Jardiance

Empagliflozin.

JARDIANCE film-coated tablets contain 10 mg or 25 mg empagliflozin.
Physicochemical properties: Chemical Structure: Empagliflozin is a white to yellowish powder. It is very slightly soluble in water, slightly soluble in acetonitrile and ethanol, sparingly soluble in methanol and practically insoluble in toluene. Empagliflozin is not hygroscopic and no polymorphism has been observed. It is neither a hydrate nor a solvate. Partition coefficient: log P = log D (pH 7.4): 1.7.
Chemical name: (1S)-1,5-anhydro-1-(4-chloro-3-{4-[(3S)-tetrahydrofuran-3-yloxy]benzyl}phenyl)-D-glucitol.
Molecular formula: C₂₃H₂₇ClO₇.
Molecular weight: 450.91.
CAS number: 864070-44-0.
Excipients with known effect: The JARDIANCE 10 mg and 25 mg tablets contain 162.5 mg and 113 mg of lactose monohydrate per tablet, respectively.
Excipients/Inactive Ingredients: Tablet core: lactose monohydrate, microcrystalline cellulose, hydroxypropylcellulose, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate.
Tablet coating: hypromellose, titanium dioxide, purified talc, macrogol 400, iron oxide yellow.

Pharmacotherapeutic group: SGLT2 Inhibitor. ATC code: A10BK03.
Pharmacology: Pharmacodynamics: Mechanism of action: Empagliflozin is a reversible competitive inhibitor of SGLT2 with an IC₅₀ of 1.3 nM. It has a 5000-fold selectivity over human SGLT1 (IC₅₀ of 6278 nM), 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 re-absorption of glucose from the glomerular filtrate back into the circulation. In patients with type 2 diabetes mellitus (T2DM) and hyperglycaemia a higher amount of glucose is filtered and reabsorbed.
Empagliflozin improves glycaemic control in patients with T2DM by reducing renal glucose re-absorption. The amount of glucose removed by the kidney through this glucuretic mechanism is dependent upon the blood glucose concentration and glomerular filtration rate (GFR). Through inhibition of SGLT2 in patients with T2DM and hyperglycaemia, excess glucose is excreted in the urine.
In patients with T2DM, 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 4-week treatment period, averaging approximately 78 g/day with empagliflozin 25 mg once daily. Increased urinary glucose excretion resulted in an immediate reduction in plasma glucose levels in patients with T2DM.
Empagliflozin (10 mg and 25 mg) improves both fasting and post-prandial plasma glucose levels.
There is no direct effect on changes in β cell function and insulin secretion / action, and this contributes to a low risk of hypoglycaemia. Improvement of surrogate markers of beta cell function including Homeostasis Model Assessment-β (HOMA-β) and proinsulin to insulin ratio were 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 (BP).
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, and downregulating of sympathetic activity and reducing left ventricular wall stress as evidenced by lower NT-proBNP values and beneficial effects on cardiac remodeling, filling pressures and diastolic function.
Clinical Trials: Type 2 diabetes mellitus: A total of 17,331 patients with T2DM were evaluated in 15 double-blind, placebo- and active-controlled clinical studies, of which 4603 patients received empagliflozin 10 mg and 5567 received empagliflozin 25 mg. Six studies had a treatment duration of 24 weeks; in extensions of applicable studies, and other trials, patients were exposed to JARDIANCE for up to 102 weeks.
Treatment with empagliflozin (10 mg and 25 mg) as monotherapy and in combination with metformin, pioglitazone, sulfonylurea, dipeptidyl peptidase 4 (DPP-4) inhibitors, and insulin lead to clinically relevant improvements in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), body weight, systolic and diastolic BP (SBP and DBP, respectively). Administration of empagliflozin 25 mg resulted in a higher proportion of patients achieving an HbA1c goal of ≤7% and fewer patients needing glycaemic rescue compared to empagliflozin 10 mg and placebo. There was a clinically meaningful improvement in HbA1c in all subgroups of gender, race, geographic region, time since diagnosis of T2DM, BMI, insulin resistance based on HOMA-IR, and beta cell function based on HOMA-β. Higher baseline HbA1c was associated with a greater reduction in HbA1c. Clinically meaningful HbA1c reduction was seen in patients with eGFR >30 mL/min/1.73m² (see Patients with renal impairment under Dosage & Administration). In patients aged 75 years and older, reduced efficacy of JARDIANCE was observed.
Empagliflozin as monotherapy: The efficacy and safety of empagliflozin (10 mg and 25 mg) as monotherapy was evaluated in a double-blind, placebo- and active-controlled study of 24 weeks duration in treatment-naïve patients. The primary endpoint was the change from baseline in HbA1c after 24 weeks of treatment. The key secondary endpoints were the change from baseline in body weight and blood pressure (systolic, SBP and diastolic, DBP) after 24 weeks of treatment.
Treatment with JARDIANCE resulted in statistically significant reductions in HbA1c, body weight and SBP compared to placebo (Table 1) and a clinically meaningful decrease in FPG. A numerical decrease in DBP was seen but did not reach statistical significance versus placebo (-1.0 mmHg for empagliflozin 10 mg, -1.9 mmHg for empagliflozin 25 mg, -0.5 mmHg for placebo, and +0.7 mmHg for sitagliptin).
In a prespecified analysis of patients (n=201) with a baseline HbA1c ≥8.5% to ≤10% empagliflozin resulted in a reduction in HbA1c from baseline of -1.44% for empagliflozin 10 mg, -1.43% for empagliflozin 25 mg, +0.01% for placebo, and -1.04% for sitagliptin.
In the double-blind placebo-controlled extension of this study, reductions of HbA1c (change from baseline of -0.65% for empagliflozin 10 mg, -0.76% for empagliflozin 25 mg, +0.13% for placebo, and -0.53% for sitagliptin), body weight (change from baseline of -2.24 kg for empagliflozin 10 mg, -2.45 kg for empagliflozin 25 mg, -0.43 kg for placebo, and +0.10 kg for sitagliptin) and BP (SBP: change from baseline of -4.1 mmHg for empagliflozin 10 mg, -4.2 mmHg for empagliflozin 25 mg, -0.7 mmHg for placebo, and -0.3 mmHg for sitagliptin, DBP: change from baseline of -1.6 mmHg for empagliflozin 10 mg, -1.6 mmHg for empagliflozin 25 mg, -0.6 mmHg for placebo, and -0.1 mmHg for sitagliptin) were sustained up to 76 weeks of treatment.
Treatment with JARDIANCE daily significantly improved marker of beta cell function, including HOMA-β. (See Table 1.)

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Empagliflozin as add on to metformin therapy: A double-blind, placebo-controlled study of 24 weeks duration was conducted to evaluate the efficacy and safety of empagliflozin in patients with T2DM not controlled on metformin. The primary endpoint was the change from baseline in HbA1c after 24 weeks of treatment. The key secondary endpoints were the change from baseline in body weight and mean daily plasma glucose (MDG) after 24 weeks of treatment.
Treatment with JARDIANCE resulted in statistically significant improvements in HbA1c and body weight, and clinically meaningful reductions in FPG and BP compared to placebo (Table 2).
In the double-blind placebo-controlled extension of this study, reductions of HbA1c (change from baseline of -0.62% for empagliflozin 10 mg, -0.74% for empagliflozin 25 mg and -0.01% for placebo), body weight (change from baseline of -2.39 kg for empagliflozin 10 mg, -2.65 kg for empagliflozin 25 mg and -0.46 kg for placebo) and BP (SBP: change from baseline of -5.2 mmHg for empagliflozin 10 mg, -4.5 mmHg for empagliflozin 25 mg and -0.8 mmHg for placebo, DBP: change from baseline of -2.5 mmHg for empagliflozin 10 mg, -1.9 mmHg for empagliflozin 25 mg and -0.5 mmHg for placebo) were sustained up to 76 weeks of treatment. (See Table 2.)

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Empagliflozin and metformin combination therapy 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. The majority of patients had been diagnosed with diabetes for up to a year (55.8%) or for between one and five years (28.6%). Their mean age was 52.6 years and mean BMI was 30.37 kg/m². 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 and led to significantly greater reductions in FPG and body weight compared to the individual components. A greater proportion of patients with a baseline HbA1c ≥7.0% and treated with empagliflozin in combination with metformin achieved a target HbA1c <7% compared to the individual components (Tables 3 and 4). (See Tables 3 and 4.)

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Empagliflozin as add on to a combination of metformin and sulfonylurea therapy: A double-blind, placebo-controlled study of 24 weeks duration was conducted to evaluate the efficacy and safety of empagliflozin in patients not sufficiently treated with a combination of metformin and a sulfonylurea. The primary endpoint was the change from baseline in HbA1c after 24 weeks of treatment. The key secondary endpoints were the change from baseline in body weight and mean daily plasma glucose (MDG) after 24 weeks of treatment.
Treatment with JARDIANCE resulted in statistically significant improvements in HbA1c and body weight and clinically meaningful reductions in FPG and BP compared to placebo (Table 5).
In the double-blind placebo-controlled extension of this study, reductions of HbA1c (change from baseline of -0.74% for empagliflozin 10 mg, -0.72% for empagliflozin 25 mg and -0.03% for placebo), body weight (change from baseline of -2.44 kg for empagliflozin 10 mg, -2.28 kg for empagliflozin and -0.63 kg for placebo) and BP (SBP: change from baseline of -3.8 mmHg for empagliflozin 10 mg, -3.7 mmHg for empagliflozin 25 mg and -1.6 mmHg for placebo, DBP: change from baseline of -2.6 mmHg for empagliflozin 10 mg, -2.3 mmHg for empagliflozin 25 mg and -1.4 mmHg for placebo) were sustained up to 76 weeks of treatment. (See Table 5.)

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2 hour post-prandial glucose: Treatment with empagliflozin as add-on to metformin or metformin plus sulfonylurea resulted in clinically meaningful improvement of 2-hour post-prandial glucose (meal tolerance test) at 24 weeks (add-on to metformin: -2.55 mmol/L for empagliflozin 10 mg (n=52), -2.47 mmol/L for empagliflozin 25 mg (n=58) and +0.33 mmol/L for placebo (n=57); add-on to metformin plus sulfonylurea: -1.98 mmol/L for empagliflozin 10 mg (n=44), -2.03 mmol/L for empagliflozin 25 mg (n=46) and -0.13 mmol/L for placebo (n=35)).
Empagliflozin as add on to a combination of pioglitazone therapy (+/- metformin): The efficacy and safety of empagliflozin was evaluated in a double-blind, placebo-controlled study of 24 weeks duration in patients with T2DM not controlled on a combination of metformin and pioglitazone or pioglitazone alone. The primary endpoint was the change from baseline in HbA1c after 24 weeks of treatment. The key secondary endpoints were the change from baseline in FPG and body weight after 24 weeks of treatment.
Empagliflozin in combination with pioglitazone (dose ≥30 mg) with or without metformin resulted in statistically significant reductions in HbA1c, FPG, and body weight and clinically meaningful reductions in BP compared to placebo (Table 6).
In the double-blind placebo-controlled extension of this study, reductions of HbA1c (change from baseline of -0.61% for empagliflozin 10 mg, -0.70% for empagliflozin 25 mg and -0.01% for placebo), body weight (change from baseline of -1.47 kg for empagliflozin 10 mg, -1.21 kg for empagliflozin 25 mg and +0.50 kg for placebo) and BP (SBP: change from baseline of -1.7 mmHg for empagliflozin 10 mg, -3.4 mmHg for empagliflozin 25 mg and +0.3 mmHg for placebo, DBP: change from baseline of -1.3 mmHg for empagliflozin 10 mg, -2.0 mmHg for empagliflozin 25 mg and +0.2 mmHg for placebo) were sustained up to 76 weeks of treatment. (See Table 6.)

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Empagliflozin 2-year data, as add on to metformin in comparison to glimepiride: In a study comparing the efficacy and safety of empagliflozin 25 mg versus glimepiride (4 mg) in patients with inadequate glycaemic control on metformin alone, treatment with empagliflozin daily resulted in superior reduction in HbA1c, and a clinically meaningful reduction in FPG, compared to glimepiride (Table 7). Empagliflozin daily resulted in a statistically significant reduction in body weight, systolic and diastolic blood pressure.
Treatment with empagliflozin resulted in 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 7.)

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Empagliflozin as add on to basal insulin therapy: The efficacy and safety of empagliflozin (10 mg or 25 mg) as add on to basal insulin with or without concomitant metformin and/or sulfonylurea therapy was evaluated in a double-blind, placebo-controlled trial of 78 weeks duration. The primary endpoint was the change from baseline in HbA1c after 18 weeks of treatment. The key secondary endpoints were the change from baseline in dose of basal insulin dose after 78 weeks of treatment and change from baseline in HbA1c after 78 weeks of treatment.
During the initial 18 weeks the insulin dose was to be kept stable, but was adjusted to achieve a FPG <6.10 mmol/L in the following 60 weeks.
At week 18, empagliflozin (10 mg or 25 mg) provided statistically significant improvement in HbA1c compared to placebo. A greater proportion of patients with a baseline HbA1c ≥7.0% achieved a target HbA1c of <7% compared to placebo. At 78 weeks, empagliflozin resulted in a statistically significant decrease in HbA1c and insulin sparing compared to placebo (Table 8).
At week 78, empagliflozin resulted in a reduction in FPG (-0.58 mmol/L for empagliflozin 10 mg, -0.97 mmol/L for empagliflozin 25 mg and -0.30 mmol/L for placebo), body weight (-2.47 kg for empagliflozin 10 mg, -1.96 kg for empagliflozin 25 mg and +1.16 kg for placebo, p<0.0001), BP (SBP: -4.1 mmHg for empagliflozin 10 mg, -2.4 mmHg for empagliflozin 25 mg and +0.1 mmHg for placebo, DBP: -2.9 mmHg for empagliflozin 10 mg, -1.5 mmHg for empagliflozin 25 mg and -0.3 mmHg for placebo). (See Table 8.)

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Empagliflozin as add on to multiple daily injection (MDI) insulin therapy and metformin: The efficacy and safety of empagliflozin as add-on to multiple daily insulin with or without concomitant metformin therapy (71.0% of all patients were on metformin background) 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 to be kept stable, but was adjusted to achieve pre-prandial glucose levels <5.5 mmol/L, and post-prandial glucose levels <7.8 mmol/L between Weeks 19 and 40.
At Week 18, empagliflozin provided statistically significant improvement in HbA1c compared with placebo (Table 9). A greater proportion of patients with a baseline HbA1c ≥7.0% (19.5% empagliflozin 10 mg, 31.0% empagliflozin 25 mg) achieved a target HbA1c of <7% compared with placebo (15.1%).
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 (change from baseline of -0.02 mmol/L for placebo, -1.09 mmol/L for empagliflozin 10 mg, and -1.31 mmol/L for empagliflozin 25 mg), body weight, and blood pressure (SBP: change from baseline of -2.6 mmHg for placebo, -3.9 mmHg for empagliflozin 10 mg and -4.0 mmHg for empagliflozin 25 mg, DBP: change from baseline of -1.0 mmHg for placebo, -1.4 mmHg for empagliflozin 10 mg and -2.6 mmHg for empagliflozin 25 mg). (See Table 9.)

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Empagliflozin as add on to DPP-4 inhibitor therapy: The efficacy and safety of empagliflozin as add on to DPP-4 inhibitors plus metformin, with or without one additional oral anti-diabetic drug was evaluated in 160 patients with T2DM and high cardiovascular risk. Treatment with empagliflozin for 28 weeks reduced Hb1Ac compared to placebo (change from baseline -0.54% for empagliflozin 10 mg, -0.52% for empagliflozin 25 mg and -0.02% for placebo).
Empagliflozin vs. placebo in patients inadequately controlled on metformin and linagliptin: In patients inadequately controlled on metformin and linagliptin, 24-weeks treatment with both doses (10 mg and 25 mg) of empagliflozin provided statistically significant improvements in HbA1c, FPG and body weight compared to placebo (background linagliptin 5 mg). A statistically significantly greater number of patients with a baseline HbA1c ≥7.0% and treated with empagliflozin achieved a target HbA1c of <7% compared to placebo (background linagliptin 5 mg) (Table 10). After 24 weeks' treatment with empagliflozin, both SBPs and DBPs were reduced, -2.6/-1.1 mmHg (n.s. versus placebo for SBP and DBP) for empagliflozin 25 mg/linagliptin 5 mg and -1.3/-0.1 mmHg (n.s. versus placebo for SBP and DBP) for empagliflozin 10 mg/linagliptin 5 mg.
After 24 weeks, rescue therapy was used in 4 (3.6%) patients treated with empagliflozin 25 mg/linagliptin 5 mg and in 2 (1.8%) patients treated with empagliflozin 10 mg/linagliptin 5 mg, compared to 13 (12.0%) patients treated with placebo (background linagliptin 5 mg). (See Table 10.)

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In a prespecified subgroup of patients with baseline HbA1c greater or equal than 8.5% the reduction from baseline in HbA1c with empagliflozin 25 mg / linagliptin 5 mg was -1.3% at 24 weeks (p<0.0001 versus placebo [background linagliptin 5 mg]) and with empagliflozin 10 mg/linagliptin 5 mg -1.3% at 24 weeks (p<0.0001 versus placebo [background linagliptin 5 mg]).
Patients with renal impairment, 52 weeks placebo controlled data: The efficacy and safety of empagliflozin as add on to anti-diabetic therapy was evaluated in patients with mild and moderate renal impairment in a double-blind, placebo-controlled study for 52 weeks.
Treatment with JARDIANCE led to statistically significant reduction of HbA1c and clinically meaningful improvement in FPG, body weight and BP compared to placebo at Week 24 (Table 11). The improvement in HbA1c, FPG, body weight, and BP was sustained up to 52 weeks. (See Table 11.)

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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 (-3.27%) at week 24.
Body weight: In a pre-specified pooled analysis of 4 placebo controlled studies, treatment with empagliflozin resulted in body weight reduction compared to placebo at week 24 (-2.04 kg for empagliflozin 10 mg, -2.26 kg for empagliflozin 25 mg and -0.24 kg for placebo) that was maintained up to week 52 (-1.96 kg for empagliflozin 10 mg, -2.25 kg for empagliflozin 25 mg and -0.16 kg for placebo).
Waist circumference: At 24 weeks, treatment with empagliflozin as monotherapy or as add-on to metformin, pioglitazone, or metformin plus sulfonylurea resulted in sustained reduction of waist circumference over the duration of studies in a range of -1.7 cm to -0.9 cm for empagliflozin and -0.5 cm to +0.2 cm for placebo.
Blood pressure: The efficacy and safety of empagliflozin (10 mg and 25 mg) was evaluated in a double-blind, placebo-controlled study of 12 weeks duration in patients with T2DM and high BP on different oral anti-diabetic drugs and up to 2 antihypertensive agents (Table 12). Treatment with empagliflozin once daily resulted in statistically significant improvement in HbA1c and reduction in 24-hour mean SBP and DBP as determined by ambulatory BP monitoring. Treatment with empagliflozin also provided reductions in seated SBP (change from baseline of -0.67 mmHg for placebo, -4.60 mmHg for empagliflozin 10 mg and -5.47 mmHg for empagliflozin 25 mg) and seated DBP (change from baseline of -1.13 mmHg for placebo, -3.06 mmHg for empagliflozin 10 mg and -3.02 mmHg for empagliflozin 25 mg). (See Table 12.)

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In a pre-specified pooled analysis of 4 placebo-controlled studies, treatment with empagliflozin resulted in a reduction in SBP (-3.9 mmHg for empagliflozin 10 mg and -4.3 mmHg for empagliflozin 25 mg) compared with placebo (-0.5 mmHg), and in DBP (-1.8 mmHg for empagliflozin 10 mg and -2.0 mmHg for empagliflozin 25 mg) compared with placebo (-0.5 mmHg), at week 24, that were maintained up to week 52.
Cardiovascular outcome: The EMPA-REG OUTCOME study is a multi-centre, multi-national, randomised, double-blind, placebo-controlled trial investigating the effect of JARDIANCE as adjunct to standard care therapy in reducing cardiovascular (CV) events in patients with type 2 diabetes and one or more CV risk factors, including coronary artery disease, peripheral artery disease, history of myocardial infarction (MI), or history of stroke. The primary endpoint was the time to first event in the composite of CV death, nonfatal MI, or non-fatal stroke (Major Adverse Cardiovascular Events (MACE-3)). Additional pre-specified endpoints addressing clinically relevant outcomes tested in an exploratory manner included CV death, the composite of heart failure requiring hospitalisation or CV death, all-cause mortality and the composite of new or worsening nephropathy.
A total of 7020 patients were treated with JARDIANCE (empagliflozin 10 mg: 2345, empagliflozin 25 mg: 2342, placebo: 2333) and followed for a median of 3.1 years.
The population was 72.4% Caucasian, 21.6% Asian, and 5.1% Black. The mean age was 63 years and 71.5% were male. At baseline, approximately 81% of patients were being treated with renin angiotensin system inhibitors, 65% with beta-blockers, 43% with diuretics, 89% with anticoagulants, and 81% with lipid lowering medication. Approximately 74% of patients were being treated with metformin at baseline, 48% with insulin and 43% with sulfonylurea. The baseline HbA1c was <7% in 6.0% of the patients, 7 to <8% in 43.7% of the patients, 8 to <9% in 33.2% of the patients, and ≥9% in 17.0% of the patients. The time since diagnosis of diabetes was ≤5 years for 18.0% of the patients, >5 to 10 years for 24.9% of the patients, and >10 years for 57.1% of the patients.
About half of the patients (52.2%) had an eGFR of 60-90 mL/min/1.73m², 17.8% of 45-60 mL/min/1.73m² and 7.7% of 30-45 mL/min/1.73m². Mean systolic BP was 136 mmHg, diastolic BP 76 mmHg, low density lipoprotein (LDL) 2.2 mmol/L, and high density lipoprotein (HDL) 1.1 mmol/L. The urinary albumin to creatinine ratio (UACR) was normal in 59.4% of the patients, 28.7% had microalbuminuria, and 11% had macroalbuminuria.
Reductions in risk of CV death and all-cause mortality: JARDIANCE was superior in reducing the primary composite endpoint of cardiovascular death, non-fatal MI, or non-fatal stroke compared to placebo. The incidence rate was 37.1 for JARDIANCE (10 and 25 mg, pooled) compared to 43.9 with placebo. The treatment effect reflected a significant reduction in cardiovascular death with no significant change in non-fatal MI, or non-fatal stroke (Table 13 and Figure 1).
JARDIANCE also improved all-cause mortality (Table 13), which was driven by a reduction in cardiovascular death with JARDIANCE. There was no statistically significant difference between empagliflozin and placebo in non-cardiovascular mortality. (See Table 13 and Figure 1.)

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Reductions in risk of heart failure requiring hospitalisation or CV death: JARDIANCE significantly reduced the risk of hospitalisation for heart failure and cardiovascular death or hospitalisation for heart failure compared with placebo (Table 14 and Figure 2). (See Table 14 and Figure 2.)

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The cardiovascular benefits (CV death and hospitalisation for heart failure or CV death) of JARDIANCE observed were consistent across major demographic and disease subgroups.
Diabetic kidney disease: In the EMPA-REG OUTCOME study population, the risk of new or worsening nephropathy (defined as onset of macroalbuminuria, doubling of serum creatinine, and initiation of renal replacement therapy (i.e. haemodialysis)) was significantly reduced in empagliflozin group compared to placebo (Table 15 and Figure 3).
JARDIANCE compared with placebo showed a significantly higher occurrence of sustained normo- or microalbuminuria in patients with baseline macroalbuminuria (HR 1.82, 95% CI 1.40, 2.37). (See Table 15 and Figure 3.)

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Treatment with empagliflozin preserved eGFR and eGFR increased during the post treatment 4-week follow up. However, the placebo group showed a gradual decline in GFR during the course of the study with no further change during 4-week follow up (see Figure 4).

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Thorough QTc study: In a randomised, placebo-controlled, active-comparator, crossover study of 30 healthy subjects no increase in QTc was observed with either 25 mg or 200 mg empagliflozin.
Heart failure: Empagliflozin in patients with heart failure and reduced ejection fraction: A randomized, 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 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. 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 randomized 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 (Table 16; Figures 5 and 6). (See Table 16, Figures 5 and 6.)

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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 patients with heart failure, with or without type 2 diabetes mellitus and with or without renal impairment (down to an eGFR of 20 ml/min/1.73 m²).
During treatment, eGFR decline over time was slower in the empagliflozin group compared to the placebo group (Figure 3). Treatment with empagliflozin 10 mg significantly reduced the rate of eGFR decline (Table 11) and the effect was consistent across all pre-specified subgroups. 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 6.)

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Empagliflozin in patients with heart failure and preserved ejection fraction: A randomised, double-blind, placebo-controlled study (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 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 2 997 patients were randomised to empagliflozin 10 mg (placebo: 2 991) 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 (Table 17, 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).
During treatment, eGFR decline over time was slower in the empagliflozin group compared to the placebo group (see Figure 8). Treatment with empagliflozin 10 mg significantly reduced the rate of eGFR decline and the effect was consistent across all pre-specified subgroups (see Table 17). 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 8.)

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Pharmacokinetics: Absorption: The pharmacokinetics of empagliflozin have been extensively characterised in healthy volunteers and patients with T2DM. After oral administration, empagliflozin was rapidly absorbed with peak plasma concentrations (C_max) with a median time to reach C_max (t_max) of 1.5 h 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 area under the curve (AUC) was 4740 nmol·h/L and C_max was 687 nmol/L with 25 mg empagliflozin once daily. Systemic exposure of empagliflozin increased in a dose-proportional manner. The single-dose and steady-state pharmacokinetics 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 T2DM.
Administration of 25 mg empagliflozin after intake of a high-fat and high calorie meal resulted in slightly lower exposure; AUC decreased by approximately 16% and C_max decreased 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 a population pharmacokinetic analysis. Following administration of an oral [¹⁴C]-empagliflozin solution to healthy subjects, the red blood cell partitioning was approximately 36.8% and plasma protein binding was 86.2%.
Metabolism: No major metabolites of empagliflozin were detected in human plasma and the most abundant metabolites were three glucuronide conjugates (2-O-, 3-O-, 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.
Excretion: The apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 h and apparent oral clearance was 10.6 L/h based on the population pharmacokinetic analysis. 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 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 subjects, approximately 95.6% of the drug related radioactivity was eliminated in faeces (41.2%) or urine (54.4%). 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.
Pharmacokinetics in special patient groups: Pharmacokinetics in children: Studies characterising the pharmacokinetics of empagliflozin in paediatric patients have not been performed.
Pharmacokinetics in the elderly: Age did not have a clinically meaningful impact on the pharmacokinetics of empagliflozin based on the population pharmacokinetic analysis.
Pharmacokinetics in patients with renal impairment: In patients with mild (eGFR: 60 - <90 mL/min/1.73m²), moderate (eGFR: 30 - <60 mL/min/1.73m²), severe (eGFR: <30 mL/min/1.73m²) renal impairment and patients with kidney failure/end stage renal disease (ESRD) patients, 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/ESRD 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. In line with the Phase I study, 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. Based on pharmacokinetics, no dosage adjustment is recommended in patients with renal insufficiency. However, due to the mechanism of action, the efficacy of JARDIANCE is dependent on renal function, and therefore, JARDIANCE is contraindicated for use in patients with eGFR <30 mL/min/1.73m² (see Dosage & Administration, Contraindications and Precautions).
Pharmacokinetics in patients with 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. Based on pharmacokinetics, no dosage adjustment is recommended in patients with hepatic impairment.
Body Mass Index (BMI): No dosage adjustment is necessary based on BMI. Body mass index had no clinically relevant effect on the pharmacokinetics of empagliflozin based on the population pharmacokinetic analysis.
Gender: No dosage adjustment is necessary based on gender. Gender had no clinically relevant effect on the pharmacokinetics of empagliflozin based on the population pharmacokinetic analysis.
Race: No dosage adjustment is necessary based on race. Based on the population pharmacokinetic analysis, AUC was estimated to be 13.5% higher in Asian patients with a BMI of 25 kg/m² compared to non-Asian patients with a BMI of 25 kg/m².
Toxicology: Preclinical safety data: Genotoxicity: Empagliflozin was not mutagenic or clastogenic in a battery of genotoxicity studies, including the Ames bacterial mutagenicity assay (bacterial reverse mutation), in vitro mouse lymphoma tk assays and in vivo rat bone marrow micronucleus assays.
Carcinogenicity: Two-year oral carcinogenicity studies were conducted in mice and rats. There was an increase in renal adenomas and carcinomas in male mice given empagliflozin at 1000 mg/kg/day. No renal tumours were seen at 300 mg/kg/day (11- and 28-times the exposure at the clinical dose of 25 mg and 10 mg, respectively). These tumours are likely associated with a metabolic pathway not present in humans, and are considered to be irrelevant to patients given 10 or 25 mg empagliflozin. No drug-related tumours were seen in female mice or female rats at doses up to 1000 and 700 mg/kg/day, respectively, resulting in exposures at least 60 times that expected at the clinical dose of 10 or 25 mg empagliflozin. In male rats, treatment-related benign vascular proliferative lesions (haemangiomas) of the mesenteric lymph node, were observed at 700 mg/kg/day, but not at 300 mg/kg/day (approximately 26- and 65-times the exposure at the clinical does of 25 mg and 10 mg, respectively). These tumours are common in rats and are unlikely to be relevant to humans.

Type 2 diabetes mellitus: Glycaemic control: 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 Pharmacology: Pharmacodynamics: Clinical Trials under Actions).
Reduction of risk of cardiovascular death: JARDIANCE is indicated in patients with type 2 diabetes mellitus and established cardiovascular disease to reduce the risk of cardiovascular death (see Pharmacology: Pharmacodynamics: Clinical Trials under Actions).
Heart failure: Jardiance is indicated in adults for the treatment of symptomatic chronic heart failure.

Type 2 diabetes mellitus: The recommended starting dose of JARDIANCE is 10 mg once daily. In patients tolerating empagliflozin 10 mg once daily and requiring additional glycaemic control, the dose can be increased to 25 mg once daily.
Combination therapy: When JARDIANCE is used in combination with a sulfonylurea or with insulin, a lower dose of the sulfonylurea or insulin may be considered to reduce the risk of hypoglycaemia (see Interactions and Adverse Reactions).
Heart failure: The recommend dose is 10 mg empagliflozin once daily.
JARDIANCE can be taken with or without food.
Patients with renal impairment: Assess renal function prior to initiation of empagliflozin and periodically thereafter. (See Table 18.)

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For treatment of heart failure in patients with or without type 2 diabetes mellitus, empagliflozin 10 mg may be initiated or continued down to an eGFR of 20 mL/min/1.73m² or CrCl of 20 mL/min.
Patients with 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.
Elderly Patients: No dosage adjustment is recommended based on age. Therapeutic experience in patients aged 85 years and older is limited. Initiation of empagliflozin therapy in this population is not recommended (see Precautions). Patients age 75 years and older should be prescribed with caution (see Precautions).
Paediatric population: Safety and effectiveness of JARDIANCE in children under 18 years of age have not been established.

During controlled clinical trials in healthy subjects, single doses of up to 800 mg empagliflozin, were well tolerated.
Treatment: In the event of an overdose, supportive treatment should be initiated as appropriate to the patient's clinical status. The removal of empagliflozin by haemodialysis has not been studied.

Hypersensitivity to empagliflozin or any of the excipients in JARDIANCE.
For the treatment of Type 2 diabetes, JARDIANCE should not be used in patients with severe renal impairment (eGFR <30 mL/min/1.73m²), end-stage renal disease and patients on dialysis, as glycaemic efficacy depends on renal function (see Precautions).
In case of rare hereditary conditions that may be incompatible with an excipient of the product, the use of the product is contraindicated. The JARDIANCE 10 mg tablet contains 162.5 mg of lactose monohydrate and the JARDIANCE 25 mg tablet contains 113 mg of lactose monohydrate per tablet. Patients with the rare hereditary conditions of galactose intolerance e.g. galactosaemia should not take this medicine.

General: JARDIANCE should not be used in patients with type 1 diabetes (see Indications/Uses).
Ketoacidosis: Rare cases of ketoacidosis, including life-threatening and fatal cases, have been reported in patients with diabetes mellitus treated with SGLT2 inhibitors, including empagliflozin. 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 empagliflozin.
The risk of diabetic ketoacidosis must be considered in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness. Patients should be assessed for ketoacidosis immediately if these symptoms occur, regardless of blood glucose level.
In patients where ketoacidosis is suspected or diagnosed, treatment with empagliflozin 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 recommended in these patients. Measurement of blood ketone levels is preferred to urine. Treatment with empagliflozin may be restarted when the ketone values are normal and the patient's condition has stabilised.
Before initiating empagliflozin, factors in the patient history that may predispose to ketoacidosis should be considered.
Patients who may be at higher risk of ketoacidosis include patients with a low beta-cell function reserve (e.g. type 2 diabetes patients with low C-peptide or latent autoimmune diabetes in adults (LADA) or patients with a history of pancreatitis), patients with conditions that lead to restricted food intake or severe dehydration, patients for whom insulin doses are reduced and patients with increased insulin requirements due to acute medical illness, surgery or alcohol abuse. SGLT2 inhibitors should be used with caution in these patients.
Restarting SGLT2 inhibitor treatment in patients with previous ketoacidosis while on SGLT-2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified and resolved.
Jardiance should not be used for treatment of patients with type 1 diabetes. Data from a clinical trial program in patients with type 1 diabetes showed increased ketoacidosis occurrence with common frequency in patients treated with empagliflozin 10 mg and 25 mg as an adjunct to insulin compared to placebo.
Surgery: Treatment with JARDIANCE should be ceased prior to major surgery. An increase in other glucose lowering agents may be required during this time.
Patients scheduled for non-urgent surgery who have not ceased empagliflozin should be assessed and consideration should be given to postponing the procedure.
Treatment with JARDIANCE may be restarted once the patient's condition has stabilised and oral intake is normal.
Complicated urinary tract infections: Cases of complicated urinary tract infections including urosepsis and pyelonephritis requiring hospitalization have been reported in patients receiving SGLT2 inhibitors, including JARDIANCE (see Adverse Reactions). Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated (see Adverse Reactions). Patients should be alerted to the symptoms of urinary tract infection, and advised to seek treatment promptly.
Discontinuation of empagliflozin may be considered in cases of recurrent urinary tract infections.
Necrotizing Fasciitis of the Perineum (Fournier's Gangrene): Reports of necrotizing fasciitis of the perineum (Fournier's Gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in patients with diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.
Patients treated with empagliflozin presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue empagliflozin, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.
Use in patients at risk for volume depletion: Based on the mode of action of SGLT2 inhibitors, osmotic diuresis accompanying glucosuria may lead to a modest decrease in BP. Therefore, caution should be exercised in patients for whom an empagliflozin-induced drop in BP could pose a risk, such as patients with known cardiovascular disease, patients on diuretics, patients 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, BP 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.
Lower limb amputations: An increase in cases of lower limb amputation (primarily of the toe) has been observed in a long-term clinical study with another SGLT2 inhibitor. The medicine in that study is not empagliflozin. However, it is unknown whether this constitutes a class effect. In a pooled safety analysis of 12,620 patients with T2DM the frequency of patients with lower limb amputations was similar between empagliflozin and placebo. In the largest placebo-controlled trial in 7020 patients (EMPA-REG OUTCOME trial), in which 88% of all the cases of amputations were reported, lower limb amputations occurred in 1.8% of patients treated with empagliflozin 10 mg, in 2.0% of patients treated with empagliflozin 25 mg, and in 1.8% of patients in the placebo arm. It is important to regularly examine the feet and counsel all diabetic patients on routine preventative footcare.
Use in renal impairment: Empagliflozin increases serum creatinine and decreases eGFR (see Adverse Reactions). Renal function abnormalities can occur after initiating empagliflozin. Patients with hypovolaemia may be more susceptible to these changes.
There have been postmarketing reports of acute kidney injury, some requiring hospitalisation and dialysis, in patients receiving SGLT2 inhibitors, including empagliflozin; some reports involved patients younger than 65 years of age.
Type 2 diabetes mellitus: JARDIANCE is contraindicated for use in patients with eGFR <30 mL/min/1.73m² (see Patients with renal impairment under Dosage & Administration and Contraindications).
Heart failure: JARDIANCE is not recommended in patients with eGFR <20 ml/min/1.73m² (see Patients with renal impairment under Dosage & Administration).
Monitoring of renal function: Assessment of renal function is recommended: prior to empagliflozin initiation and periodically during treatment, i.e. at least yearly; prior to initiation of concomitant medicines that may reduce renal function and periodically thereafter.
Patients treated with empagliflozin can experience an initial fall in eGFR. More intensive monitoring of renal function is recommended, particularly following treatment initiation, if empagliflozin is used in patients with an eGFR <60 mL/min/1.73m², especially if the eGFR is <45 mL/min/1.73m².
Effect on laboratory tests: Urine will test positive for glucose while patients are taking JARDIANCE due to the nature of the mechanism of action of the SGLT2 inhibitors (see Pharmacology: Pharmacodynamics under Actions).
Interference with 1,5-anhydroglucitol (1,5-AG) assay: Monitoring glycaemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycaemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycaemic control.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed.
Use in the elderly: Patients aged 75 years and older may be at increased risk of volume depletion, therefore, JARDIANCE should be prescribed with caution in these patients (see Adverse Reactions).
Therapeutic experience in patients aged 85 years and older is limited. Initiation of JARDIANCE therapy in this population is not recommended.
Use in children: Safety and effectiveness of JARDIANCE in children under 18 years of age have not been established.

Effects on fertility: No studies on the effect on human fertility have been conducted for JARDIANCE. Studies in rats at doses up to 700 mg/kg/day, do not indicate direct or indirect harmful effects with respect to fertility. In female rats this dose was 90- and 155-fold the systemic AUC exposure anticipated with a human dose of 10 and 25 mg.
Use in pregnancy (Category D): There are limited data from the use of JARDIANCE in pregnant women. It is recommended to avoid the use of JARDIANCE during pregnancy unless clearly needed.
Empagliflozin administered during the period of organogenesis was not teratogenic at doses up to 300 mg/kg in the rat or rabbit, which corresponds to approximately 48- and 122-times or 128- and 325-times the clinical dose of empagliflozin based on AUC exposure associated with the 25 mg and 10 mg doses, respectively. Doses of empagliflozin causing maternal toxicity in the rat also caused the malformation of bent limb bones at exposures approximately 155- and 393-times the clinical dose associated with the 25 mg and 10 mg doses, respectively. Maternally toxic doses in the rabbit also caused increased embryofetal loss at doses approximately 139- and 353-times the clinical dose associated with the 25 mg and 10 mg doses, respectively.
Empagliflozin administered to female rats from gestation day 6 to lactation day 20 resulted in reduced weight gain in offspring at >30 mg/kg/day (maternal exposures approximately 4- and 11-times those seen with a clinical dose of 25 mg and 10 mg, respectively). No adverse effects on postnatal development were noted at 10 mg/kg/day (maternal exposures approximately equivalent to those seen with a clinical dose of 25 mg).
Specialised studies in rats with other members of the pharmacological class have shown toxicity to the developing kidney in the time period corresponding to the second and third trimesters of human pregnancy. Similar effects have been seen for empagliflozin at approximately 11 times the clinical AUC exposure associated with the 25 mg dose. These findings were absent after a 13-week drug-free recovery period. JARDIANCE should be used in pregnancy only if the expected benefit to the patients justifies the potential risk to the fetus.
Use in lactation: No data in humans are available on excretion of empagliflozin into milk. Available nonclinical data in animals have shown excretion of empagliflozin in milk. Reduced body weight was observed in rats exposed to empagliflozin in utero and through the consumption of maternal milk (see Use in pregnancy (Category D) as previously mentioned). Adverse effects on renal development have been observed in juvenile rats treated with other members of this pharmacological class. Similar effects were seen with empagliflozin but the findings were absent after a 13 week drug-free recovery. A risk to human newborns/infants cannot be excluded. It is recommended to discontinue breast feeding during treatment with JARDIANCE.

Type 2 diabetes mellitus: A total of 15,582 patients with T2DM were treated in clinical studies to evaluate the safety of empagliflozin, of which 10,004 patients were treated with empagliflozin, either alone or in combination with metformin, a sulfonylurea, a PPARγ agonist, DPP4 inhibitors, or insulin. This pool includes the EMPA-REG OUTCOME study involving 7020 patients at high cardiovascular risk (mean age 63.1 years, 9.3% patients at least 75 years old, 28.5% women) treated with JARDIANCE 10 mg/day (n=2345), JARDIANCE 25 mg/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 previously described trials, the frequency of adverse effects leading to discontinuation was similar by treatment groups for placebo (5.6%), JARDIANCE 10 mg (5.0%) and JARDIANCE 25 mg (5.3%).
Placebo controlled double-blinded trials of 18 to 24 weeks of exposure included 3534 patients, of which 1183 were treated with placebo, 1185 were treated with JARDIANCE 10 mg and 1166 were treated with JARDIANCE 25 mg (Table 19).
The most frequent adverse drug reaction was hypoglycaemia, which depended on the type of background therapy used in the respective studies (Table 20).
Heart failure: The EMPEROR studies included patients with heart failure and either reduced ejection fraction (N=3 726) or preserved ejection fraction (N=5 985) treated with empagliflozin 10 mg or placebo. Approximately half of the patients had type 2 diabetes mellitus. The most frequent adverse reaction of the pooled EMPEROR-Reduced and EMPEROR-Preserved studies was volume depletion (empagliflozin 10 mg: 11.4%. placebo: 9.7%).
The overall safety profile of empagliflozin was generally consistent across the studied indications. (See Table 19.)

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Hypoglycaemia: The frequency of hypoglycaemia depended on the background therapy in the respective studies and was similar for JARDIANCE and placebo as monotherapy, as add-on to metformin, add-on to pioglitazone +/- metformin, and as add-on with linagliptin + metformin. The frequency of patients with hypoglycaemia was increased in patients treated with JARDIANCE compared to placebo when given as add-on to metformin plus sulfonylurea, and as add-on to insulin +/- metformin and +/- sulfonylurea (Table 20).
In the EMPEROR heart failure studies, similar frequency of hypoglycaemia was noted when used add-on to sulphonylurea or insulin (empagliflozin 10 mg: 6.5%, placebo: 6.7%).
Major hypoglycaemia (events requiring assistance): The frequency of patients with major hypoglycaemic events was low (<1%) and similar for JARDIANCE and placebo as monotherapy, as add-on to metformin +/- sulfonylurea, as add-on to pioglitazone +/- metformin, and as add-on with linagliptin + metformin.
The frequency of patients with major hypoglycaemic events was increased in patients treated with JARDIANCE compared to placebo when given as add-on to insulin +/- metformin and +/- sulfonylurea.
In the EMPEROR heart failure studies, major hypoglycaemia was observed at similar frequencies in patients with diabetes mellitus when treated with empagliflozin and placebo as add-on to sulphonylurea or insulin (empagliflozin 10 mg: 2.2%, placebo: 1.9%). (See Table 20.)

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Urinary tract infection: The overall frequency of urinary tract infection adverse events was similar in patients treated with JARDIANCE 25 mg and placebo (7.0% and 7.2%), and higher in patients treated with JARDIANCE 10 mg (8.8%). Similar to placebo, urinary tract infection was reported more frequently for JARDIANCE in patients with a history of chronic or recurrent urinary tract infections. The intensity of urinary tract infections was similar to placebo for mild, moderate, and severe intensity reports. Urinary tract infection events were reported more frequently for empagliflozin compared to placebo in female patients, but not in male patients.
Vaginal moniliasis, vulvovaginitis, balanitis and other genital infection: Vaginal moniliasis, vulvovaginitis, balanitis and other genital infections were reported more frequently for JARDIANCE 10 mg (4.0%) and JARDIANCE 25 mg (3.9%) compared to placebo (1.0%). These adverse events were reported more frequently for empagliflozin compared to placebo in female patients, and the difference in frequency was less pronounced in male patients. The genital tract infections were mild and moderate in intensity, none was severe in intensity.
In the EMPEROR heart failure studies, the frequency of these infections was more pronounced in patients with diabetes mellitus (empagliflozin 10 mg: 2.3%; placebo: 0.8%) than in patients without diabetes mellitus (empagliflozin 10 mg: 1.7%; placebo: 0.7%) when treated with empagliflozin compared to placebo.
Increased urination: As expected via its mechanism of action, increased urination (as assessed by preferred term search including pollakiuria, polyuria, nocturia) was observed at higher frequencies in patients treated with JARDIANCE 10 mg (3.5%) and JARDIANCE 25 mg (3.3%) compared to placebo (1.4%). Increased urination was mostly mild or moderate in intensity. The frequency of reported nocturia was comparable between placebo and JARDIANCE (<1%).
In the EMPEROR heart failure studies, increased urination was observed at similar frequencies in patients treated with empagliflozin and placebo (empagliflozin 10 mg: 0.9%, placebo 0.5%).
Volume depletion: The overall frequency of volume depletion (including the predefined terms BP (ambulatory) decreased, SBP decreased, dehydration, hypotension, hypovolaemia, orthostatic hypotension and syncope) was similar to placebo (0.6% for JARDIANCE 10 mg, 0.4% for JARDIANCE 25 mg and 0.3% for placebo). The effect of empagliflozin on urinary glucose excretion is associated with osmotic diuresis, which could affect hydration status of patients aged 75 years and older. In patients ≥75 years of age (pooling of all patients with diabetes, n=13,402) the frequency of volume depletion events was similar for JARDIANCE 10 mg (2.3%) compared to placebo (2.1%), but it increased with JARDIANCE 25 mg (4.3%).
Blood creatinine increased and glomerular filtration rate decreased: Use of empagliflozin was associated with increases in serum creatinine and decreases in eGFR. These changes were observed to reverse after treatment discontinuation, suggesting acute haemodynamic changes play a role in the renal function abnormalities observed with empagliflozin.
Renal-related adverse reactions (e.g. acute kidney injury, renal impairment, acute prerenal failure) may occur in patients treated with empagliflozin.
The overall frequency of patients with increased blood creatinine and decreased glomerular filtration rate was similar between empagliflozin and placebo (blood creatinine increased: JARDIANCE 10 mg 0.6%, JARDIANCE 25 mg 0.1%, placebo 0.5%; glomerular filtration rate decreased: empagliflozin 10 mg 0.1%, empagliflozin 25 mg 0%, placebo 0.3%).
In placebo-controlled, double-blind studies up to 76 weeks, initial transient increases in creatinine (mean change from baseline after 12 weeks: JARDIANCE 10 mg 0.0011 mmol/L, JARDIANCE 25 mg 0.0006 mmol/L) and initial transient decreases in estimated glomerular filtration rates (mean change from baseline after 12 weeks: JARDIANCE 10 mg -1.34 mL/min/1.73m², JARDIANCE 25 mg -1.37 mL/min/1.73m²) have been observed. These changes were generally reversible during continuous treatment or after drug discontinuation (see Pharmacology: Pharmacodynamics: Clinical Trials: Cardiovascular outcome (Figure 4) under Actions for the eGFR course in the EMPA-REG OUTCOME study).
Laboratory parameters: Haematocrit increased: In a pooled safety analysis (pooling of all patients with diabetes, n=13,402), mean changes from baseline in haematocrit were 3.4% and 3.6% for empagliflozin 10 mg and 25 mg, respectively, compared to -0.1% for placebo. In the EMPA-REG OUTCOME study, haematocrit values returned towards baseline values after a follow-up period of 30 days after treatment stop.
Serum lipids increased: In a pooled safety analysis (pooling of all patients with diabetes, n=13,402), mean percent increases from baseline for empagliflozin 10 mg and 25 mg versus placebo, respectively, were total cholesterol 4.9% and 5.7% versus 3.5%; HDL-cholesterol 3.3% and 3.6% versus 0.4%; LDL-cholesterol 9.5% and 10.0% versus 7.5%; triglycerides 9.2% and 9.9% versus 10.5%.
Postmarketing experience: The following postmarketing case reports have been reported during post-approval use of JARDIANCE. Because these cases are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency.
Metabolism and nutrition disorders: Ketoacidosis (observed in patients with diabetes mellitus).
Infections and infestations: Pyelonephritis, urosepsis, necrotising fasciitis of the perineum (Fournier's gangrene).
Immune system disorders: Allergic skin reactions (e.g. rash, urticaria), angioedema.
Reproductive system and breast disorders: Phimosis.

Pharmacodynamic Interactions: Diuretics: Empagliflozin may add to the diuretic effect of thiazide and loop diuretics and may increase the risk of dehydration and hypotension.
Insulin and insulin secretagogues: Insulin and insulin secretagogues, such as sulfonylureas, 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).
Pharmacokinetic Interactions: In vitro assessment of drug interactions: Empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms. In vitro data suggest that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9. Empagliflozin does not notably inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9 or UGT2B7. At therapeutic doses, the potential for empagliflozin to reversibly inhibit or inactivate the major CYP450 and UGT isoforms is remote. Drug-drug interactions involving the major CYP450 and UGT isoforms with empagliflozin and concomitantly administered substrates of these enzymes are therefore considered unlikely.
Empagliflozin is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein, but it does not inhibit these efflux transporters at therapeutic doses. Based on in vitro studies, empagliflozin is considered unlikely to cause interactions with drugs that are P-gp substrates. Empagliflozin is a substrate of the human uptake transporters OAT3, OATP1B1, and OATP1B3, but not OAT1 and OCT2. Empagliflozin does not inhibit any of these human uptake transporters at clinically relevant plasma concentrations and, as such, drug-drug interactions with substrates of these uptake transporters are considered unlikely.
In vivo assessment of drug interactions: No clinically meaningful pharmacokinetic interactions were observed when empagliflozin was co-administered with other commonly used medicinal products. Based on results of pharmacokinetic studies no dose adjustment of JARDIANCE is recommended when co-administered with commonly prescribed medicinal products.
Empagliflozin pharmacokinetics were similar with and without co-administration of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, simvastatin, in healthy volunteers and with or without co-administration of torasemide and hydrochlorothiazide in patients with T2DM. Increases in overall exposure (AUC) of empagliflozin were seen following co-administration with gemfibrozil (59%), rifampicin (35%), or probenecid (53%). These changes were not considered to be clinically meaningful.
Empagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, digoxin, ramipril, simvastatin, hydrochlorothiazide, and oral contraceptives when co-administered in healthy volunteers.

Incompatibilities: Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

Antidiabetic Agents

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

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