Diabetes: Sodium-glucose co-transporter 2 (SGLT2) inhibitors

INDICATIONS AND USAGE
FARXIGA is a sodium-glucose cotransporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. (1)

Limitation of use: Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

DOSAGE AND ADMINISTRATION
•The recommended starting dose is 5 mg once daily, taken in the morning, with or without food.
•Dose can be increased to 10 mg once daily in patients tolerating FARXIGA who require additional glycemic control.
•Assess renal function before initiating FARXIGA. Do not initiate FARXIGA if eGFR is below 60 mL/min/1.73 m2.
•Discontinue FARXIGA if eGFR falls persistently below 60 mL/min/1.73 m2.

DOSAGE FORMS AND STRENGTHS:
Tablets: 5 mg and 10 mg

CONTRAINDICATIONS
History of serious hypersensitivity reaction to FARXIGA.
Severe renal impairment, end-stage renal disease, or dialysis.

WARNINGS AND PRECAUTIONS
•Hypotension: Before initiating FARXIGA, assess volume status and correct hypovolemia in elderly, in patients with renal impairment or low systolic blood pressure, and in patients on diuretics. Monitor for signs and symtoms during therapy.
•Impairment in renal function: Monitor renal function during therapy.
•Hypoglycemia: In patients taking insulin or an insulin secretagogue with FARXIGA, consider a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia.
•Genital mycotic infections: Monitor and treat if indicated.
•Increased LDL-C: Monitor and treat per standard of care.
•Bladder Cancer: An imbalance in bladder cancers was observed in clinical trials. FARXIGA should not be used in patients with active bladder cancer and should be used with caution in patients with a prior history of bladder cancer.
•Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with FARXIGA or any other antidiabetic drug.

ADVERSE REACTIONS
The most common adverse reactions associated with FARXIGA (5% or greater incidence) were female genital mycotic infections, nasopharyngitis, and urinary tract infections. 

To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

 USE IN SPECIFIC POPULATIONS
•Pregnancy: There are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus.
•Nursing Mothers: Discontinue FARXIGA or discontinue nursing.
•Geriatrics: Higher incidence of adverse reactions related to reduced intravascular volume.
•Renal Impairment: Higher incidence of adverse reactions related to reduced intravascular volume and renal function.

Limitation of Use:
Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis

DOSAGE AND ADMINISTRATION:

The recommended starting dose is 100 mg once daily, taken before the first meal of the day.

Dose can be increased to 300 mg once daily in patients tolerating INVOKANA 100 mg once daily who have an eGFR of 60 mL/min/1.73 m² or greater and require additional glycemic control.

INVOKANA is limited to 100 mg once daily in patients who have an eGFR of 45 to less than 60 mL/min/1.73 m².

Assess renal function before initiating INVOKANA. Do not initiate INVOKANA if eGFR is below 45 mL/min/1.73 m².

Discontinue INVOKANA if eGFR falls below 45 mL/min/1.73 m².

DOSAGE FORMS AND STRENGTHS
Tablets: 100 mg, 300 mg

Local monograph- additional information

Initial U.S. Approval:  2014

Mechanism of Action: Sodium-glucose co-transporter 2 (SGLT2) is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Empagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.

HOW SUPPLIED:  Tablets: 10 mg, 25 mg

DESCRIPTION:  JARDIANCE tablets contain empagliflozin, an orally-active inhibitor of the sodium-glucose co-transporter 2 (SGLT2).
The chemical name of empagliflozin is D-Glucitol,1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-, (1S).
Its molecular formula is C23H27ClO7 and the molecular weight is 450.91.

Mechanism of Action
Sodium-glucose co-transporter 2 (SGLT2) is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Empagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.

INDICATIONS AND USAGE
JARDIANCE is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Limitation of Use
JARDIANCE is not recommended for patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

USE IN SPECIFIC POPULATIONS:
Pregnancy: No adequate and well-controlled studies in pregnant women. Use during pregnancy only if the potential benefits justifies the potential risk to the fetus.
Nursing mothers: Discontinue JARDIANCE or discontinue nursing
Geriatric patients: Higher incidence of adverse reactions related to volume depletion and reduced renal function
Patients with renal impairment: Higher incidence of adverse reactions related to reduced renal function.

DOSAGE AND ADMINISTRATION
Recommended Dosage
The recommended dose of JARDIANCE is 10 mg once daily in the morning, taken with or without food. In patients tolerating JARDIANCE, the dose may be increased to 25 mg.

In patients with volume depletion, correcting this condition prior to initiation of JARDIANCE is recommended.

Patients with Renal Impairment
Assessment of renal function is recommended prior to initiation of JARDIANCE and periodically thereafter.

JARDIANCE should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m2.

No dose adjustment is needed in patients with an eGFR greater than or equal to 45 mL/min/1.73 m2.

JARDIANCE should be discontinued if eGFR is persistently less than 45 mL/min/1.73 m2

WARNINGS AND PRECAUTIONS:

• Hypotension: Before initiating JARDIANCE assess and correct volume status in patients with renal impairment, the elderly, in patients with low systolic blood pressure, and in patients on diuretics. Monitor for signs and symptoms during therapy.
• Impairment in renal function: Monitor renal function during therapy. More frequent monitoring is recommended in patients with eGFR below 60 mL/min/1.73 m2
• Hypoglycemia: Consider lowering the dose of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating JARDIANCE
• Genital mycotic infections: Monitor and treat as appropriate
• Urinary tract infections: Monitor and treat as appropriate
• Increased LDL-C: Monitor and treat as appropriate
• Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JARDIANCE

CONTRAINDICATIONS
History of serious hypersensitivity to JARDIANCE.
Severe renal impairment, end-stage renal disease, or dialysis.

DOSAGE FORMS AND STRENGTHS
JARDIANCE (empagliflozin) 10 mg tablets are pale yellow, round, biconvex and bevel-edged, film-coated tablets debossed with “S 10” on one side and the Boehringer Ingelheim company symbol on the other side.
JARDIANCE (empagliflozin) 25 mg tablets are pale yellow, oval, biconvex, film-coated tablets debossed with “S 25” on one side and the Boehringer Ingelheim company symbol on the other side.

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Initial U.S. Approval:  2015

Mechanism of Action:
GLYXAMBI
GLYXAMBI combines 2 antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor.

Empagliflozin
Sodium-glucose co-transporter 2 (SGLT2) is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Empagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.

Linagliptin
Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones are secreted at a low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose levels. Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha cells, resulting in a reduction in hepatic glucose output.

INDICATIONS AND USAGE:  GLYXAMBI tablets are 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 linagliptin is appropriate [see Clinical Studies (14)].

1.1 Limitations of Use
GLYXAMBI is not recommended for patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
GLYXAMBI has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using GLYXAMBI.

HOW SUPPLIED: GLYXAMBI is a combination of empagliflozin and linagliptin. GLYXAMBI is available in the following dosage forms and strengths:
10 mg empagliflozin/5 mg linagliptin tablets are pale yellow, arc triangular, flat-faced, bevel-edged film-coated tablets. One side is debossed with the Boehringer Ingelheim company symbol; the other side is debossed with "10/5".

25 mg empagliflozin/5 mg linagliptin tablets are pale pink, arc triangular, flat-faced, bevel-edged film-coated tablets. One side is debossed with the Boehringer Ingelheim company symbol; the other side is debossed with "25/5".

Initial U.S. Approval:  2015

Mechanism of Action:
SYNJARDY
SYNJARDY combines 2 antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and metformin, a member of the biguanide class.

Empagliflozin
Sodium-glucose co-transporter 2 (SGLT2) is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Empagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.

Metformin hydrochloride
Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. It is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike SUs, metformin does not produce hypoglycemia in either patients with type 2 diabetes mellitus or normal subjects (except in special circumstances) [see Warnings and Precautions (5.7)] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

INDICATIONS AND USAGE:  SYNJARDY is a combination of empagliflozin and metformin HCl indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are not adequately controlled on a regimen containing empagliflozin or metformin, or in patients already being treated with both empagliflozin and metformin [see Clinical Studies (14)].

1.1 Limitation of Use
SYNJARDY is not recommended for patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

HOW SUPPLIED: 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