Steglujan Drug Information

STEGLUJAN ® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. 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.

Prior to Initiation of STEGLUJAN

Assess renal function before initiating STEGLUJAN and as clinically indicated. Assess volume status. In patients with volume depletion, correct this condition before initiating STEGLUJAN.

Recommended Dosage

The recommended starting dosage of STEGLUJAN is 5 mg ertugliflozin/100 mg sitagliptin orally once daily, taken in the morning, with or without food. For patients treated with ertugliflozin who are being switched to STEGLUJAN, the dosage of ertugliflozin can be maintained. For additional glycemic control, the dosage may be increased to 15 mg ertugliflozin/100 mg sitagliptin orally once daily in patients tolerating STEGLUJAN.

Use is not recommended in patients with an estimated glomerular filtration rate (eGFR) less than 45 mL/min/1.73 m 2. Use of STEGLUJAN is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ), end-stage renal disease (ESRD) or on dialysis.

Temporary Interruption for Surgery Withhold STEGLUJAN for at least 4 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume STEGLUJAN when the patient is clinically stable and has resumed oral intake.

Recommendations Regarding Missed Dose If a dose is missed, instruct patients to take the dose as soon as possible. Advise patients not to double up the next dose.

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. 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. 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. 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. Table 1 shows common adverse reactions associated with the use of ertugliflozin.

These adverse reactions were not present at baseline, occurred more commonly on ertugliflozin than on placebo, and occurred in at least 2% of patients treated with either ertugliflozin 5 mg or ertugliflozin 15 mg. Table 1: Adverse Reactions Reported in ≥2% of Patients with Type 2 Diabetes Mellitus Treated with Ertugliflozin The three placebo controlled studies included one monotherapy trial and two add-on combination trials with metformin HCl or with metformin HCl and sitagliptin. and Greater than Placebo in Pooled Placebo-Controlled Clinical Studies of Ertugliflozin Monotherapy or Combination Therapy Volume Depletion Ertugliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion, particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m 2 ). In patients with moderate renal impairment, adverse reactions related to volume depletion (e.g., dehydration, dizziness postural, presyncope, syncope, hypotension, and orthostatic hypotension) were reported in 0%, 4.4%, and 1.9% of patients treated with placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively.

Ertugliflozin may also increase the risk of hypotension in other patients at risk for volume contraction. Hypoglycemia The incidence of hypoglycemia by study is shown in Table 2. Table 2: Incidence of Overall Overall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL. and Severe Severe hypoglycemic events: required assistance, lost consciousness, or experienced a seizure regardless of blood glucose.

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. 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 HCl 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 HCl 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 HCl) 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 HCl) 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. Laboratory Tests Ertugliflozin Changes in Serum Creatinine and eGFR Initiation of ertugliflozin causes an increase in serum creatinine and decrease in eGFR within weeks of starting therapy and then these changes stabilize. In a study of patients with moderate renal impairment, larger mean changes were observed.

Acute hemodynamic changes may play a role in the early renal function changes observed with ertugliflozin since they are reversed after treatment discontinuation. Increases in Low-Density Lipoprotein Cholesterol (LDL-C) In the pool of three placebo-controlled trials, dose-related increases in LDL-C were observed in patients treated with ertugliflozin. The range of mean baseline LDL-C was 96.6 to 97.7 mg/dL across treatment groups.

The range of mean baseline hemoglobin was 13.90 to 14.00 g/dL across treatment groups. The range of mean baseline serum phosphate was 3.53 to 3.54 mg/dL across treatment groups. 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 and in patients treated with placebo. The clinical significance of this added increase in serum creatinine relative to placebo is not known.

Postmarketing Experience

Additional adverse reactions have been identified during postapproval use of ertugliflozin or sitagliptin, both components of STEGLUJAN. 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. Ertugliflozin Infections: necrotizing fasciitis of the perineum (Fournier’s Gangrene) Skin and Subcutaneous Tissue Disorders: angioedema, rash Sitagliptin Skin and Subcutaneous Tissue Disorders: hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, bullous pemphigoid, exfoliative skin conditions including Stevens-Johnson syndrome, and pruritus Investigations: hepatic enzyme elevations Gastrointestinal Disorders: acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis, constipation, vomiting, mouth ulceration, and stomatitis Renal and Urinary Disorders: worsening renal function, including acute renal failure (sometimes requiring dialysis), and tubulointerstitial nephritis Musculoskeletal and Connective Tissue Disorders: severe and disabling arthralgia, myalgia, pain in extremity, back pain, and rhabdomyolysis Nervous System Disorders: headache

Table 3: Clinically Significant Drug Interactions with STEGLUJAN See full prescribing information for information on drug interactions and interference of STEGLUJAN with laboratory tests.

Pregnancy 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.

Pediatric Use Safety and effectiveness of STEGLUJAN in pediatric patients under 18 years of age have not been established.

STEGLUJAN is contraindicated in patients with: Severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ), end-stage renal disease (ESRD), or on dialysis. Hypersensitivity to sitagliptin, ertugliflozin, or any excipient, in STEGLUJAN. Reactions such as anaphylaxis or angioedema have occurred.

STEGLUJAN In the event of an overdose with STEGLUJAN, contact the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Employ the usual supportive measures as dictated by the patient's clinical status. Ertugliflozin Removal of ertugliflozin by hemodialysis has not been studied.

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.