Data from FDA - Curated by EPG Health - Last updated 05 June 2018

Indication(s)

1 INDICATIONS AND USAGE STEGLATRO™ is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. STEGLATRO is a sodium glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. (1) Limitations of Use: Not for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. (1) Limitations of Use STEGLATRO is not recommended in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

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Advisory information

contraindications
4 CONTRAINDICATIONS Severe renal impairment, end-stage renal disease (ESRD), or dialysis [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)]. History of a serious hypersensitivity reaction to STEGLATRO. Severe renal impairment, end-stage renal disease, or dialysis. (4, 5.3) History of serious hypersensitivity reaction to STEGLATRO. (4)
Adverse reactions
6 ADVERSE REACTIONS The following important adverse reactions are described elsewhere in the labeling: Hypotension [see Warnings and Precautions (5.1)] Ketoacidosis [see Warnings and Precautions (5.2)] Acute Kidney Injury and Impairment in Renal Function [see Warnings and Precautions (5.3)] Urosepsis and Pyelonephritis [see Warnings and Precautions (5.4)] Lower Limb Amputation [see Warnings and Precautions (5.5)] Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.6)] Genital Mycotic Infections [see Warnings and Precautions (5.7)] Increases in Low-Density Lipoprotein Cholesterol (LDL-C) [see Warnings and Precautions (5.8)] The most common adverse reactions associated with STEGLATRO (incidence ≥ 5%) were female genital mycotic infections. (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. Pool of Placebo-Controlled Trials Evaluating STEGLATRO 5 and 15 mg The data in Table 1 are derived from a pool of three 26-week, placebo-controlled trials. STEGLATRO 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 STEGLATRO with a mean exposure duration of approximately 25 weeks. Patients received STEGLATRO 5 mg (N=519), STEGLATRO 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 STEGLATRO. These adverse reactions were not present at baseline, occurred more commonly on STEGLATRO than on placebo, and occurred in at least 2% of patients treated with either STEGLATRO 5 mg or STEGLATRO 15 mg. Table 1: Adverse Reactions Reported in ≥2% of Patients with Type 2 Diabetes Mellitus Treated with STEGLATROThe 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 STEGLATRO Monotherapy or Combination Therapy Number (%) of Patients Placebo N = 515 STEGLATRO 5 mg N = 519 STEGLATRO 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), STEGLATRO 5 mg (N=252), STEGLATRO 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), STEGLATRO 5 mg (N=267), STEGLATRO 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 STEGLATRO 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, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively. STEGLATRO 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 (5.2)]. Impairment in Renal Function Treatment with STEGLATRO 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 STEGLATRO 5 mg N=519 STEGLATRO 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 STEGLATRO 5 mg N=158 STEGLATRO 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 STEGLATRO, 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, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively. Lower Limb Amputation Across seven Phase 3 clinical trials in which STEGLATRO 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-STEGLATRO group, 3 of 1,716 (0.2%) in the STEGLATRO 5 mg group, and 8 of 1,693 (0.5%) in the STEGLATRO 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 Monotherapy (26 weeks) Placebo (N = 153) STEGLATRO 5 mg (N =156) STEGLATRO 15 mg (N = 152) Overall [N (%)] 1 (0.7) 4 (2.6) 4 (2.6) Severe [N (%)] 0 (0.0) 0 (0.0) 2 (1.3) Add-on Combination Therapy with Metformin (26 weeks) Placebo (N = 209) STEGLATRO 5 mg (N = 207) STEGLATRO 15 mg (N = 205) Overall [N (%)] 9 (4.3) 15 (7.2) 16 (7.8) Severe [N (%)] 1 (0.5) 1 (0.5) 0 (0.0) Add-on Combination Therapy with Metformin and Sitagliptin (26 weeks) Placebo (N = 153) STEGLATRO 5 mg (N = 156) STEGLATRO 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) In Combination with Insulin and/or an Insulin Secretagogue in Patients with Moderate Renal Impairment Placebo (N = 133) STEGLATRO 5 mg (N = 148) STEGLATRO 15 mg (N = 143) Overall [N (%)] 48 (36.1) 53 (35.8) 39 (27.3) Severe [N (%)] 3 (2.3) 5 (3.4) 3 (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, STEGLATRO 5 mg, and STEGLATRO 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 STEGLATRO, 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, STEGLATRO 5 mg, and STEGLATRO 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 STEGLATRO, respectively. Phimosis was reported in 8 of 1729 (0.5%) male ertugliflozin-treated patients, of which four required circumcision. Laboratory Tests 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 STEGLATRO. Mean percent changes from baseline to Week 26 in LDL-C relative to placebo were 2.6% and 5.4% with STEGLATRO 5 mg and STEGLATRO 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 (5.8)]. 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 STEGLATRO 5 mg, and 0.48 g/dL (3.5%) with STEGLATRO 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, STEGLATRO 5 mg, and STEGLATRO 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 STEGLATRO 5 mg, and 0.26 mg/dL (8.5%) with STEGLATRO 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 STEGLATRO 5 mg, and 0.24 mg/dL (7.8%) with STEGLATRO 15 mg.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Recommended starting dose is 5 mg once daily, taken in the morning, with or without food. (2.1) Increase dose to 15 mg once daily in those tolerating STEGLATRO and needing additional glycemic control. (2.1) Assess renal function before initiating STEGLATRO and periodically thereafter (2.2): Do not use in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m2. Initiation is not recommended in patients with an eGFR of 30 to less than 60 mL/minute/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 STEGLATRO is 5 mg once daily, taken in the morning, with or without food. In patients tolerating STEGLATRO 5 mg once daily, the dose may be increased to a maximum recommended dose of 15 mg once daily if additional glycemic control is needed. In patients with volume depletion, correct this condition prior to initiation of STEGLATRO [see Warnings and Precautions (5.1)]. 2.2 Patients with Renal Impairment Assess renal function prior to initiation of STEGLATRO and periodically thereafter [see Warnings and Precautions (5.3)]. Use of STEGLATRO is contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m2 [see Contraindications (4)]. Initiation of STEGLATRO 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 (5.3) and Use in Specific Populations (8.6)]. Continued use of STEGLATRO is not recommended when eGFR is persistently between 30 and less than 60 mL/minute/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. (5.1, 8.5) Renal Impairment: Higher incidence of adverse reactions related to reduced intravascular volume and renal function. (5.1, 5.3, 8.6) 8.1 Pregnancy Risk Summary Based on animal data showing adverse renal effects, STEGLATRO is not recommended during the second and third trimesters of pregnancy. The limited available data with STEGLATRO in pregnant women 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). 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 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). 8.2 Lactation Risk Summary There is no information regarding the presence of STEGLATRO in human milk, the effects on the breastfed infant, or the effects on milk production. Ertugliflozin is 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. Because of the potential for serious adverse reactions in a breastfed infant, advise women that the use of STEGLATRO is not recommended while breastfeeding. Data Animal Data 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 STEGLATRO 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). 8.4 Pediatric Use Safety and effectiveness of STEGLATRO in pediatric patients under 18 years of age have not been established. 8.5 Geriatric Use No dosage adjustment of STEGLATRO is recommended based on age. Across the clinical program, a total of 876 (25.7%) patients treated with STEGLATRO were 65 years and older, and 152 (4.5%) patients treated with STEGLATRO were 75 years and older. Patients 65 years and older had a higher incidence of adverse reactions related to volume depletion compared to younger patients; events were reported in 1.1%, 2.2%, and 2.6% of patients treated with comparator, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. STEGLATRO is expected to have diminished efficacy in elderly patients with renal impairment [see Use in Specific Populations (8.6)]. 8.6 Renal Impairment The safety and efficacy of STEGLATRO have not been established in patients with type 2 diabetes mellitus and moderate renal impairment [see Clinical Studies (14.4)]. Compared to placebo-treated patients, patients with moderate renal impairment treated with STEGLATRO did not have improvement in glycemic control [see Clinical Studies (14.4)], 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 (5.3) and Adverse Reactions (6.1)]. Therefore, STEGLATRO is not recommended in this population. STEGLATRO is contraindicated in patients with severe renal impairment, ESRD, or receiving dialysis. STEGLATRO 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 STEGLATRO is necessary in patients with mild or moderate hepatic impairment. Ertugliflozin has not been studied in patients with severe hepatic impairment and is not recommended for use in this patient population [see Clinical Pharmacology (12.3)].

Interactions

7 DRUG INTERACTIONS 7.1 Concomitant Use with Insulin and Insulin Secretagogues STEGLATRO may increase the risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue [see Adverse Reactions (6.1)]. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with STEGLATRO [see Warnings and Precautions (5.6)]. 7.2 Positive Urine Glucose Test Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors 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 SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

More information

Category Value
Authorisation number NDA209803
Agency product number MLU731K321
Orphan designation No
Product NDC 0006-5364,0006-5363
Date Last Revised 19-12-2017
Type HUMAN PRESCRIPTION DRUG
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.