SEGLUROMET (ertugliflozin pidolate 2.5 mg metformin hydrochloride 500 mg) Dailymed

Recent Major Changes Section

Indications and Usage (1) Dosage and Administration (2.1, 2.4) Warnings and Precautions (5.2)

09/2023 09/2023 09/2023

Warning: Lactic Acidosis

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio, and metformin plasma levels generally >5 mcg/mL [seeWarnings and Precautions (5.1)].

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 [seeDosage and Administration (2.2),Contraindications (4),Warnings and Precautions (5.1),Drug Interactions (7), andUse in Specific Populations (8.6,8.7)].

If metformin-associated lactic acidosis is suspected, immediately discontinue SEGLUROMET and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [seeWarnings and Precautions (5.1)].


WARNING: LACTIC ACIDOSIS

See full prescribing information for complete boxed warning.

• Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio, and metformin plasma levels generally >5 mcg/mL. (5.1)
• Risk factors include renal impairment, concomitant use of certain drugs, age ≥65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information. (5.1)
• If lactic acidosis is suspected, discontinue SEGLUROMET and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. (5.1)

1 Indications And Usage

SEGLUROMET^® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.


SEGLUROMET is a combination of ertugliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, and metformin, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. (1)

Limitations of Use:

Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. (1)

Limitations of Use

Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see Warnings and Precautions (5.2)].

• Assess renal function prior to initiation and as clinically indicated. (2.1)
• Correct volume depletion before initiation. (2.1)
• Individualize the starting dose based on the patient's current regimen. (2.2)
• Maximum recommended dose is 7.5 mg ertugliflozin/1,000 mg metformin twice daily. (2.2)
• Take twice daily with meals, with gradual dose escalation. (2.2)
  • Do not use in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m².
  • Use is not recommended in patients with an eGFR less than 45 mL/min/1.73 m². (2.2)
  • Use is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²), end stage-renal disease (ESRD), or on dialysis. (2.2)
• SEGLUROMET may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. (2.3)
• Withhold SEGLUROMET for at least 4 days, if possible, prior to major surgery or procedures associated with prolonged fasting. (2.4)

2.1Prior to Initiation of SEGLUROMET

• Assess renal function prior to initiation of SEGLUROMET and as clinically indicated [see Warnings and Precautions (5.2)].
• Assess volume status. In patients with volume depletion, correct this condition before initiating SEGLUROMET [see Warnings and Precautions (5.4), Use in Specific Populations (8.5, 8.6)].

2.2Recommended Dosage

• Individualize the starting dose of SEGLUROMET, ertugliflozin and metformin hydrochloride (HCl), based on the patient’s current regimen, while not exceeding the maximum recommended daily dose of 15 mg ertugliflozin and 2,000 mg metformin HCl:
  • In patients on metformin HCl, switch to SEGLUROMET tablets containing 2.5 mg ertugliflozin, with a similar total daily dose of metformin HCl.
  • In patients on ertugliflozin, switch to SEGLUROMET tablets containing 500 mg metformin HCl, with a similar total daily dose of ertugliflozin.
  • In patients already treated with ertugliflozin and metformin HCl, switch to SEGLUROMET tablets containing the same total daily dose of ertugliflozin and a similar daily dose of metformin HCl.
• Take SEGLUROMET twice daily with meals, with gradual dose escalation for those initiating metformin HCl to reduce the gastrointestinal side effects due to metformin [seeAdverse Reactions (6.1)].
• Dosing may be adjusted based on effectiveness and tolerability.
• Use of SEGLUROMET is not recommended in patients with an eGFR less than 45 mL/min/1.73 m².
• Use of SEGLUROMET is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²), end stage-renal disease (ESRD), or on dialysis [see Contraindications (4)].

2.3Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue SEGLUROMET 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 SEGLUROMET if renal function is stable [seeWarnings and Precautions (5.1)].

2.4 Temporary Interruption for Surgery

Withhold SEGLUROMET for at least 4 days, if possible, prior to major surgery or procedures associated with prolonged fasting. Resume SEGLUROMET when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)].

3 Dosage Forms And Strengths

• Tablets: ertugliflozin 2.5 mg and metformin HCl 500 mg, pink, oval, debossed with "2.5/500" on one side and plain on the other side.
• Tablets: ertugliflozin 2.5 mg and metformin HCl 1,000 mg, pink, oval, debossed with "2.5/1000" on one side and plain on the other side.
• Tablets: ertugliflozin 7.5 mg and metformin HCl 500 mg, red, oval, debossed with "7.5/500" on one side and plain on the other side.
• Tablets: ertugliflozin 7.5 mg and metformin HCl 1,000 mg, red, oval, debossed with "7.5/1000" on one side and plain on the other side.

Tablets:

• Ertugliflozin 2.5 mg and metformin hydrochloride 500 mg (3)
• Ertugliflozin 2.5 mg and metformin hydrochloride 1,000 mg (3)
• Ertugliflozin 7.5 mg and metformin hydrochloride 500 mg (3)
• Ertugliflozin 7.5 mg and metformin hydrochloride 1,000 mg (3)

4 Contraindications

• Hypersensitivity to ertugliflozin, metformin, or any excipient in SEGLUROMET, reactions such as angioedema or anaphylaxis have occurred [see Adverse Reactions (6.2)].
• Patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²), end stage-renal disease (ESRD), or on dialysis [see Use in Specific Populations (8.6)].
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.

• Severe renal impairment (eGFR less than 30 mL/min/1.73 m²), end stage-renal disease, or patients on dialysis. (4)
• Metabolic acidosis, including diabetic ketoacidosis. (4)
• Hypersensitivity to ertugliflozin, metformin or any excipient. (4)

5 Warnings And Precautions

• Lactic Acidosis: See boxed warning. (5.1)
• Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: Consider ketone monitoring in patients at risk for ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue SEGLUROMET if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting. (5.2)
• Lower Limb Amputation: Consider factors that may increase the risk of amputation before initiating SEGLUROMET. Monitor patients for infections or ulcers of lower limbs, and discontinue if these occur. (5.3)
• Volume Depletion: May result in acute kidney injury. Before initiating, assess and correct volume status in patients with renal impairment, low systolic blood pressure, elderly patients, or patients on diuretics. Monitor for signs and symptoms during therapy. (5.4)
• Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated. (5.5)
• Hypoglycemia: Consider a lower dose of insulin or insulin secretagogue to reduce risk of hypoglycemia when used in combination. (5.6)
• Necrotizing Fasciitis of the Perineum (Fournier's Gangrene): Serious, life-threatening cases have occurred in both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment. (5.7)
• Genital Mycotic Infections: Monitor and treat if indicated. (5.8)
• Vitamin B₁₂ Deficiency: Metformin may lower vitamin B₁₂ levels. Measure hematological parameters annually. (5.9)

5.1Lactic 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 were 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 SEGLUROMET. In SEGLUROMET-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 SEGLUROMET 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 [seeWarnings and Precautions (5.4)andClinical Pharmacology (12.3)].

• Before initiating SEGLUROMET, obtain an eGFR.
• Use of SEGLUROMET is not recommended in patients with an eGFR less than 45 mL/min/1.73 m².
• SEGLUROMET is contraindicated in patients with severe renal impairment (an eGFR less than 30 mL/min/1.73 m²), end stage-renal disease (ESRD), or on dialysis.
• Obtain an eGFR at least annually in all patients taking SEGLUROMET. 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 SEGLUROMET 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 (e.g., cationic drugs) [seeDrug 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 [seeUse 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 SEGLUROMET 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 SEGLUROMET 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. SEGLUROMET 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 pre-renal azotemia. When such events occur, discontinue SEGLUROMET.

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 SEGLUROMET.

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

5.2 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis

In patients with type 1 diabetes mellitus, SEGLUROMET significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium glucose transporter 2 (SGLT2) inhibitors compared to patients who received placebo; this risk may be greater with higher doses. SEGLUROMET is not indicated for glycemic control in patients with type 1 diabetes mellitus.

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

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

Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 4 days after discontinuing SEGLUROMET [see Clinical Pharmacology (12.2)]; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors.

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

Withhold SEGLUROMET, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume SEGLUROMET when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.4)].

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

5.3Lower Limb Amputation

In a long-term cardiovascular outcomes study [seeClinical Studies (14.2)], in patients with type 2 diabetes and established cardiovascular disease, the occurrence of non-traumatic lower limb amputations was reported with event rates of 4.7, 5.7, and 6.0 events per 1,000 patient-years in the placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg treatment arms, respectively.

Amputation of the toe and foot were most frequent (81 out of 109 patients with lower limb amputations). Some patients had multiple amputations, some involving both lower limbs.

Lower limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation. Patients with amputations were more likely to be male, have higher A1C (%) at baseline, have a history of peripheral arterial disease, amputation or peripheral revascularization procedure, diabetic foot, and to have been taking diuretics or insulin.

Across seven ertugliflozin clinical trials, non-traumatic lower limb amputations were reported in 1 (0.1%) patient in the comparator group, 3 (0.2%) patients in the ertugliflozin 5 mg group, and 8 (0.5%) patients in the ertugliflozin 15 mg group.

Before initiating SEGLUROMET, consider factors in the patient history that may predispose them to the need for amputations, such as a history of prior amputation, peripheral vascular disease, neuropathy and diabetic foot ulcers. Counsel patients about the importance of routine preventative foot care. Monitor patients receiving SEGLUROMET for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue SEGLUROMET if these complications occur.

5.4Volume Depletion

SEGLUROMET can cause intravascular volume contraction which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine [see Adverse Reactions (6.1)]. There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including SEGLUROMET. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m²) [see Use in Specific Populations (8.6)], elderly patients, patients with low systolic blood pressure, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating SEGLUROMET in patients with one or more of these characteristics, assess volume status and renal function. In patients with volume depletion, correct this condition before initiating SEGLUROMET. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.

5.5Urosepsis and Pyelonephritis

There have been postmarketing reports of serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization in patients receiving medicines containing SGLT2 inhibitors. Treatment with medicines containing SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6)].

5.6Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. SEGLUROMET may increase the risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue [seeAdverse Reactions (6.1)]. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with SEGLUROMET.

5.7Necrotizing Fasciitis of the Perineum (Fournier's Gangrene)

Reports of necrotizing fasciitis of the perineum (Fournier’s Gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including ertugliflozin. Cases have been reported in females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.

Patients treated with SEGLUROMET presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue SEGLUROMET, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

5.8Genital Mycotic Infections

Ertugliflozin increases the risk of genital mycotic infections. Patients who have a history of genital mycotic infections or who are uncircumcised are more likely to develop genital mycotic infections [seeAdverse Reactions (6.1)]. Monitor and treat appropriately.

5.9 Vitamin B Deficiency

In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B₁₂ levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B₁₂ absorption from the B₁₂-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B₁₂ supplementation. Certain individuals (those with inadequate vitamin B₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B₁₂ levels. Measure hematologic parameters on an annual basis and vitamin B₁₂ at 2 to 3 year intervals in patients on metformin and manage any abnormalities [see Adverse Reactions (6.1)].

6 Adverse Reactions

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

• Lactic Acidosis [seeBoxed WarningandWarnings and Precautions (5.1)]
• Diabetic Ketoacidosis in Patients with Type 1 Diabetes and Other Ketoacidosis [seeWarnings and Precautions (5.2)]
• Lower Limb Amputation [seeWarnings and Precautions (5.3)]
• Volume Depletion [seeWarnings and Precautions (5.4)]
• Urosepsis and Pyelonephritis [seeWarnings and Precautions (5.5)]
• Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [seeWarnings and Precautions (5.6)]
• Necrotizing Fasciitis of the Perineum (Fournier's Gangrene) [see Warnings and Precautions (5.7)]
• Genital Mycotic Infections [seeWarnings and Precautions (5.8)]
• Vitamin B₁₂ Deficiency [seeWarnings and Precautions (5.9)]

• Most common adverse reactions associated with ertugliflozin (incidence ≥5%) were female genital mycotic infections. (6.1)
• Most common adverse reactions associated with metformin (incidence ≥5%) were diarrhea, nausea, vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical Trials Experience

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.

Ertugliflozin and Metformin Hydrochloride

The incidence and type of adverse reactions in the two 26-week, placebo-controlled trials of ertugliflozin 5 mg and 15 mg added to metformin, representing a majority of data from the three 26-week, placebo-controlled trials, were similar to the adverse reactions described in Table 1.

Ertugliflozin

Metformin

The most common (5% or greater incidence) established adverse reactions due to initiation of metformin therapy are diarrhea, nausea, vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache.

In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B₁₂ levels was observed in approximately 7% of patients.

Laboratory Tests

6.2Postmarketing Experience

Additional adverse reactions have been identified during post approval use. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Necrotizing fasciitis of the perineum (Fournier’s Gangrene)
• Angioedema
• Rash
• Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.

7 Drug Interactions

Table 3: Clinically Significant Drug Interactions with SEGLUROMET

Carbonic Anhydrase Inhibitors
Clinical Impact:	The risk of lactic acidosis may increase due to concomitant use of Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) with metformin. These drugs frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis.
Intervention:	more frequent monitoring of these patients.
Drugs that Reduce Metformin Clearance
Clinical Impact:	The risk of lactic acidosis may increase due to 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) which increase systemic exposure to metformin
Intervention	Consider the benefits and risks of concomitant use.
Alcohol
Clinical Impact:	Potentiate the effect of metformin on lactate metabolism.
Intervention:	Warn patients against excessive alcohol intake while receiving SEGLUROMET.
Insulin and Insulin Secretagogues
Clinical Impact:	The risk of hypoglycemia when ertugliflozin is used in combination with insulin and/or an insulin secretagogue.
Intervention:	A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with SEGLUROMET.
Drugs that Affect 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 a patient is receiving SEGLUROMET along with such drugs, the patient should be closely observed to maintain adequate glycemic control.
Lithium
Clinical Impact:	Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations.
Intervention:	Monitor serum lithium concentration more frequently during SEGLUROMET 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 SEGLUROMET. Use alternative methods to monitor glycemic control.
Interference with 1,5-anhydroglucitol (1,5-AG) Assay
Clinical Impact:	Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors.
Intervention:	Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control.

• Carbonic Anhydrase Inhibitors: May increase risk of lactic acidosis. Consider more frequent monitoring. (7.2)
• Drugs that Reduce Metformin Clearance: May increase risk of lactic acidosis. Consider benefits and risks of concomitant use. (7.2)
• See full prescribing information for additional drug interactions and information on interference of SEGLUROMET with laboratory tests. (7)

8 Use In Specific Populations

• Pregnancy: Advise females of the potential risk to a fetus, especially during the second and third trimesters. (8.1)
• Lactation: Breastfeeding not recommended. (8.2)
• Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. (8.3)
• Geriatrics: Higher incidence of adverse reactions related to reduced intravascular volume. (8.5)
• Renal impairment: Higher incidence of adverse reactions related to reduced intravascular volume and renal function. (8.6)
• Hepatic impairment : Avoid use in patients with hepatic impairment. (8.7)

8.1 Pregnancy

Risk Summary

Based on animal data showing adverse renal effects, from ertugliflozin, SEGLUROMET is not recommended during the second and third trimesters of pregnancy. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk (seeData).

The limited available data with SEGLUROMET in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (seeClinical Considerations).

In animal studies, adverse renal changes were observed in rats when ertugliflozin was 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 and renal mineralization that were not fully reversible. There was no evidence of fetal harm in rats or rabbits at exposures of ertugliflozin approximately 300 times higher than the maximal clinical dose of 15 mg/day when administered during organogenesis (seeData).

The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% 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 2-4% and 15-20%, 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 and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin 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

8.2 Lactation

Risk Summary

There is no information regarding the presence of SEGLUROMET or ertugliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk (seeData). However, there is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Ertugliflozin (seeData) and metformin are present in the milk of lactating rats. 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, based on data with ertugliflozin. Because of the potential for serious adverse reactions in a breastfed infant, advise women that the use of SEGLUROMET is not recommended while breastfeeding.

Data

The lacteal excretion of radiolabeled ertugliflozin in lactating rats was evaluated 10 to 12 days after parturition. Ertugliflozin derived radioactivity exposure in milk and plasma were similar, with a milk/plasma ratio of 1.07, based on AUC. Juvenile rats directly exposed to ertugliflozin during a developmental period corresponding to human kidney maturation were associated with a risk to the developing kidney (persistent increased organ weight, renal mineralization, and renal pelvic and tubular dilatations).

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 during lactation because of small sample size and limited adverse event data collected in infants.

8.3 Females and Males of Reproductive Potential

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

8.4 Pediatric Use

Safety and effectiveness of SEGLUROMET in pediatric patients under 18 years of age have not been established.

8.5 Geriatric Use

SEGLUROMET

No dosage adjustment of SEGLUROMET is recommended based on age. Elderly patients are more likely to have decreased renal function. Because renal function abnormalities can occur after initiating ertugliflozin, and metformin is known to be substantially excreted by the kidneys, care should be taken in dose selection in the elderly. Assess renal function in elderly patients prior to initiating dosing and periodically thereafter [see Dosage and Administration (2.1) and Warnings and Precautions (5.1, 5.4)].

Ertugliflozin

In ertugliflozin clinical trials, a total of 876 (25.7%) patients treated with ertugliflozin were 65 years and older, and 152 (4.5%) patients treated with ertugliflozin were 75 years and older. Patients 65 years and older had a higher incidence of adverse reactions related to volume depletion compared to younger patients; events were reported in 1.1%, 2.2%, and 2.6% of patients treated with comparator, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

In VERTIS CV, a total of 2780 (50.5%) patients treated with ertugliflozin were 65 years and older, and 595 (10.8%) patients treated with ertugliflozin were 75 years and older. Safety and efficacy were generally similar for patients age 65 years and older compared to patients younger than 65.

Metformin HCl

Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [seeContraindications (4),Warnings and Precautions (5.1), andClinical Pharmacology (12.3)].

8.6Renal Impairment

A 26-week placebo-controlled study of 313 patients with Stage 3 Chronic Kidney Disease (eGFR ≥30 to less than 60 mL/min/1.73 m²) treated with ertugliflozin did not have improvement in glycemic control.

In the VERTIS CV study, there were 1370 patients (25%) with an eGFR ≥90 mL/min/1.73 m², 2929 patients (53%) with an eGFR of ≥60 to less than 90 mL/min/1.73 m², 879 patients (16%) with an eGFR of ≥45 to less than 60 mL/min/1.73 m², and 299 patients (5%) with eGFR of 30 to <45 mL/min/1.73 m² treated with ertugliflozin. Similar effects on glycemic control at Week 18 were observed in patients treated with ertugliflozin in each eGFR subgroup and also in the overall patient population.

SEGLUROMET is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²), ESRD, or on dialysis [seeContraindications (4)].

No dosage adjustment is needed in patients with eGFR ≥45 mL/min/1.73 m².

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

8.7Hepatic Impairment

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. SEGLUROMET is not recommended in patients with hepatic impairment [seeWarnings and Precautions (5.1)].