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 --------------------------­
`
`
`Indications and Usage (1)
`09/2021
`
`
`
`Dosage and Administration (2.1, 2.2)
`09/2021
`
`
`09/2021
`Contraindications (4)
`
`
`
`
`Warnings and Precautions (5.2, 5.3, 5.4, 5.5, 5.6, 5.7,5.9)
`09/2021
`
`
`
`
`----------------------------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, is indicated as an adjunct to diet and exercise to
`
`improve glycemic control in adults with type 2 diabetes mellitus.
`
`
`Limitations of Use:
`• Not for the treatment of type 1 diabetes mellitus or diabetic
`
`
`
`
`
`
`
`
`
`ketoacidosis. It may increase the risk of diabetic ketoacidosis in these
`
`patients. (1)
`• Has not been studied in patients with a history of pancreatitis. (1, 5.1)
`
`
`
` ---------- DOSAGE AND ADMINISTRATION ------------­
`
`
`
`
`
`
`• Assess renal function before initiating STEGLUJAN and as clinically
`
`
`
`
` indicated (2.1):
`
`
`• Correct volume depletion before initiating STEGLUJAN (2.1)
`
`
`
`
`• Recommended starting dose is 5 mg ertugliflozin/100 mg sitagliptin
`
`
`
` once daily, taken in the morning, with or without food. (2.2)
`
`• Increase dose to 15 mg ertugliflozin/100 mg sitagliptin once daily in
`
`
`
` those tolerating STEGLUJAN and needing additional glycemic
`
`
`
` control. (2.2)
`• Use is not recommended in patients with an eGFR less than 45
`
`
`mL/min/1.73 m2. (2.2)
`
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS --------------------­
`
`
`
`
`Tablets:
`
`• Ertugliflozin 5 mg and sitagliptin 100 mg (3)
`
`
`• Ertugliflozin 15 mg and sitagliptin 100 mg (3)
`
`
`
`-------------------------------CONTRAINDICATIONS ------------------------------­
`
`
`
`
`• Patients with severe renal impairment (<30 mL/min/1.73 m2), end-
`
`
`
`stage renal disease, or dialysis. (4, 5.4)
`
`• Hypersensitivity to sitagliptin, ertugliflozin, or any excipient, such as
`
`
`
`
`anaphylaxis or angioedema. (4, 5.11, 6.2)
`
`
`----------------------- 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)
`
`• 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. (5.2)
`
`• Lower Limb Amputation: Consider factors that may increase the risk
`
`
`of amputation before initiating STEGLUJAN. Monitor patients for
`
`infections or ulcers of lower limbs, and discontinue if these occur. (5.3)
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Prior to Initiation of STEGLUJAN
`
`
`2.2 Recommended Dosage
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Pancreatitis
`
`
`5.2 Ketoacidosis
`
`
`5.3 Lower Limb Amputation
`
`
`
`Reference ID: 4858989
`
`• Acute Renal Failure: There have been postmarketing reports of acute
`
`
`
`
`
`renal failure in patients taking sitagliptin, sometimes requiring dialysis.
`
`Monitor renal function. (5.4)
`
`• Volume Depletion: May result in acute kidney injury. Before initiating,
`
`
`
`assess and correct volume status in patients with renal impairment,
`or low systolic blood pressure elderly patients, or patients on diuretics.
`
`
`
`
`Monitor for signs and symptoms during therapy. (5.5)
`
`
`• Urosepsis and Pyelonephritis: Evaluate patients for signs and
`
`
`symptoms of urinary tract infections and treat promptly, if indicated.
`
`
`
`
`(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)
`
`• Hypoglycemia: Consider a
`insulin
`insulin or
`lower dose of
`
`
`
`
`
`
`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
`treatment, and
`initiate alternative
`
`treatment for diabetes. (5.11)
`
`• 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.
`
`
`(5.12)
`
`• Pemphigoid: There have been postmarketing reports of bullous
`
`
`
`pemphigoid requiring hospitalization
`taking DPP-4
`in patients
`inhibitors. Tell patients to report development of blisters or erosions.
`If bullous pemphigoid is suspected, discontinue. (5.13)
`
`
`------------------------------ 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
`
`≥5%): upper
`respiratory
`tract
`infection, nasopharyngitis and
`
`
`
`
`
`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. (5.5, 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: 09/2021
`
`
`5.4 Acute Renal Failure
`
`
`5.5 Volume Depletion
`
`
`5.6 Urosepsis and Pyelonephritis
`
`
`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 Severe and Disabling Arthralgia
`
`
`5.13 Bullous Pemphigoid
`
`
`
`

`

`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`6.2 Postmarketing Experience
`
`
`
`
`7 DRUG INTERACTIONS
`
`
`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 Glycemic Control Trials in Patients with Type 2 Diabetes
`
`Mellitus
`14.2 Ertugliflozin Cardiovascular Outcomes in Patients with Type
`
`
`
`
`2 Diabetes Mellitus and Established Cardiovascular Disease
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`*Sections or subsections omitted from the full prescribing information
`
`are not listed.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4858989
`
`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.
`
`
`
`Limitations of Use
`
`
`
`• Not recommended in patients with type 1 diabetes mellitus. It may increase the risk of diabetic
`
`
`
`
`
`
`
`
`
`
`
`
`
`ketoacidosis in these patients [see Warnings and Precautions (5.2)].
`
`
`
`• 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
`
`
`
`2.2
`
`
`3
`
`
`4
`
`
`
`Prior to Initiation of STEGLUJAN
`• Assess renal function prior to initiation of STEGLUJAN and as clinically indicated [see Warnings
`
`
`
`
`
`
`
`
`
`
`
`
`and Precautions (5.4)].
`
`In patients with volume depletion, correct this condition before initiating STEGLUJAN [see
`
`
`
`
`
`
`
`
`Warnings and Precautions (5.5), Use in Specific Populations (8.5, 8.6)].
`
`•
`
`
`
`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.
`• For patients treated with ertugliflozin who are being switched to STEGLUJAN, the dose of
`
`
`
`ertugliflozin can be maintained.
`• For additional glycemic control, the dose may be increased to 15 mg ertugliflozin/100 mg sitagliptin
`
`
`
`
`
`
`
`
`
`
`
`
`once daily in patients tolerating STEGLUJAN.
`• Use is not recommended in patients with an eGFR less than 45 mL/min/1.73 m2.
`
`
`
`
`
`
`
`
`
`
`• Use of STEGLUJAN is contraindicated in patients with severe renal impairment (<30
`
`
`
`
`
`
`
`
` mL/min/1.73 m2), end-stage renal disease (ESRD) or on dialysis [see Contraindications (4)].
`
`
`
`
`
`
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`
`• STEGLUJAN 5 mg/100 mg tablets: contain ertugliflozin 5 mg and sitagliptin 100 mg and are beige,
`
`
`
`
`
`
`almond-shaped debossed with “554” on one side and plain on the other side.
`
`
`
`• STEGLUJAN 15 mg/100 mg tablets: contain ertugliflozin 15 mg and sitagliptin 100 mg and are
`
`
`
`
`
`brown, almond-shaped debossed with “555” on one side and plain on the other side.
`
`
`
`
`
`CONTRAINDICATIONS
`
`• Patients with severe renal impairment (<30 mL/min/1.73 m2), end-stage renal disease (ESRD), or
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`on dialysis [see Warnings and Precautions (5.4) and Use in Specific Populations (8.6)].
`
`
`
`• Hypersensitivity to sitagliptin, ertugliflozin, or any excipient, in STEGLUJAN, reactions such as
`
`
`
`
`
`
`
`anaphylaxis or angioedema have occurred [see Warnings and Precautions (5.11) and Adverse
`
`Reactions (6.2)].
`
`
`
`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
`
`
`
`
`
`
`
`
`
`
`
`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.
`
`
`Reference ID: 4858989
`
`3
`
`
`
`

`

`
`
`
`
`
`
`
`5.2 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 including
`
`ertugliflozin [see Adverse Reactions (6.1)]. Fatal cases of ketoacidosis have been reported in patients
`
`
`
`
`
`
`
`
`
`
`taking SGLT2 inhibitors. In placebo-controlled trials of patients with type 1 diabetes, the risk of ketoacidosis
`
`
`
`
`
`
`
`was increased in patients who received SGLT2 inhibitors compared to patients who received placebo. The
`
`
`
`
`
`
`
`
`
`
`
`
`
`risk of ketoacidosis may be greater with higher doses. 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.
`
`
`
`5.3 Lower Limb Amputation
`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.
`
`
`
`
`
`
`
`
`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.
`
`
`
`Reference ID: 4858989
`
`4
`
`
`
`

`

`
`
`
`
`
`
`
`
`5.4 Acute Renal Failure
`
`
`
`
`
`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 Volume Depletion
`
`
`
`STEGLUJAN 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 STEGLUJAN. Patients with
` impaired renal function (eGFR less than 60 mL/min/1.73 m2) [see Use in Specific Populations (8.6)], elderly
`
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`
`
`
`
`
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`
`
`
`
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`
`
`patients, patients with low systolic blood pressure, or patients on loop diuretics may be at increased risk for
`volume depletion or hypotension. Before initiating STEGLUJAN 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 STEGLUJAN. Monitor for signs and symptoms of volume depletion, and renal
`
`
`function after initiating therapy.
`
`
`
`
`5.6 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.
`
`Treatment with medicines containing SGLT2 inhibitors increases the risk for urinary tract infections.
`Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see
`
`
`Adverse Reactions (6)].
`
`
`
`
`
`5.7 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
`
`
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`
`
`
`risks and benefits of STEGLUJAN prior to initiating treatment in patients at risk for heart failure, such as
`
`
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`
`
`
`
`
`
`
`those with a prior history of heart failure and a history of renal impairment, and observe these patients for
`
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`
`
`
`
`
`
`
`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,
`
`may increase the risk of hypoglycemia when used in combination with insulin and/or an insulin
`
`
`secretagogue [see Adverse Reactions (6.1)]. When sitagliptin, was used in combination with a sulfonylurea
`
`
`
`
`
`
`
`
`
`
`
`or with insulin, the incidence of hypoglycemia was increased over that of placebo used in combination with
`a sulfonylurea or with insulin. [See Adverse Reactions (6.1).] A lower dose of insulin or insulin secretagogue
`
`
`
`
`
`
`
`
`
`
`may be required to minimize the risk of hypoglycemia when used in combination with STEGLUJAN.
`
`
`
`
`
`
`
`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-
`
`
`
`
`
`threatening necrotizing
`infection requiring urgent surgical
`intervention, have been
`identified
`in
`
`postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including
`
`
`
`
`ertugliflozin. Cases have been reported in females and males. Serious outcomes have included
`
`
`
`hospitalization, multiple surgeries, and death.
`
`
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`
`
`
`
`Patients treated with STEGLUJAN presenting with pain or tenderness, erythema, or swelling in the
`
`
`
`
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`
`
`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
`
`Reference ID: 4858989
`
`5
`
`
`
`

`

`
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`
`
`
`
`
`debridement. Discontinue STEGLUJAN, closely monitor blood glucose levels, and provide appropriate
`
`
`
`
`alternative therapy for glycemic control.
`
`
`
`
`
`5.10 Genital Mycotic Infections
`
`
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`
`
`
`
`
`
`
`
`Ertugliflozin, increases the risk of genital mycotic infections. Patients who have a history of genital
`mycotic infections or who are uncircumcised are more likely to develop genital mycotic infections [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. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including
`
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`
`
`Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of
`
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`
`
`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).]
`
`
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`
`
`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 Severe and Disabling Arthralgia
`
`
`
`There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4
`
`
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`
`
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`
`
`
`
`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.
`
`
`
`
`5.13 Bullous Pemphigoid
`
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`
`
`Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP­
`
`
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`
`
`
`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
`
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`
`
`
`discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.
`
`
`
`6
`
`
`ADVERSE REACTIONS
`
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`
`
`The following important adverse reactions are described elsewhere in the labeling:
`• Pancreatitis [see Warnings and Precautions (5.1)]
`
`
`
`
`
`• Ketoacidosis [see Warnings and Precautions (5.2)]
`
`
`
`
`
`• Lower Limb Amputation [see Warnings and Precautions (5.3)]
`
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`
`
`• Acute Renal Failure [see Warnings and Precautions (5.4)]
`
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`
`
`• Volume Depletion [see Warnings and Precautions (5.5)]
`
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`
`• Urosepsis and Pyelonephritis [see Warnings and Precautions (5.6)]
`
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`
`
`• Heart Failure [see Warnings and Precautions (5.7)]
`
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`
`
`• 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
`
`
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`
`
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`
`
`(5.9)]
`
`• Genital Mycotic Infections [see Warnings and Precautions (5.10)]
`
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`
`• Hypersensitivity Reactions [see Warnings and Precautions (5.11)]
`
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`
`• Severe and Disabling Arthralgia [see Warnings and Precautions (5.12)]
`
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`• Bullous Pemphigoid [see Warnings and Precautions (5.13)]
`
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`
`
`Reference ID: 4858989
`
`6
`
`
`
`

`

`
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`
`
`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
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`drug and may not reflect the rates observed in practice.
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`Ertugliflozin and Sitagliptin
`
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`
`The safety of concomitantly administered ertugliflozin and sitagliptin has been evaluated in
`
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`990 patients with type 2 diabetes mellitus treated for 26 weeks in three studies; a factorial study of
`
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`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
`
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`
`
`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
`
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`
`
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`
`
`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
`
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`
`
`
`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
`
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`
`data reflect exposure of 1,029 patients to ertugliflozin with a mean exposure duration of approximately
`
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`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.
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`Fifty-three percent (53%) of the population was male and 73% were Caucasian, 15% were Asian, and 7%
`
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`
`
`
`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
`
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`
`occurred in at least 2% of patients treated with either ertugliflozin 5 mg or ertugliflozin 15 mg.
`
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`
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`
`
`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: 4858989
`
`7
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`
`
`

`

`
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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%
`
`
`
` 2.8%
`
`
`
` 2.7%
`
`
`2.5%
`
`
`1.7%
`
`
`1.2%
`
`
`
` 2.7%
`
`
`
` 12.2%
`
`
`
` 4.2%
`
`
`
` 4.1%
`
`
`2.9%
`
`
`
` 2.4%
`
`
`
` 2.4%
`
`
`2.0%
`
`
`2.5%
`
`
`2.4%
`
`
`
` 1.4%
`
`†
`
`
`
`* The three placebo controlled studies included one monotherapy trial and two add-on combination trials with metformin or with
`
`
`
`
`
`
`
`
`metformin and sitagliptin.
`Includes: genital candidiasis, genital infection fungal, vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic
`
`
`
`infection, and vulvovaginitis. Percentages calculated with the number of female patients in each group as denominator: placebo
`(N=235), ertugliflozin 5 mg (N=252), ertugliflozin 15 mg (N=245).
`
`
`
`Includes: balanitis candida, balanoposthitis, genital infection, and genital infection fungal. Percentages calculated with the number
`
`of male patients in each group as denominator: placebo (N=280), ertugliflozin 5 mg (N=267), ertugliflozin 15 mg (N=265).
`
`
`
`Includes: cystitis, dysuria, streptococcal urinary tract infection, urethritis, urinary tract infection.
`
`Includes: vulvovaginal pruritus and pruritus genital. Percentages calculated with the number of female patients in each group as
`
`
`
`
`
`
`
`denominator: placebo (N=235), ertugliflozin 5 mg (N=252), ertugliflozin 15 mg (N=245).
`
`
`
`
`
` # Includes: pollakiuria, micturition urgency, polyuria, urine output increased, and nocturia.
`
`
`Þ
`Includes: thirst, dry mouth, polydipsia, and dry throat.
`
`
`‡
`
`
`§
`
`¶
`
`
`
`
`Ketoacidosis
`
`
`In a long-term cardiovascular outcomes study [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 c