Jardiance

Jardiance

empagliflozin

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Boehringer Ingelheim
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Contents
Empagliflozin.
Description
JARDIANCE film-coated tablets contain 10 or 25 mg empagliflozin.
Excipients/Inactive Ingredients: Lactose monohydrate, Cellulose microcrystalline, Hydroxypropylcellulose, Croscarmellose sodium, Colloidal anhydrous silica, Magnesium stearate, Opadry Yellow 02B38190.
Action
Pharmacotherapeutic group: SGLT2 Inhibitor. ATC code: A10BK03.
Pharmacology: Mode of action: Empagliflozin is a reversible, highly potent and selective 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. Furthermore high selectivity could be shown toward other glucose transporters (GLUTs) responsible for glucose homeostasis in the different tissues.
SGLT-2 is highly expressed in the kidney, whereas expression in other tissues is absent or very low. It is responsible as the predominant transporter for reabsorption 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 reabsorption. The amount of glucose removed by the kidney through this glucuretic mechanism is dependent upon the blood glucose concentration and GFR. Through inhibition of SGLT-2 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.
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-B (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.
Clinical Trials: A total of 17331 patients with type 2 diabetes 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, DPP-4 inhibitors, and insulin lead to clinically relevant improvements in HbA1c, fasting plasma glucose (FPG), body weight, systolic and diastolic blood pressure (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, body mass index, 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 for patients with eGFR> 30 mL/min/1.73m2 (see Special populations: 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. Treatment with JARDIANCE resulted in statistically significant reductions in HbA1c, body weight and systolic blood pressure (SBP) compared to placebo (Table 2) and a clinically meaningful decrease in fasting plasma glucose (FPG). A numerical decrease in diastolic blood pressure (DPB) 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 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 blood pressure (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 Week 76.
Treatment with Jardiance daily significantly improved marker of beta cell function HOMA-B. (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 not sufficiently treated with metformin. Treatment with JARDIANCE resulted in statistically significant improvements in HbA1c and body weight, and clinically meaningful reductions in FPG and blood pressure 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 blood pressure (SBP: change from baseline of -5.2mmHg 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 Week 76. (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. 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 sulphonylurea 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 sulphonylurea. Treatment with JARDIANCE resulted in statistically significant improvements in HbA1c and body weight and clinically meaningful reductions in FPG and blood pressure 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 25 mg and -0.63 kg for placebo) and blood pressure (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 Week 76. (See Table 5.)


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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 not sufficiently treated with a combination of metformin and pioglitazone or pioglitazone alone. 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 blood pressure 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 blood pressure (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 Week 76. (See Table 6.)


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Empagliflozin and linagliptin in treatment naïve patients: After 24-weeks treatment, empagliflozin 25 mg/linagliptin 5 mg in treatment naïve patients provided statistically significant improvement in A1C compared to linagliptin 5 mg but there was no statistically significant difference between the FDC empagliflozin 25 mg/linagliptin 5 mg and empagliflozin 25 mg (Table 5). Compared to linagliptin 5 mg, both doses of the empagliflozin/linagliptin FDC provided statistically relevant improvements in body weight. After 24 weeks' treatment with empagliflozin/linagliptin, both SBPs and DBPs were reduced, -2.9/-1.1 mmHg (n.s. versus linagliptin 5 mg for SBP and DBP) for empagliflozin 25 mg/linagliptin 5 mg and -3.6/-0.7 mmHg (p<0.05 versus linagliptin 5 mg for SBP, n.s. for DBP) for empagliflozin 10 mg/linagliptin 5 mg. Rescue therapy was used in 2 (1.5%) patients treated with empagliflozin 25 mg/linagliptin 5 mg and in 1 (0.7%) patient treated with empagliflozin 10 mg/linagliptin 5 mg compared to 11 (8.3%) patients treated with linagliptin 5 mg, 1 (0.8%) patients treated with empagliflozin 25 mg and 4 (3.0%) patients treated with empagliflozin 10 mg. Clinically meaningful reductions in HbA1c (Table 7) and SBPs were observed at week 52, -2.0 mmHg (n.s. versus linagliptin 5 mg) for empagliflozin 25 mg/linagliptin 5 mg and -1.7 mmHg (n.s. versus linagliptin 5 mg) for empagliflozin 10 mg/linagliptin 5 mg. (See Table 7.)


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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 -1.9% at 24 weeks (p<0.0001 versus linagliptin 5 mg, n.s. versus empagliflozin 25 mg) and -2.0% at 52 weeks (p<0.0001 versus linagliptin 5 mg, p<0.05 versus empagliflozin 25 mg) and with empagliflozin 10 mg/linagliptin 5 mg -1.9% at 24 weeks (p<0.0001 versus linagliptin 5 mg, p<0.05 versus empagliflozin 10 mg) and -2.0% at 52 weeks (p<0.0001 versus linagliptin 5 mg, p<0.05 versus empagliflozin 10 mg).
Empagliflozin and linagliptin as add on therapy to metformin: In patients inadequately controlled on metformin 24-weeks treatment with both doses of the empagliflozin/linagliptin FDC provided statistically significant improvements in HbA1c and fasting plasma glucose (FPG) compared to linagliptin 5 mg and also compared to empagliflozin 10 or 25 mg. Compared to linagliptin 5 mg both doses of the empagliflozin/linagliptin FDC provided statistically significant improvements in body weight.
A greater proportion of patients with a baseline HbA1c ≥7.0% and treated with the empagliflozin/linagliptin FDC achieved a target HbA1c of <7% compared to the individual components (Table 8).
After 24 weeks' treatment with empagliflozin/linagliptin, both SBPs and DBPs were reduced, -5.6/-3.6 mmHg (p<0.001 versus linagliptin 5 mg for SBP and DBP) for empagliflozin 25 mg/linagliptin 5 mg and -4.1/-2.6 mmHg (p<0.05 versus linagliptin 5 mg for SBP, n.s. for DBP) for empagliflozin 10 mg/linagliptin 5 mg. Clinically meaningful reductions in HbA1c (Table 6) and both SBPs and DBPs were observed at week 52, -3.8/-1.6 mmHg (p<0.05 versus linagliptin 5 mg for SBP and DBP) for empagliflozin 25 mg/linagliptin 5 mg and -3.1/-1.6 mmHg (p<0.05 versus linagliptin 5 mg for SBP, n.s. for DBP) for empagliflozin 10 mg/linagliptin 5 mg.
After 24 weeks, rescue therapy was used in 1 (0.7%) patient treated with empagliflozin 25 mg/linagliptin 5 mg and in 3 (2.2%) patients treated with empagliflozin 10 mg/linagliptin 5 mg, compared to 4 (3.1%) patients treated with linagliptin 5 mg and 6 (4.3%) patients treated with empagliflozin 25 mg and 1 (0.7%) patient treated with empagliflozin 10 mg. (See Table 8.)


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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 -1.8% at 24 weeks (p<0.0001 versus linagliptin 5 mg, p<0.001 versus empagliflozin 25 mg) and -1.8% at 52 weeks (p<0.0001 versus linagliptin 5 mg, p<0.05 versus empagliflozin 25 mg) and with empagliflozin 10 mg/5 mg linagliptin -1.6% at 24 weeks (p<0.01 versus linagliptin 5 mg, n.s. versus empagliflozin 10 mg) and -1.5% at 52 weeks (p<0.01 versus linagliptin 5 mg, n.s. versus empagliflozin 10 mg).
Empagliflozin vs. placebo in patients inadequately controlled on metformin and linagliptin [46]: 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 significant 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 9). 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 9.)


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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]).
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 25 mg daily resulted in superior reduction in HbA1c, and a clinically meaningful reduction in FPG, compared to glimepiride (Table 10). Empagliflozin 25 mg daily resulted in a statistically significant reduction in body weight, systolic and diastolic blood pressure (change from baseline in DBP of -1.8 mmHg for empagliflozin and +0.9 mmHg for glimepiride, p<0.0001).
Treatment with empagliflozin 25 mg daily resulted in statistically significantly lower proportion of patients with hypoglycaemic events compared to glimepiride (2.5% for empagliflozin 25mg, 24.2% for glimepiride, p<0.0001). (See Table 10.)


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Empagliflozin as add on to 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 <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 11). 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 -0.3 mg/dl [-0.02 mmol/l] for placebo, -19.7 mg/dl [-1.09 mmol/l] for empagliflozin 10 mg, and -23.7 mg/dl [-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 11.)


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Empagliflozin as add on to basal insulin therapy: The efficacy and safety of empagliflozin (10 mg and 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. 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 (10 mg and 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 11).
At week 78, empagliflozin resulted in a reduction in FPG -10.51 mg/dl [-0.58 mmol/l] for empagliflozin 10 mg, -17.43 mg/dL [0.3 mmol/L] for empagliflozin 25 mg and -5.48 mg/dL [-0.97 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), blood pressure (SBP: -4.1 mmHg for empagliflozin 10 mg, -2.4 mmHg for empagliflozin 25 mg and +0.1 mmHg for placebo, DPB: -2.9 mmHg for empagliflozin 10 mg, -1.5 mmHg for empagliflozin 25 mg and -0.3 mmHg for placebo). (See Table 12.)


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Empagliflozin as add on to dipeptidyl peptidase 4 (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 antidiabetes drug was evaluated in 160 patients with high cardiovascular risk. Treatment with empagliflozin for 28 weeks reduced HbA1c compared to placebo (change from baseline -0.54% for empagliflozin 10 mg, -0.52% for empagliflozin 25mg and -0.02% for placebo).
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 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 (fasting plasma glucose), body weight and blood pressure compared to placebo at Week 24 (Table 13). The improvement in HbA1c, FPG, body weight, and blood pressure was sustained up to 52 weeks. (See Table 13.)


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2 hour post-prandial glucose: Treatment with empagliflozin (10 mg and 25 mg) 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, placebo (n=57) +5.9 mg/dL, empagliflozin 10 mg (n=52): -46.0 mg/dl, empagliflozin 25 mg (n=58) -44.6 mg/dL; add-on to metformin plus sulphonylurea, placebo (n=35): -2.3 mg/dL, empagliflozin 10 mg (n=44): -35.7 mg/dl, empagliflozin 25 mg (n=46): -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 (-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).
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 type 2 diabetes and high blood pressure on different antidiabetic and up to 2 antihypertensive therapies (Table 14). Treatment with empagliflozin once daily resulted in statistically significant improvement in HbA1c, 24 hour mean systolic and diastolic blood pressure as determined by ambulatory blood pressure monitoring. Treatment with empagliflozin 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 14.)


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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.
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%.
Cardiovascular outcome: The EMPA-REG OUTCOME study is a multi-centre, multi-national, randomized, double-blind, placebo-controlled trial investigating the effect of JARDIANCE as adjunct to standard care therapy in reducing cardiovascular events in patients with type 2 diabetes and one or more cardiovascular 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 sulphonylurea.
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. Mean systolic BP was 136 mmHg, diastolic BP 76 mmHg, LDL 86 mg/dL, HDL 44 mg/dL, and urinary albumin to creatinine ratio (UACR) 175 mg/g at baseline.
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 treatment effect reflected a significant reduction in cardiovascular death with no significant change in non-fatal MI, or non-fatal stroke (Table 15 and Figure 1).
JARDIANCE also improved overall survival (Table 15 and Figure 2), 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 15 and Figures 1 and 2.)


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Reductions in risk of heart failure requiring hospitalization or CV death: JARDIANCE significantly reduced the risk of hospitalization for heart failure and cardiovascular death or hospitalization for heart failure compared with placebo (Table 16 and Figure 3). (See Table 16 and Figure 3.)


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The cardiovascular benefits of JARDIANCE observed were consistent across the subgroups depicted in Figure 4. (See Figure 4.)


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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. hemodialysis)) was significantly reduced in empagliflozin group compared to placebo (Table 17 and Figure 5.)
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 17 and Figure 5.)


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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 6.)


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Thorough QTc study: In a randomized, placebo-controlled, active-comparator, crossover study of 30 healthy subjects, no increase in QTc was observed with either 25 mg or 200 mg empagliflozin.
Pharmacokinetics: Absorption: The pharmacokinetics of empagliflozin have been extensively characterized in healthy volunteers and patients with T2DM. After oral administration, empagliflozin was rapidly absorbed with peak plasma concentrations occurring at a median tmax 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 AUC was 4740 nmol.h/L and Cmax was 687 nmol/L with 25 mg empagliflozin once daily (qd). 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 type 2 diabetes mellitus.
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 Cmax 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.
Elimination: 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.
Specific Populations: Renal Impairment: In patients with mild (eGFR: 60 - <90 mL/min/1.73 m2), moderate (eGFR: 30 - <60 mL/min/1.73 m2), severe (eGFR: <30 mL/min/1.73 m2) renal impairment and patients with kidney failure/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.
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 Cmax by approximately 4%, 23%, and 48%, respectively, compared to subjects with normal hepatic function.
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.
Geriatric: Age did not have a clinically meaningful impact on the pharmacokinetics of empagliflozin based on the population pharmacokinetic analysis.
Paediatric: Studies characterizing the pharmacokinetics of empagliflozin in paediatric patients have not been performed.
Indications/Uses
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 Precautions, Interactions and Pharmacology under Actions for available data on different combinations).
Jardiance is indicated to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease.
Dosage/Direction for Use
Posology: Monotherapy and add-on combination: The recommended starting dose is 10 mg empagliflozin once daily for monotherapy and add-on combination therapy with other glucose-lowering medicinal products including insulin. In patients tolerating empagliflozin 10 mg once daily who have an eGFR ≥45 ml/min/1.73 m2 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).
Special populations: Renal impairment: Due to the mechanism of action, the glycaemic efficacy of empagliflozin is dependent on renal function. No dose adjustment is required for patients with an eGFR ≥45 ml/min/1.73 m2 or CrCl ≥45 ml/min.
Empagliflozin should not be initiated in patients with an eGFR <45 ml/min/1.73 m2 or CrCl <45 ml/min. Empagliflozin should be discontinued when eGFR is persistently below 45 ml/min/1.73 m2 or CrCl persistently below 45 ml/min and is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 (see Precautions, Adverse Reactions, Pharmacology and Pharmacology: Pharmacokinetics under Actions).
Empagliflozin should not be used in patients with end stage renal disease (ESRD) or in patients on dialysis as it is not expected to be effective in these patients (see Precautions and Pharmacology: Pharmacokinetics under Actions).
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: 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). In patients aged 85 years and older, initiation of empagliflozin therapy is not recommended due to the limited therapeutic experience (see Precautions).
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.
Overdosage
Symptoms: During controlled clinical trials in healthy subjects, single doses of up to 800 mg empagliflozin, equivalent to 32 times the maximum recommended daily dose, were well tolerated.
Therapy: 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.
Contraindications
Hypersensitivity to the empagliflozin or any of the excipients.
In case of rare hereditary conditions that may be incompatible with an excipient of the product (refer to Precautions), the use of the product is contraindicated.
Special Precautions
General: Jardiance should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Diabetic ketoacidosis: Cases of diabetic ketoacidosis (DKA), a serious life-threatening condition requiring urgent hospitalization, have been reported in patients treated with empagliflozin, including fatal cases. 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.
If ketoacidosis is suspected, JARDIANCE should be discontinued, patient should be evaluated, and prompt treatment should be instituted.
Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses. In both cases, treatment with empagliflozin may be restarted once 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 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 patients 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).
Restarting SGLT2 inhibitor treatment in patients with previous DKA while on SGLT-2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified and resolved.
The safety and efficacy of empagliflozin in patients with type 1 diabetes have not been established and empagliflozin should not be used for treatment of patients with type 1 diabetes. Limited data from clinical trials suggest that DKA occurs with common frequency when patients with type 1 diabetes are treated with SGLT2 inhibitors.
Necrotizing fasciitis of the perineum (Fournier's gangrene): Postmarketing 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).
Renal impairment: Jardiance should not be initiated in patients with an eGFR below 45 ml/min/1.73 m2 or CrCl <45 ml/min. Empagliflozin should be discontinued when eGFR is persistently below 45 ml/min/1.73 m2 or CrCl persistently below 45 ml/min and is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2. Empagliflozin should not be used in patients with ESRD or in patients on dialysis as it is not expected to be effective in these patients (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Monitoring of renal function: Due to the mechanism of action, the glycaemic efficacy of empagliflozin is dependent on renal function. Therefore assessment of renal function is recommended as follows: Prior to empagliflozin initiation and periodically during treatment, i.e. at least yearly (see Dosage & Administration, Pharmacology and Pharmacology: 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.
Risk for volume depletion: Based on the mode of action of SGLT-2 inhibitors, osmotic diuresis accompanying therapeutic glucosuria may lead to a modest decrease in blood pressure (see Pharmacology 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.
Urinary tract infections: In the pooled placebo-controlled double-blind trials of 18 to 24 weeks duration, the overall frequency of urinary tract infection reported as adverse event was similar in patients treated with empagliflozin 25 mg and placebo and higher in patients treated with empagliflozin 10 mg (see Adverse Reactions). Post-marketing cases of complicated urinary tract infections including pyelonephritis and urosepsis have been reported in patients treated with empagliflozin. Temporary interruption of JARDIANCE should be considered in patients with complicated urinary tract infections.
Cardiac failure: Experience in New York Heart Association (NYHA) class I-II is limited, and there is no experience in clinical studies with empagliflozin in NYHA class III-IV. In the EMPA-REG OUTCOME study, 10.1% of the patients were reported with cardiac failure at baseline. The reduction of cardiovascular death in these patients was consistent with the overall study population.
Urine laboratory assessments: Due to its mechanism of action, patients taking Jardiance 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: Jardiance 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 Jardiance 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).
Therapeutic experience in patients aged 85 years and older is limited. Initiation of JARDIANCE therapy in this population is not recommended (see Dosage & Administration).
Use In Pregnancy & Lactation
Pregnancy: There are limited data from the use of JARDIANCE in pregnant women. Nonclinical studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure it is recommended to avoid the use of JARDIANCE during pregnancy unless clearly needed.
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. A risk to human newborns/infants cannot be excluded. It is recommended to discontinue breast feeding during treatment with JARDIANCE.
Fertility: No studies on the effect on human fertility have been conducted for JARDIANCE. Nonclinical studies in animals do not indicate direct or indirect harmful effects with respect to fertility.
Adverse Reactions
Summary of the safety profile: A total of 15,582 patients with type 2 diabetes were included in clinical studies to evaluate the safety of empagliflozin. 10,004, either alone or in combination with metformin, a sulphonylurea, pioglitazone, DPP-4 inhibitors, or insulin.
This pool includes the EMPA-REG OUTCOME study involving 7,020 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 6 placebo-controlled trials of 18 to 24 weeks duration, 3,534 patients were included of which 1,183 were treated with placebo and 2,351 with empagliflozin. 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).
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 18).
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 18.)


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, and 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 metformin and a sulfonylurea (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 empagliflozin 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 (events 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 sulfonylurea, 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 sulfonylurea (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: 1.6%, empagliflozin 25 mg: 0.5%, placebo: 1.6% during initial 18 weeks treatment when insulin could not be adjusted and over the 52-week trial).
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 aged 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 10 mg 0.6%, empagliflozin 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: empagliflozin 10 mg 0.02 mg/dL, empagliflozin 25 mg 0.01 mg/dL) and initial transient decreases in estimated glomerular filtration rates (mean change from baseline after 12 weeks: empagliflozin 10 mg -1.34 mL/min/1.73m2, empagliflozin 25 mg -1.37 mL/min/1.73m2) have been observed. These changes were generally reversible during continuous treatment or after drug discontinuation (see Figure 6 in Pharmacology: Clinical Trials under Actions for the eGFR course in the EMPA-REG outcome study).
Inform the doctor or pharmacist immediately about side effects that occur while taking the drug.
Drug Interactions
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, 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).
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 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 (BCRP), 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 coadministered 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, torasemide and oral contraceptives when co-administered in healthy volunteers.
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.
Caution For Usage
Incompatibilities: Not applicable.
Storage
Do not store above 30 °C.
Shelf life: 36 months.
MIMS Class
ATC Classification
A10BK03 - empagliflozin ; Belongs to the class of sodium-glucose co-transporter 2 (SGLT2) inhibitors. Used in the treatment of diabetes.
Presentation/Packing
FC tab 10 mg (pale yellow, round, biconvex, bevel-edged, debossed on one side with Boehringer Ingelheim company symbol and "S10" on other side) x 3 x 10's. 25 mg (pale yellow, oval, biconvex, debossed on one side with Boehringer Ingelheim company symbol and "S25" on other side) x 3 x 10's.
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