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 (5.1)].

2.1 Prior to Initiation of STEGLATRO

• Assess renal function prior to initiation of STEGLATRO and as clinically indicated [see Warnings and Precautions (5.3)].
• In patients with volume depletion, correct this condition before initiating STEGLATRO [see Warnings and Precautions (5.3), Use in Specific Populations (8.5, 8.6)].

2.2 Recommended Dosage

• The recommended starting dose of STEGLATRO is 5 mg once daily, taken in the morning, with or without food.
• For additional glycemic control, the dose may be increased to 15 mg once daily in patients tolerating STEGLATRO.
• Use of STEGLATRO is not recommended in patients with an eGFR less than 45 mL/min/1.73 m2.
• STEGLATRO is contraindicated in patients on dialysis.

5.1 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 sodium glucose co-transporter-2 (SGLT2) inhibitors including STEGLATRO [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. STEGLATRO is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications and Usage (1)].

Patients treated with STEGLATRO 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 STEGLATRO may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, STEGLATRO 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 STEGLATRO, 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 STEGLATRO for at least 4 days prior to surgery [see Clinical Pharmacology (12.2, 12.3)].

Consider monitoring for ketoacidosis and temporarily discontinuing STEGLATRO 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 STEGLATRO.

Educate 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 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 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.

Before initiating STEGLATRO, 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 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 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 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 and 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 and/or an insulin secretagogue [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 STEGLATRO.

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.

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.

6.2 Postmarketing Experience

Additional adverse reactions have been identified during postapproval use. 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.

• Necrotizing fasciitis of the perineum (Fournier's Gangrene)
• Angioedema

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness of STEGLATRO in pediatric patients under 18 years of age have not been established.

8.5 Geriatric Use

No dosage adjustment of STEGLATRO is recommended based on age. In STEGLATRO clinical trials, a total of 876 (25.7%) patients treated with STEGLATRO were 65 years and older, and 152 (4.5%) patients treated with STEGLATRO were 75 years and older. Patients 65 years and older had a higher incidence of adverse reactions related to volume depletion compared to younger patients; events were reported in 1.1%, 2.2%, and 2.6% of patients treated with comparator, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

In VERTIS CV, a total of 2780 (50.5%) patients treated with STEGLATRO were 65 years and older, and 595 (10.8%) patients treated with STEGLATRO were 75 years and older. Safety and efficacy were generally similar for patients age 65 years and older compared to patients younger than 65.

8.6 Renal Impairment

A 26-week placebo-controlled study of 313 patients with Stage 3 Chronic Kidney Disease (eGFR ≥30 to less than 60 mL/min/1.73 m2) treated with STEGLATRO did not demonstrate improvement in glycemic control.

In the VERTIS CV study, there were 1370 patients (25%) with an eGFR ≥90 mL/min/1.73 m2, 2929 patients (53%) with an eGFR of ≥60 to less than 90 mL/min/1.73 m2, 879 patients (16%) with an eGFR of ≥45 to less than 60 mL/min/1.73 m2, and 299 patients (5%) with eGFR of 30 to <45 mL/min/1.73 m2 treated with STEGLATRO. Similar effects on glycemic control at Week 18 were observed in patients treated with STEGLATRO in each eGFR subgroup and also in the overall patient population.

STEGLATRO is contraindicated in patients on dialysis [see Contraindications (4)].

No dosage adjustment is needed in patients with eGFR ≥45 mL/min/1.73 m2.

8.7 Hepatic Impairment

No dosage adjustment of STEGLATRO is necessary in patients with mild or moderate hepatic impairment. Ertugliflozin has not been studied in patients with severe hepatic impairment and is not recommended for use in this patient population [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Ertugliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, ertugliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

The pharmacokinetics of ertugliflozin are similar in healthy subjects and patients with type 2 diabetes mellitus. The steady state mean plasma AUC and Cmax were 398 ng∙hr/mL and 81.3 ng/mL, respectively, with 5 mg ertugliflozin once-daily treatment, and 1,193 ng∙hr/mL and 268 ng/mL, respectively, with 15 mg ertugliflozin once-daily treatment. Steady-state is reached after 4 to 6 days of once-daily dosing with ertugliflozin. Ertugliflozin does not exhibit time-dependent pharmacokinetics and accumulates in plasma up to 10-40% following multiple dosing.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Glycemic Control Trials in Patients with Type 2 Diabetes Mellitus

STEGLATRO has been studied as monotherapy and in combination with metformin, sitagliptin, a sulfonylurea, insulin (with or without metformin), metformin plus sitagliptin, metformin plus a sulfonylurea and compared to a sulfonylurea (glimepiride). STEGLATRO has also been studied in patients with type 2 diabetes mellitus and moderate renal impairment.

In patients with type 2 diabetes mellitus treatment with STEGLATRO reduced hemoglobin A1c (HbA1c) compared to placebo. Reduction in HbA1c was generally similar across subgroups defined by age, sex, race, geographic region, baseline body mass index (BMI), and duration of type 2 diabetes mellitus.

Monotherapy

A total of 461 patients with type 2 diabetes mellitus inadequately controlled (HbA1c between 7% and 10.5%) on diet and exercise participated in a randomized, double-blind, multi-center, 26-week, placebo-controlled study (NCT01958671) to evaluate the efficacy and safety of STEGLATRO monotherapy. These patients, who were either treatment naïve or not receiving any background antihyperglycemic treatment ≥8 weeks, entered a 2-week, single-blind, placebo run-in period and were randomized to placebo, STEGLATRO 5 mg, or STEGLATRO 15 mg, administered once daily.

At Week 26, treatment with STEGLATRO at 5 mg or 15 mg daily provided statistically significant reductions in HbA1c compared to placebo. STEGLATRO also resulted in a greater proportion of patients achieving an HbA1c <7% compared with placebo (see Table 4 and Figure 3).

The mean baseline body weight was 94.2 kg, 94.0 kg, and 90.6 kg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The mean changes from baseline to Week 26 were -1.0 kg, -3.0 kg, and -3.1 kg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The difference from placebo (95% CI) for STEGLATRO 5 mg was -2.0 kg (-2.8, -1.2) and for STEGLATRO 15 mg was -2.1 kg (-2.9, -1.3).

Combination Therapy

Add-on Combination Therapy with Insulin (with or without Metformin)

In an 18-week randomized, double-blind, multi-center, placebo-controlled, glycemic sub-study of VERTIS CV (eValuation of ERTugliflozin efficacy and Safety CardioVascular, NCT01986881, study details see 14.2), a total of 1065 patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease with inadequate glycemic control (HbA1c between 7% and 10.5%) on background therapy of insulin ≥20 units/day (59% also on metformin ≥1,500 mg/day) were randomized to placebo, STEGLATRO 5 mg or STEGLATRO 15 mg once daily treatment.

At Week 18, treatment with STEGLATRO at 5 mg or 15 mg daily provided statistically significant reductions in HbA1c compared to placebo (see Table 8).

The mean baseline body weights were 93.3 kg, 93.8 kg, and 92.1 kg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The mean changes from baseline to Week 18 were - 0.2 kg, -1.6 kg, and -1.9 kg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The differences from placebo (95% CI) for STEGLATRO 5 mg were - 1.4 kg (- 1.9, - 0.9) and for STEGLATRO 15 mg was -1.6 kg (-2.1, -1.1).

The mean baseline systolic blood pressures were 134.0 mmHg, 135.6 mmHg, and 133.7 mmHg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The mean changes from baseline to Week 18 were 0.7 mmHg, -2.2 mmHg, and -1.7 mmHg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The differences from placebo (95% CI) for STEGLATRO 5 mg was – 2.9 mmHg (-4.9, -1.0) and for STEGLATRO 15 mg were -2.5 mmHg (- 4.4, - 0.5).

Add-on Combination Therapy with Metformin and Sulfonylurea

In an 18-week randomized, double-blind, multi-center, placebo-controlled, glycemic sub-study of VERTIS CV (NCT01986881, study details see 14.2), a total of 330 patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease with inadequate glycemic control (HbA1c between 7% and 10.5%) with background therapy of metformin ≥1,500 mg/day and a sulfonylurea (SU) were randomized to placebo, STEGLATRO 5 mg or STEGLATRO 15 mg once daily treatment.

At Week 18, treatment with STEGLATRO at 5 mg or 15 mg daily provided statistically significant reductions in HbA1c compared to placebo (see Table 9).

The mean baseline body weights were 90.5 kg, 92.1 kg, and 92.9 kg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The mean changes from baseline to Week 18 were - 0.6 kg, -2.0 kg, and - 2.2 kg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The differences from placebo (95% CI) for STEGLATRO 5 mg were - 1.4 kg (- 2.2, - 0.7) and for STEGLATRO 15 mg was - 1.6 kg (- 2.3, - 0.9).

Use in Patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment

26-Week Placebo-Controlled Study

The efficacy of STEGLATRO was assessed in a multicenter, randomized, double-blind, placebo-controlled study (NCT01986855) of patients with type 2 diabetes mellitus and moderate renal impairment (468 patients with eGFR ≥30 to <60 mL/min/1.73 m2). In this study, 202 patients exposed to STEGLATRO (5 mg or 15 mg) had an eGFR between 45 and 60 mL/min/1.73 m2 and 111 patients exposed to STEGLATRO (5 mg or 15 mg) had an eGFR between 30 and 45 mL/min/1.73 m2. The mean duration of diabetes for the study population was approximately 14 years, and the majority of patients were receiving background insulin (55.9%) and/or sulfonylurea (40.3%) therapy. Approximately 50% had a history of cardiovascular disease or heart failure.

STEGLATRO did not show efficacy in this study. The HbA1c reductions from baseline to Week 26 were not significantly different between placebo and STEGLATRO 5 mg or 15 mg [see Use in Specific Populations (8.6)].

14.2 Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus and Established Cardiovascular Disease

The effect of STEGLATRO on cardiovascular risk in adult patients with type 2 diabetes and established atherosclerotic cardiovascular disease was evaluated in the VERTIS CV study (NCT01986881), a multicenter, multi-national, randomized, double-blind, placebo-controlled, event-driven trial. The study compared the risk of experiencing a major adverse cardiovascular event (MACE) between STEGLATRO and placebo when these were added to and used concomitantly with standard of care treatments for diabetes and atherosclerotic cardiovascular disease.

A total of 8246 patients were randomized (placebo N=2747, STEGLATRO 5 mg N=2752, STEGLATRO 15 mg N=2747) and followed for a median of 3 years. Approximately 88% of the study population was Caucasian, 6% Asian, and 3% Black. The mean age was 64 years and approximately 70% were male.

All patients in the study had inadequately controlled type 2 diabetes mellitus at baseline (HbA1c greater than or equal to 7%). The mean duration of type 2 diabetes mellitus was 13 years, the mean HbA1c at baseline was 8.2% and the mean eGFR was 76 mL/min/1.73 m2. At baseline, patients were treated with one (32%) or more (67%) antidiabetic medications including biguanides (metformin) (76%), insulin (47%), sulfonylureas (41%) DPP-4 inhibitors (11%) and GLP-1 receptor agonists (3%).

Almost all patients (99%) had established atherosclerotic cardiovascular disease at baseline including: a documented history of coronary artery disease (76%), cerebrovascular disease (23%) or peripheral artery disease (19%). Approximately 24% patients had a history of heart failure (HF). At baseline, the mean systolic blood pressure was 133 mmHg, the mean diastolic blood pressure was 77 mmHg, the mean LDL was 89 mg/dL, and the mean HDL was 44 mg/dL. At baseline, approximately 81% of patients were treated with renin angiotensin system inhibitors, 69% with beta-blockers, 43% with diuretics, 82% with statins, 4% with ezetimibe, and 89% with antiplatelet agents.

The primary endpoint in VERTIS CV was the time to first occurrence of MACE. A major adverse cardiovascular event was defined as occurrence of either a cardiovascular death or a nonfatal myocardial infarction (MI) or a nonfatal stroke. The statistical analysis plan pre-specified that the 5 and 15 mg doses would be combined for the analysis. A Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio of MACE. Type-1 error was controlled across multiple tests using a hierarchical testing strategy.

The incidence rate of MACE was similar between the STEGLATRO-treated and placebo-treated patients. The estimated hazard ratio of MACE associated with STEGLATRO relative to placebo was 0.97 with 95.6% confidence interval (0.85, 1.11). The upper bound of this confidence interval excluded a risk larger than 1.3 (Table 10). Results for the individual 5 mg and 15 mg doses were consistent with results for the combined dose group.

Store at 20°C -25°C (68°F -77°F), excursions permitted between 15°C -30°C (between 59°F -86°F) [see USP Controlled Room Temperature]. Protect from moisture. Store in a dry place.

Ketoacidosis

Inform patients that ketoacidosis is a serious life-threatening condition and that cases of ketoacidosis have been reported during use of STEGLATRO, sometimes associated with illness or surgery among other risk factors. Instruct patients to check ketones (when possible) if symptoms consistent with ketoacidosis occur even if blood glucose is not elevated. If symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing) occur, instruct patients to discontinue STEGLATRO and seek medical attention immediately [see Warnings and Precautions (5.1)].

Amputation

Inform patients of the potential for an increased risk of amputations. Counsel patients about the importance of routine preventative foot care. Instruct patients to monitor for new pain or tenderness, sores or ulcers, or infections involving the leg or foot and to seek medical advice immediately if such signs or symptoms develop [see Warnings and Precautions (5.2)].

Volume Depletion

Inform patients that symptomatic hypotension may occur with STEGLATRO and advise them to contact their doctor if they experience such symptoms [see Warnings and Precautions (5.3)]. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake.

Serious Urinary Tract Infections

Inform patients of the potential for urinary tract infections, which may be serious. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice if such symptoms occur [see Warnings and Precautions (5.4)].

Hypoglycemia with Concomitant Use of Insulin and/or Insulin Secretagogue

Inform patients that the incidence of hypoglycemia may increase when STEGLATRO is added to insulin and/or an insulin secretagogue and that a lower dose of insulin or insulin secretagogue may be required to reduce the risk of hypoglycemia [see Warnings and Precautions (5.5)].

Necrotizing Fasciitis of the Perineum (Fournier's Gangrene)

Inform patients that necrotizing infections of the perineum (Fournier's Gangrene) have occurred with SGLT2 inhibitors. Counsel patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever above 100.4°F or malaise [see Warnings and Precautions (5.6)].

Genital Mycotic Infections in Females (e.g., Vulvovaginitis)

Inform female patients that vaginal yeast infections may occur and provide them with information on the signs and symptoms of vaginal yeast infection. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.7)].

Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis)

Inform male patients that yeast infections of the penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.7)].

Fetal Toxicity

Advise pregnant patients of the potential risk to a fetus with treatment with STEGLATRO. Instruct patients to immediately inform their healthcare provider if pregnant or planning to become pregnant [see Use in Specific Populations (8.1)].

Lactation

Advise patients that use of STEGLATRO is not recommended while breastfeeding [see Use in Specific Populations (8.2)].

Laboratory Tests

Due to its mechanism of action, inform patients that their urine will test positive for glucose while taking STEGLATRO.

Missed Dose

Instruct patients to take STEGLATRO only as prescribed. If a dose is missed, it should be taken as soon as the patient remembers. Advise patients not to double their next dose.