Jardiance film-coated tablets 10 mg blister No. 30

Instructions Jardines film-coated tablets 10 mg blister No. 30

Composition

active ingredient: empagliflozin;

1 tablet contains empagliflozin 10 mg or 25 mg;

excipients: lactose monohydrate; microcrystalline cellulose; hydroxypropylcellulose; croscarmellose sodium; colloidal anhydrous silica; magnesium stearate; Opadry® Yellow 02B38190 coating (hypromellose 2910, titanium dioxide (E171), talc, macrogol 400, iron oxide yellow (E172)).

Dosage form

Film-coated tablets.

Main physicochemical properties:

10 mg tablets: round, biconvex, film-coated tablets, pale yellow in color with beveled edges, embossed with the Boehringer Ingelheim company symbol on one side and embossed with “S10” on the other;

25 mg tablets: oval, biconvex, film-coated tablets, pale yellow in color with beveled edges, embossed with the Boehringer Ingelheim company symbol on one side and embossed with “S25” on the other.

Pharmacotherapeutic group

Drugs used in diabetes mellitus, inhibitors of sodium-dependent glucose co-transporter type 2 (NSCG2i). ATC code A10B K03.

Pharmacological properties

Pharmacodynamics.

Mechanism of action

Empagliflozin is a reversible potent (IC50 1.3 nmol) and selective competitive inhibitor of sodium-dependent glucose co-transporter 2 (SDG-2). Empagliflozin does not inhibit other glucose transporters that play an important role in glucose delivery to peripheral tissues and is 5000-fold more selective for SDG-2 compared to SDG-1, the main transporter responsible for glucose absorption in the intestine. SDG-2 is expressed at high levels in the kidney, while expression in other tissues is absent or very low. As the main transporter, it is responsible for the reabsorption of glucose from the tubular lumen back into the bloodstream. In patients with type 2 diabetes and hyperglycemia, more glucose is filtered and absorbed.

Empagliflozin improves glycemic control in patients with type 2 diabetes mellitus by reducing the renal reabsorption of glucose. The amount of glucose excreted by the kidneys through this glucuretic mechanism depends on the blood glucose concentration and glomerular filtration rate (GFR). Inhibition of NGKTG-2 in patients with type 2 diabetes mellitus and hyperglycemia results in increased urinary glucose excretion. In addition, empagliflozin increases sodium excretion, leading to osmotic diuresis and intravascular volume depletion.

In patients with type 2 diabetes, glucose excretion increased immediately after the first dose of empagliflozin and was maintained over the 24-hour dosing interval. The increase in urinary glucose excretion was maintained at the end of the 4-week treatment period and averaged approximately 78 g/day. The increase in urinary glucose excretion resulted in an immediate reduction in plasma glucose levels in patients with type 2 diabetes.

Empagliflozin improves plasma glucose levels both in the fasting and postprandial state. The mechanism of action of empagliflozin is independent of β-cell function and the insulin pathway, which contributes to a reduced risk of hypoglycemia. Improvements in markers of β-cell function, including the homeostatic model of β-cell function assessment (HOMA-β), have been observed. In addition, urinary glucose excretion results in calorie loss associated with fat loss and weight loss. The glucosuria observed with empagliflozin is accompanied by diuresis, which may contribute to a long-term and modest reduction in blood pressure.

Empagliflozin also reduces sodium reabsorption and increases sodium delivery to the distal tubules. This may affect several physiological functions, including increased tubular-glomerular feedback and decreased intraglomerular pressure, decreased cardiac pre/afterload and inhibition of sympathetic activity, and decreased left ventricular wall stress, as evidenced by lower NT-proBNP values and beneficial effects on cardiac remodeling, filling pressure, and diastolic function.

Clinical efficacy and safety

Type 2 diabetes

Improving glycemic control and reducing cardiovascular disease and mortality are integral parts of the treatment of type 2 diabetes.

Empagliflozin alone and in combination with metformin, pioglitazone, sulphonylureas, DPP-4 inhibitors and insulin resulted in clinically meaningful improvements in HbA1c, fasting plasma glucose, body weight, systolic and diastolic blood pressure. Empagliflozin 25 mg increased the proportion of patients achieving a target HbA1c of less than 7% and reduced the number of patients requiring glycemic control compared with empagliflozin 10 mg and placebo. The higher the baseline HbA1c, the greater the reduction in HbA1c.

In addition, empagliflozin, as an add-on to standard therapy, reduces cardiovascular mortality and cardiovascular disease in patients with type 2 diabetes.

The double-blind, placebo-controlled EMPA-REG OUTCOME study compared the efficacy of empagliflozin 10 mg and 25 mg and placebo as an adjunct to standard therapy in patients with type 2 diabetes and established cardiovascular disease.

Empagliflozin was superior to placebo in preventing cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. The effect was driven by a significant reduction in the risk of cardiovascular death without significant changes in non-fatal myocardial infarction or non-fatal stroke. The reduction in cardiovascular death was comparable for empagliflozin 10 mg and 25 mg (see graph below) and was supported by an improvement in overall survival (Table 1).

The effect of empagliflozin on the primary composite endpoint of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke was largely independent of glycaemic control or renal function, which was generally defined as an eGFR of 30 mL/min/1.73 m2 or greater in all patient groups in the EMPA-REG OUTCOME study.

The efficacy in preventing cardiovascular mortality has not been definitively established in patients receiving empagliflozin concomitantly with DPP-4 inhibitors and in patients of black race, as the representation of these groups in the EMPA-REG OUTCOME study was limited.

Table 1

Treatment effect by main evaluation criteria, their components and mortalitya

a Data obtained from treated patients (i.e. patients who received at least one dose of study drug).

b Combined doses of empagliflozin 10 mg and 25 mg.

* Since the study results were included in the interim analysis, a two-sided confidence interval of 95.02% is used, which corresponds to a p value of < 0.0498 for significance.

Fig. 1. Time to death from cardiovascular disease in the EMPA-REG OUTCOME study.

Heart failure requiring hospitalization

In the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of developing heart failure requiring hospitalization compared with placebo (empagliflozin group – 2.7%; placebo group – 4.1%; HR 0.65, 95% CI 0.50, 0.85).

Nephropathy

In the EMPA-REG OUTCOME study, the HR for time to first episode of nephropathy was 0.61 (95% CI 0.53; 0.70) in the empagliflozin group (12.7%) compared with the placebo group (18.8%).

In addition, empagliflozin increased the risk (HR 1.82; 95% CI 1.40; 2.37) of developing persistent normo- or microalbuminuria (49.7%) in patients with macroalbuminuria at baseline compared with placebo (28.8%).

Heart failure

Use of empagliflozin in patients with heart failure and reduced ejection fraction

1863 patients were randomised to empagliflozin 10 mg (placebo: 1867). The median duration of treatment was 15.7 months. The study population consisted of 76.1% men and 23.9% women, with a mean age of 66.8 years (range: 25-94 years); 26.8% of patients were over 75 years of age. 70.5% of the study population was Caucasian, 18.0% was Asian, and 6.9% was Black/African American. At randomisation, 75.1% of patients had NYHA class II heart failure, 24.4% had NYHA class III heart failure, and 0.5% had NYHA class IV heart failure. The mean LVEF was 27.5%. At baseline, the mean eGFR was 62.0 mL/min/1.73 m2 and the mean urine albumin/creatinine ratio (UACR) was 22 mg/h. Approximately half of the patients (51.7%) had an eGFR ≥60 mL/min/1.73 m2, 24.1% had an eGFR between 45 and <60 mL/min/1.73 m2, 18.6% had an eGFR between 30 and <45 mL/min/1.73 m2, and 5.3% had an eGFR between 20 and <30 mL/min/1.73 m2.

Empagliflozin demonstrated the greatest efficacy in reducing the risk of the primary composite endpoint of CV death or hospitalization for heart failure compared with placebo. In addition, empagliflozin significantly reduced the risk of HF (first and second) and significantly reduced the rate of decline in eGFR (Table 2).

Table 2

Treatment effect on the primary composite endpoint, its components, and two key secondary endpoints included in the pre-specified confirmatory trial

CV = cardiovascular, FCH = hospitalization for heart failure, eGFR = estimated glomerular filtration rate, CKD EPI = epidemiologic alignment in chronic kidney disease

* cardiovascular death and hospitalization for heart failure were determined by an independent clinical events committee and monitored based on a randomized recruitment

** Estimated glomerular filtration rate was analyzed based on the treated set. The delay was -0.95 mL/min/1.73 m2 for placebo and -3.02 mL/min/1.73 m2 for empagliflozin. The delay represents the acute effect on estimated glomerular filtration rate while the slope represents the long-term effect.

Fig. 2 Time to first confirmed event of cardiovascular death or hospitalization for heart failure

The results for the primary composite endpoint were generally consistent with a hazard ratio (HR) below 1 in all pre-specified subgroups, including patients with heart failure, with or without type 2 diabetes, and with or without renal impairment (estimated glomerular filtration rate (eGFR) not lower than 20 mL/min/1.73 m2).

Use of empagliflozin in patients with heart failure and preserved ejection fraction

A randomized, blinded, placebo-controlled trial (EMPEROR-Preserved) was conducted in 5,988 patients with chronic heart failure (NYHA II-IV) and preserved ejection fraction (LVEF > 40%) to evaluate the efficacy and safety of empagliflozin 10 mg once daily as an add-on to standard therapy. The primary endpoint was time to first cardiovascular death or confirmed heart failure (HF) hospitalization. Confirmed HF hospitalization (first and repeat) and slope of change from baseline in eGFR (CKD-EPI) were included in confirmatory testing. Background therapy included ACE inhibitors/angiotensin receptor blockers/angiotensin receptor blockers/neprilysin receptor blockers (80.7%), beta-blockers (86.3%), mineralocorticoid receptor antagonists (37.5%), and diuretics (86.2%).

Empagliflozin demonstrated the greatest efficacy in reducing the risk of the primary endpoint of cardiovascular death or hospitalization for heart failure compared with placebo. In addition, empagliflozin significantly reduced the risk of hospitalization for HF (first and second) and significantly slowed the rate of decline in eGFR.

Table 3

Treatment effect on the primary composite endpoint, its components, and two key secondary endpoints included in the prespecified validated trial

CV – cardiovascular, HF – heart failure, eGFR – estimated glomerular filtration rate, CKD EPI – epidemiological alignment in chronic kidney disease.

* Death from cardiovascular disease and hospitalization for heart failure were determined by an independent clinical events committee and monitored based on randomized recruitment.

** Estimated glomerular filtration rate was analyzed based on the treated set. The delay was -0.95 mL/min/1.73 m2 for placebo and -3.02 mL/min/1.73 m2 for empagliflozin. The delay represents the acute effect on estimated glomerular filtration rate while the slope represents the long-term effect.

Fig. 3 Time to first confirmed event of cardiovascular death or hospitalization for heart failure.

The results of the primary composite endpoint were consistent across each of the pre-specified subgroups, classified, for example, by LVEF, diabetes status, or renal function (up to 20 mL/min/1.73 m2).

During treatment, the rate of decline in eGFR over time was slower in the empagliflozin group compared with the placebo group. Treatment with empagliflozin 10 mg significantly slowed the rate of decline in eGFR, and the effect was consistent across all pre-specified subgroups. Patients treated with empagliflozin had an initial decline in eGFR that returned to baseline after discontinuation of treatment, supporting the role of hemodynamic changes in the acute effects of empagliflozin on eGFR.

Empagliflozin in patients hospitalized for acute heart failure

A randomized, double-blind, placebo-controlled study (EMPULSE) was conducted in 530 patients hospitalized for acute heart failure regardless of LVEF (33.0% with de novo and 67.0% with decompensated chronic heart failure) who were stabilized. The study evaluated the clinical efficacy and safety of empagliflozin 10 mg once daily as an add-on to standard therapy. Treatment was initiated in the inpatient setting and continued for 90 days. The primary endpoints were clinical benefit, composite of death, number of heart failure events (including heart failure hospitalizations, urgent heart failure visits, and unscheduled outpatient visits), time to first heart failure event, and change from baseline in the Kansas City Cardiomyopathy Questionnaire. The Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Score (TSS) after 90 days of treatment is assessed by the win rate. Background therapy included angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers/angiotensin receptor neprilysin inhibitor (70.0%), beta-blockers (79.4%), and diuretics (90.6%).

In the primary analysis, each patient in the empagliflozin group was compared with each patient in the placebo group in each stratum (de novo or decompensated chronic HF). Pairwise comparisons were made in a hierarchical order using time to death, followed by the number of heart failure events, time to first heart failure, and ≥5-point difference in change from baseline in the PAD-OCC, which defined the severity and frequency of HF symptoms. Stratified odds ratios were then calculated by combining the number of wins in the empagliflozin group divided by the number of losses between strata. Patients receiving empagliflozin were 36% more likely to experience clinical benefit compared with placebo (odds ratio 1.36, 95% CI 1.09, 1.68; p = 0.0054.

Patients taking empagliflozin were 36% more likely to experience clinical benefit compared with placebo (odds ratio 1.36, 95% CI 1.09, 1.68; p = 0.0054 (see Table 4).

Table 4

Clinical benefit-benefit ratio

HF – complications of heart failure. KSCC-CCS – Kansas City Cardiomyopathy Questionnaire Total Score.

1 Pairs of patients were analyzed within the odds ratio using weights similar to the Mantel-Haenszel approach.

2 Frequency is due to complications in censored patients.

3 Based on imputation of missing data with 100 iterations.

4 Variance calculated using the asymptotic normal statistics approach.

The primary endpoint results were generally consistent across pre-specified subgroups, including de novo heart failure and decompensated chronic heart failure, and were independent of LVEF.

The safety data obtained in this study were consistent with the previously known safety profile of empagliflozin.

Pharmacokinetics.

Absorption

The pharmacokinetics of empagliflozin have been extensively characterized in healthy volunteers and patients with type 2 diabetes. After oral administration, empagliflozin was rapidly absorbed, with peak plasma concentrations occurring at a mean tmax of 1.5 hours after dosing. Thereafter, plasma concentrations declined in a biphasic manner, with a rapid distribution phase and a relatively slow terminal phase. Mean steady-state plasma area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax) were 1870 nmol/h and 259 nmol/l for empagliflozin 10 mg and 4740 nmol/h and 687 nmol/l for empagliflozin 25 mg once daily. Systemic exposure to empagliflozin increased in a dose-proportional manner. The pharmacokinetic parameters of empagliflozin at rest after single-dose administration were similar, indicating linear pharmacokinetics over time. There were no clinically relevant differences in the pharmacokinetics of empagliflozin between healthy volunteers and patients with type 2 diabetes.

Administration of empagliflozin 25 mg after a high-calorie, high-fat meal resulted in a slight decrease in exposure: AUC was decreased by approximately 16% and Cmax by approximately 37% compared to the fasted state. This effect of food on the pharmacokinetics of empagliflozin is not considered clinically relevant. Empagliflozin can be taken without regard to food.

Distribution

The volume of distribution at rest is 73.8 L. Following oral administration of [14C]-empagliflozin solution to healthy volunteers, erythrocyte distribution was approximately 37% and plasma protein binding was 86%.

Biotransformation

No significant metabolites of empagliflozin were detected in human plasma. The most abundant metabolites were three glucuronide conjugates (2-, 3- and 6-O-glucuronide). The systemic exposure of each metabolite was less than 10% of the total drug exposure. In vitro studies indicate that the major route of metabolism of empagliflozin in humans is glucuronidation by the uridine-5'-diphosphoglucuronosyltransferases UGT2B7, UGT1A3, UGT1A8 and UGT1A9.

Breeding

The terminal half-life of empagliflozin is 12.4 hours and the apparent oral clearance is 10.6 L/h. The inter-subject and intra-subject variability for oral empagliflozin clearance was 39.1% and 35.8%, respectively. With once-daily dosing, steady-state plasma concentrations of empagliflozin were achieved by the 5th dose. Consistent with the half-life, up to 22% accumulation (relative to plasma AUC) was observed at steady state. Following oral administration of [14C]-empagliflozin solution to healthy volunteers, approximately 96% of the label was excreted in the feces (41%) and urine (54%). The majority of the label was excreted unchanged in the feces and approximately half of the label was excreted unchanged in the urine.

Patients with renal insufficiency

In patients with mild, moderate or severe renal impairment (eGFR < 30-< 90 mL/min/1.73 m2) and patients with renal insufficiency/end-stage renal disease (ESRD), the AUC of empagliflozin increased by approximately 18%, 20%, 66% and 48%, respectively, compared to subjects with normal renal function. Peak plasma levels of empagliflozin were similar in patients with moderate renal impairment and renal insufficiency/ESRD compared to subjects with normal renal function. Peak plasma levels of empagliflozin were approximately 20% higher in patients with mild and severe renal impairment compared to subjects with normal renal function. Based on pharmacokinetics in subjects, the apparent oral clearance of empagliflozin decreased with decreasing eGFR, resulting in enhanced drug exposure.

Patients with hepatic insufficiency

In subjects with mild, moderate and severe hepatic impairment according to Child-Pugh classification, the AUC of empagliflozin was increased by approximately 23%, 47% and 75%, and the Cmax was increased by approximately 4%, 23% and 48%, respectively, compared to subjects with normal hepatic function.

Body mass index

Body mass index had no clinically relevant effect on the pharmacokinetics of empagliflozin. AUC was 5.82%, 10.4%, and 17.3% lower in patients with a BMI of 30, 35, and 45 kg/m2, respectively, compared to patients with a BMI of 25 kg/m2.

Sex

Gender had no clinically significant effect on the pharmacokinetics of empagliflozin.

Race

The AUC was 13.5% higher in patients of the Mongoloid race with a body mass index of 25 kg/m2 compared to patients of other races with a body mass index of 25 kg/m2.

Elderly patients

Age had no clinically significant effect on the pharmacokinetics of empagliflozin.

Children

Clinical trials of empagliflozin in children aged 10–18 years with type 2 diabetes have been initiated. The pharmacokinetic and pharmacodynamic data obtained to date are comparable to those in adults.

Indication

Type 2 diabetes

Treatment of type 2 diabetes mellitus in adults when diet and exercise alone do not provide adequate glycaemic control:

- as monotherapy in case of intolerance to metformin;

- in combination with other hypoglycemic drugs.

For the results of studies of combination therapy, in particular glycaemic control and cardiovascular complications, see sections “Special warnings and precautions for use”, “Interaction with other medicinal products and other types of interactions” and “Pharmacological properties”.

Heart failure

JARDINES is indicated in adult patients for the treatment of symptomatic chronic heart failure.

Contraindication

Hypersensitivity to the active substance or to any of the excipients.

Interaction with other medicinal products and other types of interactions

Pharmacodynamic interactions

Diuretics

Empagliflozin may enhance the diuretic effect of thiazide and loop 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 may increase the risk of hypoglycaemia. To reduce the risk of hypoglycaemia, a lower dose of insulin or insulin secretagogue may be recommended when used in combination with empagliflozin (see sections 4.2 and 4.8).

Pharmacokinetic interactions

Effects of other medicinal products on empagliflozin

In vitro data indicate that the major metabolic pathway of empagliflozin in humans is glucuronidation by uridine-5'-diphosphoglucuronosyltransferases UGT1A3, UGT1A8, UGT1A9 and UGT2B7. Empagliflozin is a substrate of the human uptake transporters OAT3, OATP1B1 and OATP1B3, but not OAT1 and OCT2. Empagliflozin is transported by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

Co-administration of empagliflozin with probenecid, an inhibitor of the enzymes uridine diphosphoglucuronosyltransferase (UGT) and OAT3, resulted in a 26% increase in peak plasma concentrations of empagliflozin and a 53% increase in AUC. These changes were not considered clinically relevant.

The effect of UGT induction (including induction by rifampicin or phenytoin) on empagliflozin has not been studied. Concomitant treatment with known inducers of UGT enzymes is not recommended due to the potential risk of reduced efficacy. If a UGT enzyme inducer must be co-administered, monitoring of glycemic control to assess response to JARDINAX is appropriate.

An in vitro interaction study with gemfibrozil, an inhibitor of OAT3 and OATP1B1/1B3 transporters, showed that the Cmax of empagliflozin increased by 15% and the AUC decreased by 59% after co-administration. These changes were not considered clinically relevant.

Inhibition of OATP1B1/1B3 transporters when co-administered with rifampicin resulted in a 75% increase in Cmax and a 35% decrease in AUC of empagliflozin. These changes were not considered clinically relevant.

Interaction studies in healthy volunteers indicate that the pharmacokinetics of empagliflozin are not affected by co-administration of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, simvastatin, torasemide and hydrochlorothiazide.

Effects of empagliflozin on other medicinal products

Empagliflozin may increase renal excretion of lithium and decrease serum lithium levels. Serum lithium levels should be monitored more frequently after initiation of empagliflozin and dose adjustments. The patient should be referred to the physician who prescribed the lithium medication for monitoring of serum lithium levels.

Empagliflozin does not inhibit, inactivate or induce CYP450 isoforms in in vitro studies. Empagliflozin does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9 or UGT2B7. Drug-drug interactions involving major CYP450 or UGT isoforms with empagliflozin and co-administered substrates of these enzymes are considered unlikely.

Empagliflozin does not inhibit P-gp at therapeutic doses. Based on in vitro studies, empagliflozin is unlikely to cause interactions with active substances that are P-gp substrates. Co-administration of digoxin, a P-gp substrate, with empagliflozin resulted in an increase in AUC and Cmax of digoxin of up to 6% and 14%, respectively. These changes were not considered clinically relevant.

Empagliflozin does not inhibit human uptake transporters such as OAT3, OATP1B1 and OATP1B3 in vitro at clinically relevant concentrations, i.e. drug-drug interactions with substrates of these uptake transporters are considered unlikely.

Interaction studies conducted in healthy volunteers indicate that empagliflozin has no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, simvastatin, warfarin, ramipril, digoxin, diuretics, and oral contraceptives.

Application features

Ketoacidosis

Rare cases of ketoacidosis, including life-threatening and fatal cases, have been reported in patients with diabetes treated with ACE inhibitors (including empagliflozin). In a few cases, ketoacidosis has been atypical, with only modest increases in blood glucose (below 14 mmol/L (250 mg/dL)). It is unknown whether increasing the dose of empagliflozin affects the likelihood of ketoacidosis.

The risk of ketoacidosis should be considered in the event of nonspecific symptoms such as nausea, vomiting, loss of appetite, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or drowsiness. Patients should be evaluated immediately for ketoacidosis if these symptoms occur, regardless of blood glucose levels.

If ketoacidosis is suspected or diagnosed in a patient, empagliflozin should be discontinued immediately.

If the patient is hospitalized for major surgical procedures or if a serious acute illness occurs, treatment should be interrupted. Monitoring of ketones is recommended in these patients. Measurement of urine ketones is a priority over blood ketones. Empagliflozin treatment may be resumed when ketone levels return to normal and the patient's condition stabilizes.

Before initiating empagliflozin, the patient's medical history should be reviewed for factors that may indicate a predisposition to ketoacidosis.

Patients with low β-cell function (e.g., type 2 diabetes with low C-peptide, latent autoimmune diabetes in adults, or a history of pancreatitis); patients with conditions that result in food restriction or severe dehydration; patients whose insulin dose is being reduced; and patients with increased insulin requirements due to acute illness, surgery, or alcohol abuse may be at high risk for ketoacidosis. NGK-2 inhibitors should be used with caution in these patients.