ENTRESTO
Generic: SACUBITRIL AND VALSARTAN
Basic Information
Manufacturer
Aphena Pharma Solutions - Tennessee, LLC
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
14bf8041-0b7f-9acb-e063-6294a90a8256
Indications & Usage
1 INDICATIONS AND USAGE ENTRESTO is indicated: to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure.
Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.
( 1.1 ) for the treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older.
ENTRESTO reduces NT-proBNP and is expected to improve cardiovascular outcomes.
( 1.2 ) 1.1 Adult Heart Failure ENTRESTO is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure.
Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.
LVEF is a variable measure, so use clinical judgment in deciding whom to treat [see Clinical Studies (14.1)] .
1.2 Pediatric Heart Failure ENTRESTO is indicated for the treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older.
ENTRESTO reduces NT-proBNP and is expected to improve cardiovascular outcomes.
Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.
( 1.1 ) for the treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older.
ENTRESTO reduces NT-proBNP and is expected to improve cardiovascular outcomes.
( 1.2 ) 1.1 Adult Heart Failure ENTRESTO is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure.
Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.
LVEF is a variable measure, so use clinical judgment in deciding whom to treat [see Clinical Studies (14.1)] .
1.2 Pediatric Heart Failure ENTRESTO is indicated for the treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older.
ENTRESTO reduces NT-proBNP and is expected to improve cardiovascular outcomes.
Adverse Reactions
6 ADVERSE REACTIONS Clinically significant adverse reactions that appear in other sections of the labeling include: Angioedema [see Warnings and Precautions (5.2)] Hypotension [see Warnings and Precautions (5.3)] Impaired Renal Function [see Warnings and Precautions (5.4)] Hyperkalemia [see Warnings and Precautions (5.5)] Adverse reactions occurring ≥ 5% are hypotension, hyperkalemia, cough, dizziness, and renal failure.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
A total of 6,622 heart failure patients were treated with ENTRESTO in the PARADIGM-HF (vs.
enalapril) and PARAGON-HF (vs.
valsartan) clinical trials.
Of these, 5,085 were exposed for at least 1 year.
Adult Heart Failure In PARADIGM-HF, patients were required to complete sequential enalapril and ENTRESTO run-in periods of (median) 15 and 29 days, respectively, prior to entering the randomized double-blind period comparing ENTRESTO and enalapril.
During the enalapril run-in period, 1,102 patients (10.5%) were permanently discontinued from the study, 5.6% because of an adverse event, most commonly renal dysfunction (1.7%), hyperkalemia (1.7%) and hypotension (1.4%).
During the ENTRESTO run-in period, an additional 10.4% of patients permanently discontinued treatment, 5.9% because of an adverse event, most commonly renal dysfunction (1.8%), hypotension (1.7%) and hyperkalemia (1.3%).
Because of this run-in design, the adverse reaction rates described below are lower than expected in practice.
In the double-blind period, safety was evaluated in 4,203 patients treated with ENTRESTO and 4,229 treated with enalapril.
In PARADIGM-HF, patients randomized to ENTRESTO received treatment for up to 4.3 years, with a median duration of exposure of 24 months; 3,271 patients were treated for more than one year.
Discontinuation of therapy because of an adverse event during the double-blind period occurred in 450 (10.7%) of ENTRESTO treated patients and 516 (12.2%) of patients receiving enalapril.
Adverse reactions occurring at an incidence of ≥ 5% in patients who were treated with ENTRESTO in the double-blind period of PARADIGM-HF are shown in Table 2.
In PARADIGM-HF, the incidence of angioedema was 0.1% in both the enalapril and ENTRESTO run-in periods.
In the double-blind period, the incidence of angioedema was higher in patients treated with ENTRESTO than enalapril (0.5% and 0.2%, respectively).
The incidence of angioedema in Black patients was 2.4% with ENTRESTO and 0.5% with enalapril [see Warnings and Precautions (5.2)] .
Orthostasis was reported in 2.1% of patients treated with ENTRESTO compared to 1.1% of patients treated with enalapril during the double-blind period of PARADIGM-HF.
Falls were reported in 1.9% of patients treated with ENTRESTO compared to 1.3% of patients treated with enalapril.
Table 2: Adverse Reactions Reported in ≥ 5% of Patients Treated with ENTRESTO in the Double-Blind Period of PARADIGM-HF ENTRESTO (n = 4,203) % Enalapril (n = 4,229) % Hypotension 18 12 Hyperkalemia 12 14 Cough 9 13 Dizziness 6 5 Renal failure/acute renal failure 5 5 In PARAGON-HF, no new adverse reactions were identified.
Pediatric Heart Failure The adverse reactions observed in pediatric patients 1 to < 18 years old who received treatment with ENTRESTO were consistent with those observed in adult patients.
Laboratory Abnormalities Hemoglobin and Hematocrit Decreases in hemoglobin/hematocrit of > 20% were observed in approximately 5% of both ENTRESTO- and enalapril-treated patients in the double-blind period in PARADIGM-HF.
Decreases in hemoglobin/hematocrit of >20% were observed in approximately 7% of ENTRESTO-treated patients and 9% of valsartan-treated patients in the double-blind period in PARAGON-HF.
Serum Creatinine During the double-blind period in PARADIGM-HF, approximately 16% of both ENTRESTO- and enalapril-treated patients had increases in serum creatinine of > 50%.
During the double-blind period in PARAGON-HF, approximately 17% of ENTRESTO-treated patients and 21% of valsartan-treated patients had increases in serum creatinine of > 50%.
Serum Potassium During the double-blind period of PARADIGM-HF, approximately 16% of both ENTRESTO- and enalapril-treated patients had potassium concentrations > 5.5 mEq/L.
During the double-blind period of PARAGON-HF, approximately 18% of ENTRESTO-treated patients and 20% of valsartan-treated patients had potassium concentrations > 5.5 mEq/L.
6.2 Postmarketing Experience The following additional adverse reactions have been reported in postmarketing experience.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hypersensitivity including rash, pruritus, and anaphylactic reaction
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
A total of 6,622 heart failure patients were treated with ENTRESTO in the PARADIGM-HF (vs.
enalapril) and PARAGON-HF (vs.
valsartan) clinical trials.
Of these, 5,085 were exposed for at least 1 year.
Adult Heart Failure In PARADIGM-HF, patients were required to complete sequential enalapril and ENTRESTO run-in periods of (median) 15 and 29 days, respectively, prior to entering the randomized double-blind period comparing ENTRESTO and enalapril.
During the enalapril run-in period, 1,102 patients (10.5%) were permanently discontinued from the study, 5.6% because of an adverse event, most commonly renal dysfunction (1.7%), hyperkalemia (1.7%) and hypotension (1.4%).
During the ENTRESTO run-in period, an additional 10.4% of patients permanently discontinued treatment, 5.9% because of an adverse event, most commonly renal dysfunction (1.8%), hypotension (1.7%) and hyperkalemia (1.3%).
Because of this run-in design, the adverse reaction rates described below are lower than expected in practice.
In the double-blind period, safety was evaluated in 4,203 patients treated with ENTRESTO and 4,229 treated with enalapril.
In PARADIGM-HF, patients randomized to ENTRESTO received treatment for up to 4.3 years, with a median duration of exposure of 24 months; 3,271 patients were treated for more than one year.
Discontinuation of therapy because of an adverse event during the double-blind period occurred in 450 (10.7%) of ENTRESTO treated patients and 516 (12.2%) of patients receiving enalapril.
Adverse reactions occurring at an incidence of ≥ 5% in patients who were treated with ENTRESTO in the double-blind period of PARADIGM-HF are shown in Table 2.
In PARADIGM-HF, the incidence of angioedema was 0.1% in both the enalapril and ENTRESTO run-in periods.
In the double-blind period, the incidence of angioedema was higher in patients treated with ENTRESTO than enalapril (0.5% and 0.2%, respectively).
The incidence of angioedema in Black patients was 2.4% with ENTRESTO and 0.5% with enalapril [see Warnings and Precautions (5.2)] .
Orthostasis was reported in 2.1% of patients treated with ENTRESTO compared to 1.1% of patients treated with enalapril during the double-blind period of PARADIGM-HF.
Falls were reported in 1.9% of patients treated with ENTRESTO compared to 1.3% of patients treated with enalapril.
Table 2: Adverse Reactions Reported in ≥ 5% of Patients Treated with ENTRESTO in the Double-Blind Period of PARADIGM-HF ENTRESTO (n = 4,203) % Enalapril (n = 4,229) % Hypotension 18 12 Hyperkalemia 12 14 Cough 9 13 Dizziness 6 5 Renal failure/acute renal failure 5 5 In PARAGON-HF, no new adverse reactions were identified.
Pediatric Heart Failure The adverse reactions observed in pediatric patients 1 to < 18 years old who received treatment with ENTRESTO were consistent with those observed in adult patients.
Laboratory Abnormalities Hemoglobin and Hematocrit Decreases in hemoglobin/hematocrit of > 20% were observed in approximately 5% of both ENTRESTO- and enalapril-treated patients in the double-blind period in PARADIGM-HF.
Decreases in hemoglobin/hematocrit of >20% were observed in approximately 7% of ENTRESTO-treated patients and 9% of valsartan-treated patients in the double-blind period in PARAGON-HF.
Serum Creatinine During the double-blind period in PARADIGM-HF, approximately 16% of both ENTRESTO- and enalapril-treated patients had increases in serum creatinine of > 50%.
During the double-blind period in PARAGON-HF, approximately 17% of ENTRESTO-treated patients and 21% of valsartan-treated patients had increases in serum creatinine of > 50%.
Serum Potassium During the double-blind period of PARADIGM-HF, approximately 16% of both ENTRESTO- and enalapril-treated patients had potassium concentrations > 5.5 mEq/L.
During the double-blind period of PARAGON-HF, approximately 18% of ENTRESTO-treated patients and 20% of valsartan-treated patients had potassium concentrations > 5.5 mEq/L.
6.2 Postmarketing Experience The following additional adverse reactions have been reported in postmarketing experience.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hypersensitivity including rash, pruritus, and anaphylactic reaction