Data from FDA - Curated by EPG Health - Last updated 07 June 2018

Indication(s)

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 when treatment with both ertugliflozin and sitagliptin is appropriate. STEGLUJAN is a combination of ertugliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, and sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, 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. (1) Limitations of Use: Not for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. (1) Has not been studied in patients with a history of pancreatitis. (1, 5.1) 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).]

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Advisory information

contraindications
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. Severe renal impairment, end stage renal disease, or dialysis. (4, 5.4) History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema. (4, 5.10, 6.2) History of serious hypersensitivity reaction to ertugliflozin. (4)
Adverse reactions
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)] 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 Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Ertugliflozin and 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 Placebo N = 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)]. 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 Pool of 26-Week Placebo-Controlled Studies Placebo N=515 Ertugliflozin 5 mg N=519 Ertugliflozin 15 mg N=510 Baseline Mean Creatinine (mg/dL) 0.83 0.82 0.82 eGFR (mL/min/1.73 m2) 89.5 88.2 89.0 Week 6 Change Creatinine (mg/dL) 0.00 0.03 0.03 eGFR (mL/min/1.73 m2) -0.3 -2.7 -3.1 Week 26 Change Creatinine (mg/dL) -0.01 0.00 0.01 eGFR (mL/min/1.73 m2) 0.7 0.5 -0.6 Moderate Renal Impairment Study Placebo N=154 Ertugliflozin 5 mg N=158 Ertugliflozin 15 mg N=155 Baseline Creatinine (mg/dL) 1.39 1.38 1.37 eGFR (mL/min/1.73 m2) 46.0 46.8 46.9 Week 6 Change Creatinine (mg/dL) -0.02 0.11 0.12 eGFR (mL/min/1.73 m2) 0.6 -3.2 -4.1 Week 26 Change Creatinine (mg/dL) 0.02 0.08 0.10 eGFR (mL/min/1.73 m2) 0.0 -2.7 -2.6 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 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. 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 (1) 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; mouth ulceration; stomatitis.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Recommended starting dose is 5 mg ertugliflozin/100 mg sitagliptin once daily, taken in the morning, with or without food. (2.1) Increase dose to 15 mg ertugliflozin/100 mg sitagliptin once daily in those tolerating STEGLUJAN and needing additional glycemic control. (2.1) Assess renal function before initiating STEGLUJAN and periodically thereafter (2.2): Do not use in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2. Initiation is not recommended in patients with an eGFR of 30 to less than 60 mL/min/1.73 m2. Continued use is not recommended in patients with an eGFR persistently between 30 and less than 60 mL/min/1.73 m2. 2.1 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)]. 2.2 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/min/1.73 m2 [see Contraindications (4)]. Initiation of STEGLUJAN is not recommended in patients with an eGFR of 30 mL/min/1.73 m2 to less than 60 mL/min/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.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pregnancy: Advise females of the potential risk to a fetus especially during the second and third trimesters. (8.1) Lactation: Breastfeeding not recommended. (8.2) Geriatrics: Higher incidence of adverse reactions related to reduced intravascular volume. (5.2, 8.5) Renal Impairment: Higher incidence of adverse reactions related to reduced intravascular volume and renal function. (5.2, 5.4, 8.6) 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, pre-eclampsia, 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 (2.2) 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 (2.2), 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 (12.3)].

Interactions

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.

More information

Category Value
Authorisation number NDA209805
Agency product number MLU731K321
Orphan designation No
Product NDC 0006-5367,0006-5368
Date Last Revised 19-02-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 1992832
Storage and handling Storage of Bottles Store at 20°C-25°C (68°F-77°F), excursions permitted between 15°C-30°C (between 59°F-86°F) [see USP Controlled Room Temperature]. Protect from moisture. Store in a dry place.
Marketing authorisation holder Merck Sharp & Dohme Corp.