Entresto

Sacubtril, valsartan.

Entresto film coated tablets contains 50 mg (sacubitril/valsartan).*
Entresto film coated tablets contains 100 mg (sacubitril/valsartan).*
Entresto film coated tablets contains 200 mg (sacubitril/valsartan).*
* Certain dosage strengths may not be available in all countries.
Entresto contains a salt complex of the anionic forms of sacubitril and valsartan, sodium cations, and water molecules in the molar ratio of 1:1:3:2.5 respectively. The empirical formula of the complex (hemipentahydrate) is C₄₈H₅₅N₆O₈Na₃ 2.5 H2O. Its molecular mass is 957.99.
Following oral administration, the complex dissociates into sacubitril (which is further metabolized to sacubitrilat) and valsartan.
Excipients/Inactive Ingredients: Microcrystalline cellulose, low-substituted hydroxypropylcellulose, crospovidone, magnesium stearate (vegetable origin), talc and colloidal silicon dioxide.
Excipients of film coating: Hypromellose, titanium dioxide (E 171), Macrogol 4000, talc, iron oxide red (E 172).
For 50 and 200 mg: Iron oxide black (E 172). For 100 mg: Iron oxide yellow (E 172).

PHARMACOLOGY: Mechanism of action: Entresto exhibits the novel mechanism of action of an angiotensin receptor neprilysin inhibitor (ARNI) by simultaneously inhibiting neprilysin (neutral endopeptidase; NEP) via sacubitrilat, the active metabolite of the prodrug sacubitril, and by blocking the angiotensin II type-1 (AT1) receptor via valsartan. The complementary cardiovascular benefits and renal effects of Entresto in heart failure patients are attributed to the enhancement of peptides that are degraded by neprilysin, such as natriuretic peptides (NP), by sacubitrilat and the simultaneous inhibition of the deleterious effects of angiotensin II by valsartan. NPs exert their effects by activating membrane-bound guanylyl cyclase-coupled receptors, resulting in increased concentrations of the second messenger cyclic guanosine monophosphate (cGMP), thereby promoting vasodilation, natriuresis and diuresis, increased glomerular filtration rate and renal blood flow, inhibition of renin and aldosterone release, reduction of sympathetic activity, and anti-hypertrophic and anti-fibrotic effects. Sustained activation of the renin-angiotensin-aldosterone system results in vasoconstriction, renal sodium and fluid retention, activation of cellular growth and proliferation, and subsequent maladaptive cardiovascular remodeling. Valsartan inhibits detrimental cardiovascular and renal effects of angiotensin II by selectively blocking the AT1 receptor, and also inhibits angiotensin II-dependent aldosterone release.
Pharmacodynamics: The pharmacodynamic effects of Entresto were evaluated after single and multiple dose administrations in healthy subjects and in patients with heart failure, and are consistent with simultaneous neprilysin inhibition and RAAS blockade. In a 7-day valsartan-controlled study in patients with reduced ejection fraction (HFrEF), administration of Entresto resulted in a significant non-sustained increase in natriuresis, increased urine cGMP, and decreased plasma MR-proANP and NT-proBNP compared to valsartan. In a 21-day study in HFrEF patients, ENTRESTO significantly increased urine ANP and cGMP and plasma cGMP, and decreased plasma NT-proBNP, aldosterone and endothelin-1 compared to baseline. Entresto also blocked the AT1-receptor as evidenced by increased plasma renin activity and plasma renin concentrations. In PARADIGM-HF, Entresto decreased plasma NT-proBNP and increased plasma BNP and urine cGMP compared with enalapril. In PARAGON-HF, Entresto decreased NT-proBNP, troponin and soluble ST2 (sST2) and increased urine cGMP compared to valsartan. While BNP is a neprilysin substrate, NT-proBNP is not. Therefore, NT-proBNP (but not BNP) is a suitable biomarker for monitoring of heart failure patients treated with ENTRESTO.
In a thorough QTc clinical study in healthy male subjects, single doses of 400 mg and 1200 mg Entresto had no effect on cardiac repolarization.
Neprilysin is one of multiple enzymes involved in the clearance of amyloid-beta (A beta) from the brain and cerebrospinal fluid (CSF). Administration of Entresto 400 mg once daily for 2 weeks to healthy subjects was associated with an increase in CSF A beta 1-38 compared to placebo; there were no changes in concentrations of CSF A beta 1-40 and 1-42. The clinical relevance of this finding is unknown (see Toxicology: NON-CLINICAL SAFETY DATA as follows).
CLINICAL STUDIES: PARADIGM-HF: PARADIGM-HF was a multinational, randomized, double-blind study of 8,442 patients comparing Entresto to enalapril, both given to adult patients with chronic heart failure, NYHA class II - IV, and systolic dysfunction (left ventricular ejection fraction ≤ 40%), in addition to other heart failure therapy. The primary endpoint was the composite of cardiovascular (CV) death or hospitalization for heart failure (HF).
Prior to study participation, patients were well treated with standard of care therapy which included ACE inhibitors/ARBs (>99%), beta-blockers (94%), mineralocorticoid antagonists (58%), and diuretics (83%). The median follow-up duration was 27 months and patients were treated for up to 4.3 years.
Patients were required to discontinue their existing ACE inhibitor or ARB therapy and entered a sequential single-blind run-in period during which patients received treatment with enalapril 10 mg twice daily, followed by treatment with Entresto 100 mg twice daily, increasing to 200 mg twice daily. Patients were then randomized to the double-blind period of the study to receive either Entresto 200 mg or enalapril 10 mg twice daily [Entresto (n= 4,209); enalapril (n= 4,233)].
The mean age of the population studied was 64 years of age and 19% were 75 years or older. At randomization, 70% of patients were NYHA Class II and 25% were Class III/IV.
In the Entresto group, 76% of patients remained on the target dose of 200 mg twice daily at the end of the study (mean daily dose of 375 mg). In the enalapril group, 75% of patients remained on the target dose of 10 mg twice daily at the end of the study (mean daily dose of 18.9 mg).
Entresto demonstrated clinically relevant and statistically significant superiority to enalapril, reducing the risk of cardiovascular death or heart failure hospitalizations by 20% (hazard ratio (HR): 0.80, 95% CI [0.73; 0.87], 1-sided p =0.0000002) versus enalapril. This effect was observed early and was sustained throughout the duration of the trial. The absolute risk reduction was 4.69%. A statistically significant reduction for CV death and first HF hospitalization was observed (CV death, RRR 20%, HR 0.80; 95% CI [0.71, 0.89], 1-sided p= 0.00004; and hospitalization for heart failure RRR 21%; HR 0.79; 95% CI 0.71, 0.89], 1-sided p= 0.00004); see Table 1 and Figure 1. Sudden death accounted for 45% of cardiovascular deaths and was reduced by 20% in Entresto treated patients compared to enalapril treated patients (HR 0.80, p= 0.0082). Pump failure accounted for 26% of cardiovascular deaths and was reduced by 21% in Entresto treated patients compared to enalapril treated patients (HR 0.79, p = 0.0338).
This risk reduction was consistently observed across subgroups including: age, gender, race, geography, NYHA class, ejection fraction, renal function, history of diabetes or hypertension, prior heart failure therapy, and atrial fibrillation.
Entresto also significantly reduced all-cause mortality by 16% compared with enalapril (RRR 16%, HR 0.84; 95% CI [0.76 to 0.93], 1-sided p=0.0005) (Table 1). The absolute risk reduction was 2.84%. (See Table 1.)

Click on icon to see table/diagram/image

The Kaplan-Meier presented in the figure as follows (left) shows time to first occurrence of the primary composite endpoint of CV death or heart failure hospitalization. Entresto treatment effect was evident early and sustained for the duration of the study. The Kaplan-Meier figure presented as follows (right) shows the time to CV death endpoint. (See Figure 1.)

Click on icon to see table/diagram/image

Overall, there were fewer all cause hospital admissions in patients treated with Entresto compared to enalapril, including a 12% relative risk reduction for the first hospitalization (HR 0.88 [95% CI: 0.82, 0.94], P<0.001), and a 16% relative rate reduction for total number of hospitalizations (RR 0.84 [95% CI: 0.78, 0.91], P<0.001).
Entresto demonstrated a significantly better clinical summary score for the domains related to HF symptoms and physical limitations as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ), a self-administered questionnaire. More patients had improved NYHA functional class from baseline to Month 8 on Entresto (16%) compared to enalapril (14%), and fewer patients had worsened NYHA functional class (10% vs 13%, respectively).
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 preserved ejection fraction (left ventricular ejection fraction ≥45%), and structural heart disease [either left atrial enlargement (LAE) or left ventricular hypertrophy (LVH)]. Patients with a systolic blood pressure of < 110 mmHg and patients with any prior echocardiographic LVEF < 40% at screening were excluded.
The primary endpoint of PARAGON-HF was the composite 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 1-2 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 4.7 years.
The mean age of the population studied 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 < 60 mL/min/1.73 m², and 43% had diabetes mellitus. Most patients were taking beta-blockers (80%) and diuretics (95%).
In PARAGON-HF, Entresto reduced 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, by 13% compared to valsartan (rate ratio [RR]; 0.87; 95% CI [0.75, 1.01], p = 0.059). The treatment effect was primarily driven by the reduction in total HF hospitalizations in patients randomized to Entresto of 15% (RR 0.85; 95% CI [0.72, 1.00]).
Entresto reduced by 14% the rate of the composite endpoint of total worsening heart failure (HF hospitalizations and urgent HF visits) and CV death (RR 0.86; 95% CI [0.75, 0.99]).
A wide range of demographic characteristics, baseline disease characteristics, and baseline concomitant medications were examined for their influence on outcomes (Figure 2). (See Figure 2.)

Click on icon to see table/diagram/image

In an analysis of the relationship between LVEF and outcome in PARADIGM-HF and PARAGON-HF, patients with LVEF below normal (up to approximately 60%) treated with Entresto experienced greater risk reduction (Table 2 and Figure 3, and Figure 4). LVEF is a variable measure that can change over time, and the normal range differs according to patient characteristics and method of assessment; prescribers should use clinical judgment in deciding whom to treat. In both studies the treatment effect with Entresto was demonstrated early and sustained throughout the duration of the trials (Figures 1 and 4). (See Table 2, Figures 3 and 4.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

TITRATION: TITRATION was a 12 week safety and tolerability study in 538 patients with chronic heart failure (NYHA class II-IV) and systolic dysfunction (left ventricular ejection fraction ≤ 35%) naive to ACE inhibitor or ARB therapy or on varying doses of ACE inhibitors or ARBs prior to study entry. Patients initiated Entresto 50 mg twice daily, were uptitrated to 100 mg twice daily and then to the target dose of 200 mg twice daily with either a 3-week or 6-week regimen.
Overall, 76% of patients achieved and maintained the target dose of Entresto 200 mg twice daily without any dose interruption or down-titration over 12-weeks. More patients who were naïve to previous ACE inhibitor or ARB therapy or on low dose therapy (equivalent to < 10 mg of enalapril/day) were able to achieve and maintain Entresto 200 mg when uptitrated over 6 weeks versus 3 weeks.
PARAMOUNT: PARAMOUNT, a randomized, double-blind trial in patients with left ventricular ejection fraction ≥ 45% comparing 200 mg of Entresto (n=149) to 160 mg of valsartan (n=152) twice daily, demonstrated statistically greater reduction (p= 0.0050) in NT pro-BNP from baseline to Week 12. The reduction from baseline in NT-proBNP was similar at Weeks 12 and 36 in patients treated with Entresto, while NT-proBNP decreased from Week 12 to 36 in patients treated with valsartan. Significant reductions in left atrial size, both left atrial volume index (p=0.0069) and left atrial dimension (p=0.0337) were observed at Week 36. A statistically significant improvement in NYHA class was noted at Week 36 (p=0.0488).
Pharmacokinetics: Absorption: Following oral administration, Entresto dissociates into sacubitril, which is further metabolized to sacubitrilat, and valsartan, which reach peak plasma concentrations in 0.5 hours, 2 hours, and 1.5 hours, respectively. The oral absolute bioavailability of sacubitril and valsartan is estimated to be ≥ 60% and 23%, respectively. The valsartan in Entresto is more bioavailable than the valsartan in other marketed tablet formulations.
Following twice daily dosing of Entresto, steady state levels of sacubitril, sacubitrilat, and valsartan are reached in 3 days. At steady state, sacubitril and valsartan do not accumulate significantly, while sacubitrilat accumulates by 1.6-fold. Entresto administration with food has no clinically significant impact on the systemic exposures of sacubitril, sacubitrilat and valsartan. Although there is a decrease in exposure to valsartan when Entresto is administered with food, this decrease is not accompanied by a clinically significant reduction in the therapeutic effect. Entresto can therefore be administered with or without food.
Distribution: Entresto is highly bound to plasma proteins (94% - 97%). Based on the comparison of plasma and CSF exposures, sacubitrilat does cross the blood brain barrier to a limited extent (0.28%). Entresto has an apparent volume of distribution ranging from 75 L to 103 L.
Biotransformation/metabolism: Sacubitril is readily converted to sacubitrilat by esterases; sacubitrilat is not further metabolized to a significant extent. Valsartan is minimally metabolized, as only about 20% of the dose is recovered as metabolites. A hydroxyl metabolite has been identified in plasma at low concentrations (<10%). Since CYP450 enzyme mediated metabolism of sacubitril and valsartan is minimal, co-administration with drugs that impact CYP450 enzymes is not expected to impact the pharmacokinetics.
Elimination: Following oral administration, 52 - 68% of sacubitril (primarily as sacubitrilat) and ~13% of valsartan and its metabolites are excreted in urine; 37-48% of sacubitril (primarily as sacubitrilat), and 86% of valsartan and its metabolites are excreted in feces.
Sacubitril, sacubitrilat, and valsartan are eliminated from plasma with a mean elimination half-life (T½) of approximately 1.43 hours, 11.48 hours, and 9.90 hours, respectively.
Linearity/non-linearity: The pharmacokinetics of sacubitril, sacubitrilat, and valsartan are linear in the dose range tested (50 - 400 mg of Entresto).
Special populations: Pediatric patients (aged below 18 years of age): Entresto has not been studied in pediatric patients.
Geriatric patients (65 years of age and above): The exposures of sacubitrilat and valsartan are increased in elderly subjects by 42% and 30%, respectively, compared to younger subjects. However, this is not associated with clinically relevant effects and therefore no dosage adjustment is necessary.
Gender: The pharmacokinetics of Entresto (sacubitril, sacubitrilat and valsartan) are similar between male and female subjects.
Race/Ethnicity: The pharmacokinetics of Entresto (sacubitril, sacubitrilat and valsartan) are comparable across different race and ethnic groups (Caucasians, Blacks, Asians, Japanese and others).
Renal impairment: A correlation was observed between renal function and systemic exposure to sacubitrilat, but not to valsartan. In patients with mild (60 mL/min/1.73 m² <eGFR<90 mL/min/1.73 m²) to moderate (30 mL/min/1.73 m² ≤ eGFR< 60 mL/min/1.73 m²) renal impairment the AUC for sacubitrilat was up to 2-fold higher. No dosage adjustment is required in patients with mild or moderate renal impairment. A 2.7-fold higher AUC for sacubitrilat was observed in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²). A starting dose of 50 mg twice daily is recommended in patients with severe renal impairment. Caution is recommended when administering Entresto to these patients due to limited data.
No studies have been performed in patients undergoing dialysis. However, sacubitrilat and valsartan are highly bound to plasma protein and, therefore, unlikely to be effectively removed by dialysis.
Hepatic impairment: In patients with mild to moderate hepatic impairment, the exposures of sacubitril increased by 1.5- and 3.4-fold, sacubitrilat increased by 1.5- and 1.9-fold, and valsartan increased by 1.2-fold and 2.1-fold, respectively, compared to matching healthy subjects. No dosage adjustments is recommended when administering Entresto to patients with mild hepatic impairment (Child-Pugh A classification) including patients with biliary obstructive disorders. In patients with moderate hepatic impairment (Child-Pugh B classification), a starting dose of 50 mg twice daily is recommended. Entresto has not been studied in patients with severe hepatic impairment. Therefore, its use is not recommended in patients with severe hepatic impairment.
Toxicology: NON-CLINICAL SAFETY DATA: Non-clinical safety studies conducted with Entresto included assessment of safety pharmacology, repeated dose toxicity genotoxicity carcinogenicity and reproductive and development toxicity Entresto had no adverse effects on vital organ systems. Most findings seen in repeated toxicity studies were reversible and attributable to the pharmacology of AT₁ receptor blockade.
Carcinogenicity, mutagenesis and genetic toxicity: Carcinogenicity studies conducted in mice and rats with sacubitril and valsartan did not identify any carcinogenic potential for Entresto. The doses of sacubitril studied (high dose of 1200 and 400 mg/kg/day in mice and rats, respectively) were about 29 and 19 times, respectively, the maximum recommended human dose (MRHD) on a mg/m² basis. The doses of valsartan studied (high dose of 160 and 200 mg/kg/day in mice and rats, respectively) were about 4 and 10 times, respectively, the maximum recommended human dose on a mg/m² basis.
Mutagenicity and clastogenicity studies conducted with Entresto, sacubitril, and valsartan did not reveal any effects at either the gene or chromosome level.
Fertility, reproduction and development: See USE IN PREGNANCY & LACTATION.
Other preclinical findings: The effects of Entresto on amyloid-beta concentrations in cerebrospinal fluid (CSF) and brain tissue were assessed in young (2-4 years old) cynomolgus monkeys treated with Entresto (50 mg/kg/day) for 2 weeks. In this study, Entresto had a pharmacodynamic effect on CSF A beta clearance in cynomolgus monkeys, increasing CSF Aβ 1-40, 1-42, and 1-38 levels; there was no corresponding increase in A beta levels in the brain. Increases in CSF A beta 1-40 and 1-42 were not observed in a 2 week healthy volunteer study in humans (see Pharmacology as previously mentioned). Additionally, in a toxicology study in cynomolgus monkeys treated with Entresto at 300 mg/kg/day for 39-weeks, there was no amyloid-beta accumulation in the brain.

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.
Clinical judgment should be used in deciding whom to treat as LVEF is a variable measure.
Entresto is administered in place of an ACE inhibitor or ARB.

Dosage regimen: The target dose of Entresto is 200 mg twice daily.
The recommended starting dose of Entresto is 100 mg twice daily. A starting dose of 50 mg twice daily is recommended for patients not currently taking an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB), and should be considered for patients previously taking low doses of these agents (see Pharmacology: Pharmacodynamics: CLINICAL STUDIES under Actions).
The dose of Entresto should be doubled every 2-4 weeks to the target dose of 200 mg twice daily, as tolerated by the patient.
Due to the potential risk of angioedema when used concomitantly with an ACE inhibitor, Entresto must not be started until 36 hours after discontinuing ACE inhibitor therapy (see CONTRAINDICATIONS).
Entresto should not be co-administered with an ARB due to the angiotensin II receptor blocking activity of Entresto (see PRECAUTIONS and INTERACTIONS).
If patients experience tolerability issues (symptomatic hypotension, hyperkalemia, renal dysfunction), consideration should be given to adjustment of concomitant medications, or to temporary down-titration of Entresto.
Special populations: Renal impairment: A starting dose of 50 mg twice daily is recommended in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²). Caution is recommended when using Entresto in these patients due to limited data (see PHARMACOLOGY under Actions).
No dose adjustment is required in patients with mild (eGFR 60-90 mL/min/1.73 m²) to moderate (eGFR 30-60 mL/min/1.73 m²) renal impairment.
Hepatic impairment: A starting dose of 50 mg twice daily is recommended for patients with moderate hepatic impairment (Child-Pugh B classification).
No dose adjustment is required when administering Entresto to patients with mild hepatic impairment (Child-Pugh A classification).
No studies have been conducted in patients with severe hepatic impairment (Child-Pugh C classification). Therefore use of Entresto in these patients is not recommended (see PHARMACOLOGY under Actions).
Pediatric patients (below 18 years of age): The safety and efficacy of Entresto in pediatric patients aged below 18 years has not been established.
Geriatric patients (65 years of age and above): No dosage adjustment is required in patients 65 years of age and above.
Method of administration: For oral use. Entresto may be administered with or without food (see PHARMACOLOGY under Actions).

Limited data are available with regards to overdosage in human subjects with Entresto. In healthy volunteers, a single dose of Entresto 1200 mg, and 900 mg multiple doses (14 days) have been studied and were well tolerated.
Hypotension is the most likely symptom of overdosage due to the blood pressure lowering effects of Entresto. Symptomatic treatment should be provided.
Entresto is unlikely to be removed by hemodialysis due to high protein binding.

Hypersensitivity to the active substance, sacubitril, valsartan, or to any of the excipients.
Concomitant use with ACE inhibitors (see PRECAUTIONS, DOSAGE & ADMINISTRATION and INTERACTIONS). Entresto must not be administered until 36 hours after discontinuing ACE inhibitor therapy.
Known history of angioedema related to previous ACE inhibitor or ARB therapy.
Hereditary angioedema.
Concomitant use with aliskiren in patients with Type 2 diabetes (see PRECAUTIONS and INTERACTIONS).
Pregnancy (see USE IN PREGNANCY & LACTATION).

Dual blockade of the Renin-Angiotensin-Aldosterone System (RAAS): Entresto must not be administered with an ACE inhibitor due to the risk of angioedema. Entresto must not be initiated until 36 hours after taking the last dose of ACE inhibitor therapy. If treatment with Entresto is stopped, ACE inhibitor therapy must not be initiated until 36 hours after the last dose of Entresto (see CONTRAINDICATIONS, DOSAGE & ADMINISTRATION and INTERACTIONS).
Caution is required while co-administering Entresto with direct renin inhibitors such as aliskiren (see CONTRAINDICATIONS and INTERACTIONS). Entresto must not be administered with aliskiren in patients with Type 2 diabetes (see CONTRAINDICATIONS).
Entresto should not be co-administered with an ARB due to the angiotensin II receptor blocking activity of Entresto (see DOSAGE & ADMINISTRATION and INTERACTIONS).
Hypotension: Cases of symptomatic hypotension have been reported in patients treated with Entresto during clinical trials. If hypotension occurs, dose adjustment of diuretics, concomitant antihypertensive drugs, and treatment of other causes of hypotension (e.g. hypovolemia) should be considered. If hypotension persists despite such measures, the dosage of Entresto should be reduced or the product should be temporarily discontinued (see DOSAGE & ADMINISTRATION). Permanent discontinuation of therapy is usually not required. Symptomatic hypotension is more likely to occur if the patient has been volume-depleted, e.g., by diuretic therapy, dietary salt restriction, diarrhea or vomiting. Sodium and/or volume depletion should be corrected before starting treatment with Entresto.
Renal impairment: As for any drug that acts on the renin-angiotensin-aldosterone system, use of Entresto may be associated with decreased renal function. In PARADIGM-HF, the incidence of clinically relevant renal impairment was low and associated treatment discontinuation was observed less frequently in patients receiving Entresto (0.65%) compared to enalapril (1.28%). Down titration of Entresto should be considered in patients who develop a clinically significant decrease in renal function. Caution should be exercised when administering Entresto in patients with severe renal impairment (see DOSAGE & ADMINISTRATION and PHARMACOLOGY under Actions).
Hyperkalemia: As for any drug that acts on the renin-angiotensin-aldosterone system, use of Entresto may be associated with an increased risk of hyperkalemia. In PARADIGM-HF, the incidence of clinically relevant hyperkalemia was low, resulting in treatment discontinuation in 0.26% of Entresto treated patients compared to 0.35% of enalapril treated patients. Medications known to raise potassium levels (e.g. potassium-sparing diuretics, potassium supplements) should be used with caution when co-administered with Entresto. If clinically significant hyperkalemia occurs, measures such as reducing dietary potassium, or adjusting the dose of concomitant medications should be considered. Monitoring of serum potassium is recommended especially in patients with risk factors such as severe renal impairment, diabetes mellitus, hypoaldosteronism or receiving a high potassium diet (see DOSAGE & ADMINISTRATION).
Angioedema: Angioedema has been reported in patients treated with Entresto. If angioedema occurs, Entresto should be immediately discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. 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, appropriate therapy, e.g., subcutaneous epinephrine/adrenaline solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly administered.
Patients with a prior history of angioedema were not studied. As they may be at higher risk for angioedema, caution is recommended if Entresto is used in these patients. Entresto must not be used in patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy, or in patients with hereditary angioedema (see CONTRAINDICATIONS).
Black patients may have increased susceptibility to develop angioedema.
Patients with renal artery stenosis: Similar to other drugs that affect the renin-angiotensin-aldosterone system, Entresto may increase blood urea and serum creatinine levels in patients with bilateral or unilateral renal artery stenosis. Caution is required in patients with renal artery stenosis and monitoring of renal function is recommended.

Pregnancy: Risk Summary: As for other drugs that also act directly on the RAAS, Entresto must not be used during pregnancy (see CONTRAINDICATIONS). Entresto exerts its effects via angiotensin II antagonism. As a result, a risk to the fetus cannot be excluded. There have been reports of injury to the developing fetus (e.g. spontaneous abortion, oligohydramnios and newborn renal dysfunction), when pregnant women have taken valsartan. Patients should be advised to discontinue Entresto as soon as pregnancies occur and to inform their physicians.
Animal Data: Entresto treatment during organogenesis resulted in increased embryo-fetal lethality in rats at doses ≥100 mg/kg/day [≤0.72 fold the maximum recommended human dose (MRHD) on the basis of AUC] and rabbits at doses ≥ 10 mg/kg/day [2 fold and 0.03 fold the MRHD on the basis of valsartan and sacubitrilat 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 ≥ 10 mg/kg/day. The adverse embryo-fetal effects of Entresto are attributed to the angiotensin receptor antagonist activity.
Pre- and postnatal development studies in rats conducted with sacubitril at doses up to 750 mg/kg/day [2.2 fold the MRHD on the basis of 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.
Lactation: Risk Summary: It is not known whether the components of Entresto are transferred into human milk. The components of Entresto, sacubitril and valsartan were transferred into the milk of lactating rats. Because of the potential risk for adverse drug reactions in breastfed newborns/infants, Entresto is not recommended during breastfeeding. A decision should be made whether to abstain from breast-feeding or to discontinue Entresto while breast-feeding, taking into account the importance of Entresto to the mother.
Females and males of reproductive potential: Females patients of child-bearing potential should be advised about the consequences of exposure to Entresto during pregnancy and to use contraception during treatment with Entresto and for 1 week after their last dose.
Infertility: There are no available data on the effect of Entresto on human fertility. Entresto did not show any effects on fertility or early embryonic development in rats up to a dose of 150 mg/kg/day (≤1.0 fold and ≤0.18 fold the MRHD on the basis of valsartan and sacubitrilat AUC, respectively).

Summary of the safety profile: 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.
PARADIGM-HF: The safety of Entresto in patients with chronic heart failure with LVEF ≤ 40% (reduced ejection fraction) was evaluated in the pivotal phase 3 study PARADIGM-HF, which compared patients treated twice daily with Entresto 200 mg (n=4203) or enalapril 10 mg (n=4229). Patients randomized to Entresto received treatment for up to 4.3 years, with a median duration of exposure of 24 months; 3271 patients were treated for more than one year.
Discontinuation of therapy due to an AE in the double-blind period of the PARADIGM-HF trial occurred in 450 (10.71%) of Entresto treated patients and 516 (12.20%) of patients receiving enalapril. The events most commonly associated with dosage adjustment or treatment interruption were hypotension, hyperkalemia and renal impairment.
The overall incidence of adverse drug reactions (ADRs) of Entresto in heart failure patients was comparable to enalapril. The pattern of the ADRs is consistent with the pharmacology of Entresto and the patients underlying conditions.
The overall frequency of adverse reactions was not related to gender, age, or race.
Adverse drug reactions are ranked by System Organ Class and then by frequency with the most frequent first, using the following convention: 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); very rare (<1/10,000), including isolated reports. Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness. (See Table 3.)

Click on icon to see table/diagram/image

PARAGON-HF: The safety of Entresto in patients with chronic heart failure and LVEF ≥45% (preserved ejection fraction) was evaluated in the pivotal phase 3 study PARAGON-HF, which compared patients treated twice daily with Entresto 200 mg (n=2,419) or valsartan 160 mg (n=2,402). The safety profile of Entresto was consistent with the safety profile in patients with heart failure with reduced ejection fraction.
Adverse drug reactions from spontaneous reports and literature cases (frequency not known): The following adverse drug reactions have been derived from post-marketing experience with Entresto via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency, which is therefore categorized as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. (See Table 4.)

Click on icon to see table/diagram/image

Anticipated interactions resulting in a contraindication: ACE Inhibitors: The concomitant use of Entresto with ACE inhibitors is contraindicated, as the concomitant inhibition of neprilysin (NEP) and ACE inhibitor therapy may increase the risk of angioedema. Entresto must not be started until 36 hours after taking the last dose of ACE inhibitor therapy. ACE inhibitor therapy must not be started until 36 hours after the last dose of Entresto (see CONTRAINDICATIONS and DOSAGE & ADMINISTRATION).
Aliskiren: The concomitant use of Entresto with aliskiren is contraindicated in patients with Type 2 diabetes (see CONTRAINDICATIONS).
Anticipated interactions resulting in concomitant use not being recommended: Entresto should not be co-administered with an ARB due to the angiotensin II receptor blocking activity of Entresto (see PRECAUTIONS).
Concomitant use with aliskiren should be avoided in patients with renal impairment (eGFR <60 mL/min/1.73 m²) (see PRECAUTIONS).
Observed interactions to be considered: Statins: In vitro data indicates that sacubitril inhibits OATP1B1 and OATP1B3 transporters. Entresto may therefore increase the systemic exposure of OATP1B1 and OATP1B3 substrates such as statins. Co-administration of Entresto increased the Cmax of atorvastatin and its metabolites by up to 2-fold and AUC by up to 1.3-fold.
Caution should be exercised upon co-administration of Entresto with statins. No clinically relevant drug-drug interaction was observed when simvastatin and Entresto were co-administered.
Sildenafil: Addition of a single dose of sildenafil to Entresto at steady state in patients with hypertension was associated with greater BP reduction compared to administration of Entresto alone. Therefore, caution should be exercised when sildenafil or another PDE-5 inhibitor is initiated in patients treated with Entresto.
Anticipated interactions to be considered: Potassium: Concomitant use of potassium-sparing diuretics (e.g, triamterene, amiloride), mineralocorticoid antagonists (e.g. spironolactone, eplerenone), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium, and to increases in serum creatinine. Monitoring of serum potassium is recommended if Entresto is co-administered with these agents (see PRECAUTIONS).
Non-Steroidal Anti-Inflammatory Agents (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 Inhibitors): In elderly patients, volume-depleted patients (including those on diuretic therapy), or patients with compromised renal function, concomitant use of Entresto and NSAIDs may lead to an increased risk of worsening of renal function. Therefore, monitoring of renal function is recommended when initiating or modifying the treatment in patients on Entresto who are taking NSAIDs concomitantly.
Lithium: The potential for a drug interaction between Entresto and lithium has not been investigated. Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors or angiotensin II receptor antagonists. Therefore, careful monitoring of serum lithium levels is recommended during concomitant use with Entresto. If a diuretic is also used, the risk of lithium toxicity may be increased further.
Transporters: The active metabolite of sacubitril (sacubitrilat), and valsartan are OATP1B1, OATP1B3 and OAT3 substrates; valsartan is also a MRP2 substrate. Therefore, co-administration of Entresto with inhibitors of OATP1B1, OATP1B3, OAT3 (e.g. rifampin, cyclosporine) or MRP2 (e.g. ritonavir) may increase the systemic exposure to LBQ657 or valsartan, respectively. Exercise appropriate care when initiating or ending concomitant treatment with such drugs.
No significant interactions: No clinically meaningful drug-drug interaction was observed upon co-administration of Entresto and furosemide, digoxin, warfarin, hydrochlorothiazide, amlodipine, metformin, omeprazole, carvedilol, intravenous nitroglycerin or a combination of levonorgestrel/ethinyl estradiol. No interaction is expected with atenolol, indomethacin, glyburide, or cimetidine.
CYP 450 Interactions: In vitro metabolism studies indicate that the potential for CYP 450-based drug interactions is low since there is limited metabolism of Entresto via the CYP450 enzymes. Entresto does not induce or inhibit CYP450 enzymes.

INCOMPATIBILITIES: Not applicable.
INSTRUCTIONS FOR USE AND HANDLING: Not applicable.

Do not store above 30°C, protect from moisture. Store in the original package.

Other Cardiovascular Drugs

C09DX04 - valsartan and sacubitril ; Belongs to the class of angiotensin II receptor blockers (ARBs), other combinations. Used in the treatment of cardiovascular disease.

D