Jardiance

Empagliflozin.

JARDIANCE film-coated tablet 10mg: Round, pale yellow, biconvex, bevel-edged film-coated tablet debossed with "S10" on one side and the Boehringer Ingelheim logo on the other (tablet diameter: 9.1 mm).
Each tablet contains 10 mg empagliflozin.
Excipient with known effect: Each tablet contains lactose monohydrate equivalent to 154.3 mg lactose anhydrous.
JARDIANCE film-coated tablet 25mg: Oval, pale yellow, biconvex film-coated tablet debossed with "S25" on one side and the Boehringer Ingelheim logo on the other (tablet length: 11.1 mm, tablet width: 5.6 mm).
Each tablet contains 25 mg empagliflozin.
Excipient with known effect: Each tablet contains lactose monohydrate equivalent to 107.4 mg lactose anhydrous.
Excipients/Inactive Ingredients: Tablet core: Lactose monohydrate, Microcrystalline cellulose, Hydroxypropyl cellulose, Croscarmellose sodium, Colloidal anhydrous silica, Magnesium stearate.
Film coating: Hypromellose, Titanium dioxide (E171), Talc, Macrogol (400), Iron oxide yellow (E172).

Pharmacotherapeutic group: Drugs used in diabetes, Sodium-glucose co-transporter 2 (SGLT2) inhibitors. ATC code: A10BK03.
Pharmacology: Pharmacodynamics: Mechanism of action: Empagliflozin is a reversible, highly potent (IC₅₀ of 1.3 nmol) and selective competitive inhibitor of sodium-glucose co-transporter 2 (SGLT2). Empagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is 5000 times more selective for SGLT2 versus SGLT1, the major transporter responsible for glucose absorption in the gut. SGLT2 is highly expressed in the kidney, whereas expression in other tissues is absent or very low. It is responsible, as the predominant transporter, for the reabsorption of glucose from the glomerular filtrate back into the circulation. In patients with type 2 diabetes and hyperglycaemia a higher amount of glucose is filtered and reabsorbed.
Empagliflozin improves glycaemic control in patients with type 2 diabetes by reducing renal glucose reabsorption. The amount of glucose removed by the kidney through this glucuretic mechanism is dependent on blood glucose concentration and GFR. Inhibition of SGLT2 in patients with type 2 diabetes and hyperglycaemia leads to excess glucose excretion in the urine. In addition, initiation of empagliflozin increases excretion of sodium resulting in osmotic diuresis and reduced intravascular volume.
In patients with type 2 diabetes, urinary glucose excretion increased immediately following the first dose of empagliflozin and is continuous over the 24 hour dosing interval. Increased urinary glucose excretion was maintained at the end of the 4-week treatment period, averaging approximately 78 g/day. Increased urinary glucose excretion resulted in an immediate reduction in plasma glucose levels in patients with type 2 diabetes.
Empagliflozin improves both fasting and post-prandial plasma glucose levels. The mechanism of action of empagliflozin is independent of beta cell function and insulin pathway and this contributes to a low risk of hypoglycaemia. Improvement of surrogate markers of beta cell function including Homeostasis Model Assessment-β (HOMA-β) was noted. In addition, urinary glucose excretion triggers calorie loss, associated with body fat loss and body weight reduction. The glucosuria observed with empagliflozin is accompanied by mild diuresis which may contribute to sustained and moderate reduction of blood pressure.
Empagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, increasing tubuloglomerular feedback and reducing intraglomerular pressure, lowering both pre- and afterload of the heart, downregulating sympathetic activity and reducing left ventricular wall stress as evidenced by lower NT-proBNP values which may have beneficial effects on cardiac remodeling, filling pressures and diastolic function as well as preserving kidney structure and function. Other effects such as an increase in haematocrit, a reduction in body weight and blood pressure may further contribute to the beneficial cardiac and renal effects.
Clinical efficacy and safety: Type 2 diabetes mellitus: Both improvement of glycaemic control and reduction of cardiovascular morbidity and mortality are an integral part of the treatment of type 2 diabetes.
Glycaemic efficacy and cardiovascular outcomes have been assessed in a total of 14,663 patients with type 2 diabetes who were treated in 12 double-blind, placebo- and active controlled clinical studies, of which 9,295 received empagliflozin (empagliflozin 10 mg: 4,165 patients; empagliflozin 25 mg: 5,130 patients). Five studies had treatment durations of 24 weeks; extensions of those and other studies had patients exposed to empagliflozin for up to 102 weeks.
Treatment with empagliflozin as monotherapy and in combination with metformin, pioglitazone, a sulphonylurea, DPP-4 inhibitors, and insulin lead to clinically relevant improvements in HbA1c, fasting plasma glucose (FPG), body weight, and systolic and diastolic blood pressure. Administration of empagliflozin 25 mg resulted in a higher proportion of patients achieving HbA1c goal of less than 7% and fewer patients needing glycaemic rescue compared to empagliflozin 10 mg and placebo. Higher baseline HbA1c was associated with a greater reduction in HbA1c. In addition, empagliflozin as adjunct to standard care therapy reduced cardiovascular mortality in patients with type 2 diabetes and established cardiovascular disease.
Monotherapy: The efficacy and safety of empagliflozin as monotherapy was evaluated in a double-blind, placebo- and active-controlled study of 24 weeks duration in treatment-naïve patients. Treatment with empagliflozin resulted in a statistically significant (p<0.0001) reduction in HbA1c, compared to placebo (Table 1) and a clinically meaningful decrease in FPG.
In a prespecified analysis of patients (N=201) with a baseline HbA1c ≥8.5% treatment resulted in a reduction in HbA1c from baseline of -1.44% for empagliflozin 10 mg, -1.43% for empagliflozin 25 mg, -1.04% for sitagliptin, and an increase of 0.01% for placebo.
In the double-blind placebo-controlled extension of this study, reductions of HbA1c, body weight and blood pressure were sustained up to Week 76. (See Table 1.)

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Combination therapy: Empagliflozin as add on to metformin, sulphonylurea, pioglitazone: Empagliflozin as add-on to metformin, metformin and a sulphonylurea, or pioglitazone with or without metformin resulted in statistically significant (p<0.0001) reductions in HbA1c and body weight compared to placebo (Table 2). In addition it resulted in a clinically meaningful reduction in FPG, systolic and diastolic blood pressure compared to placebo.
In the double-blind placebo-controlled extension of these studies, reduction of HbA1c, body weight and blood pressure were sustained up to Week 76. (See Table 2.)

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In combination with metformin in drug-naïve patients: A factorial design study of 24 weeks duration was conducted to evaluate the efficacy and safety of empagliflozin in drug-naïve patients. Treatment with empagliflozin in combination with metformin (5 mg and 500 mg; 5 mg and 1000 mg; 12.5 mg and 500 mg, and 12.5 mg and 1000 mg given twice daily) provided statistically significant improvements in HbA1c (Table 3) and led to greater reductions in FPG (compared to the individual components) and body weight (compared to metformin). (See Table 3.)

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Empagliflozin in patients inadequately controlled with metformin and linagliptin: In patients inadequately controlled with metformin and linagliptin 5 mg, treatment with both empagliflozin 10 mg or 25 mg resulted in statistically significant (p<0.0001) reductions in HbA1c and body weight compared to placebo (Table 4). In addition it resulted in clinically meaningful reductions in FPG, systolic and diastolic blood pressure compared to placebo. (See Table 4.)

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In a pre-specified subgroup of patients with baseline HbA1c greater or equal than 8.5% the reduction from baseline in HbA1c was -1.3% with empagliflozin 10 mg or 25 mg at 24 weeks (p<0.0001) compared to placebo.
Empagliflozin 24 months data, as add on to metformin in comparison to glimepiride: In a study comparing the efficacy and safety of empagliflozin 25 mg versus glimepiride (up to 4 mg per day) in patients with inadequate glycaemic control on metformin alone, treatment with empagliflozin daily resulted in superior reduction in HbA1c (Table 5), and a clinically meaningful reduction in FPG, compared to glimepiride. Empagliflozin daily resulted in a statistically significant reduction in body weight, systolic and diastolic blood pressure and a statistically significantly lower proportion of patients with hypoglycaemic events compared to glimepiride (2.5% for empagliflozin, 24.2% for glimepiride, p<0.0001). (See Table 5.)

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Add-on to insulin therapy: Empagliflozin as add on to multiple daily insulin: The efficacy and safety of empagliflozin as add-on to multiple daily insulin with or without concomitant metformin therapy was evaluated in a double-blind, placebo-controlled trial of 52 weeks duration. During the initial 18 weeks and the last 12 weeks, the insulin dose was kept stable, but was adjusted to achieve pre-prandial glucose levels <100 mg/dl [5.5 mmol/l], and post-prandial glucose levels <140 mg/dl [7.8 mmol/l] between Weeks 19 and 40.
At Week 18, empagliflozin provided statistically significant improvement in HbA1c compared with placebo (Table 6).
At Week 52, treatment with empagliflozin resulted in a statistically significant decrease in HbA1c and insulin sparing compared with placebo and a reduction in FPG and body weight. (See Table 6.)

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Empagliflozin as add on to basal insulin: The efficacy and safety of empagliflozin as add on to basal insulin with or without metformin and/or a sulphonylurea was evaluated in a double-blind, placebo-controlled trial of 78 weeks duration. During the initial 18 weeks the insulin dose was kept stable, but was adjusted to achieve a FPG <110 mg/dl in the following 60 weeks.
At week 18, empagliflozin provided statistically significant improvement in HbA1c (Table 7).
At 78 weeks, empagliflozin resulted in a statistically significant decrease in HbA1c and insulin sparing compared to placebo. Furthermore, empagliflozin resulted in a reduction in FPG, body weight, and blood pressure. (See Table 7.)

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Patients with renal impairment, 52 week placebo controlled data: The efficacy and safety of empagliflozin as add on to antidiabetic therapy was evaluated in patients with renal impairment in a double-blind, placebo-controlled study for 52 weeks. Treatment with empagliflozin led to a statistically significant reduction of HbA1c (Table 8) and clinically meaningful improvement in FPG compared to placebo at Week 24. The improvement in HbA1c, body weight, and blood pressure was sustained up to 52 weeks. (See Table 8.)

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Cardiovascular outcome: The double-blind, placebo-controlled EMPA-REG OUTCOME study compared pooled doses of empagliflozin 10 mg and 25 mg with placebo as adjunct to standard care therapy in patients with type 2 diabetes and established cardiovascular disease. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Heart failure requiring hospitalization and nephropathy-related endpoints were included as pre-specified further secondary endpoints. A total of 7020 patients were treated (empagliflozin 10 mg: 2345, empagliflozin 25 mg: 2342, placebo: 2333) and followed for a median of 3.1 years. The mean age was 63 years, the mean HbA1c was 8.1%, and 71.5% were male. At baseline, 74% of patients were being treated with metformin, 48% with insulin, and 43% with a sulfonylurea. About half of the patients (52.2%) had an eGFR of 60-90 ml/min/1.73 m², 17.8% of 45-60 ml/min/1.73 m² and 7.7% of 30-45 ml/min/1.73 m².
At week 12, an adjusted mean (SE) improvement in HbA1c when compared to baseline of 0.11% (0.02) in the placebo group, 0.65% (0.02) and 0.71% (0.02) in the empagliflozin 10 and 25 mg groups was observed. After the first 12 weeks glycaemic control was optimized independent of investigative treatment. Therefore the effect was attenuated at week 94, with an adjusted mean (SE) improvement in HbA1c of 0.08% (0.02) in the placebo group, 0.50% (0.02) and 0.55% (0.02) in the empagliflozin 10 and 25 mg groups.
Empagliflozin was superior in reducing the primary combined endpoint of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, as compared with placebo. The treatment effect was driven by a significant reduction in cardiovascular death with no significant change in non-fatal myocardial infarction, or non-fatal stroke. The reduction of cardiovascular death was comparable for empagliflozin 10 mg and 25 mg (Figure 1) and confirmed by an improved overall survival (Table 9).
The efficacy for preventing cardiovascular mortality has not been conclusively established in users of DPP-4 inhibitors or in Black patients because the representation of these groups in the EMPA-REG OUTCOME study was limited. (See Table 9 and Figure 1.)

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Heart failure requiring hospitalization: In the EMPA-REG OUTCOME study, empagliflozin reduced the risk of heart failure requiring hospitalization compared with placebo (empagliflozin 2.7%; placebo 4.1%; HR 0.65, 95% CI 0.50, 0.85).
Nephropathy: In the EMPA-REG OUTCOME study, for time to first nephropathy event, the HR was 0.61 (95% CI 0.53, 0.70) for empagliflozin (12.7%) vs placebo (18.8%).
In addition, empagliflozin showed a higher (HR 1.82, 95% CI 1.40, 2.37) occurrence of sustained normo- or micro-albuminuria (49.7%) in patients with baseline macro-albuminuria compared with placebo (28.8%).
Fasting plasma glucose: In four placebo-controlled studies, treatment with empagliflozin as monotherapy or add-on therapy to metformin, pioglitazone, or metformin plus a sulphonylurea resulted in mean changes from baseline in FPG of -20.5 mg/dl [-1.14 mmol/l] for empagliflozin 10 mg and -23.2 mg/dl [-1.29 mmol/l] for empagliflozin 25 mg compared to placebo (7.4 mg/dl [0.41 mmol/l]). This effect was observed after 24 weeks and maintained for 76 weeks.
2-hour post-prandial glucose: Treatment with empagliflozin as add-on to metformin or metformin and a sulphonylurea resulted in a clinically meaningful reduction of 2-hour post-prandial glucose (meal tolerance test) at 24 weeks (add-on to metformin: placebo +5.9 mg/dl, empagliflozin 10 mg: -46.0 mg/dl, empagliflozin 25 mg: -44.6 mg/dl, add-on to metformin and a sulphonylurea: placebo -2.3 mg/dl, empagliflozin 10 mg: -35.7 mg/dl, empagliflozin 25 mg: -36.6 mg/dl).
Patients with high baseline HbA1c >10%: In a pre-specified pooled analysis of three phase 3 studies, treatment with open-label empagliflozin 25 mg in patients with severe hyperglycaemia (N=184, mean baseline HbA1c 11.15%) resulted in a clinically meaningful reduction in HbA1c from baseline of 3.27% at week 24; no placebo or empagliflozin 10 mg arms were included in these studies.
Body weight: In a pre-specified pooled analysis of 4 placebo controlled studies, treatment with empagliflozin resulted in body weight reduction (-0.24 kg for placebo, -2.04 kg for empagliflozin 10 mg and -2.26 kg for empagliflozin 25 mg) at week 24 that was maintained up to week 52 (-0.16 kg for placebo, -1.96 kg for empagliflozin 10 mg and -2.25 kg for empagliflozin 25 mg).
Blood pressure: The efficacy and safety of empagliflozin was evaluated in a double-blind, placebo controlled study of 12 weeks duration in patients with type 2 diabetes and high blood pressure on different antidiabetic and up to 2 antihypertensive therapies. Treatment with empagliflozin once daily resulted in statistically significant improvement in HbA1c, and 24 hour mean systolic and diastolic blood pressure as determined by ambulatory blood pressure monitoring (Table 10). Treatment with empagliflozin provided reductions in seated SBP and DBP. (See Table 10.)

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In a pre-specified pooled analysis of 4 placebo-controlled studies, treatment with empagliflozin resulted in a reduction in systolic blood pressure (empagliflozin 10 mg: -3.9 mmHg; empagliflozin 25 mg: -4.3 mmHg) compared with placebo (-0.5 mmHg) and in diastolic blood pressure (empagliflozin 10 mg: -1.8 mmHg; empagliflozin 25 mg: -2.0 mmHg) compared with placebo (-0.5 mmHg) at week 24 that were maintained up to week 52.
Heart failure: Empagliflozin in patients with heart failure and reduced ejection fraction: A randomised, double-blind, placebo-controlled study (EMPEROR-Reduced) was conducted in 3730 patients with chronic heart failure (New York Heart Association [NYHA] II-IV) and reduced ejection fraction (LVEF ≤40%) to evaluate the efficacy and safety of empagliflozin 10 mg once daily as adjunct to standard of care heart failure therapy. The primary endpoint was the time to adjudicated first event of either cardiovascular (CV) death or hospitalization for heart failure (HHF). Occurrence of adjudicated HHF (first and recurrent), and eGFR(CKD-EPI)_cr slope of change from baseline were included in the confirmatory testing. Heart Failure therapy at baseline included ACE inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitor (88.3%), beta blockers (94.7%), mineralocorticoid receptor antagonists (71.3%) and diuretics (95.0%).
A total of 1863 patients were randomised to empagliflozin 10 mg (placebo: 1867) and followed for a median of 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% were 75 years of age or older. 70.5% of the study population were White, 18.0% Asian and 6.9% Black/African American. At randomization, 75.1% of patients were NYHA class II, 24.4% were class III and 0.5% were class IV. The mean LVEF was 27.5%. At baseline, the mean eGFR was 62.0 ml/min/1.73 m² and the median urinary albumin to creatinine ratio (UACR) was 22 mg/g. About half of the patients (51.7%) had an eGFR of ≥60 ml/min/1.73 m², 24.1% of 45 to <60 ml/min/1.73 m², 18.6% of 30 to <45 ml/min/1.73 m² and 5.3% 20 to <30 ml/min/1.73 m².
Empagliflozin was superior in reducing the risk of the primary composite endpoint of cardiovascular death or hospitalization for heart failure compared with placebo.
Additionally, empagliflozin significantly reduced the risk of occurrence of HHF (first and recurrent), and significantly reduced the rate of eGFR decline. (See Table 11, Figures 2 and 3.)

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The results of the primary composite endpoint were generally consistent with a hazard ratio (HR) below 1 across the pre-specified subgroups, including heart failure patients with and without type 2 diabetes mellitus (see Figure 4).

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Renal Outcome: During treatment, eGFR decline over time was slower in the empagliflozin group compared to the placebo group (see Figure 5). Treatment with empagliflozin 10 mg significantly reduced the rate of eGFR decline and the effect was consistent across all pre-specified subgroups (see Table 11). Patients treated with empagliflozin experienced an initial drop in eGFR which returned towards baseline after treatment discontinuation supporting that haemodynamic changes play a role in the acute effects of empagliflozin on eGFR. (See Figure 5.)

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Jardiance reduced the risk of the renal composite endpoint defined as time to first event of chronic dialysis or renal transplant or sustained reduction in eGFR compared with placebo (see Table 12 and Figure 6).

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The effect of empagliflozin on heart failure symptoms at week 52 was assessed as a patient reported outcome using the change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS), which measures average of symptom frequency and burden for swelling, fatigue, and shortness of breath and physical limitations.
There was a greater improvement in the clinical summary score from baseline in the empagliflozin group than in the placebo group at Week 52 (placebo-corrected adjusted mean change from baseline 1.75, 95% CI 0.51 to 2.99, nominal p-value=0.0058), driven by all domains included (symptom frequency, symptom burden, and physical limitations).
Empagliflozin in patients with heart failure and preserved ejection fraction: A randomised, double-blind, placebo-controlled study (EMPEROR-Preserved) was conducted in 5988 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 adjunct to standard of care therapy. The primary endpoint was the time to adjudicated first event of either cardiovascular (CV) death or hospitalisation for heart failure (HHF). Occurrence of adjudicated HHF (first and recurrent), and eGFR(CKD-EPI)cr slope of change from baseline were included in the confirmatory testing. Baseline therapy included ACE inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitor (80.7%), beta blockers (86.3%), mineralocorticoid receptor antagonists (37.5%) and diuretics (86.2%).
A total of 2997 patients were randomised to empagliflozin 10 mg (placebo: 2991) and followed for a median of 26.2 months. The study population consisted of 55.3% men and 44.7% women with a mean age of 71.9 years (range: 22-100 years), 43.0% were 75 years of age or older. 75.9% of the study population were White, 13.8% Asian and 4.3% Black/African American. At randomisation, 81.5% of patients were NYHA class II, 18.1% were class III and 0.3% were class IV. The EMPEROR-Preserved study population included patients with a LVEF <50% (33.1%), with a LVEF 50 to <60% (34.4%) and a LVEF ≥60% (32.5%). At baseline, the mean eGFR was 60.6 ml/min/1.73 m² and the median urinary albumin to creatinine ratio (UACR) was 21 mg/g. About half of the patients (50.1%) had an eGFR of ≥60 ml/min/1.73 m², 26.1% of 45 to <60 ml/min/1.73 m², 18.6% of 30 to <45 ml/min/1.73 m² and 4.9% 20 to <30 ml/min/1.73 m².
Empagliflozin was superior in reducing the risk of the primary composite endpoint of cardiovascular death or hospitalization for heart failure compared with placebo. Additionally, empagliflozin significantly reduced the risk of occurrence of HHF (first and recurrent), and significantly reduced the rate of eGFR decline. (See Table 13, Figures 7 and 8.)

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The results of the primary composite endpoint were consistent across each of the pre-specified subgroups categorized by e.g., LVEF, diabetes status or renal function down to an eGFR of 20 ml/min/1.73 m² (see Figure 9).

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Renal Outcome: During treatment, eGFR decline over time was slower in the empagliflozin group compared to the placebo group (see Figure 10). Treatment with empagliflozin 10 mg significantly reduced the rate of eGFR decline and the effect was consistent across all pre-specified subgroups (see Table 13). Patients treated with empagliflozin experienced an initial drop in eGFR which returned towards baseline after treatment discontinuation supporting that haemodynamic changes play a role in the acute effects of empagliflozin on eGFR. (See Figure 10.)

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In an analysis of the composite renal endpoint (defined as time to first event of chronic dialysis or renal transplant or sustained reduction in eGFR) the hazard ratio was 0.95 (95% CI 0.73 to 1.24, nominal p-value 0.7243).
The effect of empagliflozin on heart failure symptoms at week 52 was assessed as a patient-reported outcome using the change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS), which measures average of symptom frequency and burden for swelling, fatigue, and shortness of breath and physical limitations.
There was a greater improvement in the clinical summary score from baseline in the empagliflozin group than in the placebo group at Week 52 (placebo-corrected adjusted mean change from baseline 1.32, 95% CI 0.45 to 2.19, nominal p-value=0.0028), driven by the domains symptom frequency and symptom burden.
Chronic kidney disease: A randomised, double-blind, placebo-controlled study of empagliflozin 10 mg once daily (EMPA-KIDNEY) was conducted in 6609 patients with chronic kidney disease (eGFR ≥20-<45 ml/min/1.73 m2; or eGFR ≥45-<90 ml/min/1.73 m2 with an urine albumin-to-creatinine ratio [UACR] ≥200 mg/g) to assess cardio-renal outcomes as adjunct to standard of care therapy. Once enrolled, patients were not required to discontinue therapy for worsening of eGFR to less than 20 mL/min/1.73 m² or initiation of dialysis. The primary endpoint was the time to first occurrence of kidney disease progression (sustained ≥40% eGFR decline from randomisation, sustained eGFR <10 ml/min/1.73 m², end-stage kidney disease, or renal death) or CV death. All-cause hospitalisation (first and recurrent), first occurrence of hospitalisation for heart failure or CV death, and all-cause mortality were included in the confirmatory testing. Baseline therapy included an appropriate use of a RAS-inhibitor (85.2% ACE inhibitor or angiotensin receptor blocker).
A total of 3304 patients were randomised to empagliflozin 10 mg (placebo: 3305) and followed for a median of 24.3 months. The study population consisted of 66.8% men and 33.2% women with a mean age of 63.3 years (range: 18-94 years), 23.0% were 75 years of age or older. 58.4% of the study population were White, 36.2% Asian and 4.0% Black/African American.
At baseline, the mean eGFR was 37.3 ml/min/1.73 m2, 21.2% patients had an eGFR of ≥45 ml/min/1.73 m2, 44.3% of 30 to <45 ml/min/1.73 m2 and 34.5% <30 ml/min/1.73 m2 including 254 patients with an eGFR <20 ml/min/1.73 m2. The median UACR was 329 mg/g, 20.1% patients had an UACR <30 mg/g, 28.2% had an UACR 30 to ≤300mg/g and 51.7% had an UACR >300 mg/g; 41.1% of patients had an UACR <200 mg/g. Primary causes of chronic kidney disease were diabetic nephropathy/diabetic kidney disease (31%), glomerular disease (25%), hypertensive/renovascular disease (22%) and other/unknown (22%).
Empagliflozin was superior in reducing the risk of the primary composite endpoint of kidney disease progression or CV death compared with placebo. In a pre-specified analysis, treatment with empagliflozin reduced the risk of end-stage kidney disease or CV death by 27% compared with placebo (HR 0.73, 95% CI 0.59 to 0.89, nominal p=0.0023). Additionally, empagliflozin significantly reduced the risk of all-cause hospitalisation (first and recurrent). (See Table 14, Figures 11 and 12.)

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The results of the primary composite endpoint were generally consistent across the pre-specified subgroups, including eGFR categories, underlying cause of renal disease, diabetes status, or background use of RAS inhibitors. Treatment benefits were more clearly evident in patients with higher levels of albuminuria. (See Figure 13.)

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During treatment, eGFR decline over time was slower in the empagliflozin group compared to the placebo group (Figure 14). Empagliflozin slowed the annual rate of eGFR decline compared to placebo by 1.37 ml/min/1.73 m²/year (95% CI 1.16, 1.59), based on a pre-specified analysis of all eGFR measurements taken from the 2-month visit to the final follow-up visit. Patients treated with empagliflozin experienced an initial drop in eGFR which returned towards baseline after treatment discontinuation as demonstrated in several of the empagliflozin studies, supporting that haemodynamic changes play a role in the acute effects of empagliflozin on eGFR. (See Figure 14.)

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The occurrence of lower limb amputations was reported in 28 (0.8%) patients in empagliflozin group and 19 (0.6%) patients in placebo, respectively, with toe amputation most commonly reported in both groups (0.6% in empagliflozin group and 0.4% in the placebo group).
Pharmacokinetics: Absorption: The pharmacokinetics of empagliflozin have been extensively characterised in healthy volunteers and patients with type 2 diabetes. After oral administration, empagliflozin was rapidly absorbed with peak plasma concentrations occurring at a median t_max of 1.5 hours post-dose. Thereafter, plasma concentrations declined in a biphasic manner with a rapid distribution phase and a relatively slow terminal phase. The steady state mean plasma AUC and C_max were 1870 nmol.h and 259 nmol/l with empagliflozin 10 mg and 4740 nmol.h and 687 nmol/l with empagliflozin 25 mg once daily. Systemic exposure of empagliflozin increased in a dose-proportional manner. The single-dose and steady-state pharmacokinetic parameters of empagliflozin were similar suggesting linear pharmacokinetics with respect to time. There were no clinically relevant differences in empagliflozin pharmacokinetics between healthy volunteers and patients with type 2 diabetes.
Administration of empagliflozin 25 mg after intake of a high-fat and high calorie meal resulted in slightly lower exposure; AUC decreased by approximately 16% and C_max by approximately 37% compared to fasted condition. The observed effect of food on empagliflozin pharmacokinetics was not considered clinically relevant and empagliflozin may be administered with or without food.
Distribution: The apparent steady-state volume of distribution was estimated to be 73.8 l based on the population pharmacokinetic analysis. Following administration of an oral [¹⁴C]-empagliflozin solution to healthy volunteers, the red blood cell partitioning was approximately 37% and plasma protein binding was 86%.
Biotransformation: No major metabolites of empagliflozin were detected in human plasma and the most abundant metabolites were three glucuronide conjugates (2-, 3-, and 6-O glucuronide). Systemic exposure of each metabolite was less than 10% of total drug-related material. In vitro studies suggested that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9.
Elimination: Based on the population pharmacokinetic analysis, the apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 hours and apparent oral clearance was 10.6 l/hour. The inter-subject and residual variabilities for empagliflozin oral clearance were 39.1% and 35.8%, respectively. With once-daily dosing, steady-state plasma concentrations of empagliflozin were reached by the fifth dose. Consistent with the half-life, up to 22% accumulation, with respect to plasma AUC, was observed at steady-state. Following administration of an oral [¹⁴C]-empagliflozin solution to healthy volunteers, approximately 96% of the drug-related radioactivity was eliminated in faeces (41%) or urine (54%). The majority of drug-related radioactivity recovered in faeces was unchanged parent drug and approximately half of drug related radioactivity excreted in urine was unchanged parent drug.
Special populations: Renal impairment: In patients with mild, moderate or severe renal impairment (eGFR <30-<90 ml/min/1.73 m²) and patients with kidney failure/end stage renal disease (ESKD), 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 subjects with moderate renal impairment and kidney failure/ESKD compared to patients with normal renal function. Peak plasma levels of empagliflozin were roughly 20% higher in subjects with mild and severe renal impairment as compared to subjects with normal renal function. The population pharmacokinetic analysis showed that the apparent oral clearance of empagliflozin decreased with a decrease in eGFR leading to an increase in drug exposure.
Hepatic impairment: In subjects with mild, moderate, and severe hepatic impairment according to the Child-Pugh classification, AUC of empagliflozin increased approximately by 23%, 47%, and 75% and C_max 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 based on the population pharmacokinetic analysis. In this analysis, AUC was estimated to be 5.82%, 10.4%, and 17.3% lower in subjects with BMI of 30, 35, and 45 kg/m², respectively, compared to subjects with a body mass index of 25 kg/m².
Gender: Gender had no clinically relevant effect on the pharmacokinetics of empagliflozin based on the population pharmacokinetic analysis.
Race: In the population pharmacokinetic analysis, AUC was estimated to be 13.5% higher in Asians with a body mass index of 25 kg/m² compared to non-Asians with a body mass index of 25 kg/m².
Elderly patients: Age did not have a clinically meaningful impact on the pharmacokinetics of empagliflozin based on the population pharmacokinetic analysis.
Paediatric patients: Studies characterising the pharmacokinetics of empagliflozin in paediatric patients have not been performed.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, fertility and early embryonic development.
In long term toxicity studies in rodents and dogs, signs of toxicity were observed at exposures greater than or equal to 10-times the clinical dose of empagliflozin. Most toxicity was consistent with secondary pharmacology related to urinary glucose loss and electrolyte imbalances including decreased body weight and body fat, increased food consumption, diarrhea, dehydration, decreased serum glucose and increases in other serum parameters reflective of increased protein metabolism and gluconeogenesis, urinary changes such as polyuria and glucosuria, and microscopic changes including mineralisation in kidney and some soft and vascular tissues. Microscopic evidence of the effects of exaggerated pharmacology on the kidney observed in some species included tubular dilatation, and tubular and pelvic mineralisation at approximately 4-times the clinical AUC exposure of empagliflozin associated with the 25 mg dose.
Empagliflozin is not genotoxic.
In a 2 year carcinogenicity study, empagliflozin did not increase the incidence of tumors in female rats up to the highest dose of 700 mg/kg/day, which corresponds to approximately 72-times the maximal clinical AUC exposure to empagliflozin. In male rats, treatment-related benign vascular proliferative lesions (haemangiomas) of the mesenteric lymph node were observed at the highest dose, but not at 300 mg/kg/day, which corresponds to approximately 26-times the maximal clinical exposure to empagliflozin. Interstitial cell tumors in the testes were observed with a higher incidence in rats at 300 mg/kg/day and above, but not at 100 mg/kg/day which corresponds to approximately 18-times the maximal clinical exposure to empagliflozin. Both tumors are common in rats and are unlikely to be relevant to humans.
Empagliflozin did not increase the incidence of tumors in female mice at doses up to 1000 mg/kg/day, which corresponds to approximately 62-times the maximal clinical exposure to empagliflozin. Empagliflozin induced renal tumors in male mice at 1000 mg/kg/day, but not at 300 mg/kg/day, which corresponds to approximately 11-times the maximal clinical exposure to empagliflozin. The mode of action for these tumors is dependent on the natural predisposition of the male mouse to renal pathology and a metabolic pathway not reflective of humans. The male mouse renal tumors are considered not relevant to humans.
At exposures sufficiently in excess of exposure in humans after therapeutic doses, empagliflozin had no adverse effects on fertility or early embryonic development. Empagliflozin administered during the period of organogenesis was not teratogenic. Only at maternally toxic doses, empagliflozin also caused bent limb bones in the rat and increased embryofetal loss in the rabbit.
In pre- and postnatal toxicity studies in rats, reduced weight gain of offspring was observed at maternal exposures approximately 4-times the maximal clinical exposure to empagliflozin. No such effect was seen at systemic exposure equal to the maximal clinical exposure to empagliflozin. The relevance of this finding to humans is unclear.
In a juvenile toxicity study in the rat, when empagliflozin was administrated from postnatal day 21 until postnatal day 90, non-adverse, minimal to mild renal tubular and pelvic dilation in juvenile rats was seen only at 100mg/kg/day, which is approximates 11-times the maximum clinical dose of 25mg. these findings were absent after a 13 weeks drug-free recovery period.

Type 2 diabetes mellitus: JARDIANCE is indicated in the treatment of type 2 diabetes mellitus to improve glycaemic control in adults as: Monotherapy: When diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance.
Add-on combination therapy: In combination with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control (see Precautions, Interactions and Pharmacology: Pharmacodynamics under Actions for available data on different combinations).
Add-on combination in patients with established cardiovascular disease: JARDIANCE is indicated as an adjunct to diet, exercise and standard care therapy to reduce the incidence of cardiovascular death in patients with type 2 diabetes mellitus and established cardiovascular disease who have inadequate glycemic control (see Pharmacology: Pharmacodynamics under Actions).
Heart failure (HF): JARDIANCE is indicated in adult patients with heart failure (NYHA class II-IV), with or without type 2 diabetes mellitus to reduce the risk of cardiovascular death and hospitalisation for heart failure.
Chronic kidney disease: JARDIANCE is indicated to reduce the risk of sustained decline in eGFR, end-stage kidney disease, cardiovascular death, and hospitalisation in adults with chronic kidney disease at risk of progression.

Posology: Type 2 diabetes mellitus: Monotherapy and add-on combination: The recommended starting dose is 10 mg empagliflozin once daily for monotherapy and add-on combination therapy with other medicinal products including insulin. In patients tolerating empagliflozin 10 mg once daily and need tighter glycaemic control, the dose can be increased to 25 mg once daily. The maximum daily dose is 25 mg (see as follows and Precautions).
When empagliflozin is used in combination with a sulphonylurea or with insulin, a lower dose of the sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia (see Interactions and Adverse Reactions).
Heart failure (HF): The recommended dose of JARDIANCE is 10 mg once daily.
Chronic kidney disease: The recommended dose of JARDIANCE is 10 mg once daily.
Special populations: Renal impairment: Due to limited experience, it is not recommended to initiate treatment with JARDIANCE in patients with an eGFR <20 ml/min/1.73 m².
Glycaemic efficacy of empagliflozin is dependent on renal function and reduced in patients with an eGFR <45 ml/min/1.73 m² and likely absent in patients with an eGFR<30 ml/min/1.73 m². If eGFR falls below 45 ml/min/1.73 m² the recommended dose of empagliflozin is limited to 10 mg and additional glucose lowering treatment should be considered if needed (see Precautions).
Hepatic impairment: No dose adjustment is required for patients with hepatic impairment. Empagliflozin exposure is increased in patients with severe hepatic impairment. Therapeutic experience in patients with severe hepatic impairment is limited and therefore not recommended for use in this population (see Pharmacology: Pharmacokinetics under Actions).
Elderly patients: No dose adjustment is recommended based on age. In patients 75 years and older, an increased risk for volume depletion should be taken into account (see Precautions and Adverse Reactions).
Paediatric population: The safety and efficacy of empagliflozin in children and adolescents has not yet been established. No data are available.
Method of administration: The tablets can be taken with or without food, swallowed whole with water. If a dose is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.

In controlled clinical studies single doses of up to 800 mg empagliflozin in healthy volunteers and multiple daily doses of up to 100 mg empagliflozin in patients with type 2 diabetes did not show any toxicity. Empagliflozin increased urine glucose excretion leading to an increase in urine volume. The observed increase in urine volume was not dose-dependent and is not clinically meaningful.
Therapy: In the event of an overdose, treatment should be initiated as appropriate to the patient's clinical status. The removal of empagliflozin by haemodialysis has not been studied.

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

General: Empagliflozin should not be used in patients with type 1 diabetes.
Ketoacidosis: Cases of ketoacidosis, a serious life-threatening condition requiring urgent hospitalisation, have been reported in patients with diabetes mellitus treated with empagliflozin, including fatal cases. In a number of reported cases, the presentation of the condition was atypical with only moderately increased blood glucose values, below 14 mmol/l (250 mg/dl). Although ketoacidosis is less likely to occur in patients without diabetes mellitus, cases have also been reported in these patients.
The risk of 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. If ketoacidosis is suspected, JARDIANCE should be discontinued, patient should be evaluated, and prompt treatment should be instituted.
Patients who may be at higher risk of ketoacidosis while taking JARDIANCE include patients on a very low carbohydrate diet (as the combination may further increase ketone body production), patients with an acute illness, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), insulin dose reduction (including insulin pump failure), alcohol abuse, severe dehydration, and patients with a history of ketoacidosis. JARDIANCE should be used with caution in these patients. When reducing the insulin dose [see Dosage & Administration], caution should be taken. In patient treated with JARDIANCE consider monitoring for ketoacidosis and temporarily discontinuing JARDIANCE in clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery). In these situations, consider monitoring of ketones, even if Jardiance treatment has been interrupted.
Necrotizing fasciitis of the perineum (Fournier's gangrene): Cases of necrotizing fasciitis of the perineum (also known as Fournier's gangrene), a rare, but serious and life-threatening necrotizing infection, have been reported in female and male patients with diabetes mellitus treated with SGLT2 inhibitors, including empagliflozin. Serious outcomes have included hospitalization, multiple surgeries, and death.
Patients treated with JARDIANCE who present with pain or tenderness, erythema, swelling in the genital or perineal area, fever, malaise should be evaluated for necrotizing fasciitis. If suspected, JARDIANCE should be discontinued and prompt treatment should be instituted (including broad-spectrum antibiotics and surgical debridement if necessary).
Use in patients with renal impairment: Due to limited experience, it is not recommended to initiate treatment with empagliflozin in patients with an eGFR <20 ml/min/1.73 m².
Glycaemic efficacy of empagliflozin is dependent on renal function and reduced in patients with an eGFR <45 ml/min/1.73 m² and likely absent in patients with an eGFR<30 ml/min/1.73 m² (see Dosage & Administration).
Monitoring of renal function: Assessment of renal function is recommended as follows: Prior to empagliflozin initiation and periodically during treatment, i.e. at least yearly (see Dosage & Administration and Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions).
Prior to initiation of any concomitant medicinal product that may have a negative impact on renal function.
Hepatic injury: Cases of hepatic injury have been reported with empagliflozin in clinical trials. A causal relationship between empagliflozin and hepatic injury has not been established.
Use in patients at risk for volume depletion: Based on the mode of action of SGLT-2 inhibitors, osmotic diuresis accompanying glucosuria may lead to a modest decrease in blood pressure (see Pharmacology: Pharmacodynamics under Actions). Therefore, caution should be exercised in patients for whom an empagliflozin-induced drop in blood pressure could pose a risk, such as patients with known cardiovascular disease, patients on anti-hypertensive therapy with a history of hypotension or patients aged 75 years and older.
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 empagliflozin. Temporary interruption of treatment with JARDIANCE should be considered until the fluid loss is corrected.
Complicated urinary tract infections: Cases of complicated urinary tract infections including pyelonephritis and urosepsis have been reported in patients treated with empagliflozin (see Adverse Reactions). Temporary interruption of JARDIANCE should be considered in patients with complicated urinary tract infections.
Urine laboratory assessments: Due to its mechanism of action, patients taking empagliflozin will test positive for glucose in their urine.
Lactose: The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
Effects on ability to drive and use machines: Empagliflozin has minor influence on the ability to drive and use machines. Patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines, in particular when empagliflozin is used in combination with a sulphonylurea and/or insulin.
Use in the Elderly: The effect of empagliflozin on urinary glucose excretion is associated with osmotic diuresis, which could affect the hydration status. Patients aged 75 years and older may be at an increased risk of volume depletion. A higher number of these patients treated with empagliflozin had adverse reactions related to volume depletion as compared to placebo (see Adverse Reactions).

Pregnancy: There are no data from the use of empagliflozin in pregnant women. Animal studies show that empagliflozin crosses the placenta during late gestation to a very limited extent but do not indicate direct or indirect harmful effects with respect to early embryonic development. However, animal studies have shown adverse effects on postnatal development (see Pharmacology: Toxicology: Preclinical safety data under Actions). As a precautionary measure, it is preferable to avoid the use of empagliflozin during early pregnancy. Empagliflozin is not recommended during the second and third trimester of pregnancy.
Lactation: No data in humans are available on excretion of empagliflozin into milk. Available toxicological data in animals have shown excretion of empagliflozin in milk. A risk to the newborns/infants cannot be excluded. Empagliflozin should not be used during breast-feeding.
Fertility: No studies on the effect on human fertility have been conducted for empagliflozin. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see Pharmacology: Toxicology: Preclinical safety data under Actions).

Summary of the safety profile: Type 2 diabetes mellitus: A total of 15,582 patients with type 2 diabetes were included in clinical studies to evaluate the safety of empagliflozin. 10,004 patients were treated with empagliflozin, either alone or in combination with metformin, a sulphonylurea, a PPRAγ agonist, DPP4 inhibitors, or insulin. This pool includes the EMPA-REG OUTCOME study involving 7,020 patients at high cardiovascular risk (mean age 63.1 years old, 9.3% patients at least 75 years old, 28.5% women) treated with empagliflozin 10mg/day (n=2345), empagliflozin 25mg/day (n=2342) or placebo (n=2333) up to 4.5 years. The overall safety profile of empagliflozin in this study was comparable to the previously known safety profile.
In the placebo-controlled trials of 18 to 24 weeks duration, 3,534 patients were included of which 1,183 were treated with placebo and 1.185 with empagliflozin 10mg and 1,166 with empagliflozin 25mg. The overall incidence of adverse events in patients treated with empagliflozin was similar to placebo. The most frequently reported adverse reaction was hypoglycaemia when used with sulphonylurea or insulin (see Description of selected adverse reactions as follows).
Heart failure: The EMPEROR studies included patients with heart failure and either reduced ejection fraction (N=3726) or preserved ejection fraction (N=5985) treated with 10 mg empagliflozin or placebo. Approximately half of the patients had type 2 diabetes mellitus.
The most frequent adverse drug reaction was volume depletion (empagliflozin 10 mg: 11.4%; placebo: 9.7%).
Chronic kidney disease: The EMPA-KIDNEY study included patients with chronic kidney disease (N=6609) treated with 10 mg empagliflozin or placebo. About 44% of the patients had type 2 diabetes mellitus.
No new adverse reactions were identified in the EMPA-KIDNEY study. The most frequent adverse events in the EMPA-KIDNEY study were gout (empagliflozin 7.0% vs placebo 8.0%), and acute kidney injury (empagliflozin 2.8% vs placebo 3.5%) which were more frequently reported in patients on placebo.
The overall safety profile of JARDIANCE was generally consistent across the studied indications.
Tabulated list of adverse reactions: Adverse reactions classified by system organ class and MedDRA preferred terms reported in patients who received empagliflozin in placebo-controlled studies are presented in the table as follows (Table 15).
The adverse reactions are listed by absolute frequency. Frequencies are defined as 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), or very rare (<1/10,000), and not known (cannot be estimated from the available data). (See Table 15.)

Click on icon to see table/diagram/image

Description of selected adverse reactions: Hypoglycaemia: The frequency of hypoglycaemia depended on the background therapy in the respective studies and was similar for empagliflozin and placebo as monotherapy, add-on to metformin, add-on to pioglitazone with or without metformin, as add-on to linagliptin and metformin, as adjunct to standard care therapy and for the combination of empagliflozin with metformin in drug-naïve patients compared to those treated with empagliflozin and metformin as individual components and in EMPA-REG OUTCOME study. An increased frequency was noted when given as add-on to metformin and a sulphonylurea (empagliflozin 10 mg: 16.1%, empagliflozin 25 mg: 11.5%, placebo: 8.4%), add-on to basal insulin with or without metformin and with or without a sulphonylurea (empagliflozin 10 mg: 19.5%, empagliflozin 25 mg: 28.4%, placebo: 20.6% during initial 18 weeks treatment when insulin could not be adjusted; empagliflozin 10 mg and 25 mg: 36.1%, placebo 35.3% over the 78-week trial), and add-on to MDI insulin with or without metformin (empagliflozin 10 mg: 39.8%, empagliflozin 25 mg: 41.3%, placebo: 37.2% during initial 18 weeks treatment when insulin could not be adjusted; empagliflozin 10 mg: 51.1%, empagliflozin 25 mg: 57.7%, placebo: 58% over the 52-week trial).
Major hypoglycaemia (event requiring assistance): No increase in major hypoglycaemia was observed with empagliflozin compared to placebo as monotherapy, add-on to metformin, add-on to metformin and a sulphonylurea, and add-on to pioglitazone with or without metformin, add-on to linagliptin and metformin, as adjunct to standard care therapy and for the combination of empagliflozin with metformin in drug-naïve patients compared to those treated with empagliflozin and metformin as individual components. An increased frequency was noted when given as add-on to basal insulin with or without metformin and with or without a sulphonylurea (empagliflozin 10 mg: 0%, empagliflozin 25 mg: 1.3%, placebo: 0% during initial 18 weeks treatment when insulin could not be adjusted; empagliflozin 10 mg: 0%, empagliflozin 25 mg: 1.3%, placebo 0% over the 78-week trial), and add-on to MDI insulin with or without metformin (empagliflozin 10 mg: 0.5%, empagliflozin 25 mg: 0.5%, placebo: 0.5% during initial 18 weeks treatment when insulin could not be adjusted; empagliflozin 10 mg: 1.6%, empagliflozin 25 mg: 0.5%, placebo: 1.6% over the 52-week trial). In EMPA-REG OUTCOME study, a slight decreased was observed with empagliflozin compared to placebo (empagliflozin 10mg: 1.4 mg, empagliflozin 25mg: 1.3%, placebo: 1.5%).
Vaginal moniliasis, vulvovaginitis, balanitis and other genital infection: Vaginal moniliasis, vulvovaginitis, balanitis and other genital infections were reported more frequently in patients treated with empagliflozin (empagliflozin 10 mg: 4.0%, empagliflozin 25 mg: 3.9%) compared to placebo (1.0%). These infections were reported more frequently in females treated with empagliflozin compared to placebo, and the difference in frequency was less pronounced in males. The genital tract infections were mild or moderate in intensity.
Increased urination: Increased urination (including the predefined terms pollakiuria, polyuria, and nocturia) was observed at higher frequencies in patients treated with empagliflozin (empagliflozin 10 mg: 3.5%, empagliflozin 25 mg: 3.3%) compared to placebo (1.4%). Increased urination was mostly mild or moderate in intensity. The frequency of reported nocturia was similar for placebo and empagliflozin (<1%).
Urinary tract infection: The overall frequency of urinary tract infection reported as adverse event was similar in patients treated with empagliflozin 25 mg and placebo (7.0% and 7.2%) and higher in empagliflozin 10 mg (8.8%). Similar to placebo, urinary tract infection was reported more frequently for empagliflozin in patients with a history of chronic or recurrent urinary tract infections. The intensity (mild, moderate, severe) of urinary tract infection was similar in patients treated with empagliflozin and placebo. Urinary tract infection was reported more frequently in females treated with empagliflozin compared to placebo; there was no difference in males.
Volume depletion: The overall frequency of volume depletion (including the predefined terms blood pressure (ambulatory) decreased, blood pressure systolic decreased, dehydration, hypotension, hypovolaemia, orthostatic hypotension, and syncope) was similar in patients treated with empagliflozin (empagliflozin 10 mg: 0.6%, empagliflozin 25 mg: 0.4%) and placebo (0.3%). The frequency of volume depletion events was increased in patients 75 years and older treated with empagliflozin 10 mg (2.3%) or empagliflozin 25 mg (4.3%) compared to placebo (2.1%).
Blood creatinine increased/Glomerular filtration rate decreased: The overall frequency of patients with increased blood creatinine and decreased glomerular filtration rate were similar between empagliflozin and placebo (blood creatinine increased: empagliflozin 10mg 0.6%, empagliflozin 25mg 0.1%, placebo 0.5%; glomerular filtration rate decreased: empagliflozin 10mg 0.1%, empagliflozin 25mg 0%, placebo 0.3%).
In placebo-controlled, double-blind studies up to 76 weeks, initial increases in creatinine and initial decreases in estimated glomerular filtration rates in patients treated with empagliflozin were generally transient during continuous treatment or reversible after drug discontinuation of treatment.

Pharmacodynamic interactions: Diuretics: Empagliflozin may add to the diuretic effect of thiazide and loop diuretics and may increase the risk of dehydration and hypotension (see Precautions).
Insulin and insulin secretagogues: Insulin and insulin secretagogues, such as sulphonylureas, may increase the risk of hypoglycaemia. Therefore, a lower dose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycaemia when used in combination with empagliflozin (see Dosage & Administration and Adverse Reactions).
Interference with 1,5-anhydroglucitol (1,5-AG) Assay: Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.
Pharmacokinetic interactions: Lithium: Concomitant use of SGLT2 inhibitors, including empagliflozin, with lithium may decrease blood lithium levels through increased renal lithium elimination. Therefore, serum lithium concentration should be monitored more frequently with empagliflozin initiation or following dose changes. Refer the patient to the lithium prescribing doctor in order to monitor serum concentration of lithium.
Effects of other medicinal products on empagliflozin: In vitro data suggest that the primary route of metabolism 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 a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).
Co-administration of empagliflozin with probenecid, an inhibitor of UGT enzymes and OAT3, resulted in a 26% increase in peak empagliflozin plasma concentrations (C_max) and a 53% increase in area under the concentration-time curve (AUC). These changes were not considered to be clinically meaningful.
The effect of UGT induction on empagliflozin has not been studied. Co-medication with known inducers of UGT enzymes should be avoided due to a potential risk of decreased efficacy.
An interaction study with gemfibrozil, an in vitro inhibitor of OAT3 and OATP1B1/1B3 transporters, showed that empagliflozin C_max increased by 15% and AUC increased by 59% following co-administration. These changes were not considered to be clinically meaningful.
Inhibition of OATP1B1/1B3 transporters by co-administration with rifampicin resulted in a 75% increase in C_max and a 35% increase in AUC of empagliflozin. These changes were not considered to be clinically meaningful.
Empagliflozin exposure was similar with and without co-administration with verapamil, a P-gp inhibitor, indicating that inhibition of P-gp does not have any clinically relevant effect on empagliflozin.
Interaction studies conducted in healthy volunteers suggest that the pharmacokinetics of empagliflozin were not influenced by coadministration with metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, simvastatin, torasemide and hydrochlorothiazide.
Effects of empagliflozin on other medicinal products: Based on in vitro studies, empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms. Empagliflozin does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. Drug-drug interactions involving the major CYP450 and UGT isoforms with empagliflozin and concomitantly administered substrates of these enzymes are therefore considered unlikely.
Empagliflozin does not inhibit P-gp at therapeutic doses. Based on in vitro studies, empagliflozin is considered unlikely to cause interactions with drugs that are P-gp substrates. Co-administration of digoxin, a P-gp substrate, with empagliflozin resulted in a 6% increase in AUC and 14% increase in C_max of digoxin. These changes were not considered to be clinically meaningful.
Empagliflozin does not inhibit human uptake transporters such as OAT3, OATP1B1, and OATP1B3 in vitro at clinically relevant plasma concentrations and, as such, drug-drug interactions with substrates of these uptake transporters are considered unlikely.
Interaction studies conducted in healthy volunteers suggest that empagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, simvastatin, warfarin, ramipiril, digoxin, diuretics (hydrochlorothiazide, torasemide) and oral contraceptives.

Incompatibilities: Not applicable.

Shelf life: 3 years.
Store at or below 30°C.

Antidiabetic Agents / Other Cardiovascular Drugs

A10BK03 - empagliflozin ; Belongs to the class of sodium-glucose co-transporter 2 (SGLT2) inhibitors. Used in the treatment of diabetes.

POM