Entresto Drug Information
Generic name: SACUBITRIL AND VALSARTAN
Angiotensin 2 Receptor Blocker [EPC]
Uses of Entresto
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 .
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.
Dosage & Administration of Entresto
| †Use of the oral suspension or oral pellets (see Table 2) is recommended in these patients. Recommended mg/kg doses are of the combined amount of both sacubitril and valsartan | ||||
|---|---|---|---|---|
| 1.6 mg/kg | ||||
| 24 mg/26 mg | ||||
| 49 mg/51 mg | ||||
Side Effects of Entresto
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
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 greater than or equal to 5% in patients who were treated with ENTRESTO 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 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 . 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 3: Adverse Reactions Reported in greater than or equal to 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 year to less than 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 greater than 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 greater than 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 greater than 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 greater than 50%. Serum Potassium During the double-blind period of PARADIGM-HF, approximately 16% of both ENTRESTO- and enalapril-treated patients had potassium concentrations greater than
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 greater than
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
Warnings & Cautions for Entresto
Fetal Toxicity
ENTRESTO can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. When pregnancy is detected, consider alternative drug treatment and discontinue ENTRESTO. However, if there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system, and if the drug is considered lifesaving for the mother, advise a pregnant woman of the potential risk to the fetus .
Angioedema
ENTRESTO may cause angioedema . If angioedema occurs, discontinue ENTRESTO immediately, provide appropriate therapy, and monitor for airway compromise. ENTRESTO must not be re-administered. In cases of confirmed angioedema where swelling has been confined to the face and lips, the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms.
Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, administer appropriate therapy, e.g., subcutaneous epinephrine/adrenaline solution 1:1000 (
mL to 0.5 mL) and take measures necessary to ensure maintenance of
a patent airway. ENTRESTO has been associated with a higher rate of angioedema in Black than in non-Black patients. Patients with a prior history of angioedema may be at increased risk of angioedema with ENTRESTO . ENTRESTO must not be used in patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy . ENTRESTO should not be used in patients with hereditary angioedema.
Hypotension
ENTRESTO lowers blood pressure and may cause symptomatic hypotension . Patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), are at greater risk. Correct volume or salt depletion prior to administration of ENTRESTO or start at a lower dose. If hypotension occurs, consider dose adjustment of diuretics, concomitant antihypertensive drugs, and treatment of other causes of hypotension (e.g., hypovolemia). If hypotension persists despite such measures, reduce the dosage or temporarily discontinue ENTRESTO. Permanent discontinuation of therapy is usually not required.
Impaired Renal Function As a consequence of inhibiting the renin-angiotensin-aldosterone system (RAAS)
decreases in renal function may be anticipated in susceptible individuals treated with ENTRESTO . In patients whose renal function depends upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria, progressive azotemia and, rarely, acute renal failure and death. Closely monitor serum creatinine, and down-titrate or interrupt ENTRESTO in patients who develop a clinically significant decrease in renal function . As with all drugs that affect the RAAS, ENTRESTO may increase blood urea and serum creatinine levels in patients with bilateral or unilateral renal artery stenosis. In patients with renal artery stenosis, monitor renal function.
Hyperkalemia Through its actions on the
RAAS, hyperkalemia may occur with ENTRESTO . Monitor serum potassium periodically and treat appropriately, especially in patients with risk factors for hyperkalemia such as severe renal impairment, diabetes, hypoaldosteronism, or a high potassium diet. Dosage reduction or interruption of ENTRESTO may be required .
Drug Interactions with Entresto
Dual Blockade of the Renin-Angiotensin-Aldosterone System
Concomitant use of ENTRESTO with an ACE inhibitor is contraindicated because of the increased risk of angioedema . Avoid use of ENTRESTO with an ARB, because ENTRESTO contains the angiotensin II receptor blocker valsartan. The concomitant use of ENTRESTO with aliskiren is contraindicated in patients with diabetes . Avoid use with aliskiren in patients with renal impairment (eGFR less than 60 mL/min/
m 2 ). 7.2 Potassium-Sparing Diuretics As with other drugs that block
angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium .
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, concomitant use of NSAIDs, including COX-2 inhibitors, with ENTRESTO may result in worsening of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically.
Lithium Increases in serum lithium concentrations and lithium toxicity have been reported
during concomitant administration of lithium with angiotensin II receptor antagonists. Monitor serum lithium levels during concomitant use with ENTRESTO.
Pregnancy Safety for Entresto
and 0.72 -fold the maximum recommended human dose of 97/103 mg twice-daily
on the basis of the area under the plasma drug concentration-time curve ) and rabbits at doses greater than or equal to 5 mg sacubitril/5 mg valsartan/kg/day (2-fold and 0.03-fold the MRHD on the basis of valsartan and LBQ657 AUC, respectively). ENTRESTO is teratogenic based on a low incidence of fetal hydrocephaly, associated with maternally toxic doses, which was observed in rabbits at an ENTRESTO dose of greater than or equal to 5 mg sacubitril/5 mg valsartan/kg/day. The adverse embryo-fetal effects of ENTRESTO are attributed to the angiotensin receptor antagonist activity. Pre- and postnatal development studies in rats at sacubitril doses up to 750 mg/kg/day (2.2-fold the MRHD on the basis of LBQ657 AUC) and valsartan at doses up to 600 mg/kg/day (0.86-fold the MRHD on the basis of AUC) indicate that treatment with ENTRESTO during organogenesis, gestation and lactation may affect pup development and survival.
Pediatric Use of Entresto
mg/kg twice daily) resulted in decreases in body weight, bone length, and
bone mass. The decrease in body weight was transient from PND 10 to PND 20 and the effects for most bone parameters were reversible after treatment stopped. Exposure at the No-Observed-Adverse-Effect-Level (NOAEL) of 100 mg/kg/day was approximately 0.5-fold the AUC exposure to LBQ657 at the
mg/kg twice daily dose of
ENTRESTO. The mechanism underlying bone effects in rats and the translatability to pediatric patients are unknown. Valsartan given orally to juvenile rats from PND 7 to PND 70 (an age approximately equivalent to neonatal through adulthood in humans) produced persistent, irreversible kidney damage at all dose levels. Exposure at the lowest tested dose of 1 mg/kg/day was approximately 0.2-fold the exposure at
mg/kg twice daily dose of
ENTRESTO based on AUC. These kidney effects in neonatal rats represent expected exaggerated pharmacological effects that are observed if rats are treated during the first 13 days of life. This period coincides with 36 weeks of gestation in humans, which could occasionally extend up to 44 weeks after conception in humans. In humans, nephrogenesis is thought to be complete around birth; however, maturation of other aspects of kidney function (such as glomerular filtration and tubular function) may continue until approximately 2 years of age.
It is unknown whether post-natal use of valsartan before maturation of renal function is complete has long-term deleterious effects on the kidney.
Contraindications for Entresto
is contraindicated: in patients with hypersensitivity to any component in patients with a history of angioedema related to previous ACE inhibitor or ARB therapy with concomitant use of ACE inhibitors. Do not administer within 36 hours of switching from or to an ACE inhibitor with concomitant use of aliskiren in patients with diabetes Hypersensitivity to any component. History of angioedema related to previous ACEi or ARB therapy.
Concomitant use with ACE inhibitors. Concomitant use with aliskiren in patients with diabetes.
Overdosage Information for Entresto
Limited data are available with regard to overdosage in human subjects with ENTRESTO. In healthy volunteers, a single dose of ENTRESTO 583 mg sacubitril/617 mg valsartan, and multiple doses of 437 mg sacubitril/463 mg valsartan (14 days) have been studied and were well tolerated. Hypotension is the most likely result of overdosage due to the blood pressure lowering effects of ENTRESTO. Symptomatic treatment should be provided. ENTRESTO is unlikely to be removed by hemodialysis because of high protein binding.
Clinical Studies of Entresto
Adult Heart Failure
PARADIGM-HF PARADIGM-HF was a multinational, randomized, double-blind trial comparing ENTRESTO and enalapril in 8,442 adult patients with symptomatic chronic heart failure (NYHA class II–IV) and systolic dysfunction (left ventricular ejection fraction ≤ 40%). Patients had to have been on an ACE inhibitor or ARB for at least four weeks and on maximally tolerated doses of beta-blockers. Patients with a systolic blood pressure of less than 100 mmHg at screening were excluded. The primary objective of PARADIGM-HF was to determine whether ENTRESTO, a combination of sacubitril and an RAS inhibitor (valsartan), was superior to an RAS inhibitor (enalapril) alone in reducing the risk of the combined endpoint of cardiovascular (CV) death or hospitalization for heart failure (HF). After discontinuing their existing ACE inhibitor or ARB therapy, patients entered sequential single-blind run-in periods during which they received enalapril 10 mg twice-daily, followed by ENTRESTO 100 mg twice-daily, increasing to 200 mg twice-daily.
Patients who successfully completed the sequential run-in periods were randomized to receive either ENTRESTO 200 mg (N = 4,209) twice-daily or enalapril 10 mg (N = 4,233) twice-daily. The primary endpoint was the first event in the composite of CV death or hospitalization for HF. The median follow-up duration was 27 months and patients were treated for up to
years.
The population was 66% Caucasian, 18% Asian, and 5% Black; the mean age was 64 years and 78% were male. At randomization, 70% of patients were NYHA Class II, 24% were NYHA Class III, and 0.7% were NYHA Class IV. The mean left ventricular ejection fraction was 29%. The underlying cause of heart failure was coronary artery disease in 60% of patients; 71% had a history of hypertension, 43% had a history of myocardial infarction, 37% had an eGFR less than 60 mL/min/1.73m 2, and 35% had diabetes mellitus. Most patients were taking beta-blockers (94%), mineralocorticoid antagonists (58%), and diuretics (82%). Few patients had an implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy-defibrillator (CRT-D) (15%). PARADIGM-HF demonstrated that ENTRESTO, a combination of sacubitril and an RAS inhibitor (valsartan), was superior to a RAS inhibitor (enalapril), in reducing the risk of the combined endpoint of cardiovascular death or hospitalization for heart failure, based on a time-to-event analysis (hazard ratio 0.80; 95% confidence interval, 0.73, 0.87, p < 0.0001). The treatment effect reflected a reduction in both cardiovascular death and heart failure hospitalization; see Table 4 and Figure 3. Sudden death accounted for 45% of cardiovascular deaths, followed by pump failure, which accounted for 26%. ENTRESTO also improved overall survival (HR 0.84; 95% CI, p = 0.0009) (Table 4). This finding was driven entirely by a lower incidence of cardiovascular mortality on ENTRESTO. Table 4: Treatment Effect for the Primary Composite Endpoint, Its Components, and All-cause Mortality in PARADIGM-HF * Analyses of the components of the primary composite endpoint were not prospectively planned to be adjusted for multiplicity. ** Includes patients who had heart failure hospitalization prior to death.
ENTRESTO N = 4,187 n (%) Enalapril N = 4,212 n (%) Hazard Ratio (95% CI) p -value Primary composite endpoint of cardiovascular death or heart failure hospitalization 914 1,117
< 0.0001 Cardiovascular death as first event 377 459 Heart failure hospitalization
as first event 537 658 Number of patients with events: * Cardiovascular death ** 558 693
Heart failure hospitalizations 537 658 0.79 All-cause mortality 711 835 0.84 0.0009
The Kaplan-Meier curves presented below (Figure 3) show time to first occurrence of the primary composite endpoint (3A), and time to occurrence of cardiovascular death at any time (3B) and first heart failure hospitalization (3C). Figure 3: Kaplan-Meier Curves for the Primary Composite Endpoint (A), Cardiovascular Death (B), and Heart Failure Hospitalization (C) A wide range of demographic characteristics, baseline disease characteristics, and baseline concomitant medications were examined for their influence on outcomes. The results of the primary composite endpoint were consistent across the subgroups examined (Figure 4). Figure 4: Primary Composite Endpoint (CV Death or HF Hospitalization) - Subgroup Analysis (PARADIGM-HF) Note: The figure above presents effects in various subgroups, all of which are baseline characteristics. The 95% confidence limits that are shown do not take into account the number of comparisons made, and may not reflect the effect of a particular factor after adjustment for all other factors.
Apparent homogeneity or heterogeneity among groups should not be over-interpreted. PARAGON-HF PARAGON-HF, was a multicenter, randomized, double-blind trial comparing ENTRESTO and valsartan in 4,796 adult patients with symptomatic heart failure with left ventricular ejection fraction greater than or equal to 45%, and structural heart disease. Patients with a systolic blood pressure of less than 110 mmHg and patients with any prior echocardiographic LVEF less than 40% at screening were excluded.
The primary objective of PARAGON-HF was to determine whether ENTRESTO reduced the rate of the composite endpoint of total (first and recurrent) heart failure (HF) hospitalizations and cardiovascular (CV) death. After discontinuing their existing ACE inhibitor or ARB therapy, patients entered sequential single-blind run-in periods during which they received valsartan 80 mg twice-daily, followed by ENTRESTO 100 mg twice-daily. Patients on prior low doses of an ACEi or ARB began the run-in period receiving valsartan 40 mg twice-daily for 1 to 2 weeks.
Patients who successfully completed the sequential run-in periods were randomized to receive either ENTRESTO 200 mg (N = 2,419) twice-daily or valsartan 160 mg (N = 2,403) twice-daily. The median follow-up duration was 35 months and patients were treated for up to
years.
The population was 81% Caucasian, 13% Asian, and 2% Black; the mean age was 73 years and 52% were female. At randomization, 77% of patients were NYHA Class II, 19% were NYHA Class III, and 0.4% were NYHA Class IV. The median left ventricular ejection fraction was 57%. The underlying cause of heart failure was of ischemic etiology in 36% of patients. Furthermore, 96% had a history of hypertension, 23% had a history of myocardial infarction, 46% had an eGFR less than 60 mL/min/
m 2, and 43% had diabetes mellitus. Most patients were taking beta-blockers
(80%) and diuretics (95%). PARAGON-HF demonstrated that ENTRESTO had a numerical reduction in the rate of the composite endpoint of total (first and recurrent) HF hospitalizations and CV death, based on an analysis using a proportional rates model (rate ratio 0.87; 95% CI, p = 0.06); see Table 5. The treatment effect was primarily driven by the reduction in total HF hospitalizations in patients randomized to ENTRESTO (RR 0.85; 95% CI ). Table 5: Treatment Effect for the Primary Composite Endpoint and Its Components in PARAGON-HF Abbreviations: RR = rate ratio, HR = hazard ratio. a Event rate per 100 patient-years. b Includes patients who had CV death following HF hospitalization event. ENTRESTO N = 2,407 Valsartan N = 2,389 Effect Size (95% CI) Efficacy Endpoints n Event Rate a n Event Rate a Composite of total (first and recurrent) HF hospitalizations and CV death 894
1,009 14.6 RR = 0.87 p -value 0.06 Total HF Hospitalizations 690
797 11.6 RR = 0.85 CV Death b 204 2.9 212 3.1
HR =
Figure 5 shows the mean number of composite endpoint events of total
HF hospitalizations and CV death over time. Figure 5: Mean Number of Events Over Time for the Primary Composite Endpoint of Total HF Hospitalizations and CV Death A wide range of demographic characteristics, baseline disease characteristics, and baseline concomitant medications were examined for their influence on outcomes (Figure 6). Figure 6: Primary Composite Endpoint of Total HF Hospitalizations and CV Death – Subgroup Analysis (PARAGON-HF) Note: The figure above presents effects in various subgroups, all of which are baseline characteristics. The 95% confidence limits that are shown do not take into account the number of comparisons made, and may not reflect the effect of a particular factor after adjustment for all other factors.
In an analysis of the relationship between LVEF and outcome in PARADIGM-HF and PARAGON-HF, patients with LVEF below normal treated with ENTRESTO experienced greater risk reduction (Figure 7). Figure 7: Treatment Effect for the Composite Endpoint of Time to First HF Hospitalization or CV Death by LVEF in PARADIGM-HF and PARAGON-HF Figure 3: Kaplan-Meier Curves for the Primary Composite Endpoint (A), Cardiovascular Death (B), and Heart Failure Hospitalization (C) Figure 4: Primary Composite Endpoint (CV Death or HF Hospitalization) - Subgroup Analysis Figure 5: Mean Number of Events Over Time for the Primary Composite Endpoint of Total HF Hospitalizations and CV Death Figure 6: Primary Composite Endpoint of Total HF Hospitalizations and CV Death – Subgroup Analysis (PARAGON-HF) Figure 7: Treatment Effect for the Composite Endpoint of Time to First HF Hospitalization or CV Death by LVEF in PARADIGM-HF and PARAGON-HF
Pediatric Heart Failure
The efficacy of ENTRESTO was evaluated in a multinational, randomized, double-blind trial PANORAMA-HF comparing ENTRESTO (n = 187) and enalapril (n = 188) in pediatric patients aged 1 month to less than 18 years old due to systemic left ventricular systolic dysfunction (LVEF ≤ 45% or fractional shortening ≤ 22.5%). Patients with systemic right ventricle, single ventricle, restrictive cardiomyopathy or hypertrophic cardiomyopathy were excluded from the trial. Efficacy of ENTRESTO in patients less than 1 year old was not established. At Week 52, there were 144 ENTRESTO and 133 enalapril patients with a post-baseline assessment of NT-proBNP. The estimated least squares mean percent reduction from baseline in NT-proBNP was 65% and 62% in the ENTRESTO and enalapril groups, respectively.
While the between-group difference was not nominally statistically significant, the reductions for ENTRESTO and enalapril were larger than what was seen in adults; these reductions did not appear to be attributable to post-baseline changes in background therapy. Because ENTRESTO improved outcomes and reduced NT-proBNP in adults in PARADIGM-HF, the effect on NT-proBNP was the basis to infer improved cardiovascular outcomes in pediatric patients.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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