近日，FDA批准默沙东/辉瑞联合开发的新复方片剂Steglujan（ertugliflozin/sitagliptin）上市。Steglujan(ertugliflozin/sitagliptin) 是一种葡萄糖共转运蛋白2(SGLT2) 抑制剂和二 peptidase-4(DPP-4) 抑制剂的结合, 作为膳食和运动的辅助, 以改善2型糖尿病成人的血糖控制。
Ertugliflozin被批准为单一疗法：始剂量是5毫克/100毫克，每天服用一次。

Steglujan(Ertugliflozin and Sitagliptin Tablets)
1. DESCRIPTION 
STEGLUJAN (ertugliflozin and sitagliptin) tablet for oral use contains ertugliflozin L-pyroglutamic acid, a SGLT2 inhibitor, and sitagliptin phosphate, a DPP-4 inhibitor.
Ertugliflozin
The chemical name of ertugliflozin L-pyroglutamic acid is (1S,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol, compound with (2S)-5-oxopyrrolidine-2-carboxylic acid. The chemical structure is:

Empirical formula: C27H32ClNO10 - Molecular weight: 566.00
Ertugliflozin L-pyroglutamic acid is a white to off-white powder that is soluble in ethyl alcohol and acetone, slightly soluble in ethyl acetate and acetonitrile and very slightly soluble in water.
Sitagliptin
Sitagliptin phosphate monohydrate is described chemically as 7-[(3R)-3-amino-1-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate. The structural formula is:

Empirical formula: C16H15F6N5O•H3PO4•H2O - Molecular weight: 523.32
Sitagliptin phosphate monohydrate is a white to off-white, crystalline, non-hygroscopic powder. It is soluble in water and N,N-dimethyl formamide; slightly soluble in methanol; very slightly soluble in ethanol, acetone, and acetonitrile; and insoluble in isopropanol and isopropyl acetate.
STEGLUJAN is available for oral use as film-coated tablets containing:
• 6.48 mg ertugliflozin L-pyroglutamic acid equivalent to 5 mg of ertugliflozin and 128.5 mg sitagliptin phosphate monohydrate equivalent to 100 mg sitagliptin (STEGLUJAN 5/100)
• 19.43 mg ertugliflozin L-pyroglutamic acid equivalent to 15 mg of ertugliflozin and 128.5 mg sitagliptin phosphate monohydrate equivalent to 100 mg sitagliptin (STEGLUJAN 15/100)
Inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, croscarmellose sodium, sodium stearyl fumarate, and magnesium stearate.
The film coating contains: hypromellose, hydroxypropyl cellulose, titanium dioxide, iron oxide red, iron oxide yellow, ferrosoferric oxide/black iron oxide, and carnauba wax.
2. INDICATIONS AND USAGE 
STEGLUJAN™ is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both ertugliflozin and sitagliptin is appropriate.
Limitations of Use
STEGLUJAN is not recommended in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
STEGLUJAN 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 (5.1).]
3. DOSAGE AND ADMINISTRATION 
3.1 Recommended Dosage
• The recommended starting dose of STEGLUJAN is 5 mg ertugliflozin/100 mg sitagliptin once daily, taken in the morning, with or without food. In patients tolerating STEGLUJAN, the dose may be increased to a maximum recommended dose of 15 mg ertugliflozin/100 mg sitagliptin, once daily, if additional glycemic control is needed.
• For patients treated with ertugliflozin who are being switched to STEGLUJAN, the dose of ertugliflozin can be maintained.
• In patients with volume depletion, correct this condition prior to initiation of STEGLUJAN [see Warnings and Precautions (5.2)].
3.2 Patients with Renal Impairment
• Assess renal function prior to initiation of STEGLUJAN and periodically thereafter [see Warnings and Precautions (5.4)].
• Use of STEGLUJAN is contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m2 [see Contraindications (4)].
• Initiation of STEGLUJAN is not recommended in patients with an eGFR of 30 mL/minute/1.73 m2 to less than 60 mL/minute/1.73 m2 [see Warnings and Precautions (5.4) and Use in Specific Populations (8.6)].
• Continued use of STEGLUJAN is not recommended when eGFR is persistently between 30 and less than 60 mL/min/1.73 m2.
• No dose adjustment is needed in patients with mild renal impairment.
4. CONTRAINDICATIONS 
• Severe renal impairment, end-stage renal disease (ESRD), or dialysis [see Warnings and Precautions (5.4) and Use in Specific Populations (8.6)].
• History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema [see Warnings and Precautions (5.10) and Adverse Reactions (6.2)].
• History of a serious hypersensitivity reaction to ertugliflozin.
5. WARNINGS AND PRECAUTIONS 
5.1 Pancreatitis
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.
5.2 Hypotension
Ertugliflozin, a component of STEGLUJAN, causes intravascular volume contraction. Therefore, symptomatic hypotension may occur after initiating STEGLUJAN [see Adverse Reactions (6.1)] particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2) [see Use in Specific Populations (8.6)], elderly patients (≥65 years), in patients with low systolic blood pressure, and in patients on diuretics. Before initiating STEGLUJAN, volume status should be assessed and corrected if indicated. Monitor for signs and symptoms of hypotension after initiating therapy.
5.3 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 medicines containing sodium glucose co-transporter-2 (SGLT2) inhibitors and cases have been reported in ertugliflozin-treated patients in clinical trials. Across the clinical program, ketoacidosis was identified in 3 of 3,409 (0.1%) of ertugliflozin-treated patients and 0% of comparator-treated patients. Fatal cases of ketoacidosis have been reported in patients taking medicines containing SGLT2 inhibitors. STEGLUJAN is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications and Usage (1)].
Patients treated with STEGLUJAN 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 STEGLUJAN may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, STEGLUJAN 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 due to illness or surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified.
Before initiating STEGLUJAN, consider factors in the patient history that may predispose to ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. In patients treated with STEGLUJAN consider monitoring for ketoacidosis and temporarily discontinuing STEGLUJAN in clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).
5.4 Acute Kidney Injury and Impairment in Renal Function
STEGLUJAN causes intravascular volume contraction and can cause renal impairment [see Adverse Reactions (6.1)]. There have been postmarketing reports of acute kidney injury some requiring hospitalization and dialysis in patients receiving SGLT2 inhibitors.
Before initiating STEGLUJAN, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing STEGLUJAN in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue STEGLUJAN promptly and institute treatment.
Ertugliflozin, a component of STEGLUJAN, increases serum creatinine and decreases eGFR. Patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2) may be more susceptible to these changes. Renal function abnormalities can occur after initiating STEGLUJAN [see Adverse Reactions (6.1)]. Renal function should be evaluated prior to initiating STEGLUJAN and periodically thereafter. Use of STEGLUJAN is not recommended when eGFR is persistently between 30 and less than 60 mL/min/1.73 m2 and is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Dosage and Administration (3.2), Contraindications (4), and Use in Specific Populations (8.6)].
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.
5.5 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. Cases of pyelonephritis also have been reported in ertugliflozin-treated patients in clinical trials. 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 (6.1)].
5.6 Lower Limb Amputation
An increased risk for lower limb amputation (primarily of the toe) has been observed in clinical studies with another SGLT2 inhibitor. Across seven Phase 3 clinical trials in the ertugliflozin development program, 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. A causal association between ertugliflozin and lower limb amputation has not been definitively established.
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.
5.7 Heart 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.
5.8 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. Ertugliflozin, a component of STEGLUJAN, may increase the risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue [see Adverse Reactions (6.1)]. When sitagliptin, a component of STEGLUJAN, was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin. [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 STEGLUJAN.
5.9 Genital Mycotic Infections
Ertugliflozin, a component of STEGLUJAN, 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.
5.10 Hypersensitivity Reactions
There have been postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, a component of STEGLUJAN. 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.
5.11 Increases in Low-Density Lipoprotein Cholesterol (LDL-C)
Dose-related increases in LDL-C can occur with ertugliflozin, a component of STEGLUJAN [see Adverse Reactions (6.1)]. Monitor and treat as appropriate.
5.12 Severe 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.
5.13 Bullous 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 blisters 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.
5.14 Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with STEGLUJAN.
6. ADVERSE REACTIONS 
The following important adverse reactions are described elsewhere in the labeling:
• Pancreatitis [see Warnings and Precautions (5.1)]
• Hypotension [see Warnings and Precautions (5.2)]
• Ketoacidosis [see Warnings and Precautions (5.3)]
• Acute Kidney Injury and Impairment in Renal Function [see Warnings and Precautions (5.4)]
• Urosepsis and Pyelonephritis [see Warnings and Precautions (5.5)]
• Lower Limb Amputation [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)]
• Genital Mycotic Infections [see Warnings and Precautions (5.9)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.10)]
• Increases in Low-Density Lipoprotein (LDL-C) [see Warnings and Precautions (5.11)]
• Severe and Disabling Arthralgia [see Warnings and Precautions (5.12)]
• Bullous Pemphigoid [see Warnings and Precautions (5.13)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Ertugliflozin and Sitagliptin
The safety of concomitantly administered ertugliflozin and sitagliptin has been evaluated in 990 patients with type 2 diabetes mellitus treated for 26 weeks in three studies; a factorial study of ertugliflozin 5 mg or 15 mg in combination with sitagliptin 100 mg once daily compared to the individual components, a placebo-controlled study of ertugliflozin 5 mg or 15 mg as add-on therapy to sitagliptin 100 mg and metformin 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]. 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 Ertugliflozin* and Greater than Placebo in Pooled Placebo-Controlled Clinical Studies of Ertugliflozin Monotherapy or Combination Therapy

The three placebo controlled studies included one monotherapy trial and two add-on combination trials with metformin or with metformin and sitagliptin.
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).
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).
Includes: cystitis, dysuria, streptococcal urinary tract infection, urethritis, urinary tract infection.
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).
Includes: pollakiuria, micturition urgency, polyuria, urine output increased, and nocturia.
Þ Includes: thirst, dry mouth, polydipsia, and dry throat.
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)].
Ketoacidosis
Across the clinical program, ketoacidosis was identified in 3 of 3,409 (0.1%) ertugliflozin-treated patients and 0.0% of comparator-treated patients [see Warnings and Precautions (5.3)].
Impairment in Renal Function
Treatment with ertugliflozin was associated with increases in serum creatinine and decreases in eGFR (see Table 2). Patients with moderate renal impairment at baseline had larger mean changes. In a study in patients with moderate renal impairment, these abnormal laboratory findings were observed to reverse after treatment discontinuation [see Use in Specific Populations (8.5, 8.6)].
Table 2: Changes from Baseline in Serum Creatinine and eGFR in the Pool of Three 26-Week Placebo-Controlled Studies and a 26-Week Moderate Renal Impairment Study in Patients with Type 2 Diabetes Mellitus

Renal-related adverse reactions (e.g., acute kidney injury, renal impairment, acute prerenal failure) may occur in patients treated with ertugliflozin, particularly in patients with moderate renal impairment where the incidence of renal-related adverse reactions was 0.6%, 2.5%, and 1.3% in patients treated with placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively.
Lower Limb Amputation
Across seven Phase 3 clinical trials in which ertugliflozin was studied as monotherapy and in combination with other antihyperglycemic agents, non-traumatic lower limb amputations occurred in 1 of 1,450 (0.1%) in the non-ertugliflozin group, 3 of 1,716 (0.2%) in the ertugliflozin 5 mg group, and 8 of 1,693 (0.5%) in the ertugliflozin 15 mg group.
Hypoglycemia
The incidence of hypoglycemia by study is shown in Table 3.
Table 3: Incidence of Overall* and Severe† Hypoglycemia in Placebo-Controlled Clinical Studies in Patients with Type 2 Diabetes Mellitus

Overall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL.
Severe hypoglycemic events: required assistance, lost consciousness, or experienced a seizure regardless of blood glucose.
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 1729 (0.5%) male ertugliflozin-treated patients, of which four required circumcision.
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
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 [see Warnings and Precautions (5.11)].
Increases in Hemoglobin
In the pool of three placebo-controlled trials, mean changes (percent changes) from baseline to Week 26 in hemoglobin were -0.21 g/dL (-1.4%) with placebo, 0.46 g/dL (3.5%) with ertugliflozin 5 mg, and 0.48 g/dL (3.5%) with ertugliflozin 15 mg. The range of mean baseline hemoglobin was 13.90 to 14.00 g/dL across treatment groups. At the end of treatment, 0.0%, 0.2%, and 0.4% of patients treated with placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively, had a hemoglobin increase greater than 2 g/dL and above the upper limit of normal.
Increases in Serum Phosphate
In the pool of three placebo-controlled trials, mean changes (percent changes) from baseline in serum phosphate were 0.04 mg/dL (1.9%) with placebo, 0.21 mg/dL (6.8%) with ertugliflozin 5 mg, and 0.26 mg/dL (8.5%) with ertugliflozin 15 mg. The range of mean baseline serum phosphate was 3.53 to 3.54 mg/dL across treatment groups. In a clinical trial of patients with moderate renal impairment, mean changes (percent changes) from baseline at Week 26 in serum phosphate were -0.01 mg/dL (0.8%) with placebo, 0.29 mg/dL (9.7%) with ertugliflozin 5 mg, and 0.24 mg/dL (7.8%) with ertugliflozin 15 mg.
Sitagliptin
Across clinical studies, the incidence of laboratory adverse reactions was similar in patients treated with sitagliptin 100 mg compared to patients treated with placebo. A small increase in white blood cell count (WBC) was observed due to an increase in neutrophils. This increase in WBC (of approximately 200 cells/microL vs. placebo, in four pooled placebo-controlled clinical studies, with a mean baseline WBC count of approximately 6,600 cells/microL) is not considered to be clinically relevant. In a 12-week study of 91 patients with chronic renal insufficiency, 37 patients with moderate renal insufficiency were randomized to sitagliptin 50 mg daily, while 14 patients with the same magnitude of renal impairment were randomized to placebo. Mean (SE) increases in serum creatinine were observed in patients treated with sitagliptin [0.12 mg/dL (0.04)] and in patients treated with placebo [0.07 mg/dL (0.07)]. The clinical significance of this added increase in serum creatinine relative to placebo is not known.
6.2 Postmarketing Experience
Sitagliptin
Additional adverse reactions have been identified during postapproval use of sitagliptin, a component of STEGLUJAN, as monotherapy and/or in combination with other antihyperglycemic agents. 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.
Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome [see Warnings and Precautions (5.10)]; hepatic enzyme elevations; acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis [see Indications and Usage (2) and Warnings and Precautions (5.1)]; worsening renal function, including acute renal failure (sometimes requiring dialysis) [see Warnings and Precautions (5.4)]; severe and disabling arthralgia [see Warnings and Precautions (5.12)]; bullous pemphigoid [see Warnings and Precautions (5.13)]; constipation; vomiting; headache; myalgia; pain in extremity; back pain; pruritus.
7. DRUG INTERACTIONS 
7.1 Concomitant Use with Insulin and Insulin Secretagogues
STEGLUJAN 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 STEGLUJAN [see Warnings and Precautions (5.8)].
7.2 Positive Urine Glucose Test
Monitoring glycemic control with urine glucose tests is not recommended in patients taking medicines containing an SGLT2 inhibitor as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Use alternative methods to monitor glycemic control.
7.3 Interference with 1,5-anhydroglucitol (1,5-AG) Assay
Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking medicines containing an SGLT2 inhibitor. Use alternative methods to monitor glycemic control.
7.4 Digoxin
There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (Cmax, 18%) of digoxin with the coadministration of 100 mg sitagliptin for 10 days. Patients receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or STEGLUJAN is recommended.
8. USE IN SPECIFIC POPULATIONS 
8.1 Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to sitagliptin during pregnancy. Health care providers are encouraged to report any prenatal exposure to STEGLUJAN by calling the Pregnancy Registry at 1-800-986-8999.
Risk Summary
Based on animal data showing adverse renal effects, from ertugliflozin, STEGLUJAN is not recommended during the second and third trimesters of pregnancy.
The limited available data with ertugliflozin and sitagliptin use during pregnancy are not sufficient to determine a drug associated risk of adverse developmental outcomes. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations).
In animal studies, adverse renal changes were observed in rats when ertugliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy. Doses approximately 13 times the maximum clinical dose caused renal pelvic and tubule dilatations and renal mineralization that were not fully reversible. There was no evidence of fetal harm in rats or rabbits at exposures of ertugliflozin approximately 300 times higher than the maximal clinical dose of 15 mg/day when administered during organogenesis (see Data).
In rats and rabbits, sitagliptin doses of 250 and 125 mg/kg, respectively (approximately 30 and 20 times the human exposure at the maximum recommended human dose) did not adversely affect development outcomes of either species.
The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
Poorly-controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.
Data
Animal Data
Ertugliflozin
When ertugliflozin was orally administered to juvenile rats from PND 21 to PND 90, increased kidney weight, renal tubule and renal pelvis dilatation, and renal mineralization occurred at doses greater than or equal to 5 mg/kg (13-fold human exposures, based on AUC). These effects occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development, and did not fully reverse within a 1-month recovery period.
In embryo-fetal development studies, ertugliflozin (50, 100 and 250 mg/kg/day) was administered orally to rats on gestation days 6 to 17 and to rabbits on gestation days 7 to 19. Ertugliflozin did not adversely affect developmental outcomes in rats and rabbits at maternal exposures that were approximately 300 times the human exposure at the maximum clinical dose of 15 mg/day, based on AUC. A maternally toxic dose (250 mg/kg/day) in rats (707 times the clinical dose) was associated with reduced fetal viability, and a higher incidence of a visceral malformation (membranous ventricular septal defect). In the pre-and post-natal development study in pregnant rats, ertugliflozin was administered to the dams from gestation day 6 through lactation day 21 (weaning). Decreased post-natal growth (weight gain) was observed at maternal doses ≥100 mg/kg/day (greater than or equal to 331 times the human exposure at the maximum clinical dose of 15 mg/day, based on AUC).
Sitagliptin
Sitagliptin administered to pregnant female rats and rabbits from gestation day 6 to 20 (organogenesis) did not adversely affect developmental outcomes at oral doses up to 250 mg/kg (rats) and 125 mg/kg (rabbits), or approximately 30 and 20 times human exposure at the maximum recommended human dose (MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased the incidence of rib malformations in offspring at 1,000 mg/kg, or approximately 100 times human exposure at the MRHD.
Sitagliptin administered to female rats from gestation day 6 to lactation day 21 decreased body weight in male and female offspring at 1,000 mg/kg. No functional or behavioral toxicity was observed in offspring of rats. Placental transfer of sitagliptin administered to pregnant rats was approximately 45% at 2 hours and 80% at 24 hours postdose.
Placental transfer of sitagliptin administered to pregnant rabbits was approximately 66% at 2 hours and 30% at 24 hours.
8.2 Lactation
Risk Summary
There is no information regarding the presence of STEGLUJAN, in human milk, the effects on the breastfed infant, or the effects on milk production. Ertugliflozin and sitagliptin are present in the milk of lactating rats (see Data). Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney, based on data with ertugliflozin. Because of the potential for serious adverse reactions in a breastfed infant, advise women that the use of STEGLUJAN is not recommended while breastfeeding.
Data
Animal Data
Ertugliflozin
The lacteal excretion of radiolabeled ertugliflozin in lactating rats was evaluated 10 to 12 days after parturition. Ertugliflozin derived radioactivity exposure in milk and plasma were similar, with a milk/plasma ratio of 1.07, based on AUC. Juvenile rats directly exposed to ertugliflozin during a developmental period corresponding to human kidney maturation were associated with a risk to the developing kidney (persistent increased organ weight, renal mineralization, and renal pelvic and tubular dilatations).
Sitagliptin
Sitagliptin is secreted in the milk of lactating rats at a milk to plasma ratio of 4:1.
8.4 Pediatric Use
Safety and effectiveness of STEGLUJAN in pediatric patients under 18 years of age have not been established.
8.5 Geriatric Use
STEGLUJAN
No dosage adjustment of STEGLUJAN is recommended based on age. Elderly patients are more likely to have decreased renal function. Because renal function abnormalities can occur after initiating ertugliflozin, and sitagliptin is known to be substantially excreted by the kidneys, renal function should be assessed more frequently in elderly patients [see Dosage and Administration (3.2) and Warnings and Precautions (5.4)]. STEGLUJAN is expected to have diminished efficacy in elderly patients with renal impairment [see Use in Specific Populations (8.6)].
Ertugliflozin
Across the clinical program, a total of 876 (25.7%) patients treated with ertugliflozin were 65 years and older, and 152 (4.5%) patients treated with ertugliflozin 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, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].
Sitagliptin
Of the total number of subjects (N=3,884) in pre-approval clinical safety and efficacy studies of sitagliptin, 725 patients were 65 years and over, while 61 patients were 75 years and over. No overall differences in safety or effectiveness were observed between subjects 65 years and over and younger subjects. While this and other reported clinical experience have not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.
8.6 Renal Impairment
The safety and efficacy of ertugliflozin have not been established in patients with type 2 diabetes mellitus and moderate renal impairment. Compared to placebo-treated patients, patients with moderate renal impairment treated with ertugliflozin did not have improvement in glycemic control, and had increased risks for renal impairment, renal-related adverse reactions and volume depletion adverse reactions [see Dosage and Administration (3.2), Warnings and Precautions (5.4), and Adverse Reactions (6.1)]. Therefore, STEGLUJAN is not recommended in this population.
STEGLUJAN is contraindicated in patients with severe renal impairment, ESRD, or receiving dialysis. STEGLUJAN is not expected to be effective in these patient populations [see Contraindications (4)].
No dosage adjustment or increased monitoring is needed in patients with mild renal impairment.
8.7 Hepatic Impairment
No dosage adjustment of STEGLUJAN is necessary in patients with mild or moderate hepatic impairment. STEGLUJAN has not been studied in patients with severe hepatic impairment and is not recommended for use in this patient population [see Clinical Pharmacology].
9. OVERDOSAGE 
STEGLUJAN
In the event of an overdose with STEGLUJAN, contact the Poison Control Center. Employ the usual supportive measures as dictated by the patient’s clinical status.
Ertugliflozin
Removal of ertugliflozin by hemodialysis has not been studied.
Sitagliptin
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy as dictated by the patient's clinical status.
Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3-to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.
10. MECHANISM OF ACTION 
STEGLUJAN
STEGLUJAN combines two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus: ertugliflozin, a SGLT2 inhibitor, and sitagliptin, a DPP-4 inhibitor.
Ertugliflozin
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.
Sitagliptin
Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes mellitus by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
11. PHARMACODYNAMICS  
Ertugliflozin
Urinary Glucose Excretion and Urinary Volume
Dose-dependent increases in the amount of glucose excreted in urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following single-and multiple-dose administration of ertugliflozin. Dose-response modeling indicates that ertugliflozin 5 mg and 15 mg result in near maximal urinary glucose excretion (UGE). Enhanced UGE is maintained after multiple-dose administration. UGE with ertugliflozin also results in increases in urinary volume.
Cardiac Electrophysiology
The effect of ertugliflozin on QTc interval was evaluated in a Phase 1 randomized, placebo-and positive-controlled 3-period crossover study in 42 healthy subjects. At 6.7 times the therapeutic exposures with maximum recommended dose, ertugliflozin does not prolong QTc to any clinically relevant extent.
Sitagliptin
General
In patients with type 2 diabetes mellitus, administration of sitagliptin led to inhibition of DPP-4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2-to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased responsiveness of insulin release to glucose, resulting in higher C-peptide and insulin concentrations. The rise in insulin with the decrease in glucagon was associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.
In a two-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations, whereas metformin alone increased active and total GLP-1 concentrations to similar extents. Coadministration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations. Sitagliptin, but not metformin, increased active GIP concentrations. It is unclear how these findings relate to changes in glycemic control in patients with type 2 diabetes mellitus.
In studies with healthy subjects, sitagliptin did not lower blood glucose or cause hypoglycemia.
Cardiac Electrophysiology
In a randomized, placebo controlled crossover study, 79 healthy subjects were administered a single oral dose of sitagliptin 100 mg, sitagliptin 800 mg (8 times the recommended dose), and placebo. At the recommended dose of 100 mg, there was no effect on the QTc interval obtained at the peak plasma concentration, or at any other time during the study. Following the 800 mg dose, the maximum increase in the placebo corrected mean change in QTc from baseline was observed at 3 hours postdose and was 8.0 msec. This increase is not considered to be clinically significant. At the 800 mg dose, peak sitagliptin plasma concentrations were approximately 11 times higher than the peak concentrations following a 100-mg dose.
In patients with type 2 diabetes mellitus administered sitagliptin 100 mg (N=81) or sitagliptin 200 mg (N=63) daily, there were no meaningful changes in QTc interval based on ECG data obtained at the time of expected peak plasma concentration.
12. PHARMACOKINETICS  
General Introduction
Ertugliflozin
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.
Sitagliptin
The pharmacokinetics of sitagliptin have been extensively characterized in healthy subjects and patients with type 2 diabetes mellitus. After oral administration of a 100-mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose. Plasma AUC of sitagliptin increased in a dose proportional manner. Following a single oral 100-mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 μM•hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100-mg doses at steady state compared to the first dose. The intra subject and inter subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes mellitus.
Absorption
STEGLUJAN
The effects of a high-fat meal on the pharmacokinetics of ertugliflozin and sitagliptin when administered as STEGLUJAN tablets are comparable to those reported for the individual tablets. Administration of STEGLUJAN with food decreased ertugliflozin Cmax by 29% and had no meaningful effect on ertugliflozin AUCinf, and on sitagliptin AUCinf and Cmax.
Ertugliflozin
Following single-dose oral administration of 5 mg and 15 mg of ertugliflozin, peak plasma concentrations of ertugliflozin occur at 1 hour postdose (median Tmax) under fasted conditions. Plasma Cmax and AUC of ertugliflozin increase in a dose-proportional manner following single doses from 0.5 mg (0.1 times the lowest recommended dose) to 300 mg (20 times the highest recommended dose) and following multiple doses from 1 mg (0.2 times the lowest recommended dose) to 100 mg (6.7 times the highest recommended dose). The absolute oral bioavailability of ertugliflozin following administration of a 15 mg dose is approximately 100%.
Effect of Food
Administration of ertugliflozin with a high-fat and high-calorie meal decreases ertugliflozin Cmax by 29% and prolongs Tmax by 1 hour, but does not alter AUC as compared with the fasted state. The observed effect of food on ertugliflozin pharmacokinetics is not considered clinically relevant, and ertugliflozin may be administered with or without food. In Phase 3 clinical trials, ertugliflozin was administered without regard to meals.
Sitagliptin
The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high fat meal with sitagliptin had no effect on the pharmacokinetics, sitagliptin may be administered with or without food.
Distribution
Ertugliflozin
The mean steady-state volume of distribution of ertugliflozin following an intravenous dose is 85.5 L. Plasma protein binding of ertugliflozin is 93.6% and is independent of ertugliflozin plasma concentrations. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment. The blood-to-plasma concentration ratio of ertugliflozin is 0.66.
Sitagliptin
The mean volume of distribution at steady state following a single 100-mg intravenous dose of sitagliptin to healthy subjects is approximately 198 L. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).
Elimination
Metabolism
Ertugliflozin
Metabolism is the primary clearance mechanism for ertugliflozin. The major metabolic pathway for ertugliflozin is UGT1A9 and UGT2B7-mediated O-glucuronidation to two glucuronides that are pharmacologically inactive at clinically relevant concentrations. CYP-mediated (oxidative) metabolism of ertugliflozin is minimal (12%).
Sitagliptin
Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.
Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.
Excretion
Ertugliflozin
The mean systemic plasma clearance following an intravenous 100 μg dose was 11.2 L/hr. The mean elimination half-life in type 2 diabetic patients with normal renal function was estimated to be 16.6 hours based on the population pharmacokinetic analysis. Following administration of an oral [14C]-ertugliflozin solution to healthy subjects, approximately 40.9% and 50.2% of the drug-related radioactivity was eliminated in feces and urine, respectively. Only 1.5% of the administered dose was excreted as unchanged ertugliflozin in urine and 33.8% as unchanged ertugliflozin in feces, which is likely due to biliary excretion of glucuronide metabolites and subsequent hydrolysis to parent.
Sitagliptin
Following administration of an oral [14C]-sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100-mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.
Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.
Specific Populations
Patients with Renal Impairment
STEGLUJAN
Studies characterizing the pharmacokinetics of ertugliflozin and sitagliptin after administration of STEGLUJAN in renally impaired patients have not been performed [see Dosage and Administration (3.2)].
Ertugliflozin
In a Phase 1 clinical pharmacology study in patients with type 2 diabetes mellitus and mild, moderate, or severe renal impairment (as determined by eGFR), following a single-dose administration of 15 mg ertugliflozin, the mean increases in AUC of ertugliflozin were 1.6-, 1.7-, and 1.6-fold, respectively, for mild, moderate and severe renally impaired patients, compared to subjects with normal renal function. These increases in ertugliflozin AUC are not considered clinically meaningful. The 24-hour urinary glucose excretion declined with increasing severity of renal impairment [see Warnings and Precautions (5.4) and Use in Specific Populations (8.6)]. The plasma protein binding of ertugliflozin was unaffected in patients with renal impairment.
Sitagliptin
An approximately 2-fold increase in the plasma AUC of sitagliptin was observed in patients with moderate renal impairment with eGFR of 30 to less than 45 mL/min/1.73 m2, and an approximately 4-fold increase was observed in patients with severe renal impairment, including patients with ESRD on hemodialysis, as compared to normal healthy control subjects.
Patients with Hepatic Impairment
Ertugliflozin
Moderate hepatic impairment (based on the Child-Pugh classification) did not result in an increase in exposure of ertugliflozin. The AUC of ertugliflozin decreased by approximately 13%, and Cmax decreased by approximately 21% compared to subjects with normal hepatic function. This decrease in ertugliflozin exposure is not considered clinically meaningful. There is no clinical experience in patients with Child-Pugh class C (severe) hepatic impairment. The plasma protein binding of ertugliflozin was unaffected in patients with moderate hepatic impairment [see Use in Specific Populations (8.7)].
Sitagliptin
In patients with moderate hepatic insufficiency (Child Pugh score 7 to 9), mean AUC and Cmax of sitagliptin increased approximately 21% and 13%, respectively, compared to healthy matched controls following administration of a single 100-mg dose of sitagliptin. These differences are not considered to be clinically meaningful. No dosage adjustment for sitagliptin is necessary for patients with mild or moderate hepatic insufficiency.
There is no clinical experience in patients with severe hepatic insufficiency (Child Pugh score >9) [see Use in Specific Populations (8.7)].
Pediatric Patients
No studies with STEGLUJAN, ertugliflozin, and sitagliptin have been performed in pediatric patients.
Effects of Age, Body Weight/ Body Mass Index (BMI), Gender, and Race
Ertugliflozin
Based on a population pharmacokinetic analysis, age, body weight, gender, and race do not have a clinically meaningful effect on the pharmacokinetics of ertugliflozin. Sitagliptin
Based on a population pharmacokinetic analysis or a composite analysis of available pharmacokinetic data, BMI, gender, and race do not have a clinically meaningful effect on the pharmacokinetics of sitagliptin. When the effects of age on renal function are taken into account, age alone did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis. Elderly subjects (65 to 80 years) had approximately 19% higher plasma concentrations of sitagliptin compared to younger subjects.
Drug Interaction Studies
STEGLUJAN
Coadministration of single dose of ertugliflozin (15 mg) and sitagliptin (100 mg) did not meaningfully alter the pharmacokinetics of either ertugliflozin or metformin in healthy subjects.
Pharmacokinetic drug interaction studies with STEGLUJAN have not been performed; however, such studies have been conducted with ertugliflozin and sitagliptin, the individual components of STEGLUJAN.
Ertugliflozin
In Vitro Assessment of Drug Interactions
In in vitro studies, ertugliflozin and ertugliflozin glucuronides did not inhibit CYP450 isoenzymes (CYPs) 1A2, 2C9, 2C19, 2C8, 2B6, 2D6, or 3A4, and did not induce CYPs 1A2, 2B6, or 3A4. Ertugliflozin was not a time-dependent inhibitor of CYP3A in vitro. Ertugliflozin did not inhibit UGT1A6, 1A9, or 2B7 in vitro and was a weak inhibitor (IC50 >39 μM) of UGT1A1 and 1A4. Ertugliflozin glucuronides did not inhibit UGT1A1, 1A4, 1A6, 1A9, or 2B7 in vitro. Overall, ertugliflozin is unlikely to affect the pharmacokinetics of drugs eliminated by these enzymes. Ertugliflozin is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters and is not a substrate of organic anion transporters (OAT1, OAT3), organic cation transporters (OCT1, OCT2), or organic anion transporting polypeptides (OATP1B1, OATP1B3). Ertugliflozin or ertugliflozin glucuronides do not meaningfully inhibit P-gp, OCT2, OAT1, or OAT3 transporters, or transporting polypeptides OATP1B1 and OATP1B3, at clinically relevant concentrations. Overall, ertugliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are substrates of these transporters.
In Vivo Assessment of Drug Interactions
No dose adjustment of STEGLUJAN is recommended when coadministered with commonly prescribed medicinal products. Ertugliflozin pharmacokinetics were similar with and without coadministration of metformin, glimepiride, sitagliptin, and simvastatin in healthy subjects (see Figure 1). Coadministration of ertugliflozin with multiple doses of 600 mg once daily rifampin (an inducer of UGT and CYP enzymes) resulted in approximately 39% and 15% mean reductions in ertugliflozin AUC and Cmax, respectively, relative to ertugliflozin administered alone. These changes in exposure are not considered clinically relevant. Ertugliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, sitagliptin, and simvastatin when coadministered in healthy subjects (see Figure 2). Physiologically-based PK (PBPK) modeling suggests that coadministration of mefenamic acid (UGT inhibitor) may increase the AUC and Cmax of ertugliflozin by 1.51-and 1.19-fold, respectively. These predicted changes in exposure are not considered clinically relevant.
Figure 1: Effects of Other Drugs on the Pharmacokinetics of Ertugliflozin

Figure 2: Effects of Ertugliflozin on the Pharmacokinetics of Other Drugs

Sitagliptin
In Vitro Assessment of Drug Interactions
Sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4. Sitagliptin is a p-glycoprotein substrate, but does not inhibit p-glycoprotein mediated transport of digoxin. Based on these results, sitagliptin is considered unlikely to cause interactions with other drugs that utilize these pathways.
Sitagliptin is not extensively bound to plasma proteins. Therefore, the propensity of sitagliptin to be involved in clinically meaningful drug-drug interactions mediated by plasma protein binding displacement is very low.
In Vivo Assessment of Drug Interactions
Table 4: Effect of Coadministered Drugs on Systemic Exposure of Sitagliptin

All doses administered as single dose unless otherwise specified.
AUC is reported as AUC0-∞ unless otherwise specified.
Multiple dose.
AUC0-12hr.
Table 5: Effect of Sitagliptin on Systemic Exposure of Coadministered Drugs

* All doses administered as single dose unless otherwise specified. The 200 mg dose is 2 times the maximum recommended daily dose of sitagliptin.
AUC is reported as AUC0-∞ unless otherwise specified.
Multiple dose.
AUC0-24hr.
AUC0-last.
AUC0-12hr.
13. HOW SUPPLIED/STORAGE AND HANDLING 
How Supplied:
STEGLUJAN (ertugliflozin and sitagliptin) tablets are available in the strengths listed below:
STEGLUJAN 5 mg/100 mg: ertugliflozin 5 mg and sitagliptin 100 mg tablets are beige, almond- shaped, debossed with “554” on one side and plain on the other side. They are supplied as follows:
NDC 0006-5367-03 unit-of-use bottles of 30
NDC 0006-5367-06 unit-of-use bottles of 90
NDC 0006-5367-07 bulk bottles of 500
STEGLUJAN 15 mg/100 mg: ertugliflozin 15 mg and sitagliptin 100 mg tablets are brown, almond- shaped, debossed with “555” on one side and plain on the other side. They are supplied as follows:
NDC 0006-5368-03 unit-of-use bottles of 30
NDC 0006-5368-06 unit-of-use bottles of 90
NDC 0006-5368-07 bulk bottles of 500
Storage and Handling:
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].