`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
` These highlights do not include all the information needed to use
`
`
`
`
`
`
`
` full prescribing
` STEGLUJAN safely and effectively. See
`
` information for STEGLUJAN.
`
`
`
`STEGLUJAN™ (ertugliflozin and sitagliptin) tablets, for oral use
`
`
`
`Initial U.S. Approval: 2017
`
`
`
`---------------------------RECENT MAJOR CHANGES --------------------------­
`
`
`
`
`Warnings and Precautions
`
`
`01/2020
`Ketoacidosis (5.3)
`
`
`
`
`----------------------------INDICATIONS AND USAGE ---------------------------­
`
`
`
`
`STEGLUJAN is a combination of ertugliflozin, a sodium glucose co-
`
`
`transporter 2 (SGLT2) inhibitor, and sitagliptin, a dipeptidyl peptidase-4
`
`
`
`
`
`(DPP-4) inhibitor, indicated as an adjunct to diet and exercise to improve
`
`glycemic control in adults with type 2 diabetes mellitus when treatment
`
`
`
`
`
`
`with both ertugliflozin and sitagliptin is appropriate. (1)
`
`
`
`
`Limitations of Use:
`
`• Not for the treatment of type 1 diabetes mellitus or diabetic
`
`
`
`
`
`
`
`
`
`ketoacidosis. (1)
`
`• Has not been studied in patients with a history of pancreatitis. (1, 5.1)
`
`
`
`----------------------- DOSAGE AND ADMINISTRATION ----------------------­
`
`
`
`
`
`• Recommended starting dose is 5 mg ertugliflozin/100 mg sitagliptin
`
`
`
`
`
`once daily, taken in the morning, with or without food. (2.1)
`
`
`
`• Increase dose to 15 mg ertugliflozin/100 mg sitagliptin once daily in
`
`
`those tolerating STEGLUJAN and needing additional glycemic
`
`
`
`
`control. (2.1)
`
`• Assess renal function before initiating STEGLUJAN and periodically
`
`
`
`thereafter (2.2):
`
`o Do not use in patients with an estimated glomerular filtration rate
`
`
`
`(eGFR) below 30 mL/min/1.73 m2.
`
`
`
`o Initiation is not recommended in patients with an eGFR of 30 to less
`than 60 mL/min/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.
`
`
`
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS --------------------­
`
`
`
`
`
`Tablets:
`
`• Ertugliflozin 5 mg and sitagliptin 100 mg (3)
`
`
`
`• Ertugliflozin 15 mg and sitagliptin 100 mg (3)
`
`
`-------------------------------CONTRAINDICATIONS------------------------------­
`
`
`
`
`• Severe renal impairment, end stage renal disease, or dialysis. (4, 5.4)
`
`
`• History of a serious hypersensitivity reaction to sitagliptin, such as
`
`
`
`
`anaphylaxis or angioedema. (4, 5.11, 6.2)
`
`
`• History of serious hypersensitivity reaction to ertugliflozin. (4)
`
`
`
`
`
`
`----------------------- WARNINGS AND PRECAUTIONS-----------------------­
`
`
`
`
`
`• Pancreatitis: There have been postmarketing reports of acute
`
`
`
`pancreatitis in patients taking sitagliptin, including fatal and non-fatal
`
`
`
`
`
`
`hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected,
`
`
`promptly discontinue. (5.1)
`
`
`• Hypotension: May occur particularly in patients with renal impairment,
`
`
`
`
`the elderly, or patients on diuretics. Before initiating assess and
`
`
`
`
`
`
`correct volume status. Monitor for signs and symptoms during
`
`
`therapy. (5.2)
`
`• 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)
`
`
`• Acute Kidney Injury and Impairment in Renal Function: Consider
`
`
`
`
`
`
`
`temporarily discontinuing in settings of reduced oral intake or fluid
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosage
`
`
`
`2.2 Patients with Renal Impairment
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`Reference ID: 4547668
`
`losses. If acute kidney injury occurs, discontinue and promptly treat.
`
`
`
`
`
`
`
`
`
`There have been postmarketing reports of acute renal failure in
`patients taking sitagliptin, sometimes requiring dialysis. Monitor renal
`
`
`
`
`
`function. (5.4)
`
`• Urosepsis and Pyelonephritis: Evaluate patients for signs and
`
`
`
`
`
`
`symptoms of urinary tract infections and treat promptly, if indicated.
`
`
`(5.5)
`
`• 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)
`
`• Heart Failure: Heart failure has been observed with two other
`
`
`
`
`members of the DPP-4 inhibitor class. Consider risks and benefits in
`
`
`
`
`
`
`
`
`patients who have known risk factors for heart failure. Monitor patients
`
`
`for signs and symptoms. (5.7)
`
`insulin
`insulin or
`lower dose of
`• Hypoglycemia: Consider a
`
`
`
`
`
`
`secretagogue to reduce risk of hypoglycemia when used in
`
`combination. (5.8)
`
`• 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. (5.9)
`
`
`
`
`• Genital Mycotic Infections: Monitor and treat if indicated. (5.10)
`
`
`
`
`
`• Hypersensitivity: There have been postmarketing reports of serious
`
`
`
`allergic and hypersensitivity reactions in patients treated with
`sitagliptin such as anaphylaxis, angioedema, and exfoliative skin
`
`
`conditions including Stevens-Johnson syndrome. In such cases,
`
`
`promptly discontinue, assess for other potential causes, institute
`
`
`
`appropriate monitoring and
`initiate alternative
`treatment, and
`treatment for diabetes. (5.11)
`
`• Increased LDL-C: Monitor and treat as appropriate. (5.12)
`
`
`
`
`• Severe and Disabling Arthralgia: Severe and disabling arthralgia has
`
`
`
`
`
`been reported in patients taking DPP-4 inhibitors. Consider as a
`
`
`
`
`
`possible cause for severe joint pain and discontinue if appropriate.
`
`
`
`(5.13)
`
`• Pemphigoid: There have been postmarketing reports of bullous
`
`
`
`
`in patients
`pemphigoid requiring hospitalization
`taking DPP-4
`inhibitors. Tell patients to report development of blisters or erosions.
`
`
`
`
`
`
`
`
`
`If bullous pemphigoid is suspected, discontinue. (5.14)
`
`
`
`
`------------------------------ ADVERSE REACTIONS -----------------------------­
`
`
`
`
`• Most common adverse reactions associated with ertugliflozin
`
`
`
`(incidence ≥5%): female genital mycotic infections. (6.1)
`
`
`
`
`• Most common adverse reactions associated with sitagliptin (incidence
`
`infection, nasopharyngitis and
`respiratory
`≥5%): upper
`tract
`
`headache. In the add-on to sulfonylurea and add-on to insulin studies,
`
`hypoglycemia was also more commonly reported in patients treated
`
`with sitagliptin compared to placebo. (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.
`
`
`----------------------- 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)
`
`
`
`
`• Geriatrics: Higher incidence of adverse reactions related to reduced
`
`
`
`intravascular volume. (5.2, 8.5)
`
`
`• Renal Impairment: Higher incidence of adverse reactions related to
`
`
`
`reduced intravascular volume and renal function. (5.2, 5.4, 8.6)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`
`
`Guide.
`
`
`
`
`Revised: 01/2020
`
`
`
`
`
`5.1 Pancreatitis
`
`
`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 Heart Failure
`
`
`5.8 Hypoglycemia with Concomitant Use with Insulin and Insulin
`
`Secretagogues
`
`

`

`
`
`
`
`5.9 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
`
`
`
`5.10 Genital Mycotic Infections
`
`
`
`5.11 Hypersensitivity Reactions
`
`
`
`
`5.12 Increases in Low-Density Lipoprotein Cholesterol (LDL-C)
`
`
`
`
`5.13 Severe and Disabling Arthralgia
`
`
`
`5.14 Bullous Pemphigoid
`
`
`
`5.15 Macrovascular Outcomes
`
`
`
`6 ADVERSE REACTIONS
`
`
`
`6.1 Clinical Trials Experience
`
`
`
`6.2 Postmarketing Experience
`
`
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 Concomitant Use with Insulin and Insulin Secretagogues
`
`
`
`7.2 Positive Urine Glucose Test
`
`
`
`7.3
`Interference with 1,5-anhydroglucitol (1,5-AG) Assay
`
`
`
`7.4 Digoxin
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`
`8.2 Lactation
`
`
`
`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 In Combination with Sitagliptin versus Ertugliflozin Alone and
`
`
`Sitagliptin Alone, as Add-on to Metformin
`
`
`
`14.3 Ertugliflozin as Add-on Combination Therapy with Metformin
`
`
`and Sitagliptin
`
`
`
`
`14.4 Initial Combination Therapy of Ertugliflozin and Sitagliptin
`
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`*Sections or subsections omitted from the full prescribing information
`
`
`
`are not listed.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4547668
`
`
`
` 2
`
`

`

`
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`
`1
`INDICATIONS AND USAGE
`
`
`
`
`STEGLUJAN™ is indicated as an adjunct to diet and exercise to improve glycemic control in adults
`
`
`with type 2 diabetes mellitus when treatment with both ertugliflozin and sitagliptin is appropriate.
`
`
`Limitations of Use
`
`
`
`
`
`
`
`
`
`
`STEGLUJAN is not recommended in patients with type 1 diabetes mellitus or for the treatment of
`
`diabetic ketoacidosis.
`
`
`
`
`
`
`
`
`
`
`
`
`STEGLUJAN has not been studied in patients with a history of pancreatitis. It is unknown whether
`
`
`
`patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using
`STEGLUJAN. [See Warnings and Precautions (5.1).]
`
`
`
`2
`DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosage
`
`
`
`
`
`
`• The recommended starting dose of STEGLUJAN is 5 mg ertugliflozin/100 mg sitagliptin once daily,
`
`
`
`
`
`
`
`
`
`
`
`taken in the morning, with or without food. In patients tolerating STEGLUJAN, the dose may be
`
`
`
`
`
`increased to a maximum recommended dose of 15 mg ertugliflozin/100 mg sitagliptin, once daily,
`
`
`if additional glycemic control is needed.
`
`
`
`
`• For patients treated with ertugliflozin who are being switched to STEGLUJAN, the dose of
`
`ertugliflozin can be maintained.
`
`
`
`
`• In patients with volume depletion, correct this condition prior to initiation of STEGLUJAN [see
`
`Warnings and Precautions (5.2)].
`
`
`
`
`
`2.2 Patients with Renal Impairment
`
`
`
`
`
`
`
`
`• Assess renal function prior to initiation of STEGLUJAN and periodically thereafter [see Warnings
`
`
`and Precautions (5.4)].
`
`
`
`
`
`• Use of STEGLUJAN is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see
`Contraindications (4)].
`
`
`• Initiation of STEGLUJAN is not recommended in patients with an eGFR of 30 mL/min/1.73 m2 to
`
`
`
`
`
`
`
`
`
`
`less than 60 mL/min/1.73 m2 [see Warnings and Precautions (5.4) and Use in Specific Populations
`
`
`
`(8.6)].
`
`
`
`
`
`
`
`
`
`• Continued use of STEGLUJAN is not recommended when eGFR is persistently between 30 and
`
`less than 60 mL/min/1.73 m2.
`
`
`
`
`• No dose adjustment is needed in patients with mild renal impairment.
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`
`
`
`
`
`• STEGLUJAN 5 mg/100 mg: ertugliflozin 5 mg and sitagliptin 100 mg tablets are beige, almond-
`
`shaped debossed with “554” on one side and plain on the other side.
`
`
`
`
`
`• STEGLUJAN 15 mg/100 mg: ertugliflozin 15 mg and sitagliptin 100 mg tablets are brown, almond-
`
`shaped debossed with “555” on one side and plain on the other side.
`
`CONTRAINDICATIONS
`
`
`
`
`
`
`
`
`
`
`• Severe renal impairment, end-stage renal disease (ESRD), or dialysis [see Warnings and
`
`
`
`Precautions (5.4) and Use in Specific Populations (8.6)].
`
`• History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema [see
`
`
`
`Warnings and Precautions (5.11) and Adverse Reactions (6.2)].
`
`
`
`• History of a serious hypersensitivity reaction to ertugliflozin.
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Pancreatitis
`
`
`There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal
`
`
`
`
`
`
`
`
`
`
`hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin, a component of STEGLUJAN. After
`
`
`initiation of STEGLUJAN, patients should be observed carefully for signs and symptoms of pancreatitis. If
`
`
`
`
`pancreatitis is suspected, STEGLUJAN should promptly be discontinued and appropriate management
`
`
`3
`
`
`4
`
`Reference ID: 4547668
`
`
`3
`
`

`

`
`
`
`
`
`should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the
`
`development of pancreatitis while using STEGLUJAN.
`
`
`
`5.2 Hypotension
`
`
`Ertugliflozin, a component of STEGLUJAN, causes intravascular volume contraction. Therefore,
`
`
`symptomatic hypotension may occur after initiating STEGLUJAN [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)], elderly patients (≥65 years), in patients with low systolic blood pressure, and in patients
`
`
`
`
`
`
`
`
`on diuretics. Before initiating STEGLUJAN, 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 medicines containing 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.
`
`STEGLUJAN is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications and
`
`
`
`Usage (1)].
`
`Patients treated with STEGLUJAN 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 STEGLUJAN may be present even if blood glucose levels are less than
`
`
`
`
`250 mg/dL. If ketoacidosis is suspected, STEGLUJAN 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, surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1
`
`
`diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified.
`
`
`
`
`
`
`
`
`
`
`Before initiating STEGLUJAN, 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 STEGLUJAN for at
`
`
`
`least 4 days prior to surgery [see Clinical Pharmacology (12.2, 12.3)].
`
`
`
`
`Consider monitoring for ketoacidosis and temporarily discontinuing STEGLUJAN 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 STEGLUJAN.
`
`Educate patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue
`
`
`
`STEGLUJAN and seek medical attention immediately if signs and symptoms occur.
`
`
`
`
`5.4 Acute Kidney Injury and Impairment in Renal Function
`
`
`
`
`
`
`STEGLUJAN 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 STEGLUJAN, 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 STEGLUJAN 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 STEGLUJAN promptly and institute treatment.
`
`
`
`Ertugliflozin, a component of STEGLUJAN, 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
`
`
`
`
`Reference ID: 4547668
`
`4
`
`
`

`

`
`
`
`
`
`
`susceptible to these changes. Renal function abnormalities can occur after initiating STEGLUJAN [see
`
`
`
`
`
`
`Adverse Reactions (6.1)]. Renal function should be evaluated prior to initiating STEGLUJAN and
`
`
`
`
`
`
`
`
`
`
`
`
`periodically thereafter. Use of STEGLUJAN is not recommended when eGFR is persistently between 30
`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), and Use in Specific Populations (8.6)].
`
`
`
`
`There have been postmarketing reports with sitagliptin of worsening renal function, including acute
`
`
`
`
`
`
`
`
`
`renal failure, sometimes requiring dialysis. A subset of these reports involved patients with renal
`
`
`
`
`
`
`
`
`
`
`insufficiency, some of whom were prescribed inappropriate doses of sitagliptin. A return to baseline levels
`
`
`of renal insufficiency has been observed with supportive treatment and discontinuation of potentially
`
`causative agents. Consideration can be given to cautiously reinitiating STEGLUJAN if another etiology is
`
`
`
`
`
`
`
`deemed likely to have precipitated the acute worsening of renal function.
`
`
`
`
`
`
`Sitagliptin has not been found to be nephrotoxic in preclinical studies at clinically relevant doses, or
`
`
`
`in clinical trials.
`
`
`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 STEGLUJAN, 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 STEGLUJAN for signs and symptoms of infection (including osteomyelitis), new pain or
`
`
`
`
`tenderness, sores or ulcers involving the lower limbs, and discontinue STEGLUJAN if these complications
`
`
`
`
`occur.
`
`
`5.7 Heart Failure
`
`
`
`An association between dipeptidyl peptidase-4 (DPP-4) inhibitor treatment and heart failure has been
`
`
`
`observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials
`
`
`evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Consider the
`
`
`risks and benefits of STEGLUJAN prior to initiating treatment in patients at risk for heart failure, such as
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`those with a prior history of heart failure and a history of renal impairment, and observe these patients for
`
`
`
`
`signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart
`
`failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according
`
`
`to current standards of care and consider discontinuation of STEGLUJAN.
`
`
`
`5.8 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
`
`
`
`
`Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. Ertugliflozin,
`
`a component of STEGLUJAN, may increase the risk of hypoglycemia when used in combination with insulin
`
`
`
`and/or an insulin secretagogue [see Adverse Reactions (6.1)]. When sitagliptin, a component of
`
`
`
`
`STEGLUJAN, was used in combination with a sulfonylurea or with insulin, medications known to cause
`
`
`
`
`
`
`
`
`
`
`
`
`hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in combination with
`a sulfonylurea or with insulin. [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
`STEGLUJAN.
`
`
`
`Reference ID: 4547668
`
`
`5
`
`

`

`
`
`
`
`
`
`
`
`5.9 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
`
`
`
`
`
`
`Reports of necrotizing fasciitis of the perineum (Fournier’s gangrene), a rare but serious and life-
`
`
`
`
`
`
`
`in
`infection requiring urgent surgical
`intervention, have been
`identified
`threatening necrotizing
`
`
`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 STEGLUJAN 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 STEGLUJAN, closely monitor blood glucose levels, and provide appropriate
`
`alternative therapy for glycemic control.
`
`
`
`5.10 Genital Mycotic Infections
`
`
`
`
`
`
`Ertugliflozin, a component of STEGLUJAN, 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.
`
`
`
`5.11 Hypersensitivity Reactions
`There have been postmarketing reports of serious hypersensitivity reactions in patients treated with
`
`
`sitagliptin, a component of STEGLUJAN. These reactions include anaphylaxis, angioedema, and exfoliative
`
`
`
`
`
`
`skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3
`
`
`months after initiation of treatment with sitagliptin, with some reports occurring after the first dose. If a
`
`hypersensitivity reaction is suspected, discontinue STEGLUJAN, assess for other potential causes for the
`
`
`
`event, and institute alternative treatment for diabetes. [See Adverse Reactions (6.2).]
`
`
`
`
`Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution
`
`
`
`
`in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such
`
`
`patients will be predisposed to angioedema with STEGLUJAN.
`
`
`
`5.12 Increases in Low-Density Lipoprotein Cholesterol (LDL-C)
`
`
`Dose-related increases in LDL-C can occur with ertugliflozin, a component of STEGLUJAN [see
`
`
`
`Adverse Reactions (6.1)]. Monitor and treat as appropriate.
`
`
`
`
`5.13 Severe and Disabling Arthralgia
`
`
`
`
`There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4
`
`
`
`inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years.
`
`
`Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients
`
`
`experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor.
`
`
`Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.
`
`
`
`5.14 Bullous Pemphigoid
`Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP­
`4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive
`
`
`treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or
`
`
`
`erosions while receiving STEGLUJAN. If bullous pemphigoid is suspected, STEGLUJAN should be
`
`discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.
`
`
`
`5.15 Macrovascular Outcomes
`
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction
`
`
`with STEGLUJAN.
`
`
`ADVERSE REACTIONS
`6
`
`The following important adverse reactions are described elsewhere in the labeling:
`
`
`
`
`
`• Pancreatitis [see Warnings and Precautions (5.1)]
`
`
`
`• Hypotension [see Warnings and Precautions (5.2)]
`
`
`
`• Ketoacidosis [see Warnings and Precautions (5.3)]
`
`Reference ID: 4547668
`
`
`6
`
`

`

`
`
`
`
`
`
`• Acute Kidney Injury and Impairment in Renal Function [see Warnings and Precautions (5.4)]
`
`
`
`• Urosepsis and Pyelonephritis [see Warnings and Precautions (5.5)]
`
`
`
`
`• Lower Limb Amputation [see Warnings and Precautions (5.6)]
`
`
`• Heart Failure [see Warnings and Precautions (5.7)]
`
`
`• Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings
`
`
`
`
`and Precautions (5.8)]
`• Necrotizing Fasciitis of the Perineum (Fournier’s gangrene) [see Warnings and Precautions
`
`
`
`
`
`(5.9)]
`• Genital Mycotic Infections [see Warnings and Precautions (5.10)]
`
`
`
`
`• Hypersensitivity Reactions [see Warnings and Precautions (5.11)]
`
`
`
`Increases in Low-Density Lipoprotein (LDL-C) [see Warnings and Precautions (5.12)]
`
`
`
`
`•
`• Severe and Disabling Arthralgia [see Warnings and Precautions (5.13)]
`
`
`• Bullous Pemphigoid [see Warnings and Precautions (5.14)]
`
`
`
`
`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 Sitagliptin
`
`
`
`
`The safety of concomitantly administered ertugliflozin and sitagliptin has been evaluated in
`
`
`
`
`
`
`990 patients with type 2 diabetes mellitus treated for 26 weeks in three studies; a factorial study of
`
`
`
`
`
`
`ertugliflozin 5 mg or 15 mg in combination with sitagliptin 100 mg once daily compared to the individual
`
`
`
`
`components, a placebo-controlled study of ertugliflozin 5 mg or 15 mg as add-on therapy to sitagliptin
`
`
`
`
`
`
`
`
`100 mg and metformin once daily, and a placebo-controlled study of initial therapy with ertugliflozin 5 mg
`
`
`
`
`
`
`or 15 mg once daily in combination with sitagliptin 100 mg once daily [see Clinical Studies (14)]. The
`
`
`incidence and type of adverse reactions in these three studies were similar to the adverse reactions seen
`
`
`with ertugliflozin and described below 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 diabetes for an average of 7.5 years, had
`
`
`
`a mean HbA1c of 8.1%, and 19.4% had established microvascular complications of diabetes. Baseline
`renal function (mean eGFR 88.9 mL/min/1.73 m2) was normal or mildly impaired in 97% of patients and
`
`
`
`
`
`
`
`
`
`
`
`
`
`moderately impaired in 3% of patients.
`
`
`Table 1 shows common adverse reactions associated with the use of ertugliflozin. These adverse
`
`
`
`
`
`
`
`
`
`
`reactions were not present at baseline, occurred more commonly on ertugliflozin than on placebo, and
`
`
`
`
`occurred in at least 2% of patients treated with either ertugliflozin 5 mg or ertugliflozin 15 mg.
`
`
`
`
`
`
`
`
`Table 1: Adverse Reactions Reported in ≥2% of Patients with Type 2 Diabetes Mellitus
`
`
`
`
`
`
`
`
`
`
`
`Treated with Ertugliflozin* and Greater than Placebo in Pooled Placebo-Controlled Clinical Studies
`
`
`of Ertugliflozin Monotherapy or Combination Therapy
`
`
`Reference ID: 4547668
`
`
`7
`
`

`

`
`
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`
`
`
`
`Female genital mycotic infections†
`
`
`
`Male genital mycotic infections‡
`
`
`Urinary tract infections§
`
`
`
`Headache
`
`
`Vaginal pruritus¶
`
`
`
`Increased urination#
`
`
`Nasopharyngitis
`
`
`Back pain
`
`
`Weight decreased
`
`
`
`ThirstÞ
`
`
`
`Number (%) of Patients
`
`Placebo
`
`N = 515
`
`
`Ertugliflozin 5 mg
`
`
`N = 519
`
`
`Ertugliflozin 15 mg
`
`
`N = 510
`
`
`
`
` 3.0%
`
`
`
` 0.4%
`
`
`
` 3.9%
`
`2.3%
`
`
`
`
` 0.4%
`
`
`
` 1.0%
`
`2.3%
`
`
`2.3%
`
`
`1.0%
`
`
`
`
` 0.6%
`
`
`
` 9.1%
`
`
`
` 3.7%
`
`
`
` 4.0%
`
`3.5%
`