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
`
` --------------------------- RECENT MAJOR CHANGES ---------------------------
`Indications and Usage (1)
`09/2021
`Dosage and Administration (2.1, 2.2)
`09/2021
`Contraindications (4)
`09/2021
`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)
`• Acute Renal Failure: There have been postmarketing reports of acute
`renal failure in patients taking sitagliptin, sometimes requiring dialysis.
`Monitor renal function. (5.4)
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`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
`
`Reference ID: 5001733
`
`• 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)
`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
`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
`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 ------------------------------
`• 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 LLC 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: 06/2022
`
`5.3 Lower Limb Amputation
`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.
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`Reference ID: 5001733
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`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)].
`DOSAGE AND ADMINISTRATION
`2
`2.1 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)].
`
`•
`
`3
`
`4
`
`
`2.2 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.
`impairment
`• Use of STEGLUJAN
`is contraindicated
`in patients with severe
`renal
`(<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: 5001733
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`3
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`

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`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.
`
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`Reference ID: 5001733
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`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
`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
`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,
`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.
`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
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`Reference ID: 5001733
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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
`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
`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 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-
`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.
`
`ADVERSE REACTIONS
`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)]
`• Acute Renal Failure [see Warnings and Precautions (5.4)]
`• Volume Depletion [see Warnings and Precautions (5.5)]
`• Urosepsis and Pyelonephritis [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)]
`• Severe and Disabling Arthralgia [see Warnings and Precautions (5.12)]
`• Bullous Pemphigoid [see Warnings and Precautions (5.13)]
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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
`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
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`Reference ID: 5001733
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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 comparator-
`treated patients [see Warnings and Precautions (5.2)].
`
`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)].
`
`Hypoglycemia
`The incidence of hypoglycemia by study is shown in Table 2.
`
`Reference ID: 5001733
`
`8
`
`

`

`
`Table 2: Incidence of Overall* and Severe† Hypoglycemia in Placebo-Controlled Clinical Studies in
`Patients with Type 2 Diabetes Mellitus
`Factorial Study with Sitagliptin as
`
`Ertugliflozin 5 mg
`Add-on Combination Therapy with
`+ Sitagliptin
`Metformin (26 weeks)
`(N = 243)
`13 (5.3)
`0 (0.0)
`
`
`
`
`Ertugliflozin 15 mg
`+ Sitagliptin
`(N = 244)
`22 (9.0)
`1 (0.4)
`
`
`
`
`
`Overall [N (%)]
`Severe [N (%)]
`Add-on Combination Therapy with
`Metformin and Sitagliptin
`(26 weeks)
`Overall [N (%)]
`Severe [N (%)]
`
`Initial Combination Therapy with
`Sitagliptin (26 weeks)
`
`Overall [N (%)]
`Severe [N (%)]
`
`Placebo
`(N = 153)
`
`5 (3.3)
`1 (0.7)
`
`Placebo
`(N = 97)
`
`1 (1.0)
`0 (0.0)
`
`Ertugliflozin 5 mg
`(N = 156)
`
`Ertugliflozin 15 mg
`(N = 153)
`
`7 (4.5)
`1 (0.6)
`Ertugliflozin 5 mg
`+ Sitagliptin
`(N = 98)
`6 (6.1)
`0 (0.0)
`
`3 (2.0)
`0 (0.0)
`Ertugliflozin 15 mg
`+ Sitagliptin
`(N = 96)
`3 (3.1)
`2 (2.1)
`
`
`
`* Overall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL.
`† Severe hypoglycemic events: required assistance, lost consciousness, or experienced a seizure regardless of
`blood glucose.
`
`
`Genital Mycotic Infections
`In the pool of three placebo-controlled clinical trials, the incidence of female genital mycotic infections
`(e.g., genital candidiasis, genital infection fungal, vaginal infection, vulvitis, vulvovaginal candidiasis,
`vulvovaginal mycotic infection, vulvovaginitis) occurred in 3%, 9.1%, and 12.2% of females treated with
`placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively (see Table 1). In females, discontinuation
`due to genital mycotic infections occurred in 0% and 0.6% of patients treated with placebo and ertugliflozin,
`respectively.
`In the same pool, male genital mycotic infections (e.g., balanitis candida, balanoposthitis, genital
`infection, genital infection fungal) occurred in 0.4%, 3.7%, and 4.2% of males treated with placebo,
`ertugliflozin 5 mg, ertugliflozin 15 mg, respectively (see Table 1). Male genital mycotic infections occurred
`more commonly in uncircumcised males. In males, discontinuations due to genital mycotic infections
`occurred in 0% and 0.2% of patients treated with placebo and ertugliflozin, respectively. Phimosis was
`reported in 8 of 1,729 (0.5%) male ertugliflozin-treated patients, of which four required circumcision.
`
`Urinary Tract Infections
`In VERTIS CV, urinary tract infections (e.g., urinary tract infection, cystitis, dysuria) occurred in
`10.2%, 12.2% and 1