and neurologic reactions have been reported postmarketing.
• The decrease in vitamin B12 levels appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation.
• Measurement of hematologic parameters on an annual basis is advised in patients on SYNJARDY and any apparent abnormalities should be appropriately investigated and managed.
• Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels.
• In these patients, routine serum vitamin B12 measurement at 2- to 3-year intervals may be useful.

Increased Low-Density Lipoprotein Cholesterol (LDL-C)

• Increases in LDL-C can occur with empagliflozin.
• Monitor and treat as appropriate.

Macrovascular Outcomes

• There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with SYNJARDY.

Adverse Reactions

Clinical Trials Experience

The following are the important adverse reactions:

• Lactic Acidosis
• Hypotension
• Ketoacidosis
• Acute Kidney Injury and Impairment in Renal Function
• Urosepsis and Pyelonephritis
• Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
• Genital Mycotic Infections
• Vitamin B12 Deficiency
• Increased Low-Density Lipoprotein Cholesterol (LDL-C).
• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
• The safety of concomitantly administered empagliflozin (daily dose 10 mg and 25 mg) and metformin hydrochloride (mean daily dose of approximately 1800 mg) has been evaluated in 3456 patients with type 2 diabetes mellitus treated for 16 to 24 weeks, of which 926 patients received placebo, 1271 patients received a daily dose of empagliflozin 10 mg, and 1259 patients received a daily dose of empagliflozin 25 mg.
• Discontinuation of therapy due to adverse events across treatment groups was 3.0%, 2.8%, and 2.9% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.

Empagliflozin Add-On Combination Therapy with Metformin

• In a 24-week placebo-controlled trial of empagliflozin 10 mg and 25 mg administered once daily added to metformin, there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo.

Empagliflozin Add-On Combination Therapy with Metformin and Sulfonylurea

• In a 24-week placebo-controlled trial of empagliflozin 10 mg and 25 mg administered once daily added to metformin and sulfonylurea, adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo are presented in Table 1.

Postmarketing Experience

There is limited information regarding Empagliflozin and metformin hydrochloride Postmarketing Experience in the drug label.

Drug Interactions

There is limited information regarding Empagliflozin and metformin hydrochloride Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There is no FDA guidance on usage of Empagliflozin and metformin hydrochloride in women who are pregnant.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Empagliflozin and metformin hydrochloride in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Empagliflozin and metformin hydrochloride during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Empagliflozin and metformin hydrochloride in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of Empagliflozin and metformin hydrochloride in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Empagliflozin and metformin hydrochloride in geriatric settings.

Gender

There is no FDA guidance on the use of Empagliflozin and metformin hydrochloride with respect to specific gender populations.

Race

There is no FDA guidance on the use of Empagliflozin and metformin hydrochloride with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Empagliflozin and metformin hydrochloride in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Empagliflozin and metformin hydrochloride in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Empagliflozin and metformin hydrochloride in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Empagliflozin and metformin hydrochloride in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Empagliflozin and metformin hydrochloride Administration in the drug label.

Monitoring

There is limited information regarding Empagliflozin and metformin hydrochloride Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Empagliflozin and metformin hydrochloride and IV administrations.

Overdosage

There is limited information regarding Empagliflozin and metformin hydrochloride overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Empagliflozin and metformin hydrochloride Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Empagliflozin and metformin hydrochloride Mechanism of Action in the drug label.

Structure

There is limited information regarding Empagliflozin and metformin hydrochloride Structure in the drug label.

Pharmacodynamics

There is limited information regarding Empagliflozin and metformin hydrochloride Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Empagliflozin and metformin hydrochloride Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Empagliflozin and metformin hydrochloride Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Empagliflozin and metformin hydrochloride Clinical Studies in the drug label.

How Supplied

There is limited information regarding Empagliflozin and metformin hydrochloride How Supplied in the drug label.

Storage

There is limited information regarding Empagliflozin and metformin hydrochloride Storage in the drug label.

Images

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Patient Counseling Information

There is limited information regarding Empagliflozin and metformin hydrochloride Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Empagliflozin and metformin hydrochloride interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Empagliflozin and metformin hydrochloride Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Empagliflozin and metformin hydrochloride Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.