` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`209806Orig1s000
`
`
`LABELING
`
`

`

`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`SEGLUROMET safely and effectively. See
`full prescribing
`information for SEGLUROMET.
`
`SEGLUROMET™ (ertugliflozin and metformin hydrochloride)
`tablets, for oral use
`Initial U.S. Approval: 2017
`
`WARNING: LACTIC ACIDOSIS
`See full prescribing information for complete boxed warning.
`
`(cid:120) Post-marketing 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)
`(cid:120) Risk factors include renal impairment, concomitant use of
`(cid:70)(cid:72)(cid:85)(cid:87)(cid:68)(cid:76)(cid:81) (cid:71)(cid:85)(cid:88)(cid:74)(cid:86)(cid:15) (cid:68)(cid:74)(cid:72) (cid:149)(cid:25)(cid:24) 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)
`(cid:120) If lactic acidosis is suspected, discontinue SEGLUROMET and
`institute general supportive measures in a hospital setting.
`Prompt hemodialysis is recommended. (5.1)
`
`----------------------------INDICATIONS AND USAGE----------------------------
`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 who are not adequately controlled on a
`regimen containing ertugliflozin or metformin, or in patients who are
`already treated with both ertugliflozin and metformin. (1)
`
`is 7.5 mg ertugliflozin/1,000 mg
`
`Limitations of Use:
`(cid:120) Not for the treatment of type 1 diabetes mellitus or diabetic
`ketoacidosis. (1)
`----------------------- DOSAGE AND ADMINISTRATION -----------------------
`(cid:120) Individualize the starting dose based on the patient’s current
`regimen. (2.1)
`(cid:120) Maximum recommended dose
`metformin twice daily. (2.1)
`(cid:120) Take twice daily with meals, with gradual dose escalation. (2.1)
`(cid:120) Assess renal function before initiating SEGLUROMET (2.2):
`o Do not use in patients with an estimated glomerular filtration rate
`(eGFR) below 30 mL/minute/1.73 m2.
`o Initiation is not recommended in patients with an eGFR of 30 to
`less than 60 mL/minute/1.73 m2.
`o Continued use is not recommended in patients with an eGFR
`persistently between 30 and less than 60 mL/min/1.73 m2.
`(cid:120) SEGLUROMET may need to be discontinued at time of, or prior to,
`iodinated contrast imaging procedures. (2.3)
`--------------------- DOSAGE FORMS AND STRENGTHS ---------------------
`Tablets:
`(cid:120) Ertugliflozin 2.5 mg and metformin hydrochloride 500 mg (3)
`(cid:120) Ertugliflozin 2.5 mg and metformin hydrochloride 1,000 mg (3)
`(cid:120) Ertugliflozin 7.5 mg and metformin hydrochloride 500 mg (3)
`(cid:120) Ertugliflozin 7.5 mg and metformin hydrochloride 1,000 mg (3)
`-------------------------------CONTRAINDICATIONS-------------------------------
`(cid:120) Severe renal impairment, end stage renal disease, or dialysis. (4,
`5.1, 5.4)
`(cid:120) Metabolic acidosis, including diabetic ketoacidosis. (4, 5.1)
`to ertugliflozin or
`(cid:120) History of serious hypersensitivity reaction
`metformin. (4)
`
`----------------------- WARNINGS AND PRECAUTIONS -----------------------
`(cid:120) Lactic Acidosis: See boxed warning. (5.1)
`renal
`in patients with
`(cid:120) Hypotension: May occur particularly
`impairment, the elderly, or patients on diuretics. Before initiating,
`assess and correct volume status. Monitor for signs and symptoms
`during therapy. (5.2)
`(cid:120) Ketoacidosis: Assess patients who present with signs and
`symptoms of metabolic acidosis for ketoacidosis, regardless of
`blood glucose level. If suspected, discontinue, evaluate, and treat
`promptly. Before initiating, consider risk factors for ketoacidosis.
`Patients may require monitoring and temporary discontinuation of
`therapy in clinical situations known to predispose to ketoacidosis.
`(5.3)
`(cid:120) Acute Kidney Injury and Impairment in Renal Function: Consider
`temporarily discontinuing in settings of reduced oral intake or fluid
`losses. If acute kidney injury occurs, discontinue and promptly treat.
`Monitor renal function. (5.4)
`(cid:120) Urosepsis and Pyelonephritis: Evaluate patients for signs and
`symptoms of urinary tract infections and treat promptly, if indicated.
`(5.5)
`(cid:120) Lower Limb Amputation: Before initiating, consider factors that may
`increase risk of amputation. Monitor patients for infections or ulcers
`of lower limbs, and discontinue if these occur. (5.6)
`insulin
`lower dose of
`insulin or
`(cid:120) Hypoglycemia: Consider a
`secretagogue to reduce risk of hypoglycemia when used in
`combination. (5.7)
`(cid:120) Genital Mycotic Infections: Monitor and treat if indicated. (5.8)
`(cid:120) Vitamin B12 Deficiency: Metformin may lower vitamin B12 levels.
`Measure hematological parameters annually. (5.9)
`(cid:120) Increased LDL-C: Monitor and treat as appropriate. (5.10)
`------------------------------ ADVERSE REACTIONS ------------------------------
`(cid:120) The most common adverse reactions associated with ertugliflozin
`((cid:76)(cid:81)(cid:70)(cid:76)(cid:71)(cid:72)(cid:81)(cid:70)(cid:72) (cid:149)5%) were female genital mycotic infections. (6.1)
`reactions associated with metformin
`(cid:120) Most common adverse
`((cid:76)(cid:81)(cid:70)(cid:76)(cid:71)(cid:72)(cid:81)(cid:70)(cid:72) (cid:149)5%): diarrhea, nausea, vomiting, flatulence, abdominal
`discomfort, indigestion, asthenia, and headache. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Merck
`Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-
`888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`-------------------------------DRUG INTERACTIONS-------------------------------
`(cid:120) Carbonic anhydrase inhibitors may increase risk of lactic acidosis.
`Consider more frequent monitoring. (7.2)
`(cid:120) Drugs that reduce metformin clearance (such as ranolazine,
`vandetanib, dolutegravir, and cimetidine) may
`increase
`the
`accumulation of metformin. Consider the benefits and risks of
`concomitant use. (7.2)
`(cid:120) Alcohol can potentiate the effect of metformin on lactate metabolism.
`Warn patients against excessive alcohol intake. (7.2)
`----------------------- USE IN SPECIFIC POPULATIONS -----------------------
`(cid:120) Pregnancy: Advise females of the potential risk to a fetus, especially
`during the second and third trimesters. (8.1)
`(cid:120) Lactation: Breastfeeding not recommended. (8.2)
`(cid:120) Females and Males of Reproductive Potential: Advise
`premenopausal
`females of
`the potential
`for an unintended
`pregnancy. (8.3)
`(cid:120) Geriatrics: Higher incidence of adverse reactions related to reduced
`intravascular volume. (5.2, 8.5)
`(cid:120) Renal impairment: Higher incidence of adverse reactions related to
`reduced intravascular volume and renal function. (5.1, 5.4, 8.6)
`(cid:120) Hepatic impairment: Avoid use in patients with hepatic impairment.
`(8.7)
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`Revised: 12/2017
`
`Reference ID: 4197754
`
`

`

`Females and Males of Reproductive Potential
`8.3
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Overview of Clinical Studies in Patients with Type 2
`Diabetes Mellitus
`14.2 Ertugliflozin as Add-on Combination Therapy with
`Metformin
`14.3 In Combination with Sitagliptin versus Ertugliflozin Alone
`and Sitagliptin Alone, as Add-on to Metformin
`14.4 Ertugliflozin as Add-on Combination Therapy with
`Metformin and Sitagliptin
`14.5 Active Controlled Study of Ertugliflozin Versus Glimepiride
`as Add-on Combination Therapy with Metformin
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: LACTIC ACIDOSIS
`1
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`2.2 Patients with Renal Impairment
`2.3 Discontinuation for Iodinated Contrast Imaging Procedures
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1
`Lactic Acidosis
`5.2 Hypotension
`5.3 Ketoacidosis
`5.4 Acute Kidney Injury and Impairment in Renal Function
`5.5 Urosepsis and Pyelonephritis
`5.6
`Lower Limb Amputation
`5.7 Hypoglycemia with Concomitant Use with Insulin and
`Insulin Secretagogues
`5.8 Genital Mycotic Infections
`5.9 Vitamin B12 Levels
`5.10 Increases in Low-Density Lipoprotein Cholesterol (LDL-C)
`5.11 Macrovascular Outcomes
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`DRUG INTERACTIONS
`7.1 Drug Interactions with Ertugliflozin
`7.2 Drug Interactions with Metformin Hydrochloride
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2
`Lactation
`
`6
`
`7
`
`8
`
`Reference ID: 4197754
`
`

`

`FULL PRESCRIBING INFORMATION
`WARNING: LACTIC ACIDOSIS
`
`Post-marketing cases of metformin-associated lactic acidosis have resulted in death,
`hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated
`lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise,
`myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic
`acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis
`(without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio, and metformin
`plasma levels generally >5 mcg/mL [see Warnings 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 [see Dosage and Administration (2.2),
`Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Use in Specific
`Populations (8.6, 8.7)].
`immediately discontinue
`is suspected,
`lactic acidosis
`If metformin-associated
`SEGLUROMET and
`institute general supportive measures
`in a hospital setting. Prompt
`hemodialysis is recommended [see Warnings and Precautions (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 who are not adequately controlled on a regimen containing
`ertugliflozin or metformin, or in patients who are already treated with both ertugliflozin and metformin.
`
`Limitations of Use
`SEGLUROMET is not recommended in patients with type 1 diabetes mellitus or for the
`(cid:120)
`treatment of diabetic ketoacidosis.
`DOSAGE AND ADMINISTRATION
`2
`2.1 Recommended Dosage
`Individualize the starting dose of SEGLUROMET (ertugliflozin and metformin hydrochloride)
`(cid:120)
`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:
`o
`In patients on metformin, switch to SEGLUROMET tablets containing 2.5 mg ertugliflozin,
`with a similar total daily dose of metformin.
`o
`In patients on ertugliflozin, switch to SEGLUROMET tablets containing 500 mg metformin,
`with a similar total daily dose of ertugliflozin.
`o
`In patients already treated with ertugliflozin and metformin, switch to SEGLUROMET
`tablets containing the same total daily dose of ertugliflozin and a similar daily dose of
`metformin.
`Take SEGLUROMET twice daily with meals, with gradual dose escalation for those initiating
`metformin to reduce the gastrointestinal side effects due to metformin [see Adverse Reactions
`(6.1)].
`In patients with volume depletion not previously treated with ertugliflozin, correct this condition
`prior to initiation of SEGLUROMET [see Warnings and Precautions (5.2)].
`(cid:120) Dosing may be adjusted based on effectiveness and tolerability.
`
`(cid:120)
`
`(cid:120)
`
`2.2 Patients with Renal Impairment
`Assess renal function prior to initiation of SEGLUROMET and periodically thereafter [see
`(cid:120)
`Warnings and Precautions (5.4)].
`(cid:120) Use of SEGLUROMET is contraindicated
`30 mL/minute/1.73 m2 [see Contraindications (4)].
`
`than
`
`in patients with an eGFR
`
`less
`
`Reference ID: 4197754
`
`3
`
`

`

`(cid:120)
`
`in patients with an eGFR of
`recommended
`Initiation of SEGLUROMET is not
`30 mL/minute/1.73 m2 to less than 60 mL/minute/1.73 m2 [see Warnings and Precautions (5.4)
`and Use in Specific Populations (8.6)].
`(cid:120) Continued use of SEGLUROMET is not recommended when eGFR is persistently between 30
`and less than 60 mL/min/1.73 m2.
`(cid:120) No dose adjustment is needed in patients with mild renal impairment.
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
`2.3 Discontinuation 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 [see Warnings and
`Precautions (5.1)].
`3
`DOSAGE FORMS AND STRENGTHS
`Tablets: ertugliflozin 2.5 mg and metformin hydrochloride 500 mg, pink, oval, debossed with
`(cid:120)
`“2.5/500” on one side and plain on the other side.
`Tablets: ertugliflozin 2.5 mg and metformin hydrochloride 1000 mg, pink, oval, debossed with
`“2.5/1000” on one side and plain on the other side.
`Tablets: ertugliflozin 7.5 mg and metformin hydrochloride 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 hydrochloride 1000 mg, red, oval, debossed with
`“7.5/1000” on one side and plain on the other side.
`CONTRAINDICATIONS
`Severe renal impairment, end stage renal disease (ESRD), or patients on dialysis [see
`(cid:120)
`Warnings and Precautions (5.1, 5.4) and Use in Specific Populations (8.6)].
`Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
`(cid:120)
`(cid:120) History of a serious hypersensitivity reaction to SEGLUROMET, ertugliflozin, or metformin
`hydrochloride.
`WARNINGS AND PRECAUTIONS
`Lactic Acidosis
`There have been post-marketing 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:
`
`4
`
`5
`5.1
`
`Reference ID: 4197754
`
`4
`
`

`

`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 [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
`Before initiating SEGLUROMET, obtain an eGFR.
`
`SEGLUROMET is contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m2.
`
`recommended
`is not
`Initiation of SEGLUROMET
`30 mL/minute/1.73 m2 to less than 60 mL/min/1.73 m2.
`
`in patients with an eGFR of
`
`(cid:120) Continued use of SEGLUROMET is not recommended when eGFR is persistently between
`30 and less than 60 mL/min/1.73 m2.
`
`(cid:120) Renal function should be evaluated prior to initiating SEGLUROMET and periodically thereafter.
`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) [see
`Drug Interactions (7)]. Therefore, consider more frequent monitoring of patients.
`
`Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age
`because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than
`younger patients. Assess renal function more frequently in elderly patients [see Use in Specific
`Populations (8.5)].
`
`Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in
`metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic
`acidosis. Stop 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.
`
`Reference ID: 4197754
`
`5
`
`

`

`5.2 Hypotension
`Ertugliflozin, a component of SEGLUROMET, causes intravascular volume contraction. Therefore,
`symptomatic hypotension may occur after initiating SEGLUROMET [see Adverse Reactions (6.1)]
`particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2) [see Use in
`Specific Populations (8.6)](cid:15) (cid:72)(cid:79)(cid:71)(cid:72)(cid:85)(cid:79)(cid:92) (cid:83)(cid:68)(cid:87)(cid:76)(cid:72)(cid:81)(cid:87)(cid:86) (cid:11)(cid:149)(cid:25)(cid:24) years), in patients with low systolic blood pressure, and
`in patients on diuretics. Before initiating SEGLUROMET, volume status should be assessed and
`corrected if indicated. Monitor for signs and symptoms of hypotension after initiating therapy.
`
`5.3 Ketoacidosis
`Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, have
`been identified in clinical trials and postmarketing surveillance in patients with type 1 and type 2 diabetes
`mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors and cases have been reported in
`ertugliflozin-treated patients in clinical trials. Across the clinical program, ketoacidosis was identified in 3
`of 3,409 (0.1%) of ertugliflozin-treated patients and 0% of comparator-treated patients. Fatal cases of
`ketoacidosis have been
`reported
`in patients
`taking medicines containing SGLT2
`inhibitors.
`SEGLUROMET is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications
`and Usage (1)].
`Patients treated with SEGLUROMET 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 SEGLUROMET may be present even if blood glucose levels are less than
`250 mg/dL. If ketoacidosis is suspected, SEGLUROMET 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 reported cases, 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 SEGLUROMET, 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 SEGLUROMET consider monitoring for ketoacidosis and temporarily
`discontinuing SEGLUROMET in clinical situations known to predispose to ketoacidosis (e.g., prolonged
`fasting due to acute illness or surgery).
`
`5.4 Acute Kidney Injury and Impairment in Renal Function
`SEGLUROMET causes intravascular volume contraction and can cause renal impairment [see
`Adverse Reactions (6.1)]. There have been postmarketing reports of acute kidney injury some requiring
`hospitalization and dialysis in patients receiving SGLT2 inhibitors.
`Before initiating SEGLUROMET, 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
`SEGLUROMET 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 SEGLUROMET promptly and institute treatment.
`Ertugliflozin, a component of SEGLUROMET, increases serum creatinine and decreases eGFR.
`Patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2) may be more
`susceptible to these changes. Renal function abnormalities can occur after initiating SEGLUROMET [see
`Adverse Reactions (6.1)]. Renal function should be evaluated prior to initiating SEGLUROMET and
`periodically thereafter. Use of SEGLUROMET is not recommended when eGFR is persistently between
`30 mL/min/1.73 m2 and less than 60 mL/min/1.73 m2 and is contraindicated in patients with an eGFR less
`than 30 mL/min/1.73 m2 [see Dosage and Administration (2.2), Contraindications (4), Use in Specific
`Populations (8.6)].
`
`Reference ID: 4197754
`
`6
`
`

`

`5.5 Urosepsis 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.
`Cases of pyelonephritis also have been reported in ertugliflozin-treated patients in clinical trials.
`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 (6.1)].
`
`5.6
`
`Lower Limb Amputation
`An increased risk for lower limb amputation (primarily of the toe) has been observed in clinical
`studies with another SGLT2 inhibitor. Across seven Phase 3 clinical trials in the ertugliflozin development
`program, 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. A causal association between ertugliflozin and lower limb amputation has not been definitively
`established.
`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.
`
`5.7 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
`Ertugliflozin
`Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia.
`Ertugliflozin, a component of SEGLUROMET, may increase the risk of hypoglycemia when used in
`combination with insulin and/or an insulin secretagogue [see Adverse 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.
`Metformin
`Hypoglycemia does not occur in patients receiving metformin, a component of SEGLUROMET,
`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 sulfonylureas 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
`(cid:83)(cid:72)(cid:82)(cid:83)(cid:79)(cid:72) (cid:90)(cid:75)(cid:82) (cid:68)(cid:85)(cid:72) (cid:87)(cid:68)(cid:78)(cid:76)(cid:81)(cid:74) (cid:533)-adrenergic blocking drugs.
`
`5.8 Genital Mycotic Infections
`Ertugliflozin, a component of SEGLUROMET, 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 [see Adverse Reactions (6.1)]. Monitor and treat appropriately.
`
`5.9 Vitamin B12 Levels
`In controlled clinical trials of metformin, a component of SEGLUROMET, of 29 weeks duration, a
`levels, without clinical
`decrease to subnormal levels of previously normal serum vitamin B12
`manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to
`interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated
`with anemia and 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
`SEGLUROMET 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
`measurements at two- to three-year intervals may be useful.
`
`Reference ID: 4197754
`
`7
`
`

`

`5.10 Increases in Low-Density Lipoprotein Cholesterol (LDL-C)
`Dose-related increases in LDL-C can occur with ertugliflozin, a component of SEGLUROMET [see
`Adverse Reactions (6.1)]. Monitor and treat as appropriate.
`
`5.11 Macrovascular Outcomes
`There have been no clinical studies establishing conclusive evidence of macrovascular risk
`reduction with SEGLUROMET.
`6
`ADVERSE REACTIONS
`The following important adverse reactions are described elsewhere in the labeling:
`
`Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)]
`(cid:120)
`(cid:120) Hypotension [see Warnings and Precautions (5.2)]
`Ketoacidosis [see Warnings and Precautions (5.3)]
`(cid:120)
`Acute Kidney Injury and Impairment in Renal Function [see Warnings and Precautions
`(cid:120)
`(5.4)]
`(cid:120) Urosepsis and Pyelonephritis [see Warnings and Precautions (5.5)]
`Lower Limb Amputation [see Warnings and Precautions (5.6)]
`(cid:120)
`(cid:120) Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings
`and Precautions (5.7)]
`(cid:120) Genital Mycotic Infections [see Warnings and Precautions (5.8)]
`Vitamin B12 Levels [see Warnings and Precautions (5.9)]
`(cid:120)
`Increases in Low-Density Lipoprotein Cholesterol (LDL-C) [see Warnings and Precautions
`(cid:120)
`(5.10)]
`
`6.1 Clinical 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
`Pool of Placebo-Controlled Trials
`The data in Table 1 are derived from a pool of three 26-week, placebo-controlled trials. Ertugliflozin
`was used as monotherapy in one trial and as add-on therapy in two trials [see Clinical Studies (14)].
`These data reflect exposure of 1,029 patients to ertugliflozin with a mean exposure duration of
`approximately 25 weeks. Patients received ertugliflozin 5 mg (N=519), ertugliflozin 15 mg (N=510), or
`placebo (N=515) once daily. The mean age of the population was 57 years and 2% were older than
`75 years of age. Fifty-three percent (53%) of the population was male and 73% were Caucasian, 15%
`were Asian, and 7% were Black or African American. At baseline the population had di