Sacubitril and Valsartan
Generic: SACUBITRIL AND VALSARTAN
Basic Information
Manufacturer
Aphena Pharma Solutions - Tennessee, LLC
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
48714b95-b4ac-ef3c-e063-6294a90a9a5b
Indications & Usage
1 INDICATIONS AND USAGE Sacubitril and valsartan tablets are a combination of sacubitril, a neprilisin inhibitor, and valsartan, an angiotensin II receptor blocker, and sacubitril and valsartan tablets are 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.
Sacubitril and Valsartan reduces NT-proBNP and is expected to improve cardiovascular outcomes.
( 1.2 ) 1.1 Adult Heart Failure Sacubitril and valsartan tablets are 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 Sacubitril and valsartan tablets are indicated for the treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older.
Sacubitril and valsartan tablets 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.
Sacubitril and Valsartan reduces NT-proBNP and is expected to improve cardiovascular outcomes.
( 1.2 ) 1.1 Adult Heart Failure Sacubitril and valsartan tablets are 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 Sacubitril and valsartan tablets are indicated for the treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older.
Sacubitril and valsartan tablets 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 greater than or equal to 5% are hypotension, hyperkalemia, cough, dizziness, and renal failure.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact XLCare Pharmaceuticals, Inc.
at 1-866-495-1995 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 sacubitril and valsartan 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 sacubitril and valsartan tablets run-in periods of (median) 15 and 29 days, respectively, prior to entering the randomized double-blind period comparing sacubitril and valsartan tablets 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 sacubitril and valsartan tablets 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 sacubitril and valsartan tablets and 4,229 treated with enalapril.
In PARADIGM-HF, patients randomized to sacubitril and valsartan tablets 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 sacubitril and valsartan tablets-treated patients and 516 (12.2%) of patients receiving enalapril.
Adverse reactions occurring at an incidence of greater than or equal to 5% in patients who were treated with sacubitril and valsartan tablets in the double-blind period of PARADIGM-HF are shown in Table 3.
In PARADIGM-HF, the incidence of angioedema was 0.1% in both the enalapril and sacubitril and valsartan tablets run-in periods.
In the double-blind period, the incidence of angioedema was higher in patients treated with sacubitril and valsartan tablets than enalapril (0.5% and 0.2%, respectively).
The incidence of angioedema in Black patients was 2.4% with sacubitril and valsartan tablets and 0.5% with enalapril [see Warnings and Precautions ( 5.2 )] .
Orthostasis was reported in 2.1% of patients treated with sacubitril and valsartan 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 sacubitril and valsartan tablets compared to 1.3% of patients treated with enalapril.
Table 3: Adverse Reactions Reported in greater than or equal to 5% of Patients Treated with Sacubitril and valsartan tablets in the Double-Blind Period of PARADIGM-HF Sacubitril and valsartan tablets (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 year to less than 18 years old who received treatment with sacubitril and valsartan tablets were consistent with those observed in adult patients.
Laboratory Abnormalities Hemoglobin and Hematocrit Decreases in hemoglobin/hematocrit of greater than 20% were observed in approximately 5% of both sacubitril and valsartan tablets-and enalapril-treated patients in the double-blind period in PARADIGM-HF.
Decreases in hemoglobin/hematocrit of greater than 20% were observed in approximately 7% of sacubitril and valsartan tablets-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 sacubitril and valsartan tablets- and enalapril-treated patients had increases in serum creatinine of greater than 50%.
During the double-blind period in PARAGON-HF, approximately 17% of sacubitril and valsartan tablets -treated patients and 21% of valsartan-treated patients had increases in serum creatinine of greater than 50%.
Serum Potassium During the double-blind period of PARADIGM-HF, approximately 16% of both sacubitril and valsartan tablets- and enalapril-treated patients had potassium concentrations greater than 5.5 mEq/L.
During the double-blind period of PARAGON-HF, approximately 18% of sacubitril and valsartan tablets -treated patients and 20% of valsartan-treated patients had potassium concentrations greater than 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 XLCare Pharmaceuticals, Inc.
at 1-866-495-1995 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 sacubitril and valsartan 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 sacubitril and valsartan tablets run-in periods of (median) 15 and 29 days, respectively, prior to entering the randomized double-blind period comparing sacubitril and valsartan tablets 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 sacubitril and valsartan tablets 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 sacubitril and valsartan tablets and 4,229 treated with enalapril.
In PARADIGM-HF, patients randomized to sacubitril and valsartan tablets 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 sacubitril and valsartan tablets-treated patients and 516 (12.2%) of patients receiving enalapril.
Adverse reactions occurring at an incidence of greater than or equal to 5% in patients who were treated with sacubitril and valsartan tablets in the double-blind period of PARADIGM-HF are shown in Table 3.
In PARADIGM-HF, the incidence of angioedema was 0.1% in both the enalapril and sacubitril and valsartan tablets run-in periods.
In the double-blind period, the incidence of angioedema was higher in patients treated with sacubitril and valsartan tablets than enalapril (0.5% and 0.2%, respectively).
The incidence of angioedema in Black patients was 2.4% with sacubitril and valsartan tablets and 0.5% with enalapril [see Warnings and Precautions ( 5.2 )] .
Orthostasis was reported in 2.1% of patients treated with sacubitril and valsartan 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 sacubitril and valsartan tablets compared to 1.3% of patients treated with enalapril.
Table 3: Adverse Reactions Reported in greater than or equal to 5% of Patients Treated with Sacubitril and valsartan tablets in the Double-Blind Period of PARADIGM-HF Sacubitril and valsartan tablets (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 year to less than 18 years old who received treatment with sacubitril and valsartan tablets were consistent with those observed in adult patients.
Laboratory Abnormalities Hemoglobin and Hematocrit Decreases in hemoglobin/hematocrit of greater than 20% were observed in approximately 5% of both sacubitril and valsartan tablets-and enalapril-treated patients in the double-blind period in PARADIGM-HF.
Decreases in hemoglobin/hematocrit of greater than 20% were observed in approximately 7% of sacubitril and valsartan tablets-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 sacubitril and valsartan tablets- and enalapril-treated patients had increases in serum creatinine of greater than 50%.
During the double-blind period in PARAGON-HF, approximately 17% of sacubitril and valsartan tablets -treated patients and 21% of valsartan-treated patients had increases in serum creatinine of greater than 50%.
Serum Potassium During the double-blind period of PARADIGM-HF, approximately 16% of both sacubitril and valsartan tablets- and enalapril-treated patients had potassium concentrations greater than 5.5 mEq/L.
During the double-blind period of PARAGON-HF, approximately 18% of sacubitril and valsartan tablets -treated patients and 20% of valsartan-treated patients had potassium concentrations greater than 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