Steglatro · 4.1 Therapeutic indications · 1

HOS-098090 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile 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 evaluating Steglatro 5 mg and 15 mg 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 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). Tabulated list of adverse reactions Adverse reactions listed below are classified according to frequency and system organ class (SOC), within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. 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). 8 Table 1: Adverse reactions from placebo- and active comparator-controlled clinical trials and post-marketing experience System organ class Adverse reaction Frequency Infections and infestations Very common Urinary tract infections† Vulvovaginal mycotic infection and other female genital mycotic infections*,† Common Balanitis candida and other male genital

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HOS-098086 · has-contraindication-information · PDF-Seite 4

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

HOS-098085 · has-indication-information · PDF-Seite 2

Steglatro is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise: • as monotherapy when metformin is considered inappropriate due to intolerance or contraindications. • in addition to other medicinal products for the treatment of diabetes. For study results with respect to combinations of therapies, effects on glycaemic control, cardiovascular events, and the populations studied, see sections 4.4, 4.5, and 5.1. 2

HOS-098088 · has-interaction-information · PDF-Seite 7

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 ertugliflozin (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. 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 increases in simvastatin and simvastatin acid is unknown and is not perpetrated through organic anion transporting polypeptide (OATP) inhibition by ertugliflozin. These increases are not considered to be clinically meaningful.

HOS-098089 · has-pregnancy-information · PDF-Seite 7

Pregnancy 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, Steglatro should not be used during pregnancy. 7 Breast-feeding There is no information regarding the presence of ertugliflozin in human milk, the effects on the breast-fed infant, or the effects on milk production. Ertugliflozin is present in the milk of lactating rats and caused effects in the offspring of lactating rats. Pharmacologically-mediated effects were observed in juvenile rats (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. Steglatro should not be used during breast-feeding. Fertility The effect of ertugliflozin on fertility in humans has not been studied. No effects on fertility were observed in animal studies (see section 5.3).

HOS-098087 · has-warning-information · PDF-Seite 4

General Steglatro should not be used in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis (DKA) in these patients. Hypotension/Volume depletion Ertugliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction. Therefore, symptomatic hypotension may occur after initiating Steglatro (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 Steglatro, 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 ertugliflozin. Temporary interruption of treatment with ertugliflozin 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 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 DKA 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 ertugliflozin should be discontinued immediately. Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses. Monitoring of ketones is recomme

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