STEGLUJAN Dailymed

Recent Major Changes Section

Indications and Usage (1)	09/2023
Dosage and Administration (2.1, 2.3)	09/2023
Warnings and Precautions (5.1)	09/2023

1 Indications And Usage

STEGLUJAN^® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Limitations of Use

• Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see Warnings and Precautions (5.1)].
• Has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using STEGLUJAN [see Warnings and Precautions (5.2)].

STEGLUJAN is a combination of ertugliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, and sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Limitations of Use:

• Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. (1)
• Has not been studied in patients with a history of pancreatitis. (1, 5.2)

• Assess renal function before initiating and as clinically indicated. (2.1)
• Correct volume depletion before initiating. (2.1)
• Recommended starting dose is 5 mg ertugliflozin/100 mg sitagliptin once daily, taken in the morning, with or without food. (2.2)
• Increase dose to 15 mg ertugliflozin/100 mg sitagliptin once daily in those tolerating STEGLUJAN and needing additional glycemic control. (2.2)
• Use is not recommended in patients with an eGFR less than 45 mL/min/1.73 m². (2.2)
• Withhold STEGLUJAN for at least 4 days, if possible, prior to major surgery or procedures associated with prolonged fasting. (2.3)

2.1Prior to Initiation of STEGLUJAN

• Assess renal function prior to initiation of STEGLUJAN and as clinically indicated [see Warnings and Precautions (5.4)].
• Assess volume status. In patients with volume depletion, correct this condition before initiating STEGLUJAN [see Warnings and Precautions (5.5), Use in Specific Populations (8.5, 8.6)].

2.2Recommended Dosage

• The recommended starting dose of STEGLUJAN is 5 mg ertugliflozin/100 mg sitagliptin once daily, taken in the morning, with or without food.
• For patients treated with ertugliflozin who are being switched to STEGLUJAN, the dose of ertugliflozin can be maintained.
• For additional glycemic control, the dose may be increased to 15 mg ertugliflozin/100 mg sitagliptin once daily in patients tolerating STEGLUJAN.
• Use is not recommended in patients with an eGFR less than 45 mL/min/1.73 m².
• Use of STEGLUJAN is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²), end-stage renal disease (ESRD) or on dialysis [see Contraindications (4)].

2.3Temporary Interruption for Surgery

Withhold STEGLUJAN for at least 4 days, if possible, prior to major surgery or procedures associated with prolonged fasting. Resume STEGLUJAN when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)].

3 Dosage Forms And Strengths

• STEGLUJAN 5 mg/100 mg tablets: contain ertugliflozin 5 mg and sitagliptin 100 mg and are beige, almond-shaped debossed with "554" on one side and plain on the other side.
• STEGLUJAN 15 mg/100 mg tablets: contain ertugliflozin 15 mg and sitagliptin 100 mg and are brown, almond-shaped debossed with "555" on one side and plain on the other side.

Tablets:

• Ertugliflozin 5 mg and sitagliptin 100 mg (3)
• Ertugliflozin 15 mg and sitagliptin 100 mg (3)

4 Contraindications

• Patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²), end-stage renal disease (ESRD), or on dialysis [see Warnings and Precautions (5.4) and Use in Specific Populations (8.6)].
• Hypersensitivity to sitagliptin, ertugliflozin, or any excipient, in STEGLUJAN, reactions such as anaphylaxis or angioedema have occurred [see Warnings and Precautions (5.11) and Adverse Reactions (6.2)].

• Severe renal impairment (eGFR less than 30 mL/min/1.73 m²), end-stage renal disease, or dialysis. (4)
• Hypersensitivity to sitagliptin, ertugliflozin, or any excipient in STEGLUJAN. (4, 5.11, 6.2)

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 STEGLUJAN if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting. (5.1)
• Pancreatitis: There have been postmarketing reports of acute pancreatitis in patients taking sitagliptin, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue. (5.2)
• Lower Limb Amputation: Consider factors that may increase the risk of amputation before initiating STEGLUJAN. Monitor patients for infections or ulcers of lower limbs, and discontinue if these occur. (5.3)
• Acute Renal Failure: There have been postmarketing reports of acute renal failure in patients taking sitagliptin, sometimes requiring dialysis. Monitor renal function. (5.4)
• Volume Depletion: May result in acute kidney injury. Before initiating, assess and correct volume status in patients with renal impairment, or low systolic blood pressure elderly patients, or patients on diuretics. Monitor for signs and symptoms during therapy. (5.5)
• Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated. (5.6)
• Heart Failure: Heart failure has been observed with two other members of the DPP-4 inhibitor class. Consider risks and benefits in patients who have known risk factors for heart failure. Monitor patients for signs and symptoms. (5.7)
• Hypoglycemia: Consider a lower dose of insulin or insulin secretagogue to reduce risk of hypoglycemia when used in combination. (5.8)
• Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Serious, life-threatening cases have occurred in both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment. (5.9)
• Genital Mycotic Infections: Monitor and treat if indicated. (5.10)
• Hypersensitivity: There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. In such cases, promptly discontinue, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. (5.11)
• Severe and Disabling Arthralgia: Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as a possible cause for severe joint pain and discontinue if appropriate. (5.12)
• Pemphigoid: There have been postmarketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of bulers or erosions. If bullous pemphigoid is suspected, discontinue. (5.13)

5.1Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis

In patients with type 1 diabetes mellitus, STEGLUJAN 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. STEGLUJAN 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 STEGLUJAN [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 STEGLUJAN, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting STEGLUJAN.

Withhold STEGLUJAN, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume STEGLUJAN 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 STEGLUJAN and seek medical attention immediately if signs and symptoms occur.

5.2Pancreatitis

There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin, a component of STEGLUJAN. After initiation of STEGLUJAN, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, STEGLUJAN should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using STEGLUJAN.

5.3Lower Limb Amputation

In a long-term cardiovascular outcomes study [see Clinical Studies 14.2], in patients with type 2 diabetes and established cardiovascular disease, the occurrence of non-traumatic lower limb amputations was reported with event rates of 4.7, 5.7, and 6.0 events per 1000 patient-years in the placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg treatment arms, respectively.

Amputation of the toe and foot were most frequent (81 out of 109 patients with lower limb amputations). Some patients had multiple amputations, some involving both lower limbs.

Lower limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation. Patients with amputations were more likely to be male, have higher A1C (%) at baseline, have a history of peripheral arterial disease, amputation or peripheral revascularization procedure, diabetic foot, and to have been taking diuretics or insulin.

Across seven ertugliflozin clinical trials, non-traumatic lower limb amputations were reported in 1 (0.1%) patient in the comparator group, 3 (0.2%) patients in the ertugliflozin 5 mg group, and 8 (0.5%) patients in the ertugliflozin 15 mg group.

Before initiating STEGLUJAN, consider factors in the patient history that may predispose them to the need for amputations, such as a history of prior amputation, peripheral vascular disease, neuropathy and diabetic foot ulcers. Counsel patients about the importance of routine preventative foot care. Monitor patients receiving STEGLUJAN for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue STEGLUJAN if these complications occur.

5.4Acute Renal Failure

There have been postmarketing reports with sitagliptin of worsening renal function, including acute renal failure, sometimes requiring dialysis. A subset of these reports involved patients with renal insufficiency, some of whom were prescribed inappropriate doses of sitagliptin. A return to baseline levels of renal insufficiency has been observed with supportive treatment and discontinuation of potentially causative agents. Consideration can be given to cautiously reinitiating STEGLUJAN if another etiology is deemed likely to have precipitated the acute worsening of renal function.

Sitagliptin has not been found to be nephrotoxic in preclinical studies at clinically relevant doses, or in clinical trials.

5.5Volume Depletion

STEGLUJAN can cause intravascular volume contraction which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine [see Adverse Reactions (6.1)]. There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including STEGLUJAN. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m²) [see Use in Specific Populations (8.6)], elderly patients, patients with low systolic blood pressure, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating STEGLUJAN in patients with one or more of these characteristics, assess volume status and renal function. In patients with volume depletion, correct this condition before initiating STEGLUJAN. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.

5.6Urosepsis 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)].

5.7Heart Failure

An association between dipeptidyl peptidase-4 (DPP-4) inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Consider the risks and benefits of STEGLUJAN prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of STEGLUJAN.

5.8Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. Ertugliflozin, may increase the risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue [see Adverse Reactions (6.1)]. When sitagliptin, was used in combination with a sulfonylurea or with insulin, the incidence of hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin [see Adverse Reactions (6.1)]. A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with STEGLUJAN.

5.9Necrotizing Fasciitis of the Perineum (Fournier's Gangrene)

Reports of necrotizing fasciitis of the perineum (Fournier's Gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including ertugliflozin. Cases have been reported in females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.

Patients treated with STEGLUJAN presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue STEGLUJAN, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

5.10Genital 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.

5.11Hypersensitivity Reactions

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment with sitagliptin, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue STEGLUJAN, assess for other potential causes for the event, and institute alternative treatment for diabetes [see Adverse Reactions (6.2)].

Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with STEGLUJAN.

5.12Severe and Disabling Arthralgia

There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.

5.13Bullous Pemphigoid

Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of bulers or erosions while receiving STEGLUJAN. If bullous pemphigoid is suspected, STEGLUJAN should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

6 Adverse Reactions

The following important adverse reactions are described elsewhere in the labeling:

• Diabetic Ketoacidosis in Patients with Type 1 Diabetes and Other Ketoacidosis [see Warnings and Precautions (5.1)]
• Pancreatitis [see Warnings and Precautions (5.2)]
• Lower Limb Amputation [see Warnings and Precautions (5.3)]
• Acute Renal Failure [see Warnings and Precautions (5.4)]
• Volume Depletion [see Warnings and Precautions (5.5)]
• Urosepsis and Pyelonephritis [see Warnings and Precautions (5.6)]
• Heart Failure [see Warnings and Precautions (5.7)]
• Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.8)]
• Necrotizing Fasciitis of the Perineum (Fournier's Gangrene) [see Warnings and Precautions (5.9)]
• Genital Mycotic Infections [see Warnings and Precautions (5.10)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.11)]
• Severe and Disabling Arthralgia [see Warnings and Precautions (5.12)]
• Bullous Pemphigoid [see Warnings and Precautions (5.13)]

• Most common adverse reactions associated with ertugliflozin (incidence ≥5%): female genital mycotic infections. (6.1)
• Most common adverse reactions associated with sitagliptin (incidence ≥5%): upper respiratory tract infection, nasopharyngitis and headache. In the add-on to sulfonylurea and add-on to insulin studies, hypoglycemia was also more commonly reported in patients treated with sitagliptin compared to placebo. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Ertugliflozin and Sitagliptin

The safety of concomitantly administered ertugliflozin and sitagliptin has been evaluated in 990 patients with type 2 diabetes mellitus treated for 26 weeks in three studies; a factorial study of ertugliflozin 5 mg or 15 mg in combination with sitagliptin 100 mg once daily compared to the individual components, a placebo-controlled study of ertugliflozin 5 mg or 15 mg as add-on therapy to sitagliptin 100 mg and metformin once daily, and a placebo-controlled study of initial therapy with ertugliflozin 5 mg or 15 mg once daily in combination with sitagliptin 100 mg once daily [see Clinical Studies (14)]. The incidence and type of adverse reactions in these three studies were similar to the adverse reactions seen with ertugliflozin and described below in Table 1.

Ertugliflozin

Pool of Placebo-Controlled Trials

The data in Table 1 are derived from a pool of three 26-week, placebo-controlled trials. Ertugliflozin was used as monotherapy in one trial and as add-on therapy in two trials [see Clinical Studies (14)]. These data reflect exposure of 1,029 patients to ertugliflozin with a mean exposure duration of approximately 25 weeks. Patients received ertugliflozin 5 mg (N=519), ertugliflozin 15 mg (N=510), or placebo (N=515) once daily. The mean age of the population was 57 years and 2% were older than 75 years of age. Fifty-three percent (53%) of the population was male and 73% were Caucasian, 15% were Asian, and 7% were Black or African American. At baseline the population had diabetes for an average of 7.5 years, had a mean HbA1c of 8.1%, and 19.4% had established microvascular complications of diabetes. Baseline renal function (mean eGFR 88.9 mL/min/1.73 m²) was normal or mildly impaired in 97% of patients and moderately impaired in 3% of patients.

Table 1 shows common adverse reactions associated with the use of ertugliflozin. These adverse reactions were not present at baseline, occurred more commonly on ertugliflozin than on placebo, and occurred in at least 2% of patients treated with either ertugliflozin 5 mg or ertugliflozin 15 mg.

Table 1: Adverse Reactions Reported in ≥2% of Patients with Type 2 Diabetes Mellitus Treated with ErtugliflozinThe 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
	PlaceboN = 515	Ertugliflozin 5 mg N = 519	Ertugliflozin 15 mg N = 510
Female genital mycotic infectionsIncludes: 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 infectionsIncludes: 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 infectionsIncludes: cystitis, dysuria, streptococcal urinary tract infection, urethritis, urinary tract infection.	3.9%	4.0%	4.1%
Headache	2.3%	3.5%	2.9%
Vaginal pruritusIncludes: 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 urinationIncludes: 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%
ThirstIncludes: thirst, dry mouth, polydipsia, and dry throat.	0.6%	2.7%	1.4%

Volume Depletion

Ertugliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion, particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m²). In patients with moderate renal impairment, adverse reactions related to volume depletion (e.g., dehydration, dizziness postural, presyncope, syncope, hypotension, and orthostatic hypotension) were reported in 0%, 4.4%, and 1.9% of patients treated with placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively. Ertugliflozin may also increase the risk of hypotension in other patients at risk for volume contraction [see Use in Specific Populations (8.5, 8.6)].

Hypoglycemia

The incidence of hypoglycemia by study is shown in Table 2.

Table 2: Incidence of OverallOverall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL. and SevereSevere hypoglycemic events: required assistance, lost consciousness, or experienced a seizure regardless of blood glucose. Hypoglycemia in Placebo-Controlled Clinical Studies in Patients with Type 2 Diabetes Mellitus

Factorial Study with Sitagliptin as Add-on Combination Therapy with Metformin (26 weeks)		Ertugliflozin 5 mg + Sitagliptin(N = 243)	Ertugliflozin 15 mg + Sitagliptin(N = 244)
Overall [N (%)]		13 (5.3)	22 (9.0)
Severe [N (%)]		0 (0.0)	1 (0.4)
Add-on Combination Therapy with Metformin and Sitagliptin (26 weeks)	Placebo(N = 153)	Ertugliflozin 5 mg(N = 156)	Ertugliflozin 15 mg(N = 153)
Overall [N (%)]	5 (3.3)	7 (4.5)	3 (2.0)
Severe [N (%)]	1 (0.7)	1 (0.6)	0 (0.0)
Initial Combination Therapy with Sitagliptin (26 weeks)	Placebo(N = 97)	Ertugliflozin 5 mg + Sitagliptin(N = 98)	Ertugliflozin 15 mg + Sitagliptin(N = 96)
Overall [N (%)]	1 (1.0)	6 (6.1)	3 (3.1)
Severe [N (%)]	0 (0.0)	0 (0.0)	2 (2.1)

Genital Mycotic Infections

In the pool of three placebo-controlled clinical trials, the incidence of female genital mycotic infections (e.g., genital candidiasis, genital infection fungal, vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis) occurred in 3%, 9.1%, and 12.2% of females treated with placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively (see Table 1). In females, discontinuation due to genital mycotic infections occurred in 0% and 0.6% of patients treated with placebo and ertugliflozin, respectively.

In the same pool, male genital mycotic infections (e.g., balanitis candida, balanoposthitis, genital infection, genital infection fungal) occurred in 0.4%, 3.7%, and 4.2% of males treated with placebo, ertugliflozin 5 mg, ertugliflozin 15 mg, respectively (see Table 1). Male genital mycotic infections occurred more commonly in uncircumcised males. In males, discontinuations due to genital mycotic infections occurred in 0% and 0.2% of patients treated with placebo and ertugliflozin, respectively. Phimosis was reported in 8 of 1,729 (0.5%) male ertugliflozin-treated patients, of which four required circumcision.

Urinary Tract Infections

In VERTIS CV, urinary tract infections (e.g., urinary tract infection, cystitis, dysuria) occurred in 10.2%, 12.2% and 12.0% of patients treated with placebo, ertugliflozin 5 mg and ertugliflozin 15 mg, respectively. The incidences of serious urinary tract infections were 0.8%, 0.9% and 0.4% with placebo, ertugliflozin 5 mg and ertugliflozin 15 mg, respectively.

Sitagliptin

The following additional adverse reactions have been reported in clinical studies with sitagliptin: upper respiratory tract infection, nasopharyngitis, headache, abdominal pain, nausea, diarrhea. In addition, in a study of sitagliptin as add-on combination therapy with metformin and rosiglitazone, peripheral edema was noted with a higher incidence than placebo.

In a pooled analysis of the two monotherapy studies, the add-on to metformin study, and the add-on to pioglitazone study, the overall incidence of adverse reactions of hypoglycemia was 1.2% in patients treated with sitagliptin 100 mg and 0.9% in patients treated with placebo. In the add-on to sulfonylurea and add-on to insulin studies, hypoglycemia was also more commonly reported in patients treated with sitagliptin compared to placebo. In the add-on to glimepiride (+/- metformin) study, the overall incidence of hypoglycemia was 12.2% in patients treated with sitagliptin 100 mg and 1.8% in patients treated with placebo. In the add-on to insulin (+/- metformin) study, the overall incidence of hypoglycemia was 15.5% in patients treated with sitagliptin 100 mg and 7.8% in patients treated with placebo. In all studies, adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia. A concurrent blood glucose measurement was not required although most (74%) reports of hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL.

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

Laboratory Tests

Ertugliflozin

Changes in Serum Creatinine and eGFR

Initiation of ertugliflozin causes an increase in serum creatinine and decrease in eGFR within weeks of starting therapy and then these changes stabilize. In a study of patients with moderate renal impairment, larger mean changes were observed. In a long-term cardiovascular outcomes trial, an initial increase in serum creatinine and a decrease in eGFR within weeks of starting therapy was observed (at Week 6 eGFR changes of -2.7, -3.8 and -0.4 mL/min/1.73 m² 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 m² in ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo arms, respectively). Acute hemodynamic changes may play a role in the early renal function changes observed with ertugliflozin since they are reversed after treatment discontinuation.

Increases in Low-Density Lipoprotein Cholesterol (LDL-C)

In the pool of three placebo-controlled trials, dose-related increases in LDL-C were observed in patients treated with ertugliflozin. Mean percent changes from baseline to Week 26 in LDL-C relative to placebo were 2.6% and 5.4% with ertugliflozin 5 mg and ertugliflozin 15 mg, respectively. The range of mean baseline LDL-C was 96.6 to 97.7 mg/dL across treatment groups.

Increases in Hemoglobin

In the pool of three placebo-controlled trials, mean changes (percent changes) from baseline to Week 26 in hemoglobin were -0.21 g/dL (-1.4%) with placebo, 0.46 g/dL (3.5%) with ertugliflozin 5 mg, and 0.48 g/dL (3.5%) with ertugliflozin 15 mg. The range of mean baseline hemoglobin was 13.90 to 14.00 g/dL across treatment groups. At the end of treatment, 0.0%, 0.2%, and 0.4% of patients treated with placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively, had a hemoglobin increase greater than 2 g/dL and above the upper limit of normal.

Increases in Serum Phosphate

In the pool of three placebo-controlled trials, mean changes (percent changes) from baseline in serum phosphate were 0.04 mg/dL (1.9%) with placebo, 0.21 mg/dL (6.8%) with ertugliflozin 5 mg, and 0.26 mg/dL (8.5%) with ertugliflozin 15 mg. The range of mean baseline serum phosphate was 3.53 to 3.54 mg/dL across treatment groups. In a clinical trial of patients with moderate renal impairment, mean changes (percent changes) from baseline at Week 26 in serum phosphate were -0.01 mg/dL (0.8%) with placebo, 0.29 mg/dL (9.7%) with ertugliflozin 5 mg, and 0.24 mg/dL (7.8%) with ertugliflozin 15 mg.

Sitagliptin

Across clinical studies, the incidence of laboratory adverse reactions was similar in patients treated with sitagliptin 100 mg compared to patients treated with placebo. A small increase in white blood cell count (WBC) was observed due to an increase in neutrophils. This increase in WBC (of approximately 200 cells/microL vs. placebo, in four pooled placebo-controlled clinical studies, with a mean baseline WBC count of approximately 6,600 cells/microL) is not considered to be clinically relevant. In a 12-week study of 91 patients with chronic renal insufficiency, 37 patients with moderate renal insufficiency were randomized to sitagliptin 50 mg daily, while 14 patients with the same magnitude of renal impairment were randomized to placebo. Mean (SE) increases in serum creatinine were observed in patients treated with sitagliptin [0.12 mg/dL (0.04)] and in patients treated with placebo [0.07 mg/dL (0.07)]. The clinical significance of this added increase in serum creatinine relative to placebo is not known.

6.2Postmarketing 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.

Sitagliptin

Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome; hepatic enzyme elevations; acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis [see Indications and Usage (1)]; worsening renal function, including acute renal failure (sometimes requiring dialysis) and tubulointerstitial nephritis; severe and disabling arthralgia; bullous pemphigoid; constipation; vomiting; headache; myalgia; pain in extremity; back pain; pruritus; mouth ulceration; stomatitis; rhabdomyolysis.

Ertugliflozin

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