Drug Safety-related Labeling Changes (SrLC)

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SEGLUROMET (NDA-209806)

(ERTUGLIFLOZIN; METFORMIN HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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08/11/2026 (SUPPL-13)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

. . .

Risk factors include renal impairment, concomitant use of certain drugs, age greater than 65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, hepatic impairment, and mitochondrial diseases. 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 Warnings and Precautions

5.1 Lactic Acidosis

Additions and/or revisions underlined:

. . .

Mitochondrial Diseases: Metformin may increase the risk of lactic acidosis in patients with mitochondrial diseases such as mitochondrial encephalomyopathy with lactic acidosis, and stroke-like episodes (MELAS) syndrome and maternally inherited diabetes and deafness (MIDD). SEGLUROMET is not recommended in patients with mitochondrial diseases such as MELAS syndrome and MIDD.

 

If a patient taking SEGLUROMET develops elevated lactic acid levels (with or without accompanying neurologic signs and symptoms), discontinue SEGLUROMET. Depending on the clinical context, consider evaluating the patient for MELAS, MIDD, or other mitochondrial disease.

. . .

 

5.3 Lower Limb Amputation

Additions and/or revisions underlined:

. . .

Monitor patients receiving SEGLUROMET for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and institute appropriate treatment.

 

5.5 Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections

Subsection title revised

Additions and/or revisions underlined:

SEGLUROMET increases urinary glucose excretion [see Clinical Pharmacology (12.2)] and increases the risk of genitourinary infections including urinary tract infections and genital mycotic infections in both male and female patients [see Adverse Reactions (6.1)].

Serious genitourinary infections, including urosepsis, pyelonephritis, and necrotizing fasciitis of the perineum (Fournier’s gangrene, a rare life-threatening infection requiring urgent surgical intervention), have occurred in patients receiving SGLT2 inhibitors [see Adverse Reactions (6.2)]. Cases have required hospitalization. In patients with Fournier’s gangrene, serious outcomes have included multiple surgeries and death.

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

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

6 Adverse Reactions

Addition of the following to the bulleted line listing:

. . .

• Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene), and Genital Mycotic Infections [see Warnings and Precautions (5.5)]

. . .

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

. . .

Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene), and Genital Mycotic Infections

Counsel patients that genitourinary infections may occur when taking SEGLUROMET and may become serious. Educate patients on the symptoms and advise them to seek medical advice if symptoms occur. Specifically, advise patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever above 100.4°F or malaise [see Warnings and Precautions (5.5)].

 

 

MEDICATION GUIDE

Additions and/or revisions underlined:

. . .

Most people who have had lactic acidosis had other conditions that, in combination with metformin use, led to the lactic acidosis. Tell your healthcare provider if you have any of the following, because you have a higher chance for getting lactic acidosis with SEGLUROMET if you:

. . .

• have a genetically inherited disease affecting mitochondria (the energy-producing parts within cells) such as mitochondrial encephalomyopathy with lactic acidosis, and stroke-like episodes (MELAS) syndrome and maternally inherited diabetes and deafness (MIDD).

. . .

Before you take SEGLUROMET, tell your healthcare provider about all of your medical conditions, including if you:

. . .

• have a genetically inherited disease affecting mitochondria (the energy-producing parts within cells) such as MELAS syndrome and MIDD.

. . .

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

. . .

Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene), and Genital Mycotic Infections

Counsel patients that genitourinary infections may occur when taking SEGLUROMET and may become serious. Educate patients on the symptoms and advise them to seek medical advice if symptoms occur. Specifically, advise patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever above 100.4°F or malaise [see Warnings and Precautions (5.5)].

 

 

MEDICATION GUIDE

Additions and/or revisions underlined:

. . .

Most people who have had lactic acidosis had other conditions that, in combination with metformin use, led to the lactic acidosis. Tell your healthcare provider if you have any of the following, because you have a higher chance for getting lactic acidosis with SEGLUROMET if you:

. . .

• have a genetically inherited disease affecting mitochondria (the energy-producing parts within cells) such as mitochondrial encephalomyopathy with lactic acidosis, and stroke-like episodes (MELAS) syndrome and maternally inherited diabetes and deafness (MIDD).

. . .

Before you take SEGLUROMET, tell your healthcare provider about all of your medical conditions, including if you:

. . .

• have a genetically inherited disease affecting mitochondria (the energy-producing parts within cells) such as MELAS syndrome and MIDD.

  . . .

08/11/2026 (SUPPL-15)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

. . .

Risk factors include renal impairment, concomitant use of certain drugs, age greater than 65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, hepatic impairment, and mitochondrial diseases. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the Full Prescribing Information.

. . .

12/20/2024 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues

Additions and/or revisions underlined:

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 or an insulin secretagogue [see Adverse Reactions (6.1)]. The risk of hypoglycemia may be lowered by a reduction in the dose of insulin or sulfonylurea (or other concomitantly administered insulin secretagogues). Inform patients using these medications concomitantly of this risk and educate them on the signs and symptoms of hypoglycemia.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Lower Limb Amputation

In a long-term cardiovascular outcomes study [see Clinical Studies (14.2)], in patients with type 2 diabetes mellitus 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.

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.

…

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Additional adverse reactions have been identified during post approval use of ertugliflozin, metformin HCl, both components of SEGLUROMET. 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.

Ertugliflozin

• Infections: necrotizing fasciitis of the perineum (Fournier’s Gangrene)

• Skin and Subcutaneous Tissue Disorders: angioedema, rash

  Metformin HCl

• Hepatobiliary Disorders: cholestatic, hepatocellular, and mixed hepatocellular liver injury

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Lower Limb Amputation

Inform patients of the potential for an increased risk of amputations. Counsel patients about the importance of routine preventative foot care. Instruct patients to monitor for new pain or tenderness, sores or ulcers, or infections involving the leg or foot and to seek medical advice immediately if such signs or symptoms develop [see Warnings and Precautions (5.3)].

…

09/12/2023 (SUPPL-10)

Approved Drug Label (PDF)

5 Warnings and Precautions

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

Subsection title revised

Additions and revisions underlined:

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 maybe 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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

Extensive changes; please refer to label

PATIENT COUNSELING INFORMATION

Additions and revisions underlined:

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

Inform patients that SEGLUROMET can cause potentially fatal ketoacidosis and that type 2 diabetes

mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are risk factors.

Educate all patients on precipitating factors (such as insulin dose reduction or missed insulin doses,

infection, reduced caloric intake, ketogenic diet, surgery, dehydration, and alcohol abuse) and symptoms

of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing). Inform

patients that blood glucose may be normal even in the presence of ketoacidosis.

Advise patients that they may be asked to monitor ketones. If symptoms of ketoacidosis occur,

instruct patients to discontinue SEGLUROMET and seek medical attention immediately [see Warnings and

Precautions (5.2)].

10/13/2022 (SUPPL-9)

Approved Drug Label (PDF)

7 Drug Interactions

Newly added information to Table 7: Clinically Significant Drug Interactions with STEGLUROMET

Lithium

Clinical Impact:

Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations.

Intervention:

Monitor serum lithium concentration more frequently during STEGLUROMET initiation and dosage changes.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

SEGLUROMET may affect the way other medicines work, and other medicines may affect how

SEGLUROMET works.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist

when you get a new medicine.

03/02/2022 (SUPPL-8)

Approved Drug Label (PDF)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions underlined

…

What are the possible side effects of SEGLUROMET?

SEGLUROMET may cause serious side effects, including:

…

Call your doctor right away if you have new pain or tenderness, any sores, ulcers, or infections in your leg or foot. Your doctor may decide to stop your SEGLUROMET for a while if you have any

of these signs or symptoms. Talk to your doctor about proper foot care.

…

09/17/2021 (SUPPL-6)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

• Hypersensitivity to ertugliflozin, metformin, or any excipient in SEGULORMET, 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)].

5 Warnings and Precautions

5.1 Lactic Acidosis

(Additions and/or revisions underlined)

• 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.

5.3 Lower Limb Amputation

(Additions and/or revisions underlined)

In a long-term cardiovascular outcomes study [see Clinical 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 1000 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.

5.4 Volume Depletion

(Newly added section)

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.

5.5 Urosepsis and Pyelonephritis

(New section heading)

5.9 Vitamin B12 Deficiency

(Section title revised)

(Additions and/or revisions underlined)

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

6.1 Clinical Trials Experience

(Newly added information)

Ketoacidosis

In a long-term cardiovascular outcomes study VERTIS CV (eValuation of ERTugliflozin effIcacy and

Safety, CardioVascular [see Clinical Studies 14.2], a study in patients with type 2 diabetes and established

cardiovascular disease, ketoacidosis was identified in 19 (0.3%) ertugliflozin-treated patients and in 2

(0.1%) placebo-treated patients. Across seven other ertugliflozin clinical trials, ketoacidosis was identified

in 3 (0.1%) ertugliflozin-treated patients and 0.0% of comparator-treated patients [see Warnings and Precautions (5.3)].

Volume Depletion

(Additions and/or revisions underlined)

Ertugliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse

reactions related to volume depletion, particularly in patients with impaired renal function (eGFR less than

60 mL/min/1.73 m2). In patients with moderate renal impairment, adverse reactions related to volume

depletion (e.g., dehydration, dizziness postural, presyncope, syncope, hypotension, and orthostatic

hypotension) were reported in 0%, 4.4%, and 1.9% of patients treated with placebo, ertugliflozin 5 mg, and

ertugliflozin 15 mg, respectively. Ertugliflozin may also increase the risk of hypotension in other patients at

risk for volume contraction [see Use in Specific Populations (8.5, 8.6)].

Urinary Tract Infections

(Newly added information)

In VERTIS CV urinary tract infections (e.g., urinary tract infection, cystitis, dysuria) occurred in 10.2%,

12.2% and 12.0% of patients treated with placebo, ertugliflozin 5 mg and ertugliflozin 15 mg, respectively.

The incidences of serious urinary tract infections were 0.8%, 0.9% and 0.4% with placebo, ertugliflozin 5

mg and ertugliflozin 15 mg, respectively.

Metformin

(Additions and/or revisions underlined)

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.

Changes in Serum Creatinine and eGFR

(Newly added information)

Initiation of ertugliflozincauses an increase in serum creatinine and decrease in eGFR within weeks of

starting therapy and then these changes stabilize. In a study of patients with moderate renal impairment,

larger mean changes were observed. In a long-term cardiovascular outcomes trial, an initial increase in

serum creatinine and a decrease in eGFR within weeks of starting therapy was observed (at Week 6 eGFR

changes of -2.7, -3.8 and -0.4 mL/min/1.73 m2 in the ertugliflozin 5 mg, ertugliflozin 15 mg and placebo

arms, respectively). The initial decline was followed by a recovery toward baseline to Week 52 (eGFR

change from baseline of - 0.4, - 1.1 and - 0.2 ml/min/1.73 m2 in ertugliflozin 5 mg, ertugliflozin 15 mg, and

placebo arms, respectively). Acute hemodynamic changes may play a role in the early renal function

changes observed with ertugliflozin since they are reversed after treatment discontinuation.

6.2 Postmarketing Experience

(Newly added information)

• Angioedema

• Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with

postmarketing use of metformin.

7 Drug Interactions

(Addition of Tables 3, 4, and 5: Clinically Significant Drug Interactions with METFORMIN, ERTUGLIFLOZIN, and SEGLUROMET)

(Extensive changes; please refer to label)

8 Use in Specific Populations

8.5 Geriatric Use

(Newly added information)

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.

8.6 Renal Impairment

(Additions and/or revisions underlined)

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 [see Contraindications (4)].

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

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

(Additions and/or revisions underlined)

• SEGLUROMET contains 2 prescription medicines called ertugliflozin (STEGLATRO®) and

metformin hydrochloride. SEGLUROMET is used in adults with type 2 diabetes to improve blood

sugar (glucose) along with diet and exercise.

• SEGLUROMET is not for people with type 1 diabetes. It may increase the risk of diabetic

ketoacidosis (increased ketones in blood or urine) in these people.

Do not take SEGLUROMET if you:

• have severe kidney problems, have end stage renal disease (ESRD) or are on dialysis.

• Dehydration. SEGLUROMET can cause some people to become dehydrated (the loss of body

water and salt). Dehydration may cause you to feel dizzy, faint, lightheaded, or weak, especially

when you stand up (orthostatic hypotension). There have been reports of sudden worsening of

kidney function in people who are taking SEGLUROMET.

You may be at risk of dehydration if you:

o have low blood pressure

o take medicines to lower your blood pressure, including water pills (diuretics)

o have kidney problems

o are on a low sodium (salt) diet

o are 65 years of age or older

Talk to your doctor about what you can do to prevent dehydration including how much fluid you should

drink on a daily basis.

Seek medical attention immediately if you have fever above 100.4ºF or you are

feeling very weak, tired or uncomfortable (malaise) and you develop any of the following

symptoms in the area between and around your anus and genitals

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Lactic Acidosis

Inform patients of the risks of lactic acidosis due to the metformin component, its symptoms, and

conditions that predispose to its development [see Warnings and Precautions (5.1)]. Advise patients to

discontinue SEGLUROMET immediately and to notify their doctor promptly if unexplained hyperventilation,

malaise, myalgia, unusual somnolence, slow or irregular heartbeat, sensation of feeling cold (especially in

the extremities), or other nonspecific symptoms occur. GI symptoms are common during initiation of

metformin treatment and may occur during initiation of SEGLUROMET therapy; however, advise patients

to consult their doctor if they develop unexplained symptoms. Although GI symptoms that occur after

stabilization are unlikely to be drug related, such an occurrence of symptoms should be evaluated to

determine if it may be due to metformin-induced lactic acidosis or other serious disease.

Ketoacidosis

If symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing) occur,

instruct patients to discontinue SEGLUROMET and seek medical attention immediately [see Warnings and

Precautions (5.2)].

Volume Depletion

Inform patients that symptomatic hypotension may occur with SEGLUROMET and advise them to

contact their doctor if they experience such symptoms [see Warnings and Precautions (5.4)]. Inform

patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake.

Hypoglycemia with Concomitant Use of Insulin and/or Insulin Secretagogue

Inform patients that the incidence of hypoglycemia may increase when SEGLUROMET is added to

insulin and/or an insulin secretagogue and that a lower dose of insulin or insulin secretagogue may be

required to reduce the risk of hypoglycemia [see Warnings and Precautions (5.6)].

Fetal Toxicity

Advise pregnant patients of the potential risk to a fetus with treatment with SEGLUROMET. Instruct

patients to immediately inform their healthcare provider if pregnant or planning to become pregnant. [See

Use in Specific Populations (8.1).]

Lactation

Advise patients that use of SEGLUROMET is not recommended while breastfeeding [see Use in

Specific Populations (8.2)].

Pregnancy

Inform female patients that treatment with metformin may result in an unintended pregnancy in some

premenopausal anovulatory females due to its effect on ovulation [see Use in Specific Populations (8.3)].

Missed Dose

Instruct patients to take SEGLUROMET only as prescribed. If a dose is missed, it should be taken as

soon as the patient remembers. Advise patients not to double their next dose.

01/24/2020 (SUPPL-2)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Ketoacidosis

(Additions and/or revisions underlined)

Before initiating SEGLUROMET, consider factors in the patient history that may predispose to ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse.

For patients who undergo scheduled surgery, consider temporarily discontinuing SEGLUROMET for at least 4 days prior to surgery.

Consider monitoring for ketoacidosis and temporarily discontinuing SEGLUROMET in other clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or post-surgery). Ensure risk factors for ketoacidosis are resolved prior to restarting SEGLUROMET.

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

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Ketoacidosis

Inform patients that ketoacidosis is a serious life-threatening condition and that cases of ketoacidosis have been reported during use of medicines containing SGLT2 inhibitors, including ertugliflozin, sometimes associated with illness or surgery among other risk factors. Instruct patients to check ketones (when possible) if symptoms consistent with ketoacidosis occur even if blood glucose is not elevated. If symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing) occur, instruct patients to discontinue SEGLUROMET and seek medical attention immediately.

Medication Guide

(Additions and/or revisions underlined)

Ketoacidosis

Inform patients that ketoacidosis is a serious life-threatening condition and that cases of ketoacidosis have been reported during use of medicines containing SGLT2 inhibitors, including ertugliflozin, sometimes associated with illness or surgery among other risk factors. Instruct patients to check ketones (when possible) if symptoms consistent with ketoacidosis occur even if blood glucose is not elevated. If symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing) occur, instruct patients to discontinue SEGLUROMET and seek medical attention immediately.

10/26/2018 (SUPPL-1)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly created subsection:

5.8 Necrotizing 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. 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.

6 Adverse Reactions

Addition of the following the bulleted line listing:

• Necrotizing Fasciitis of the Perineum (Fournier’s gangrene)

Addition of the following subsection:

6.2 Postmarketing Experience

Additional adverse reactions have been identified during postapproval 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.

• Cases of necrotizing fasciitis of the perineum (Fournier’s gangrene) have been seen with SGLT2 inhibitors.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

What are the possible side effects of SEGLUROMET? SEGLUROMET may cause serious side effects, including:

See “What is the most important information I should know about SEGLUROMET?”

Addition of the following:

• a rare but serious bacterial infection that causes damage to the tissue under the skin (necrotizing fasciitis) in the area between and around the anus and genitals (perineum). Necrotizing fasciitis of the perineum has happened in women and men who take medicines that lower blood sugar in the same way as one of the medicines in SEGLUROMET. Necrotizing fasciitis of the perineum may lead to hospitalization, may require multiple surgeries, and may lead to death. Seek medical attention immediately if you have fever or you are feeling very weak, tired or uncomfortable (malaise) and you develop any of the following symptoms in the area between and around your anus and genitals:

• pain or tenderness             o swelling       o redness of skin (erythema)

PATIENT COUNSELING INFORMATION

Addition of the following:

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)

Inform patients that necrotizing infections of the perineum (Fournier’s gangrene) have occurred with SGLT2 inhibitors. Counsel patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever above 100.4°F or malaise.