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 for use to improve glycemic control in patients with type 1 diabetes mellitus [see Warnings and Precautions (5.1) ].

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 (5.2) ] .

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 recommended for use to improve glycemic control in patients with type 1 diabetes mellitus.

( 1 ) Has not been studied in patients with a history of pancreatitis.

( 1 , 5.2 )

6 ADVERSE REACTIONS The following important adverse reactions are described elsewhere in the labeling: Diabetic Ketoacidosis in Patients with Type 1 Diabetes and Other Ketoacidosis [see Warnings and Precautions (5.1) ] Pancreatitis [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 or 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) ] 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 .

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 HCl 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 White, 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 m 2 ) 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 The three placebo controlled studies included one monotherapy trial and two add-on combination trials with metformin HCl or with metformin HCl and sitagliptin.

and Greater than Placebo in Pooled Placebo-Controlled Clinical Studies of Ertugliflozin Monotherapy or Combination Therapy Number (%) of Patients Placebo N = 515 Ertugliflozin 5 mg N = 519 Ertugliflozin 15 mg N = 510 Female genital mycotic infections 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).

3.0% 9.1% 12.2% Male genital mycotic infections 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).

0.4% 3.7% 4.2% Urinary tract infections Includes: cystitis, dysuria, streptococcal urinary tract infection, urethritis, urinary tract infection.

3.9% 4.0% 4.1% Headache 2.3% 3.5% 2.9% Vaginal pruritus 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).

0.4% 2.8% 2.4% Increased urination Includes: pollakiuria, micturition urgency, polyuria, urine output increased, and nocturia.

1.0% 2.7% 2.4% Nasopharyngitis 2.3% 2.5% 2.0% Back pain 2.3% 1.7% 2.5% Weight decreased 1.0% 1.2% 2.4% Thirst Includes: thirst, dry mouth, polydipsia, and dry throat.

0.6% 2.7% 1.4% 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 m 2 ).

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 .

Table 2: Incidence of Overall Overall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL.

and Severe Severe hypoglycemic events: required assistance, lost consciousness, or experienced a seizure regardless of blood glucose.

Hypoglycemia in Placebo-Controlled Clinical Studies in Patients with Type 2 Diabetes Mellitus Factorial Study with Sitagliptin as Add-on Combination Therapy with Metformin HCl (26 weeks) Ertugliflozin 5 mg + Sitagliptin (N = 243) Ertugliflozin 15 mg + Sitagliptin (N = 244) Overall [N (%)] 13 (5.3) 22 (9.0) Severe [N (%)] 0 (0.0) 1 (0.4) Add-on Combination Therapy with Metformin HCl and Sitagliptin (26 weeks) Placebo (N = 153) Ertugliflozin 5 mg (N = 156) Ertugliflozin 15 mg (N = 153) Overall [N (%)] 5 (3.3) 7 (4.5) 3 (2.0) Severe [N (%)] 1 (0.7) 1 (0.6) 0 (0.0) Initial Combination Therapy with Sitagliptin (26 weeks) Placebo (N = 97) Ertugliflozin 5 mg + Sitagliptin (N = 98) Ertugliflozin 15 mg + Sitagliptin (N = 96) Overall [N (%)] 1 (1.0) 6 (6.1) 3 (3.1) Severe [N (%)] 0 (0.0) 0 (0.0) 2 (2.1) Lower Limb Amputation In a long-term cardiovascular outcomes study [see Clinical Studies (14.2) ] , in patients with type 2 diabetes mellitus 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 1,000 patient-years in the placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg treatment arms, respectively.

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.

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 12.0% of patients treated with placebo, ertugliflozin 5 mg and ertugliflozin 15 mg, respectively.

The incidences of serious urinary tract infections were 0.8%, 0.9% and 0.4% with placebo, ertugliflozin 5 mg and ertugliflozin 15 mg, respectively.

Sitagliptin The following additional adverse reactions have been reported in clinical studies with sitagliptin: upper respiratory tract infection, nasopharyngitis, headache, abdominal pain, nausea, diarrhea.

In addition, in a study of sitagliptin as add-on combination therapy with metformin HCl and rosiglitazone, peripheral edema was noted with a higher incidence than placebo.

In a pooled analysis of the two monotherapy studies, the add-on to metformin HCl study, and the add-on to pioglitazone study, the overall incidence of adverse reactions of hypoglycemia was 1.2% in patients treated with sitagliptin 100 mg and 0.9% in patients treated with placebo.

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.

In the add-on to glimepiride (+/- metformin HCl) study, the overall incidence of hypoglycemia was 12.2% in patients treated with sitagliptin 100 mg and 1.8% in patients treated with placebo.

In the add-on to insulin (+/- metformin HCl) study, the overall incidence of hypoglycemia was 15.5% in patients treated with sitagliptin 100 mg and 7.8% in patients treated with placebo.

In all studies, adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia.

A concurrent blood glucose measurement was not required although most (74%) reports of hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL.

In a pooled analysis of 19 double-blind clinical trials that included data from 10,246 patients randomized to receive sitagliptin 100 mg/day (N=5,429) or corresponding (active or placebo) control (N=4,817), the incidence of non-adjudicated acute pancreatitis events was 0.1 per 100 patient-years in each group (4 patients with an event in 4,708 patient-years for sitagliptin and 4 patients with an event in 3,942 patient-years for control).

Laboratory Tests Ertugliflozin Changes in Serum Creatinine and eGFR Initiation of ertugliflozin causes an increase in serum creatinine and decrease in eGFR within weeks of starting therapy and then these changes stabilize.

In a study of patients with moderate renal impairment, larger mean changes were observed.

In a long-term cardiovascular outcomes trial, an initial increase in serum creatinine and a decrease in eGFR within weeks of starting therapy was observed (at Week 6 eGFR changes of -2.7, -3.8 and -0.4 mL/min/1.73 m 2 in the ertugliflozin 5 mg, ertugliflozin 15 mg and placebo arms, respectively).

The initial decline was followed by a recovery toward baseline to Week 52 (eGFR change from baseline of - 0.4, - 1.1 and - 0.2 mL/min/1.73 m 2 in ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo arms, respectively).

Acute hemodynamic changes may play a role in the early renal function changes observed with ertugliflozin since they are reversed after treatment discontinuation.

Increases in Low-Density Lipoprotein Cholesterol (LDL-C) In the pool of three placebo-controlled trials, dose-related increases in LDL-C were observed in patients treated with ertugliflozin.

Mean percent changes from baseline to Week 26 in LDL-C relative to placebo were 2.6% and 5.4% with ertugliflozin 5 mg and ertugliflozin 15 mg, respectively.

The range of mean baseline LDL-C was 96.6 to 97.7 mg/dL across treatment groups.

Increases in Hemoglobin In the pool of three placebo-controlled trials, mean changes (percent changes) from baseline to Week 26 in hemoglobin were -0.21 g/dL (-1.4%) with placebo, 0.46 g/dL (3.5%) with ertugliflozin 5 mg, and 0.48 g/dL (3.5%) with ertugliflozin 15 mg.

The range of mean baseline hemoglobin was 13.90 to 14.00 g/dL across treatment groups.

At the end of treatment, 0.0%, 0.2%, and 0.4% of patients treated with placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively, had a hemoglobin increase greater than 2 g/dL and above the upper limit of normal.

Increases in Serum Phosphate In the pool of three placebo-controlled trials, mean changes (percent changes) from baseline in serum phosphate were 0.04 mg/dL (1.9%) with placebo, 0.21 mg/dL (6.8%) with ertugliflozin 5 mg, and 0.26 mg/dL (8.5%) with ertugliflozin 15 mg.

The range of mean baseline serum phosphate was 3.53 to 3.54 mg/dL across treatment groups.

In a clinical trial of patients with moderate renal impairment, mean changes (percent changes) from baseline at Week 26 in serum phosphate were -0.01 mg/dL (0.8%) with placebo, 0.29 mg/dL (9.7%) with ertugliflozin 5 mg, and 0.24 mg/dL (7.8%) with ertugliflozin 15 mg.

Sitagliptin Across clinical studies, the incidence of laboratory adverse reactions was similar in patients treated with sitagliptin 100 mg compared to patients treated with placebo.

A small increase in white blood cell count (WBC) was observed due to an increase in neutrophils.

This increase in WBC (of approximately 200 cells/microL vs.

placebo, in four pooled placebo-controlled clinical studies, with a mean baseline WBC count of approximately 6,600 cells/microL) is not considered to be clinically relevant.

In a 12-week study of 91 patients with chronic renal insufficiency, 37 patients with moderate renal insufficiency were randomized to sitagliptin 50 mg daily, while 14 patients with the same magnitude of renal impairment were randomized to placebo.

Mean (SE) increases in serum creatinine were observed in patients treated with sitagliptin [0.12 mg/dL (0.04)] and in patients treated with placebo [0.07 mg/dL (0.07)].

The clinical significance of this added increase in serum creatinine relative to placebo is not known.

6.2 Postmarketing Experience Additional adverse reactions have been identified during postapproval use of ertugliflozin or sitagliptin, both components of STEGLUJAN.

Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Ertugliflozin Infections: necrotizing fasciitis of the perineum (Fournier’s Gangrene) Skin and Subcutaneous Tissue Disorders: angioedema, rash Sitagliptin Skin and Subcutaneous Tissue Disorders: hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, bullous pemphigoid, exfoliative skin conditions including Stevens-Johnson syndrome, and pruritus Investigations: hepatic enzyme elevations Gastrointestinal Disorders: acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis, constipation, vomiting, mouth ulceration, and stomatitis Renal and Urinary Disorders: worsening renal function, including acute renal failure (sometimes requiring dialysis), and tubulointerstitial nephritis Musculoskeletal and Connective Tissue Disorders: severe and disabling arthralgia, myalgia, pain in extremity, back pain, and rhabdomyolysis Nervous System Disorders: headache