STEGLATRO

1 INDICATIONS AND USAGE STEGLATRO ® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. STEGLATRO is a sodium glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 ) Limitations of Use: Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. ( 1 ) Limitations of Use Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see Warnings and Precautions (5.1) ] .

2 DOSAGE AND ADMINISTRATION Assess renal function before initiating and as clinically indicated. ( 2.1 ) Correct volume depletion before initiating STEGLATRO. ( 2.1 ) Recommended starting dosage is 5 mg orally once daily, taken in the morning, with or without food. ( 2.2 ) Increase dosage to 15 mg orally once daily in those tolerating STEGLATRO and needing additional glycemic control. ( 2.2 ) Use is not recommended in patients with an estimated glomerular filtration rate (eGFR) less than 45 mL/min/1.73 m 2 . ( 2.2 ) Withhold STEGLATRO for at least 4 days, if possible, prior to surgery or procedures associated with prolonged fasting. ( 2.3 ) 2.1 Prior to Initiation of STEGLATRO Assess renal function before initiating STEGLATRO and as clinically indicated [see Warnings and Precautions (5.3) ] . Assess volume status. In patients with volume depletion, correct this condition before initiating STEGLATRO [see Warnings and Precautions (5.3) and Use in Specific Populations (8.5 , 8.6) ]. 2.2 Recommended Dosage The recommended starting dosage of STEGLATRO is 5 mg orally once daily, taken in the morning, with or without food. For additional glycemic control, the dosage may be increased to 15 mg orally once daily in patients tolerating STEGLATRO. Use of STEGLATRO is not recommended in patients with an estimated glomerular filtration rate (eGFR) less than 45 mL/min/1.73 m 2 . 2.3 Temporary Interruption for Surgery Withhold STEGLATRO for at least 4 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume STEGLATRO when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2) ].

4 CONTRAINDICATIONS STEGLATRO is contraindicated in patients with hypersensitivity to ertugliflozin or any excipient in STEGLATRO. Reactions such as angioedema have occurred [see Adverse Reactions (6.2) ]. Hypersensitivity to ertugliflozin or any of the excipients in STEGLATRO. ( 4 )

5 WARNINGS AND PRECAUTIONS Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: Consider ketone monitoring in patients at risk for ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue STEGLATRO if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting. ( 5.1 ) Lower Limb Amputation: Monitor patients for infections or ulcers of lower limbs, and discontinue if these occur. ( 5.2 ) 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. ( 5.3 ) Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated. ( 5.4 ) Hypoglycemia: Consider a lower dose of insulin or insulin secretagogue to reduce risk of hypoglycemia when used in combination. ( 5.5 ) 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. ( 5.6 ) Genital Mycotic Infections: Monitor and treat if indicated. ( 5.7 ) 5.1 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis In patients with type 1 diabetes mellitus, STEGLATRO significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium glucose transporter 2 (SGLT2) inhibitors compared to patients who received placebo; this risk may be greater with higher doses. STEGLATRO is not indicated for glycemic control in patients with type 1 diabetes mellitus. Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors. Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse. Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 4 days after discontinuing STEGLATRO [see Clinical Pharmacology (12.2) ]; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors. Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue STEGLATRO, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting STEGLATRO. Withhold STEGLATRO, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume STEGLATRO when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.3) ]. Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue STEGLATRO and seek medical attention immediately if signs and symptoms occur. 5.2 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, STEGLATRO 5 mg, and STEGLATRO 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 STEGLATRO clinical trials, non-traumatic lower limb amputations were reported in 1 (0.1%) patient in the comparator group, 3 (0.2%) patients in the STEGLATRO 5 mg group, and 8 (0.5%) patients in the STEGLATRO 15 mg group. Counsel patients about the importance of routine preventative foot care. Monitor patients receiving STEGLATRO for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue STEGLATRO if these complications occur. 5.3 Volume Depletion STEGLATRO 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 STEGLATRO. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m 2 ) [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 STEGLATRO 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 STEGLATRO. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy. 5.4 Urosepsis and Pyelonephritis There have been postmarketing reports of serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization in patients receiving SGLT2 inhibitors. Treatment with 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) ] . 5.5 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. STEGLATRO may increase the risk of hypoglycemia when used in combination with insulin or an insulin secretagogue [see Adverse Reactions (6.1) ] . The risk of hypoglycemia may be lowered by a reduction in the dose of insulin or sulfonylurea (or other concomitantly administered insulin secretagogues). Inform patients using these medications concomitantly of this risk and educate them on the signs and symptoms of hypoglycemia. 5.6 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 STEGLATRO. Cases have been reported in females and males. Serious outcomes have included hospitalization, multiple surgeries, and death. Patients treated with STEGLATRO presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue STEGLATRO, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control. 5.7 Genital Mycotic Infections STEGLATRO 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.

7 DRUG INTERACTIONS Table 3: Clinically Significant Drug Interactions with STEGLATRO Insulin or Insulin Secretagogues Clinical Impact: The risk of hypoglycemia is increased when STEGLATRO is used in combination with insulin or an insulin secretagogue. Intervention: A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with STEGLATRO. Lithium Clinical Impact: Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Intervention: Monitor serum lithium concentration more frequently during STEGLATRO initiation and dosage changes. Positive Urine Glucose Test Clinical Impact: SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Intervention: Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. Interference with 1,5-anhydroglucitol (1,5-AG) Assay Clinical Impact: Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Intervention: Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control. See full prescribing information for information on drug interactions and interference of STEGLATRO with laboratory tests. ( 7 )

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) ] Lower Limb Amputation [see Warnings and Precautions (5.2) ] Volume Depletion [see Warnings and Precautions (5.3) ] Urosepsis and Pyelonephritis [see Warnings and Precautions (5.4) ] Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions (5.5) ] Necrotizing Fasciitis of the Perineum (Fournier's Gangrene) [see Warnings and Precautions (5.6) ] Genital Mycotic Infections [see Warnings and Precautions (5.7) ] Most common adverse reactions (incidence ≥ 5%) were female genital mycotic infections. ( 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. Pool of Placebo-Controlled Trials Evaluating STEGLATRO 5 and 15 mg The data in Table 1 are derived from a pool of three 26-week, placebo-controlled trials. STEGLATRO 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 STEGLATRO with a mean exposure duration of approximately 25 weeks. Patients received STEGLATRO 5 mg (N=519), STEGLATRO 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 STEGLATRO. These adverse reactions were not present at baseline, occurred more commonly on STEGLATRO than on placebo, and occurred in at least 2% of patients treated with either STEGLATRO 5 mg or STEGLATRO 15 mg. Table 1: Adverse Reactions Reported in ≥2% of Patients with Type 2 Diabetes Mellitus Treated with STEGLATRO 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 STEGLATRO Monotherapy or Combination Therapy Number (%) of Patients Placebo N = 515 STEGLATRO 5 mg N = 519 STEGLATRO 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), STEGLATRO 5 mg (N=252), STEGLATRO 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), STEGLATRO 5 mg (N=267), STEGLATRO 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 STEGLATRO 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, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively. STEGLATRO 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 Monotherapy (26 weeks) Placebo (N = 153) STEGLATRO 5 mg (N =156) STEGLATRO 15 mg (N = 152) Overall [N (%)] 1 (0.7) 4 (2.6) 4 (2.6) Severe [N (%)] 0 (0.0) 0 (0.0) 2 (1.3) Add-on Combination Therapy with Metformin HCl (26 weeks) Placebo (N = 209) STEGLATRO 5 mg (N = 207) STEGLATRO 15 mg (N = 205) Overall [N (%)] 9 (4.3) 15 (7.2) 16 (7.8) Severe [N (%)] 1 (0.5) 1 (0.5) 0 (0.0) Add-on Combination Therapy with Metformin HCl and Sitagliptin (26 weeks) Placebo (N = 153) STEGLATRO 5 mg (N = 156) STEGLATRO 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) In Combination with Insulin and/or an Insulin Secretagogue in Patients with Moderate Renal Impairment (26 weeks) Placebo (N = 133) STEGLATRO 5 mg (N = 148) STEGLATRO 15 mg (N = 143) Overall [N (%)] 48 (36.1) 53 (35.8) 39 (27.3) Severe [N (%)] 3 (2.3) 5 (3.4) 3 (2.1) Add-on Combination with Insulin with or without Metformin HCl (18 weeks) Placebo (N = 347) STEGLATRO 5 mg (N = 348) STEGLATRO 15 mg (N = 370) Overall [N (%)] 130 (37.5) 137 (39.4) 144 (38.9) Severe [N (%)] 12 (3.5) 13 (3.7) 19 (5.1) Add-on Combination with a Sulfonylurea (18 weeks) Placebo (N =48) STEGLATRO 5 mg (N =55) STEGLATRO 15 mg (N =54) Overall [N (%)] 2 (4.2) 4 (7.3) 5 (9.3) Severe [N (%)] 0 (0.0) 0 (0.0) 0 (0.0) Add-on Combination with Metformin HCl and a Sulfonylurea (18 weeks) Placebo (N = 117) STEGLATRO 5 mg (N = 100) STEGLATRO 15 mg (N = 113) Overall [N (%)] 17 (14.5) 20 (20.0) 30 (26.5) Severe [N (%)] 1 (0.9) 2 (2.0) 2 (1.8) 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, STEGLATRO 5 mg, and STEGLATRO 15 mg treatment arms, respectively. Across seven STEGLATRO clinical trials, non-traumatic lower limb amputations were reported in 1 (0.1%) patient in the comparator group, 3 (0.2%) patients in the STEGLATRO 5 mg group, and 8 (0.5%) patients in the STEGLATRO 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, STEGLATRO 5 mg, and STEGLATRO 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 STEGLATRO, 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, STEGLATRO 5 mg, and STEGLATRO 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 STEGLATRO, respectively. Phimosis was reported in 8 of 1729 (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, STEGLATRO 5 mg and STEGLATRO 15 mg, respectively. The incidences of serious urinary tract infections were 0.8%, 0.9% and 0.4% with placebo, STEGLATRO 5 mg and STEGLATRO 15 mg, respectively. Laboratory Tests Changes in Serum Creatinine and eGFR Initiation of STEGLATRO 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 STEGLATRO 5 mg, STEGLATRO 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 STEGLATRO 5 mg, STEGLATRO 15 mg, and placebo arms, respectively). Acute hemodynamic changes may play a role in the early renal function changes observed with STEGLATRO 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 STEGLATRO. Mean percent changes from baseline to Week 26 in LDL-C relative to placebo were 2.6% and 5.4% with STEGLATRO 5 mg and STEGLATRO 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 STEGLATRO 5 mg, and 0.48 g/dL (3.5%) with STEGLATRO 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, STEGLATRO 5 mg, and STEGLATRO 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 STEGLATRO 5 mg, and 0.26 mg/dL (8.5%) with STEGLATRO 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 STEGLATRO 5 mg, and 0.24 mg/dL (7.8%) with STEGLATRO 15 mg. 6.2 Postmarketing Experience Additional adverse reactions have been identified during postapproval use of STEGLATRO. 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. Infections: necrotizing fasciitis of the perineum (Fournier's Gangrene) Skin and Subcutaneous Tissue Disorders: angioedema, rash

8.1 Pregnancy Risk Summary Based on animal data showing adverse renal effects, STEGLATRO is not recommended during the second and third trimesters of pregnancy. The limited available data with STEGLATRO in pregnant women are not sufficient to determine a drug-associated risk of adverse developmental outcomes. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations ) . In animal studies, adverse renal changes were observed in rats when ertugliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy. Doses approximately 13 times the maximum clinical dose caused renal pelvic and tubule dilatations and renal mineralization that were not fully reversible. There was no evidence of fetal harm in rats or rabbits at exposures of ertugliflozin approximately 300 times higher than the maximal clinical dose of 15 mg/day when administered during organogenesis (see Data ) . The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Animal Data When ertugliflozin was orally administered to juvenile rats from PND 21 to PND 90, increased kidney weight, renal tubule and renal pelvis dilatation, and renal mineralization occurred at doses greater than or equal to 5 mg/kg (13-fold human exposures, based on AUC). These effects occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development, and did not fully reverse within a 1-month recovery period. In embryo-fetal development studies, ertugliflozin (50, 100 and 250 mg/kg/day) was administered orally to rats on gestation days 6 to 17 and to rabbits on gestation days 7 to 19. Ertugliflozin did not adversely affect developmental outcomes in rats and rabbits at maternal exposures that were approximately 300 times the human exposure at the maximum clinical dose of 15 mg/day, based on AUC. A maternally toxic dose (250 mg/kg/day) in rats (707 times the clinical dose), was associated with reduced fetal viability, and a higher incidence of a visceral malformation (membranous ventricular septal defect). In the pre- and post-natal development study in pregnant rats, ertugliflozin was administered to the dams from gestation day 6 through lactation day 21 (weaning). Decreased post-natal growth (weight gain) was observed at maternal doses ≥100 mg/kg/day (greater than or equal to 331 times the human exposure at the maximum clinical dose of 15 mg/day, based on AUC).