FDA label ab53fbcd-a600-406d-b6d2-ae6017d96f92

WARNING: LACTIC ACIDOSIS Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio, and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1) ] . Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information [see Dosage and Administration (2.2) , Contraindications (4) , Warnings and Precautions (5.1) , Drug Interactions (7) , and Use in Specific Populations (8.6 , 8.7 )] . If metformin-associated lactic acidosis is suspected, immediately discontinue SEGLUROMET and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1) ] . WARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning . Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio, and metformin plasma levels generally >5 mcg/mL. ( 5.1 ) Risk factors include renal impairment, concomitant use of certain drugs, age ≥65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information. ( 5.1 ) If lactic acidosis is suspected, discontinue SEGLUROMET and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. ( 5.1 )

5 WARNINGS AND PRECAUTIONS Lactic Acidosis: See boxed warning . ( 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 SEGLUROMET. Monitor patients for infections or ulcers of lower limbs, and discontinue if these occur. ( 5.3 ) Volume Depletion: May result in acute kidney injury. Before initiating, assess and correct volume status in patients with renal impairment, low systolic blood pressure, elderly patients, or patients on diuretics. Monitor for signs and symptoms during therapy. ( 5.4 ) Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated. ( 5.5 ) Hypoglycemia: Consider a lower dose of insulin or insulin secretagogue to reduce risk of hypoglycemia when used in combination. ( 5.6 ) 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. ( 5.7 ) Genital Mycotic Infections: Monitor and treat if indicated. ( 5.8 ) Vitamin B 12 Deficiency: Metformin may lower vitamin B 12 levels. Measure hematological parameters annually. ( 5.9 ) 5.1 Lactic Acidosis There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels were generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of SEGLUROMET. In SEGLUROMET-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue SEGLUROMET and report these symptoms to their healthcare provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3) ] . Before initiating SEGLUROMET, obtain an eGFR. Use of SEGLUROMET is not recommended in patients with an eGFR less than 45 mL/min/1.73 m 2 . SEGLUROMET is contraindicated in patients with severe renal impairment (an eGFR less than 30 mL/min/1.73 m 2 ), end stage-renal disease (ESRD), or on dialysis. Obtain an eGFR at least annually in all patients taking SEGLUROMET. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. Drug Interactions: The concomitant use of SEGLUROMET with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation (e.g., cationic drugs) [see Drug Interactions (7) ] . Therefore, consider more frequent monitoring of patients. Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5) ] . Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop SEGLUROMET at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m 2 ; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart SEGLUROMET if renal function is stable. Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. SEGLUROMET should be temporarily discontinued while patients have restricted food and fluid intake. Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause pre-renal azotemia. When such events occur, discontinue SEGLUROMET. Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving SEGLUROMET. Hepatic Impairment: Patients with hepatic impairment have developed metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of SEGLUROMET in patients with clinical or laboratory evidence of hepatic disease. 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 sodium glucose co-transporter-2 (SGLT2) inhibitors including ertugliflozin [see Adverse Reactions (6.1) ]. Fatal cases of ketoacidosis have been reported in patients taking medicines containing 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. SEGLUROMET is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications and Usage (1) ] . Patients treated with SEGLUROMET 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 SEGLUROMET may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, SEGLUROMET 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 SEGLUROMET, 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 SEGLUROMET for at least 4 days prior to surgery [see Clinical Pharmacology (12.2 , 12.3) ] . Consider monitoring for ketoacidosis and temporarily discontinuing SEGLUROMET 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 SEGLUROMET. Educate patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue SEGLUROMET 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 1,000 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 SEGLUROMET, 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 SEGLUROMET for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue SEGLUROMET if these complications occur. 5.4 Volume Depletion SEGLUROMET 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 SEGLUROMET. 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 SEGLUROMET 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 SEGLUROMET. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy. 5.5 Urosepsis and Pyelonephritis There have been postmarketing reports of serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization in patients receiving medicines containing SGLT2 inhibitors. 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) ] . 5.6 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. SEGLUROMET 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 SEGLUROMET. 5.7 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 SEGLUROMET 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 SEGLUROMET, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control. 5.8 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. 5.9 Vitamin B 12 Deficiency In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. Measure hematologic parameters on an annual basis and vitamin B 12 at 2 to 3 year intervals in patients on metformin and manage any abnormalities [see Adverse Reactions (6.1) ].

6 ADVERSE REACTIONS The following important adverse reactions are described elsewhere in the labeling: Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1) ] Ketoacidosis [see Warnings and Precautions (5.2) ] Lower Limb Amputation [see Warnings and Precautions (5.3) ] Volume Depletion [see Warnings and Precautions (5.4) ] Urosepsis and Pyelonephritis [see Warnings and Precautions (5.5) ] Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.6) ] Necrotizing Fasciitis of the Perineum (Fournier's Gangrene) [see Warnings and Precautions (5.7) ] Genital Mycotic Infections [see Warnings and Precautions (5.8) ] Vitamin B 12 Deficiency [see Warnings and Precautions (5.9) ] Most common adverse reactions associated with ertugliflozin (incidence ≥5%) were female genital mycotic infections. ( 6.1 ) Most common adverse reactions associated with metformin (incidence ≥5%) were diarrhea, nausea, vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache. ( 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 Metformin Hydrochloride The incidence and type of adverse reactions in the two 26-week, placebo-controlled trials of ertugliflozin 5 mg and 15 mg added to metformin, representing a majority of data from the three 26-week, placebo-controlled trials, were similar to the adverse reactions described 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 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 or with metformin 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% Ketoacidosis In a long-term cardiovascular outcomes study VERTIS CV (eValuation of ERTugliflozin effIcacy and Safety, CardioVascular [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 (5.3) ] . 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 Add-on Combination Therapy with Metformin (26 weeks) Placebo (N = 209) Ertugliflozin 5 mg (N = 207) Ertugliflozin 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 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) Add-on Combination with Insulin with or without Metformin (18 weeks) Placebo (N = 347) Ertugliflozin 5 mg (N = 348) Ertugliflozin 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 Metformin and a Sulfonylurea (18 weeks) Placebo (N = 117) Ertugliflozin 5 mg (N = 100) Ertugliflozin 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) 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, and ertugliflozin 15 mg, respectively. 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. Metformin The most common (5% or greater incidence) established adverse reactions due to initiation of metformin therapy are diarrhea, nausea, vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache. In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. 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 (mean 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. 6.2 Postmarketing Experience Additional adverse reactions have been identified during post approval 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 Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.

<table width="80%"><caption>Table 1: Adverse Reactions Reported in &#x2265;2% of Patients with Type 2 Diabetes Mellitus Treated with Ertugliflozin<footnote ID="t1f1">The three placebo-controlled studies included one monotherapy trial and two add-on combination trials with metformin or with metformin and sitagliptin.</footnote> and Greater than Placebo in Pooled Placebo-Controlled Clinical Studies of Ertugliflozin Monotherapy or Combination Therapy</caption><col width="28%" align="left" valign="top"/><col width="24%" align="center" valign="middle"/><col width="24%" align="center" valign="middle"/><col width="24%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Botrule Rrule" colspan="3">Number (%) of Patients</th></tr><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">Placebo N = 515</th><th styleCode="Rrule">Ertugliflozin 5 mg N = 519</th><th styleCode="Rrule">Ertugliflozin 15 mg N = 510</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Female genital mycotic infections<footnote ID="t1f2">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).</footnote></td><td styleCode="Rrule">3.0%</td><td styleCode="Rrule">9.1%</td><td styleCode="Rrule">12.2%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Male genital mycotic infections<footnote ID="t1f3">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).</footnote></td><td styleCode="Rrule">0.4%</td><td styleCode="Rrule">3.7%</td><td styleCode="Rrule">4.2%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Urinary tract infections<footnote ID="t1f4">Includes: cystitis, dysuria, streptococcal urinary tract infection, urethritis, urinary tract infection. </footnote></td><td styleCode="Rrule">3.9%</td><td styleCode="Rrule">4.0%</td><td styleCode="Rrule">4.1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">2.3%</td><td styleCode="Rrule">3.5%</td><td styleCode="Rrule">2.9%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vaginal pruritus<footnote ID="t1f5">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).</footnote></td><td styleCode="Rrule">0.4%</td><td styleCode="Rrule">2.8%</td><td styleCode="Rrule">2.4%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Increased urination<footnote ID="t1f6">Includes: pollakiuria, micturition urgency, polyuria, urine output increased, and nocturia.</footnote></td><td styleCode="Rrule">1.0%</td><td styleCode="Rrule">2.7%</td><td styleCode="Rrule">2.4%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nasopharyngitis</td><td styleCode="Rrule">2.3%</td><td styleCode="Rrule">2.5%</td><td styleCode="Rrule">2.0%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Back pain</td><td styleCode="Rrule">2.3%</td><td styleCode="Rrule">1.7%</td><td styleCode="Rrule">2.5%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Weight decreased</td><td styleCode="Rrule">1.0%</td><td styleCode="Rrule">1.2%</td><td styleCode="Rrule">2.4%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Thirst<footnote ID="t1f7">Includes: thirst, dry mouth, polydipsia, and dry throat.</footnote></td><td styleCode="Rrule">0.6%</td><td styleCode="Rrule">2.7%</td><td styleCode="Rrule">1.4%</td></tr></tbody></table>

<table width="75%"><caption>Table 2: Incidence of Overall<footnote ID="t2f1">Overall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL.</footnote> and Severe<footnote ID="t2f2">Severe hypoglycemic events: required assistance, lost consciousness, or experienced a seizure regardless of blood glucose.</footnote> Hypoglycemia in Placebo-Controlled Clinical Studies in Patients with Type 2 Diabetes Mellitus</caption><col width="31%" align="left" valign="top"/><col width="23%" align="center" valign="top"/><col width="23%" align="center" valign="top"/><col width="23%" align="center" valign="top"/><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="Bold">Add-on Combination Therapy with Metformin (26 weeks)</content></td><td styleCode="Rrule"><content styleCode="Bold">Placebo (N = 209)</content></td><td styleCode="Rrule"><content styleCode="Bold">Ertugliflozin 5 mg (N = 207)</content></td><td styleCode="Rrule"><content styleCode="Bold">Ertugliflozin 15 mg (N = 205)</content></td></tr><tr><td styleCode="Lrule Rrule">Overall [N (%)] </td><td styleCode="Rrule">9 (4.3)</td><td styleCode="Rrule">15 (7.2)</td><td styleCode="Rrule">16 (7.8)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Severe [N (%)] </td><td styleCode="Rrule">1 (0.5)</td><td styleCode="Rrule">1 (0.5)</td><td styleCode="Rrule">0 (0.0)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="Bold">Add-on Combination Therapy with Metformin and Sitagliptin (26 weeks)</content></td><td styleCode="Rrule"><content styleCode="Bold">Placebo (N = 153)</content></td><td styleCode="Rrule"><content styleCode="Bold">Ertugliflozin 5 mg (N = 156)</content></td><td styleCode="Rrule"><content styleCode="Bold">Ertugliflozin 15 mg (N = 153)</content></td></tr><tr><td styleCode="Lrule Rrule">Overall [N (%)]</td><td styleCode="Rrule">5 (3.3)</td><td styleCode="Rrule">7 (4.5)</td><td styleCode="Rrule">3 (2.0)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Severe [N (%)] </td><td styleCode="Rrule">1 (0.7)</td><td styleCode="Rrule">1 (0.6)</td><td styleCode="Rrule">0 (0.0)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="Bold">Add-on Combination with Insulin with or without Metformin (18 weeks)</content></td><td styleCode="Rrule"><content styleCode="Bold">Placebo (N = 347)</content></td><td styleCode="Rrule"><content styleCode="Bold">Ertugliflozin 5 mg (N = 348)</content></td><td styleCode="Rrule"><content styleCode="Bold">Ertugliflozin 15 mg (N = 370)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Overall [N (%)]</td><td styleCode="Rrule">130 (37.5)</td><td styleCode="Rrule">137 (39.4)</td><td styleCode="Rrule">144 (38.9)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Severe [N (%)]</td><td styleCode="Rrule">12 (3.5)</td><td styleCode="Rrule">13 (3.7)</td><td styleCode="Rrule">19 (5.1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="Bold">Add-on Combination with Metformin and a Sulfonylurea (18 weeks)</content></td><td styleCode="Rrule"><content styleCode="Bold">Placebo (N = 117)</content></td><td styleCode="Rrule"><content styleCode="Bold">Ertugliflozin 5 mg (N = 100)</content></td><td styleCode="Rrule"><content styleCode="Bold">Ertugliflozin 15 mg (N = 113)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Overall [N (%)]</td><td styleCode="Rrule">17 (14.5)</td><td styleCode="Rrule">20 (20.0)</td><td styleCode="Rrule">30 (26.5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Severe [N (%)]</td><td styleCode="Rrule">1 (0.9)</td><td styleCode="Rrule">2 (2.0)</td><td styleCode="Rrule">2 (1.8)</td></tr></tbody></table>