` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`209805Orig1s000
`
`
`LABELING
`
`

`

`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`STEGLUJAN safely and effectively. See
`full prescribing
`information for STEGLUJAN.
`
`STEGLUJAN™ (ertugliflozin and sitagliptin) tablets, for oral use
`Initial U.S. Approval: 2017
`
`----------------------------INDICATIONS AND USAGE----------------------------
`STEGLUJAN is a combination of ertugliflozin, a sodium glucose co-
`transporter 2 (SGLT2) inh bitor, 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:
`(cid:120) Not for the treatment of type 1 diabetes mellitus or diabetic
`ketoacidosis. (1)
`(cid:120) Has not been studied in patients with a history of pancreatitis. (1,
`5.1)
`----------------------- DOSAGE AND ADMINISTRATION -----------------------
`(cid:120) Recommended starting dose is 5 mg ertugliflozin/100 mg sitagliptin
`once daily, taken in the morning, with or without food. (2.1)
`(cid:120) Increase dose to 15 mg ertugliflozin/100 mg sitagliptin once daily in
`those tolerating STEGLUJAN and needing additional glycemic
`control. (2.1)
`(cid:120) 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/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.
`--------------------- DOSAGE FORMS AND STRENGTHS ---------------------
`Tablets:
`(cid:120) Ertugliflozin 5 mg and sitagliptin 100 mg (3)
`(cid:120) Ertugliflozin 15 mg and sitagliptin 100 mg (3)
`-------------------------------CONTRAINDICATIONS-------------------------------
`(cid:120) Severe renal impairment, end stage renal disease, or dialysis. (4,
`5.4)
`(cid:120) History of a serious hypersensitivity reaction to sitagliptin, such as
`anaphylaxis or angioedema. (4, 5.10, 6.2)
`(cid:120) History of serious hypersensitivity reaction to ertugliflozin. (4)
`----------------------- WARNINGS AND PRECAUTIONS------------------------
`(cid:120) 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)
`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
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`2.2 Patients with Renal Impairment
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1 Pancreatitis
`
`Reference ID: 4197661
`
`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.
`There have been postmarketing reports of acute renal failure in
`patients taking sitagliptin, sometimes requiring dialysis. 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)
`(cid:120) 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
`(cid:120) Hypoglycemia: Consider a
`secretagogue to reduce risk of hypoglycemia when used in
`combination. (5.8)
`(cid:120) Genital Mycotic Infections: Monitor and treat if indicated. (5.9)
`(cid:120) 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. (5.10)
`(cid:120) Increased LDL-C: Monitor and treat as appropriate. (5.11)
`(cid:120) 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)
`(cid:120) Pemphigoid: There have been postmarketing reports of bullous
`pemphigoid requiring hospitalization
`in patients
`taking DPP-4
`inhibitors. Tell patients to report development of blisters or erosions.
`If bullous pemphigoid is suspected, discontinue. (5.13)
`------------------------------ ADVERSE REACTIONS ------------------------------
`(cid:120) 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%): female genital mycotic infections. (6.1)
`reactions associated with sitagliptin
`(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%): 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 -----------------------
`(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) 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. (5.2, 5.4, 8.6)
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`Revised: 12/2017
`
`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 Genital Mycotic Infections
`5.10 Hypersensitivity Reactions
`
`

`

`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.
`
`6
`
`7
`
`5.11 Increases in Low-Density Lipoprotein Cholesterol (LDL-C)
`5.12 Severe and Disabling Arthralgia
`5.13 Bullous Pemphigoid
`5.14 Macrovascular Outcomes
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`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
`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
`
`8
`
`Reference ID: 4197661
`
`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
`(cid:120) 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.
`(cid:120) For patients treated with ertugliflozin who are being switched to STEGLUJAN, the dose of
`ertugliflozin can be maintained.
`(cid:120) In patients with volume depletion, correct this condition prior to initiation of STEGLUJAN [see
`Warnings and Precautions (5.2)].
`
`3
`
`2.2 Patients with Renal Impairment
`(cid:120) Assess renal function prior to initiation of STEGLUJAN and periodically thereafter [see Warnings
`and Precautions (5.4)].
`(cid:120) Use of STEGLUJAN is contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m2
`[see Contraindications (4)].
`(cid:120) Initiation of STEGLUJAN is not recommended in patients with an eGFR of 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 STEGLUJAN 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.
`DOSAGE FORMS AND STRENGTHS
`(cid:120) 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.
`(cid:120) 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
`(cid:120) Severe renal impairment, end-stage renal disease (ESRD), or dialysis [see Warnings and
`Precautions (5.4) and Use in Specific Populations (8.6)].
`(cid:120) History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema
`[see Warnings and Precautions (5.10) and Adverse Reactions (6.2)].
`(cid:120) History of a serious hypersensitivity reaction to ertugliflozin.
`WARNINGS AND PRECAUTIONS
`5
`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
`
`4
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`Reference ID: 4197661
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`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)](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 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 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 STEGLUJAN, 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 STEGLUJAN consider monitoring for ketoacidosis and temporarily
`discontinuing STEGLUJAN 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
`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
`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
`
`Reference ID: 4197661
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`4
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`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
`failure, sometimes requiring dialysis. A subset of these reports involved patients with renal
`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: 4197661
`
`5
`
`

`

`5.9 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.
`
`5.10 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.
`
`5.11 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.
`
`5.12 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.
`
`5.13 Bullous Pemphigoid
`Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-
`inhibitor use.
`In
`reported cases, patients
`typically
`recovered with
`topical or systemic
`4
`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.
`
`5.14 Macrovascular Outcomes
`There have been no clinical studies establishing conclusive evidence of macrovascular risk
`reduction with STEGLUJAN.
`6
`ADVERSE REACTIONS
`The following important adverse reactions are described elsewhere in the labeling:
`
`Pancreatitis [see 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) Heart Failure [see Warnings and Precautions (5.7)]
`(cid:120) Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings
`and Precautions (5.8)]
`(cid:120) Genital Mycotic Infections [see Warnings and Precautions (5.9)]
`(cid:120) Hypersensitivity Reactions [see Warnings and Precautions (5.10)]
`Increases in Low-Density Lipoprotein (LDL-C) [see Warnings and Precautions (5.11)]
`(cid:120)
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`Reference ID: 4197661
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`6
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`

`

`(cid:120)
`(cid:120)
`
`Severe and Disabling Arthralgia [see Warnings and Precautions (5.12)]
`Bullous Pemphigoid [see Warnings and Precautions (5.13)]
`
`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 (cid:53)(cid:72)(cid:83)(cid:82)(cid:85)(cid:87)(cid:72)(cid:71) (cid:76)(cid:81) (cid:149)(cid:21)(cid:8) (cid:82)(cid:73) (cid:51)(cid:68)(cid:87)(cid:76)(cid:72)(cid:81)(cid:87)(cid:86) (cid:90)(cid:76)(cid:87)(cid:75) (cid:55)(cid:92)(cid:83)(cid:72) (cid:21) (cid:39)(cid:76)(cid:68)(cid:69)(cid:72)(cid:87)(cid:72)(cid:86) (cid:48)(cid:72)(cid:79)(cid:79)(cid:76)(cid:87)(cid:88)(cid:86)
`Treated with Ertugliflozin* and Greater than Placebo in Pooled Placebo-Controlled Clinical Studies
`of Ertugliflozin Monotherapy or Combination Therapy
`
`Reference ID: 4197661
`
`7
`
`

`

`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.
`
`‡
`
`§
`¶
`
`Volume Depletion
`Ertugliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and
`adverse reactions related to volume depletion, particularly in patients with impaired renal function (eGFR
`less than 60 mL/min/1.73 m2). In patients with moderate renal impairment, adverse reactions related to
`volume depletion (e.g., dehydration, dizziness postural, presyncope, syncope, hypotension, and
`orthostatic hypotension) were reported in 0%, 4.4%, and 1.9% of patients treated with placebo,
`ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively. Ertugliflozin may also increase the risk of
`hypotension in other patients at risk for volume contraction [see Use in Specific Populations (8.5, 8.6)].
`
`Ketoacidosis
`Across the clinical program, ketoacidosis was identified in 3 of 3,409 (0.1%) ertugliflozin-treated
`patients and 0.0% of comparator-treated patients [see Warnings and Precautions (5.3)].
`
`Impairment in Renal Function
`Treatment with ertugliflozin was associated with increases in serum creatinine and decreases in
`eGFR (see Table 2). Patients with moderate renal impairment at baseline had larger mean changes. In a
`study in patients with moderate renal impairment, these abnormal laboratory findings were observed to
`reverse after treatment discontinuation [see Use in Specific Populations (8.5, 8.6)].
`
`Reference ID: 4197661
`
`8
`
`

`

`Table 2: Changes from Baseline in Serum Creatinine and eGFR in the Pool of Three 26-Week
`Placebo-Controlled Studies and a 26-Week Moderate Renal Impairment Study in Patients with
`Type 2 Diabetes Mellitus
`Pool of 26-Week Placebo-Controlled Studies
`Placebo
`Ertugliflozin 5 mg
`Ertugliflozin 15 mg
`N=515
`N=519
`N=510
`
`Creatinine (mg/dL)
`
`Baseline Mean
`
`eGFR (mL/min/1.73 m2)
`
`Creatinine (mg/dL)
`
`Week 6 Change
`
`eGFR (mL/min/1.73 m2)
`
`Week 26 Change
`
`Creatinine (mg/dL)
`
`eGFR (mL/min/1.73 m2)
`
`0.83
`
`89.5
`
`0.00
`
`-0.3
`
`-0.01
`
`0.7
`
`0.82
`
`88.2
`
`0.03
`
`-2.7
`
`0.00
`
`0.5
`
`0.82
`
`89.0
`
`0.03
`
`-3.1
`
`0.01
`
`-0.6
`
`Placebo
`N=154
`
`Moderate Renal Impairment Study
`Ertugliflozin 5 mg
`Ertugliflozin 15 mg
`N=158
`N=155
`
`Baseline
`
`Week 6 Change
`
`Week 26 Change
`
`Creatinine (mg/dL)
`
`eGFR (mL/min/1.73 m2)
`
`Creatinine (mg/dL)
`
`eGFR (mL/min/1.73 m2)
`
`Creatinine (mg/dL)
`
`eGFR (mL/min/1.73 m2)
`
`1.39
`
`46.0
`
`-0.02
`
`0.6
`
`0.02
`
`0.0
`
`1.38
`
`46.8
`
`0.11
`
`-3.2
`
`0.08
`
`-2.7
`
`1.37
`
`46.9
`
`0.12
`
`-4.1
`
`0.10
`
`-2.6
`
`Renal-related adverse reactions (e.g., acute kidney injury, renal impairment, acute prerenal failure)
`may occur in patients treated with ertugliflozin, particularly in patients with moderate renal impairment
`where the incidence of renal-related adverse reactions was 0.6%, 2.5%, and 1.3% in patients treated with
`placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively.
`
`Lower Limb Amputation
`Across seven Phase 3 clinical trials in which ertug