Steglujan · 4.1 Therapeutic indications · 1

HOS-217579 · has-adverse-reaction-information · PDF-Seite 9

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 section 5.1). The incidence and type of adverse reactions in these three studies were similar to the adverse reactions seen with the individual monotherapies ertugliflozin and sitagliptin as described below in Table 1. Ertugliflozin The safety and tolerability of ertugliflozin were assessed in 7 placebo- or active comparator-controlled studies with a total of 3 409 patients with type 2 diabetes mellitus treated with ertugliflozin 5 mg or 15 mg. In addition, the safety and tolerability of ertugliflozin in patients with type 2 diabetes and established atherosclerotic cardiovascular disease were assessed in VERTIS CV (see section 5.1) with a total of 5 493 patients treated with ertugliflozin 5 mg or 15 mg and a mean duration of exposure of 2.9 years. 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 section 5.1). These data reflect exposure of 1 029 patients to ertugliflozin with a mean exposure 9 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 urinary tract infections, vulvovaginal mycotic infection and other female genital mycotic infections. Serious DKA occurred rarely (see section 4.4). 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 section 4.4). Tabulated list of adverse reactions Adverse reactions listed below are classified according to frequency

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HOS-217575 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

HOS-217574 · has-indication-information · PDF-Seite 2

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 sections 4.4, 4.5, and 5.1) 2

HOS-217577 · has-interaction-information · PDF-Seite 7

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 section 4.4). 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 sections 4.2, 4.4, and 4.8). 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. 7 Multiple-dose administration of rifampicin (a uridine 5’-diphospho-glucuronosyltransferase [UGT] and cytochrome P450 [CYP] inducer) decreases ertugliflozin area under the concentration-time curve (AUC) and maximum plasma concentration (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 increase

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HOS-217578 · has-pregnancy-information · PDF-Seite 8

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 section 5.3). Therefore, Steglujan should not be used during pregnancy. 8 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 section 5.3). 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 section 5.3).

HOS-217576 · has-warning-information · PDF-Seite 4

General Steglujan should not be used in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis (DKA) in these patients. 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 section 4.8), 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 section 4.8). 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, including 4 ertugliflozin. In a number of cases, the presentation of the condition was at

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