Synjardy XR (Page 9 of 11)

14.4 Empagliflozin Heart Failure Trials, Including Adult Patients with Type 2 Diabetes Mellitus

EMPEROR-Reduced Trial (Chronic Heart Failure with Left Ventricular Ejection Fraction ≤ 40%)

EMPEROR-Reduced (NCT03057977) was a double-blind trial conducted in adults with chronic heart failure (New York Heart Association [NYHA] functional class II-IV) with left ventricular ejection fraction (LVEF) ≤40% to evaluate the efficacy of empagliflozin as adjunct to standard of care heart failure therapy. Of 3,730 patients, 1,863 were randomized to empagliflozin 10 mg once daily and 1,867 to placebo once daily and were followed for a median of 16 months.

Baseline Disease Characteristics and Demographics

EMPEROR-Reduced included patients with type 2 diabetes mellitus (n=1,856) and patients without type 2 diabetes mellitus (n=1,874). The mean age of the trial population was 67 years (range: 25 to 94 years) and 76% were males, 24% were women, and 27% were 75 years of age or older. Approximately 71% of the trial population were White, 18% Asian and 7% Black or African American. At randomization, 75% of patients were NYHA class II, 24% were class III and 0.5% were class IV. The mean LVEF was 28%. At baseline, the mean eGFR was 62 mL/min/1.73 m2 and the median urinary albumin to creatinine ratio (UACR) was 22 mg/g. Approximately half of the patients (52%) had eGFR equal to or above 60 mL/min/1.73 m2 , 24% had eGFR 45 to less than 60 mL/min/1.73 m2 , and 19% had eGFR 30 to less than 45 mL/min/1.73 m2. At baseline, 88% of patients were treated with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), or angiotensin receptor-neprilysin inhibitors (ARNI), 95% with beta-blockers, 71% with mineralocorticoid receptor antagonists (MRA), and 95% with diuretics.

In EMPEROR-Reduced, history of type 2 diabetes mellitus was present in 50% of the patients, and 46% of these patients were treated with metformin (444 patients in the empagliflozin group and 418 in the placebo group) and 25% were treated with insulin. In the type 2 diabetes mellitus subpopulation, the mean age was 67 years; 77% were males; 69% White, 19% Asian and 7% Black or African American; 32% were Hispanic/Latino. In the type 2 diabetes mellitus subpopulation, at baseline, 71% of patients were classified as NYHA class II, 28% class III and 0.7% class IV; the mean LVEF was 27%; the mean baseline eGFR was 61 mL/min/1.73 m2. In this subpopulation, at baseline, 88% of patients were treated with ACE inhibitors, ARB, or ARNI, 95% with beta-blockers, 70% with MRA, and 96% with diuretics.

Results

In EMPEROR-Reduced, empagliflozin 10 mg, compared with placebo, reduced the risk of the primary composite endpoint of CV death or hospitalization for heart failure (HHF) mostly through a reduction in HHF (HR 0.75 [95% CI 0.65, 0.86]). Empagliflozin reduced the risk of first and recurrent HHF, a key secondary endpoint. Because of the metformin component, SYNJARDY and SYNJARDY XR are not indicated for use in patients with heart failure without type 2 diabetes mellitus [see Indications and Usage (1)].

The effect of empagliflozin in reducing the risk of the primary composite endpoint was consistent in patients with type 2 diabetes mellitus (HR 0.73 [95% CI 0.60, 0.87]), and in patients with type 2 diabetes mellitus and metformin as background therapy (HR 0.65 [95% CI 0.49, 0.86]).

EMPEROR-Preserved Trial (Chronic Heart Failure with Left Ventricular Ejection Fraction > 40%)

EMPEROR-Preserved (NCT03057951) was a double-blind trial conducted in patients with chronic heart failure NYHA Class II-IV with LVEF >40% to evaluate the efficacy of empagliflozin as adjunct to standard of care therapy. Of 5,988 patients, 2,997 patients were randomized to empagliflozin 10 mg once daily and 2,991 patients to placebo once daily and were followed for a median of 26 months.

Baseline Disease Characteristics and Demographics

EMPEROR-Preserved included patients with type 2 diabetes mellitus (n=2,928) and patients without type 2 diabetes mellitus (n=3,060). The mean age of the trial population was 72 years (range: 22 to 100 years) and 55% were males, 45% were women, and 43% were 75 years of age or older. Approximately 76% of the trial population were White, 14% Asian and 4% Black or African American. At randomization, 82% of patients were NYHA class II, 18% were class III and 0.3% were class IV. This trial 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 61 mL/min/1.73 m2 and the median urinary albumin to creatinine ratio (UACR) was 21 mg/g. Approximately half of the patients (50%) had eGFR equal to or above 60 mL/min/1.73 m2 , 26% had eGFR 45 to less than 60 mL/min/1.73 m2 , and 19% had eGFR 30 to less than 45 mL/min/1.73 m2. At baseline, 81% of patients were treated with ACE inhibitors, ARBs, or ARNI, 86% with beta-blockers, 38% with MRAs, and 86% with diuretics.

In EMPEROR-Preserved, history of type 2 diabetes mellitus was present in 49% of the patients, and 54% of these patients were treated with metformin (773 patients in the empagliflozin group and 803 in the placebo group) and 29% were treated with insulin. In the type 2 diabetes mellitus subpopulation, the mean age was 71 years, 57% were males, 75% White, 13% Asian and 5% Black or African American. In the type 2 diabetes mellitus subpopulation, at baseline, 79% of patients were classified as NYHA class II, 20% class III and 0.2% class IV; the trial also included type 2 diabetics with LVEF <50% (35%), with a LVEF 50 to <60% (34%) and a LVEF ≥60% (31%). For this subpopulation, the mean baseline eGFR was 60 mL/min/1.73 m2 ; and at baseline, 83% of patients were treated with ACE inhibitors, ARB, or ARNI, 88% with beta-blockers, 39% with MRA, and 89% with diuretics.

Results

In EMPEROR-Preserved, empagliflozin 10 mg, compared with placebo, reduced the risk of the primary composite endpoint (time to first event of either CV death or HHF) mostly through a reduction in hospitalization for heart failure (HR 0.79 [95% CI 0.69, 0.90]). Empagliflozin reduced the risk of first and recurrent HHF, a key secondary endpoint. Because of the metformin component, SYNJARDY and SYNJARDY XR are not indicated for use in patients with heart failure without type 2 diabetes mellitus [see Indications and Usage (1)].

The effect of empagliflozin in reducing the risk of the primary composite endpoint was consistent in patients with type 2 diabetes mellitus (HR 0.80 [95% CI 0.67, 0.95]), and in patients with type 2 diabetes mellitus and metformin as background therapy (HR 0.79 [95% CI 0.61, 1.02]).

16 HOW SUPPLIED/STORAGE AND HANDLING

SYNJARDY tablets are available as follows:

Tablet Strength Color/Shape Tablet Markings Package Size NDC Number
5 mg Empagliflozin500 mg Metformin HCl orange yellow, oval, biconvex, film-coated tablet Boehringer Ingelheim company symbol and “S5” debossed on one side; the other side is debossed with “500”. Bottles of 60Bottles of 180 0597-0159-600597-0159-18
5 mg Empagliflozin 1,000 mg Metformin HCl brownish yellow, oval, biconvex, film-coated tablet Boehringer Ingelheim company symbol and “S5” debossed on one side; the other side is debossed with “1000”. Bottles of 60Bottles of 180 0597-0175-600597-0175-18
12.5 mg Empagliflozin 500 mg Metformin HCl pale brownish purple, oval, biconvex, film-coated tablet Boehringer Ingelheim company symbol and “S12” debossed on one side; the other side is debossed with “500”. Bottles of 60Bottles of 180 0597-0180-600597-0180-18
12.5 mg Empagliflozin 1,000 mg Metformin HCl dark brownish purple, oval, biconvex, film-coated tablet Boehringer Ingelheim company symbol and “S12” debossed on one side; the other side is debossed with “1000”. Bottles of 60Bottles of 180 0597-0168-600597-0168-18

SYNJARDY XR extended-release tablets are available as follows:

Tablet Strength Color/Shape Tablet Markings Package Size NDC Number
5 mg Empagliflozin1,000 mg Metformin HCl olive green, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company symbol and “S5” on the top line and “1000 M” on the bottom line. Bottles of 60Bottles of 180 0597-0290-740597-0290-59
10 mg Empagliflozin1,000 mg Metformin HCl orange, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company symbol and “S10” on the top line and “1000 M” on the bottom line. Bottles of 30Bottles of 90 0597-0280-730597-0280-90
12.5 mg Empagliflozin 1,000 mg Metformin HCl blue, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company symbol and “S12” on the top line and “1000 M” on the bottom line. Bottles of 60Bottles of 180 0597-0300-450597-0300-93
25 mg Empagliflozin 1,000 mg Metformin HCl light green, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company symbol and “S25” on the top line and “1000 M” on the bottom line. Bottles of 30Bottles of 90 0597-0295-880597-0295-78

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

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