Steglujan

Steglujan

ertugliflozin + sitagliptin

Manufacturer:

MSD

Distributor:

Zuellig
Full Prescribing Info
Contents
Ertugliflozin, sitagliptin.
Description
Steglujan 15 mg/100 mg film-coated tablets: Each tablet contains 15 mg ertugliflozin (as ertugliflozin L-pyroglutamic acid) and 100 mg sitagliptin (as sitagliptin phosphate monohydrate).
Excipients/Inactive Ingredients: Tablet core: Microcrystalline cellulose (E460), Calcium hydrogen phosphate (anhydrous), Croscarmellose sodium, Sodium stearyl fumarate (E487), Magnesium stearate (E470b).
Tablet coat: Hypromellose (E464), Hydroxypropyl cellulose (E463), Titanium dioxide (E171), Iron oxide red (E172), Iron oxide yellow (E172), Iron oxide black (E172), Carnauba wax (E903).
Action
Pharmacotherapeutic group: Drugs used in diabetes, combinations of oral blood glucose lowering drugs. ATC code: A10BD24.
Pharmacology: Pharmacodynamics: Mechanism of action: Steglujan combines two antihyperglycaemic agents with complementary mechanisms of action to improve glycaemic control in patients with type 2 diabetes: ertugliflozin, a SGLT2 inhibitor, and sitagliptin phosphate, 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 a potent, selective, and reversible 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 member of a class of oral antihyperglycaemic agents called dipeptidyl peptidase 4 (DPP-4) inhibitors. The improvement in glycaemic control observed with this medicinal product may be mediated by enhancing the levels of active incretin 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. 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 signalling pathways involving cyclic AMP. Treatment with GLP-1 or with DPP-4 inhibitors in animal models of type 2 diabetes has been demonstrated to improve beta cell responsiveness to glucose and stimulate insulin biosynthesis and release. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells. Decreased glucagon concentrations, along with higher insulin levels, lead to reduced hepatic glucose production, resulting in a decrease in blood glucose levels. The effects of GLP-1 and GIP are glucose-dependent such that when blood glucose concentrations are low, stimulation of insulin release and suppression of glucagon secretion by GLP-1 are not observed. For both GLP-1 and GIP, stimulation of insulin release is enhanced as glucose rises above normal concentrations. Further, GLP-1 does not impair the normal glucagon response to hypoglycaemia. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly hydrolyses the incretin hormones to produce inactive products. Sitagliptin prevents the hydrolysis of incretin hormones by DPP-4, thereby increasing plasma concentrations of the active forms of GLP-1 and GIP. By enhancing active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in a glucose-dependent manner. In patients with type 2 diabetes with hyperglycaemia, these changes in insulin and glucagon levels lead to lower haemoglobin A1c (HbA1c) and lower fasting and post-prandial glucose concentrations. The glucose-dependent mechanism of sitagliptin is distinct from the mechanism of sulphonylureas, which increase insulin secretion even when glucose levels are low and can lead to hypoglycaemia in patients with type 2 diabetes and in normal subjects. Sitagliptin is a potent and highly selective inhibitor of the enzyme DPP-4 and does not inhibit the closely-related enzymes DPP-8 or DPP-9 at therapeutic concentrations.
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.
Pharmacodynamic effects: 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 modelling indicates that ertugliflozin 5 mg and 15 mg result in near maximal urinary glucose excretion (UGE) in patients with type 2 diabetes mellitus, providing 87% and 96% of maximal inhibition, respectively.
Clinical efficacy and safety: Ertugliflozin in combination with sitagliptin: The efficacy and safety of ertugliflozin in combination with sitagliptin have been studied in 3 multi-centre, randomised, double-blind, placebo- and active comparator-controlled, Phase 3 clinical studies involving 1,985 patients with type 2 diabetes. Across the 3 studies, the racial distribution ranged from 72.9% to 90.4% White, 0.0% to 20.3% Asian, 1.9% to 4.5% Black and 4.8% to 5.4% Other. Hispanic or Latino patients comprised 15.6% to 36.1% of the population. The mean age of the patients across these 3 studies ranged from 55.1 to 59.1 years (range 21 years to 85 years). Across the 3 studies, 16.2% to 29.9% of patients were ≥ 65 years of age and 2.3% to 2.8% were ≥ 75 years of age.
Factorial study with ertugliflozin and sitagliptin as add-on combination therapy with metformin: A total of 1,233 patients with type 2 diabetes participated in a randomised, double-blind, multi-centre, 26-week, active-controlled study to evaluate the efficacy and safety of ertugliflozin 5 mg or 15 mg in combination with sitagliptin 100 mg compared to the individual components. Patients with type 2 diabetes inadequately controlled on metformin monotherapy (≥ 1,500 mg/day) were randomised to one of five active-treatment arms: ertugliflozin 5 mg or 15 mg, sitagliptin 100 mg, or sitagliptin 100 mg in combination with 5 mg or 15 mg ertugliflozin administered once daily in addition to continuation of background metformin therapy (see Table 1).

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Ertugliflozin as add-on combination therapy with metformin and sitagliptin: A total of 463 patients, with type 2 diabetes inadequately controlled on metformin (≥ 1,500 mg/day) and sitagliptin 100 mg once daily participated in a randomised, double-blind, multi-centre, 26-week, placebo-controlled study to evaluate the efficacy and safety of ertugliflozin. Patients were randomised to ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo administered once daily in addition to continuation of background metformin and sitagliptin therapy (see Table 2).

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Combination therapy of ertugliflozin and sitagliptin: A total of 291 patients with type 2 diabetes inadequately controlled on diet and exercise participated in a randomised, double-blind, multi-centre, placebo-controlled 26-week study to evaluate the efficacy and safety of ertugliflozin in combination with sitagliptin. These patients, who were not receiving any background antihyperglycaemic treatment, were randomised to ertugliflozin 5 mg or ertugliflozin 15 mg in combination with sitagliptin (100 mg) or to placebo, once daily (see Table 3).

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Fasting plasma glucose: In three placebo-controlled studies, ertugliflozin resulted in statistically significant reductions in FPG. For ertugliflozin 5 mg and 15 mg, respectively, the placebo-corrected reductions in FPG were 1.92 and 2.44 mmol/l as monotherapy, 1.48 and 2.12 mmol/l as add-on to metformin, and 1.40 and 1.74 mmol/l as add-on to metformin and sitagliptin.
The combination of ertugliflozin and sitagliptin resulted in significantly greater reductions in FPG compared to sitagliptin or ertugliflozin alone or placebo. The combination of ertugliflozin 5 or 15 mg and sitagliptin resulted in incremental FPG reductions of 0.46 to 0.65 mmol/l compared to the ertugliflozin alone or 1.02 to 1.28 mmol/l compared to sitagliptin alone. The placebo-corrected reductions of ertugliflozin 5 or 15 mg in combination with sitagliptin were 2.16 and 2.56 mmol/l.
Efficacy in patients with baseline HbA1c ≥ 10%: In the study of patients inadequately controlled on metformin with baseline HbA1c from 7.5-11.0%, among the subgroup of patients with a baseline HbA1c ≥ 10%, the combination of ertugliflozin 5 mg or 15 mg with sitagliptin resulted in reductions of HbA1c of 2.35% and 2.66%, respectively, compared to 2.10%, 1.30%, and 1.82% for ertugliflozin 5 mg, ertugliflozin 15 mg, and sitagliptin alone, respectively.
Post-prandial glucose: When used in monotherapy, ertugliflozin 5 and 15 mg resulted in statistically significant placebo-corrected reductions in 2-hour post-prandial glucose (PPG) of 3.83 and 3.74 mmol/l.
The combination of ertugliflozin 5 or 15 mg with sitagliptin resulted in statistically significant placebo-corrected reductions in 2-hour PPG of 3.46 and 3.87 mmol/l.
Blood pressure: After 26-weeks of treatment, the combination of ertugliflozin 5 mg or 15 mg and sitagliptin 100 mg resulted in statistically significant reductions in systolic blood pressure (SBP) compared to sitagliptin alone (-2.8 and -3.0 mmHg for E5/S100 and E15/S100 respectively) or placebo (-4.4 and -6.4 mmHg for E5/S100 and E15/S100, respectively). Additionally, when added on to background metformin and sitagliptin therapy, ertugliflozin 5 mg and 15 mg resulted in statistically significant placebo subtracted reductions in SBP of 2.9 and 3.9 mmHg, respectively.
Subgroup analysis: In patients with type 2 diabetes treated with ertugliflozin in combination with sitagliptin, the improvement in HbA1c was similar across subgroups defined by age, sex, and race, and duration of type 2 diabetes mellitus.
TECOS Cardiovascular Safety Study: The TECOS was a randomised study in 14,671 patients in the intention-to-treat population with an HbA1c of ≥ 6.5 to 8.0% with established CV disease who received sitagliptin (7,332) 100 mg daily (or 50 mg daily if the baseline eGFR was ≥ 30 and < 50 ml/min/1.73 m2) or placebo (7,339) added to usual care targeting regional standards for HbA1c and CV risk factors. Patients with an eGFR < 30 ml/min/1.73 m2 were not to be enrolled in the study. The study population included 2,004 patients ≥ 75 years of age and 3,324 patients with renal impairment (eGFR < 60 ml/min/1.73 m2).
Over the course of the study, the overall estimated mean (SD) difference in HbA1c between the sitagliptin and placebo groups was 0.29% (0.01), 95% CI (-0.32, -0.27); p< 0.001. The primary cardiovascular endpoint was a composite of the first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. Secondary cardiovascular endpoints included the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke; first occurrence of the individual components of the primary composite; all-cause mortality; and hospital admissions for congestive heart failure.
After a median follow up of 3 years, sitagliptin, when added to usual care, did not increase the risk of major adverse cardiovascular events or the risk of hospitalisation for heart failure compared to usual care without sitagliptin in patients with type 2 diabetes (see Table 4).

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Paediatric population: The European Medicines Agency has waived the obligation to submit the results of studies with Steglujan in all subsets of the paediatric population in the treatment of type 2 diabetes (see Dosage & Administration for information on paediatric use).
Pharmacokinetics: Steglujan: Steglujan has been shown to be bioequivalent to coadministration of corresponding doses of ertugliflozin and sitagliptin tablets.
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, or on sitagliptin AUCinf and Cmax.
Ertugliflozin: General introduction: The pharmacokinetics of ertugliflozin are similar in healthy subjects and patients with type 2 diabetes. The steady state mean plasma AUC and Cmax were 398 ng·hr/ml and 81 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.
Absorption: Following single-dose oral administration of 5 mg and 15 mg of ertugliflozin, peak plasma concentrations (median Tmax) of ertugliflozin occur at 1 hour post-dose under fasted conditions. Plasma Cmax and AUC of ertugliflozin increase in a dose-proportional manner following single doses from 0.5 mg to 300 mg and following multiple doses from 1 mg to 100 mg. The absolute oral bioavailability of ertugliflozin following administration of a 15-mg dose is approximately 100%.
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.
Ertugliflozin is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters.
Distribution: The mean steady-state volume of distribution of ertugliflozin following an intravenous dose is 86 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.
Ertugliflozin is not a substrate of organic anion transporters (OAT1, OAT3), organic cation transporters (OCT1, OCT2), or organic anion transporting polypeptides (OATP1B1, OATP1B3) in vitro.
Biotransformation: 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%).
Elimination: The mean systemic plasma clearance following an intravenous 100 μg dose was 11 l/hr. The mean elimination half-life in type 2 diabetic patients with normal renal function was estimated to be 17 hours based on the population pharmacokinetic analysis. Following administration of an oral [14C]-ertugliflozin solution to healthy subjects, approximately 41% and 50% of the drug-related radioactivity was eliminated in faeces and urine, respectively. Only 1.5% of the administered dose was excreted as unchanged ertugliflozin in urine and 34% as unchanged ertugliflozin in faeces, which is likely due to biliary excretion of glucuronide metabolites and subsequent hydrolysis to parent.
Special populations: Renal impairment: In a Phase 1 clinical pharmacology study in patients with type 2 diabetes 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 ≤ 1.7-fold, compared to subjects with normal renal function. These increases in ertugliflozin AUC are not considered clinically relevant. There were no clinically meaningful differences in the ertugliflozin Cmax values among the different renal function groups. The 24-hour urinary glucose excretion declined with increasing severity of renal impairment (see Precautions). The plasma protein binding of ertugliflozin was unaffected in patients with renal impairment.
Hepatic impairment: 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.
Paediatric population: No studies with ertugliflozin have been performed in paediatric patients.
Effects of age, body weight, gender and race: 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: Absorption: Following 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 post-dose. Mean plasma AUC of sitagliptin was 8.52 μM·hr and Cmax was 950 nM. The absolute bioavailability of sitagliptin is approximately 87%. Since coadministration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics, Steglujan may be administered with or without food.
Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not established for Cmax and C24hr (Cmax increased in a greater than dose-proportional manner and C24hr increased in a less than dose-proportional manner).
Distribution: 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%).
Biotransformation: Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway. Approximately 79% of sitagliptin is excreted unchanged in the urine.
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.
In vitro data showed that sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4 and CYP1A2.
Elimination: Following administration of an oral [14C]-sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in faeces (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. Sitagliptin accumulates only minimally with multiple doses. The 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-gp, which may also be involved in mediating the renal elimination of sitagliptin. However, ciclosporin, a P-gp inhibitor, did not reduce the renal clearance of sitagliptin. Sitagliptin is not a substrate for OCT2 or OAT1 or peptide transporter 1/2 (PEPT1/2) transporters. In vitro, sitagliptin did not inhibit OAT3 (IC50=160 μM) or p-glycoprotein (up to 250 μM) mediated transport at therapeutically relevant plasma concentrations. In a clinical study sitagliptin had a small effect on plasma digoxin concentrations indicating that sitagliptin may be a mild inhibitor of P-gp.
Drug interactions: No drug interactions studies have been performed with Steglujan and other medicinal products; however, such studies have been conducted with the individual active substances.
In vitro assessment of ertugliflozin: In in vitro studies, ertugliflozin and ertugliflozin glucuronides did not inhibit or inactivate CYPs 1A2, 2C9, 2C19, 2C8, 2B6, 2D6, or 3A4, and did not induce CYPs 1A2, 2B6, or 3A4. Ertugliflozin and ertugliflozin glucuronides did not inhibit the activity of UGTs 1A6, 1A9 or 2B7 in vitro. Ertugliflozin was a weak inhibitor of UGTs 1A1 and 1A4 in vitro at higher concentrations that are not clinically relevant. Ertugliflozin glucuronides had no effect on these isoforms. Overall, ertugliflozin is unlikely to affect the pharmacokinetics of concurrently administered drugs eliminated by these enzymes.
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 in vitro. Overall, ertugliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are substrates of these transporters.
In vitro assessment of sitagliptin: In vitro data suggest that sitagliptin does not inhibit or induce CYP450 isoenzymes. In clinical studies, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and OCT. Sitagliptin may be a mild inhibitor of P-gp in vivo.
In vitro transport studies showed that sitagliptin is a substrate for P-gp and OAT3. OAT3 mediated transport of sitagliptin was inhibited in vitro by probenecid, although the risk of clinically meaningful interactions is considered to be low. Concomitant administration of OAT3 inhibitors has not been evaluated in vivo.
Characteristics in patients: The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients with type 2 diabetes.
Renal impairment: In patients with normal renal function, metabolism, including via CYP3A4, plays only a small role in the clearance of sitagliptin. Metabolism may play a more significant role in the elimination of sitagliptin in the setting of severe renal impairment or end-stage renal disease (ESRD).
Compared to normal healthy control subjects, plasma AUC of sitagliptin was increased modestly in patients with GFR ≥ 45 to < 90 mL/min. Because increases of this magnitude are not clinically relevant, dosage adjustment in these patients is not necessary.
Hepatic impairment: No dose adjustment for sitagliptin is necessary for patients with mild or moderate hepatic impairment (Child-Pugh score ≤ 9). There is no clinical experience in patients with severe hepatic impairment (Child-Pugh score > 9). However, because sitagliptin is primarily renally eliminated, severe hepatic impairment is not expected to affect the pharmacokinetics of sitagliptin.
Elderly: No dose adjustment is required based on age. Age did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis of Phase 1 and Phase 2 data. Elderly subjects (65 to 80 years) had approximately 19% higher plasma concentrations of sitagliptin compared to younger subjects.
Paediatric: No studies with sitagliptin have been performed in paediatric patients.
Other patient characteristics: No dose adjustment is necessary based on gender, race, or body mass index (BMI). These characteristics had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase 1 pharmacokinetic data and on a population pharmacokinetic analysis of Phase 1 and Phase 2 data.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, acute toxicity, repeated dose toxicity, genotoxicity, and carcinogenic potential.
Ertugliflozin: General toxicity: Repeat-dose oral toxicity studies were conducted in mice, rats, and dogs for up to 13, 26, and 39 weeks, respectively. Signs of toxicity that were considered adverse were generally observed at exposures greater than or equal to 77 times the human unbound exposure (AUC) at the maximum recommended human dose (MRHD) of 15 mg/day. Most toxicity was consistent with pharmacology related to urinary glucose loss and included decreased body weight and body fat, increased food consumption, diarrhoea, dehydration, decreased serum glucose and increases in other serum parameters reflective of increased protein metabolism, gluconeogenesis and electrolyte imbalances, and urinary changes such as polyuria, glucosuria, and calciuria. Microscopic changes related to glucosuria and/or calciuria observed only in rodents included dilatation of renal tubules, hypertrophy of zona glomerulosa in adrenal glands (rats), and increased trabecular bone (rats). Except for emesis, there were no adverse toxicity findings in dogs at 379 times the human unbound exposure (AUC) at the MRHD of 15 mg/day.
Carcinogenesis: In the 2-year mouse carcinogenicity study, ertugliflozin was administered by oral gavage at doses of 5, 15, and 40 mg/kg/day. There were no ertugliflozin-related neoplastic findings at doses up to 40 mg/kg/day (approximately 41 times human unbound exposure at the MRHD of 15 mg/day based on AUC). In the 2-year rat carcinogenicity study, ertugliflozin was administered by oral gavage at doses of 1.5, 5, and 15 mg/kg/day. Ertugliflozin-related neoplastic findings included an increased incidence of benign adrenal medullary pheochromocytoma in male rats at 15 mg/kg/day. This finding was attributed to carbohydrate malabsorption leading to altered calcium homeostasis and was not considered relevant to human risk. The no-observed-effect level (NOEL) for neoplasia was 5 mg/kg/day (approximately 16 times human unbound exposure at the MRHD of 15 mg/day).
Mutagenesis: Ertugliflozin was not mutagenic or clastogenic with or without metabolic activation in the microbial reverse mutation, in vitro cytogenetic (human lymphocytes), and in vivo rat micronucleus assays.
Reproductive toxicology: In the rat fertility and embryonic development study, male and female rats were administered ertugliflozin at 5, 25, and 250 mg/kg/day. No effects on fertility were observed at 250 mg/kg/day (approximately 386 times human unbound exposure at the MRHD of 15 mg/day based on AUC comparisons). Ertugliflozin did not adversely affect developmental outcomes in rats and rabbits at maternal exposures that were 239 and 1,069 times, respectively, the human exposure at the maximum clinical dose of 15 mg/day, based on AUC. At a maternally toxic dose in rats (250 mg/kg/day), lower foetal viability and a higher incidence of a visceral malformation were observed at maternal exposure that was 510 times the maximum clinical dose of 15 mg/day.
In the pre- and post-natal development study, decreased post-natal growth and development were observed in rats administered ertugliflozin gestation day 6 through lactation day 21 at ≥ 100 mg/kg/day (estimated 239 times the human exposure at the maximum clinical dose of 15 mg/day, based on AUC). Sexual maturation was delayed in both sexes at 250 mg/kg/day (estimated 620 times the MRHD at 15 mg/day, based on AUC).
When ertugliflozin was administered to juvenile rats from post-natal day (PND) 21 to PND 90, a period of renal development corresponding to the late second and third trimesters of human pregnancy, increased kidney weights, dilatation of the renal pelvis and tubules, and renal tubular mineralization were seen at an exposure 13 times the maximum clinical dose of 15 mg/day, based on AUC. Effects on bone (shorter femur length, increased trabecular bone in the femur) as well as effects of delayed puberty were observed at an exposure 817 times the MRHD of 15 mg/day based on AUC. The effects on kidney and bone did not fully reverse after the 1 month recovery period.
Sitagliptin: Renal and liver toxicity were observed in rodents at systemic exposure values 58 times the human exposure level, while the no-effect level was found at 19 times the human exposure level. Incisor teeth abnormalities were observed in rats at exposure levels 67 times the clinical exposure level; the no-effect level for this finding was 58-fold based on the 14-week rat study. The relevance of these findings for humans is unknown. Transient treatment-related physical signs, some of which suggest neural toxicity, such as open-mouth breathing, salivation, white foamy emesis, ataxia, trembling, decreased activity, and/or hunched posture were observed in dogs at exposure levels approximately 23 times the clinical exposure level. In addition, very slight to slight skeletal muscle degeneration was also observed histologically at doses resulting in systemic exposure levels of approximately 23 times the human exposure level. A no-effect level for these findings was found at an exposure 6-fold the clinical exposure level.
Sitagliptin has not been demonstrated to be genotoxic in preclinical studies. Sitagliptin was not carcinogenic in mice. In rats, there was an increased incidence of hepatic adenomas and carcinomas at systemic exposure levels 58 times the human exposure level. Since hepatotoxicity has been shown to correlate with induction of hepatic neoplasia in rats, this increased incidence of hepatic tumours in rats was likely secondary to chronic hepatic toxicity at this high dose. Because of the high safety margin (19-fold at this no-effect level), these neoplastic changes are not considered relevant for the situation in humans.
No adverse effects upon fertility were observed in male and female rats given sitagliptin prior to and throughout mating.
In a pre-/post-natal development study performed in rats sitagliptin showed no adverse effects.
Reproductive toxicity studies showed a slight treatment-related increased incidence of foetal rib malformations (absent, hypoplastic and wavy ribs) in the offspring of rats at systemic exposure levels more than 29 times the human exposure levels. Maternal toxicity was seen in rabbits at more than 29 times the human exposure levels. Because of the high safety margins, these findings do not suggest a relevant risk for human reproduction. Sitagliptin is secreted in considerable amounts into the milk of lactating rats (milk/plasma ratio: 4:1).
Indications/Uses
Steglujan is indicated in adults aged 18 years and older with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control: when metformin and/or a sulphonylurea (SU) and one of the monocomponents of Steglujan do not provide adequate glycaemic control; in patients already being treated with the combination of ertugliflozin and sitagliptin as separate tablets.
(For study results with respect to combinations and effects on glycaemic control, see Precautions, Interactions, and Pharmacology: Pharmacodynamics under Actions.)
Dosage/Direction for Use
Posology: The recommended starting dose is 5 mg ertugliflozin/100 mg sitagliptin once daily. In patients tolerating the starting dose, the dose may be increased to 15 mg ertugliflozin/100 mg sitagliptin, once daily, if additional glycaemic control is needed.
For patients treated with ertugliflozin who are being switched to Steglujan, the dose of ertugliflozin can be maintained.
When Steglujan is used in combination with insulin or an insulin secretagogue, a lower dose of insulin or the insulin secretagogue may be required to reduce the risk of hypoglycaemia (see Precautions, Interactions, and Adverse Reactions).
In patients with volume depletion, correcting this condition prior to initiation of Steglujan is recommended (see Precautions).
If a dose is missed, it should be taken as soon as the patient remembers. Patients should not take two doses of Steglujan on the same day.
Special populations: Renal impairment: Assessment of renal function is recommended prior to initiation of Steglujan and periodically thereafter (see Precautions).
Initiation of this medicinal product is not recommended in patients with an estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m2 or CrCl less than 60 ml/min (see Precautions).
Steglujan should be discontinued when eGFR is persistently less than 45 ml/min/1.73 m2 or CrCl is persistently less than 45 ml/min.
The fixed-dose combination of ertugliflozin and sitagliptin should not be used in patients with severe renal impairment, with end-stage renal disease (ESRD), or receiving dialysis. Ertugliflozin is not expected to be effective in these patients.
Hepatic impairment: No dose 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 these patients (see Pharmacology: Pharmacokinetics under Actions).
Elderly (≥ 65 years old): No dose 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. Renal function and risk of volume depletion should be taken into account (see Precautions and Adverse Reactions). There is limited experience with Steglujan in patients ≥ 75 years of age.
Paediatric population: The safety and efficacy of Steglujan in children under 18 years of age have not been established. No data are available.
Method of administration: Steglujan should be taken orally once daily in the morning, with or without food. In case of swallowing difficulties, the tablet could be broken or crushed as it is an immediate-release dosage form.
Overdosage
In the event of an overdose with Steglujan, employ the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring including obtaining an electrocardiogram, and institute supportive treatment) as dictated by the patient's clinical status.
Ertugliflozin: Ertugliflozin did not show any toxicity in healthy subjects at single oral doses up to 300 mg and multiple doses up to 100 mg daily for 2 weeks. No potential acute symptoms and signs of overdose were identified. Removal of ertugliflozin by haemodialysis has not been studied.
Sitagliptin: During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were administered. Minimal increases in QTc, not considered to be clinically relevant, were observed in one study at a dose of 800 mg sitagliptin. There is no experience with doses above 800 mg in clinical studies. In Phase 1 multiple-dose studies, there were no dose-related clinical adverse reactions observed with sitagliptin with doses of up to 600 mg per day for periods of up to 10 days and 400 mg per day for periods of up to 28 days.
Sitagliptin is modestly dialysable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour haemodialysis session. Prolonged haemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialysable by peritoneal dialysis.
Contraindications
Hypersensitivity to the active substances or to any of the excipients listed in Description.
Special Precautions
General: Steglujan should not be used in patients with type 1 diabetes mellitus.
Acute pancreatitis: Use of dipeptidyl peptidase-4 (DPP-4) inhibitors has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of sitagliptin (with or without supportive treatment), but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, Steglujan and other potentially suspect medicinal products should be discontinued; if acute pancreatitis is confirmed, Steglujan should not be restarted. Caution should be exercised in patients with a history of pancreatitis.
Hypotension/Volume depletion: Ertugliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction. Therefore, symptomatic hypotension may occur after initiating Steglujan (see Adverse Reactions), particularly in patients with impaired renal function (eGFR less than 60 ml/min/1.73 m2 or CrCl less than 60 ml/min), elderly patients (≥ 65 years), patients on diuretics, or patients on anti-hypertensive therapy with a history of hypotension. Before initiating Steglujan, volume status should be assessed and corrected if indicated. Monitor for signs and symptoms after initiating therapy.
Due to its mechanism of action, ertugliflozin induces an osmotic diuresis and increases serum creatinine and decreases eGFR. Increases in serum creatinine and decreases in eGFR were greater in patients with moderate renal impairment (see Adverse Reactions).
In case of conditions that may lead to fluid loss (e.g., gastrointestinal illness), careful monitoring of volume status (e.g., physical examination, blood pressure measurements, laboratory tests including haematocrit) and electrolytes is recommended for patients receiving Steglujan. Temporary interruption of treatment with Steglujan should be considered until the fluid loss is corrected.
Diabetic ketoacidosis: Rare cases of DKA, including life-threatening and fatal cases, have been reported in clinical trials and post-marketing in patients treated with sodium glucose co-transporter-2 (SGLT2) inhibitors, and cases have been reported in clinical trials with ertugliflozin. In a number of cases, the presentation of the condition was atypical with only moderately increased blood glucose values, below 14 mmol/l (250 mg/dl). It is not known if DKA is more likely to occur with higher doses of ertugliflozin.
The risk of diabetic ketoacidosis must be considered in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness. Patients should be assessed for ketoacidosis immediately if these symptoms occur, regardless of blood glucose level.
In patients where DKA is suspected or diagnosed, treatment with Steglujan should be discontinued immediately.
Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses. In both cases, treatment with Steglujan may be restarted once the patient's condition has stabilised.
Before initiating Steglujan, factors in the patient history that may predispose to ketoacidosis should be considered.
Patients who may be at higher risk of DKA include patients with a low beta-cell function reserve (e.g., type 2 diabetes patients with low C-peptide or latent autoimmune diabetes in adults (LADA) or patients with a history of pancreatitis), patients with conditions that lead to restricted food intake or severe dehydration, patients for whom insulin doses are reduced and patients with increased insulin requirements due to acute medical illness, surgery, or alcohol abuse. SGLT2 inhibitors should be used with caution in these patients.
Restarting SGLT2 inhibitor treatment in patients with previous DKA while on SGLT2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified and resolved.
The safety and efficacy of Steglujan in patients with type 1 diabetes have not been established and Steglujan should not be used for treatment of patients with type 1 diabetes. Limited data from clinical trials suggest that DKA occurs with common frequency when patients with type 1 diabetes are treated with SGLT2 inhibitors.
Lower limb amputations: An increase in cases of lower limb amputation (primarily of the toe) has been observed in long-term clinical studies with another SGLT2 inhibitor. It is unknown whether this constitutes a class effect. Like for all diabetic patients it is important to counsel patients on routine preventative foot care.
Impairment in renal function: The efficacy of ertugliflozin is dependent on renal function, and efficacy is reduced in patients who have moderate renal impairment and likely absent in patients with severe renal impairment (see Dosage & Administration).
Steglujan should not be initiated in patients with an eGFR below 60 ml/min/1.73 m2 or CrCl below 60 ml/min. Steglujan should be discontinued when eGFR is persistently below 45 ml/min/1.73 m2 or CrCl is persistently below 45 ml/min due to a reduction of efficacy.
Monitoring of renal function is recommended as follows: Prior to Steglujan initiation and periodically during treatment (see Dosage & Administration); More frequently in patients with an eGFR below 60 ml/min/1.73 m2 or a CrCl below 60 ml/min.
Hypoglycaemia with concomitant use with insulin and insulin secretagogues: Ertugliflozin may increase the risk of hypoglycaemia when used in combination with insulin and/or an insulin secretagogue, which are known to cause hypoglycaemia (see Adverse Reactions). Hypoglycaemia has been observed when sitagliptin was used in combination with insulin or a sulphonylurea. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimise the risk of hypoglycaemia when used in combination with Steglujan (see Dosage & Administration and Interactions).
Genital mycotic infections: Ertugliflozin increases the risk of genital mycotic infections. In trials with SGLT2 inhibitors, patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections (see Adverse Reactions). Patients should be monitored and treated appropriately.
Urinary tract infections: Urinary glucose excretion may be associated with an increased risk of urinary tract infections. The incidence of urinary tract infections was not notably different in the ertugliflozin 5 mg and 15 mg groups (4.0% and 4.1%) and the placebo group (3.9%). Most of the events were mild or moderate and no serious case was reported. Temporary interruption of ertugliflozin should be considered when treating pyelonephritis or urosepsis.
Hypersensitivity reactions: Post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin have been reported (see Adverse Reactions). 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 some reports occurring after the first dose. If a hypersensitivity reaction is suspected, Steglujan should be discontinued. Other potential causes for the event should be assessed, and alternative treatment for diabetes initiated.
Bullous pemphigoid: There have been post-marketing reports of bullous pemphigoid in patients taking DPP-4 inhibitors including sitagliptin. If bullous pemphigoid is suspected, Steglujan should be discontinued.
Cardiac failure: Experience in New York Heart Association (NYHA) class I-II is limited, and there is no experience in clinical studies with Steglujan in NYHA class III-IV.
Urine laboratory assessments: Due to the mechanism of action of ertugliflozin, patients taking Steglujan will test positive for glucose in their urine. Alternative methods should be used to monitor glycaemic control.
Interference with 1,5-anhydroglucitol (1,5-AG) assay: Monitoring glycaemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycaemic control in patients taking SGLT2 inhibitors. Alternative methods should be used to monitor glycaemic control.
Effects on ability to drive and use machines: Steglujan has no or negligible influence on the ability to drive and use machines. However, when driving or using machines, it should be taken into account that dizziness and somnolence have been reported with sitagliptin. In addition, patients should be alerted to the risk of hypoglycaemia when Steglujan is used in combination with insulin or an insulin secretagogue and to the elevated risk of adverse reactions related to volume depletion, such as postural dizziness (see Dosage & Administration, Precautions, and Adverse Reactions).
Use in Elderly: Elderly patients may be at an increased risk of volume depletion. Patients 65 years and older treated with ertugliflozin, had a higher incidence of adverse reactions related to volume depletion compared to younger patients. Steglujan is expected to have diminished efficacy in elderly patients with renal impairment (see Dosage & Administration and Adverse Reactions).
Use In Pregnancy & Lactation
Pregnancy: There are no data from the use of Steglujan in pregnant women. There are limited data from the use of ertugliflozin in pregnant women. Based on results from animal studies, ertugliflozin may affect renal development and maturation (see Pharmacology: Toxicology: Preclinical safety data under Actions). Therefore, Steglujan should not be used during pregnancy.
Breast-feeding: There is no information regarding the presence of Steglujan or its individual components in human milk, the effects on the breast-fed infant, or the effects on milk production. No studies in lactating animals have been conducted with the combined components of Steglujan. Ertugliflozin and sitagliptin are present in the milk of lactating rats. Ertugliflozin caused effects in the offspring of lactating rats.
Pharmacologically mediated effects were observed in juvenile rats treated with ertugliflozin (see Pharmacology: Toxicology: Preclinical safety data under Actions). Since human kidney maturation occurs in utero and during the first 2 years of life when exposure from breast-feeding may occur, a risk to newborns/infants cannot be excluded. Steglujan should not be used during breast-feeding.
Fertility: The effect of Steglujan on fertility in humans has not been studied. No effects of ertugliflozin or sitagliptin on fertility were observed in animal studies (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Adverse Reactions
Summary of the safety profile: 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 Pharmacology: Pharmacodynamics under Actions). The incidence and type of adverse reactions in these three studies were similar to the adverse reactions seen with ertugliflozin and are described as follows in Table 5. There were no additional adverse reactions identified in these three trials that included sitagliptin relative to the three placebo-controlled studies with ertugliflozin (see as follows).
Ertugliflozin: Pool of placebo-controlled trials: The primary assessment of safety was conducted in 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 Pharmacology: Pharmacodynamics under Actions). 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 most commonly reported adverse reactions across the clinical program were vulvovaginal mycotic infection and other female genital mycotic infections. Serious diabetic ketoacidosis occurred rarely. See "Description of selected adverse reactions" as follows for frequencies and see Precautions.
Sitagliptin: Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported. Hypoglycaemia has been reported in combination with sulphonylurea (4.7%-13.8%) and insulin (9.6%) (see Precautions).
Tabulated list of adverse reactions: Adverse reactions listed as follows are classified according to frequency and system organ class (SOC). Frequency categories are defined according to the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data). (See Table 5.)

Click on icon to see table/diagram/image

Description of selected adverse reactions: Volume depletion (ertugliflozin): Ertugliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion. In the pool of placebo-controlled studies, the incidence of adverse events related to volume depletion (dehydration, dizziness postural, presyncope, syncope, hypotension and orthostatic hypotension) was low (< 2%) and not notably different across the ertugliflozin and placebo groups. In the subgroup analyses in the broader pool of Phase 3 studies, subjects with eGFR < 60 mL/min/1.73 m2, subjects ≥ 65 years of age and subjects on diuretics had a higher incidence of volume depletion in the ertugliflozin groups relative to the comparator group (see Dosage & Administration and Precautions). In subjects with eGFR < 60 mL/min/1.73 m2, the incidence was 5.1%, 2.6% and 0.5% for ertugliflozin 5 mg, ertugliflozin 15 mg and the comparator group and for subjects with eGFR 45 to < 60 mL/min/1.73 m2, the incidence was 6.4%, 3.7% and 0% respectively.
Hypoglycaemia (ertugliflozin): In the pool of placebo-controlled studies, the incidence of documented hypoglycemia was increased for ertugliflozin 5 mg and 15 mg (5.0% and 4.5%) compared to placebo (2.9%). In this population, the incidence of severe hypoglycaemia was 0.4% in each group. When ertugliflozin was used as monotherapy, the incidence of hypoglycaemic events in the ertugliflozin groups was 2.6% in both groups and 0.7% in the placebo group. When used as add-on to metformin, the incidence of hypoglycaemic events was 7.2% in the ertugliflozin 5 mg group, 7.8% in the ertugliflozin 15 mg group and 4.3% in the placebo group.
When ertugliflozin was added to metformin and compared to sulphonylurea, the incidence of hypoglycaemia was higher for the sulphonylurea (27%) compared to ertugliflozin (5.6% and 8.2% for ertugliflozin 5 mg and 15 mg, respectively).
In patients with moderate renal impairment taking insulins, SU, or meglitinides as background medication, documented hypoglycaemia was 36%, 27% and 36% for ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively (see Dosage & Administration, Precautions, and Interactions).
Diabetic Ketoacidosis (ertugliflozin): Across the clinical program for ertugliflozin, ketoacidosis was identified in 3 of 3,409 (0.1%) ertugliflozin-treated patients and 0.0% of comparator-treated patients (see Precautions).
Blood creatinine increased/Glomerular filtration rate decreased and renal-related events (ertugliflozin): Initial increases in mean creatinine and decreases in mean eGFR in patients treated with ertugliflozin were generally transient during continuous treatment. Patients with moderate renal impairment at baseline had larger mean changes that did not return to baseline at Week 26; these changes reversed after treatment discontinuation.
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 2.5%, 1.3%, and 0.6% in patients treated with ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively.
Genital mycotic infections (ertugliflozin): In the pool of three placebo-controlled clinical trials, female genital mycotic infections (e.g., genital candidiasis, genital infection fungal, vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis) occurred in 9.1%, 12%, and 3.0% of females treated with ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively. In females, discontinuation due to genital mycotic infections occurred in 0.6% and 0% of patients treated with ertugliflozin and placebo, respectively (see Precautions).
In the same pool, male genital mycotic infections (e.g., balanitis candida, balanoposthitis, genital infection, genital infection fungal) occurred in 3.7%, 4.2%, and 0.4% of males treated with ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males. In males, discontinuations due to genital mycotic infections occurred in 0.2% and 0% of patients treated with ertugliflozin and placebo, respectively. In rare instances, phimosis was reported and sometimes circumcision was performed (see Precautions).
Sitagliptin: In addition to the adverse reactions described in the table previously, adverse experiences reported regardless of causal relationship to medication and occurring in at least 5% and more commonly in patients treated with sitagliptin included upper respiratory tract infection and nasopharyngitis. Additional adverse experiences reported regardless of causal relationship to medication that occurred more frequently in patients treated with sitagliptin (not reaching the 5% level, but occurring with an incidence of > 0.5% higher with sitagliptin than that in the control group) included osteoarthritis and pain in extremity.
Some adverse reactions were observed more frequently in studies of combination use of sitagliptin with other anti-diabetic medicinal products than in studies of sitagliptin monotherapy. These included hypoglycaemia (frequency very common with the combination of sulphonylurea and metformin), influenza (common with insulin (with or without metformin)), nausea and vomiting (common with metformin), flatulence (common with metformin or pioglitazone), constipation (common with the combination of sulphonylurea and metformin), peripheral oedema (common with pioglitazone or the combination of pioglitazone and metformin), somnolence and diarrhoea (uncommon with metformin), and dry mouth (uncommon with insulin (with or without metformin)).
TECOS (trial evaluating cardiovascular outcomes with sitagliptin): The cardiovascular safety study with sitagliptin (TECOS) included 7,332 patients treated with sitagliptin, 100 mg daily (or 50 mg daily if the baseline eGFR was ≥ 30 and < 50 ml/min/1.73 m2), and 7,339 patients treated with placebo in the intention-to-treat population. Both treatments were added to usual care targeting regional standards for HbA1c and CV risk factors. The overall incidence of serious adverse events in patients receiving sitagliptin was similar to that in patients receiving placebo.
In the intention-to-treat population, among patients who were using insulin and/or a sulphonylurea at baseline, the incidence of severe hypoglycaemia was 2.7% in sitagliptin-treated patients and 2.5% in placebo-treated patients; among patients who were not using insulin and/or a sulphonylurea at baseline, the incidence of severe hypoglycaemia was 1.0% in sitagliptin-treated patients and 0.7% in placebo-treated patients. The incidence of adjudication-confirmed pancreatitis events was 0.3% in sitagliptin-treated patients and 0.2% in placebo-treated patients.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.
Drug Interactions
Pharmacokinetic drug interaction studies with Steglujan have not been performed; however, such studies have been conducted with ertugliflozin and sitagliptin, the individual active substances of Steglujan.
Ertugliflozin: Pharmacodynamic interactions: Diuretics: Ertugliflozin may add to the diuretic effect of diuretics and may increase the risk of dehydration and hypotension (see Precautions).
Insulin and insulin secretagogues: Insulin and insulin secretagogues, such as sulphonylureas, cause hypoglycaemia. Ertugliflozin may increase the risk of hypoglycaemia when used in combination with insulin and/or an insulin secretagogue. Therefore, a lower dose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycaemia when used in combination with Steglujan (see Dosage & Administration, Precautions, and Adverse Reactions).
Pharmacokinetic interactions: Effects of other medicinal products on the pharmacokinetics of ertugliflozin: Metabolism by UGT1A9 and UGT2B7 is the primary clearance mechanism for ertugliflozin.
Interaction studies conducted in healthy subjects, using a single dose design, suggest that the pharmacokinetics of ertugliflozin are not altered by sitagliptin, metformin, glimepiride, or simvastatin.
Multiple-dose administration of rifampin (a UGT and CYP inducer) decreases ertugliflozin AUC and Cmax by 39% and 15%, respectively. This decrease in exposure is not considered clinically relevant and therefore, no dose adjustment is recommended. A clinically relevant effect with other inducers (e.g., carbamazepine, phenytoin, phenobarbital) is not expected.
The impact of UGT inhibitors on the pharmacokinetics of ertugliflozin has not been studied clinically, but potential increase in ertugliflozin exposure due to UGT inhibition is not considered to be clinically relevant.
Effects of ertugliflozin on the pharmacokinetics of other medicinal products: Interaction studies conducted in healthy volunteers suggest that ertugliflozin had no clinically relevant effect on the pharmacokinetics of sitagliptin, metformin, and glimepiride.
Coadministration of simvastatin with ertugliflozin resulted in a 24% and 19% increase in AUC and Cmax of simvastatin, respectively, and 30% and 16% increase in AUC and Cmax of simvastatin acid, respectively. The mechanism for the small increases in simvastatin and simvastatin acid is unknown and is not perpetrated through OATP inhibition by ertugliflozin. These increases are not considered to be clinically meaningful.
Sitagliptin: Pharmacokinetic interactions: Effects of other medicinal products on sitagliptin: Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway. In vitro studies indicate that the primary enzyme responsible for the limited metabolism of sitagliptin is CYP3A4, with contribution from CYP2C8.
Metabolism may play a more significant role in the elimination of sitagliptin in the setting of severe renal impairment or end-stage renal disease (ESRD). For this reason, it is possible that potent CYP3A4 inhibitors (i.e., ketoconazole, itraconazole, ritonavir, clarithromycin) could alter the pharmacokinetics of sitagliptin in patients with severe renal impairment or ESRD.
Interaction studies conducted in patients with type 2 diabetes or healthy volunteers suggest that metformin and ciclosporin had no clinically relevant effect on the pharmacokinetics of sitagliptin.
Effects of sitagliptin on other medicinal products: In drug interaction studies, sitagliptin did not have clinically meaningful effects on the pharmacokinetics of the following: metformin, rosiglitazone, glyburide, simvastatin, warfarin, and oral contraceptives.
Digoxin: Sitagliptin had a small effect on plasma digoxin concentrations. Following administration of 0.25 mg digoxin concomitantly with 100 mg of sitagliptin daily for 10 days, the plasma AUC of digoxin was increased on average by 11% and the plasma Cmax on average by 18%. No dose adjustment of digoxin is recommended. However, patients at risk of digoxin toxicity should be monitored for this when sitagliptin and digoxin are administered concomitantly.
Caution For Usage
Special precautions for disposal: No special requirements.
Storage
This medicinal product does not require any special storage conditions.
MIMS Class
ATC Classification
A10BD24 - sitagliptin and ertugliflozin ; Belongs to the class of combinations of oral blood glucose lowering drugs. Used in the treatment of diabetes.
Presentation/Packing
15/100 mg (brown, 12.0 x 7.4 mm, almond-shaped, debossed with "555" on one side and plain on the other side) 28's.
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