DRUG NAME: Sacubitril + Valsartan

Therapeutic Class: Heart Failure Agent

Subclass: Angiotensin Receptor-Neprilysin Inhibitor (ARNI)

Schedule (India): Schedule H

Route(s): Oral

Formulations Available in India:

Film-coated Tablets:
- Sacubitril 24.3 mg + Valsartan 25.7 mg (commonly referred to as “50 mg” tablet)
- Sacubitril 48.6 mg + Valsartan 51.4 mg (commonly referred to as “100 mg” tablet)
- Sacubitril 97.2 mg + Valsartan 102.8 mg (commonly referred to as “200 mg” tablet)

Note on nomenclature: Throughout this monograph, doses are referred to by the combined sacubitril-valsartan salt complex amount (i.e., 50 mg, 100 mg, 200 mg) for practical clarity, as commonly used in Indian prescribing.

ADULT INDICATIONS + DOSING

Primary Indications (Approved / Standard in India)

1. Heart Failure with Reduced Ejection Fraction (HFrEF) — NYHA Class II–IV, LVEF ≤ 40%

Parameter	Detail
Starting dose	100 mg twice daily — for patients currently tolerating a moderate-to-high dose ACE inhibitor (e.g., enalapril ≥ 10 mg BD or equivalent) or ARB (e.g., valsartan ≥ 160 mg daily or equivalent)
	50 mg twice daily — for patients: (a) not currently on an ACE inhibitor or ARB, (b) previously on low-dose ACE inhibitor or ARB, © with systolic BP 100–110 mmHg, (d) with moderate renal impairment (eGFR 30–60 mL/min/1.73 m²), or (e) with moderate hepatic impairment (Child-Pugh B)
Titration	Double the dose every 2–4 weeks as tolerated (50 mg BD → 100 mg BD → 200 mg BD); titrate only if systolic BP ≥ 95 mmHg, no symptomatic hypotension, no hyperkalaemia (K⁺ < 5.4 mEq/L), and no significant worsening of renal function
Usual maintenance dose	200 mg twice daily (target dose)
Maximum dose	200 mg twice daily
Key clinical notes	• Mandatory 36-hour washout from any ACE inhibitor before initiating sacubitril/valsartan — concurrent or closely timed use with ACE inhibitors markedly increases risk of angioedema • No washout required when switching from an ARB • Replaces ACE inhibitor/ARB in guideline-directed medical therapy (GDMT) for HFrEF; should be used in conjunction with a beta-blocker, mineralocorticoid receptor antagonist (MRA), and SGLT2 inhibitor as part of the four-pillar HF therapy • Based on the PARADIGM-HF trial, sacubitril/valsartan reduced cardiovascular death and heart failure hospitalisation by 20% compared with enalapril • Do not initiate in acutely decompensated heart failure requiring intravenous therapy; stabilise the patient first and initiate during the index hospitalisation before discharge or within the early post-discharge period • If a dose is missed, take the next dose at the scheduled time; do not double dose • Sacubitril inhibits neprilysin, leading to increased levels of natriuretic peptides (BNP); therefore, BNP cannot be used as a marker for monitoring HF status during treatment — use NT-proBNP instead, which is not a neprilysin substrate • Hypotension is the most common reason for dose reduction or discontinuation; optimise diuretic dosing, avoid unnecessary vasodilators, and consider reducing concomitant antihypertensives before down-titrating ARNI

Secondary Indications — Adults Only (Off-label, if any)

1. Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF) — LVEF 41–49%

OFF-LABEL — Specialist only
Dose: Same titration protocol as for HFrEF (start 50–100 mg BD, target 200 mg BD)
Duration: Long-term
Evidence basis: Pre-specified subgroup analysis of the PARAGON-HF trial demonstrated benefit in patients with LVEF below the median (particularly LVEF ≤ 57%), with the greatest benefit in the 40–50% range; 2023 ESC Focused Update on Heart Failure and 2022 AHA/ACC/HFSA Guidelines support ARNI use in HFmrEF; increasingly adopted in Indian cardiology specialist practice
Note: Initiate under cardiologist supervision; evidence is supportive but not based on a primary positive RCT endpoint for this specific subgroup

PAEDIATRIC DOSING (Specialist Only)

Primary Indications (Approved / Standard in India)

NOT AVAILABLE in India for paediatric use. Safety and efficacy of sacubitril/valsartan in children and adolescents below 18 years have not been established in Indian regulatory approval.

Secondary Indications — Paediatric Doses (Off-label, if any)

NOT AVAILABLE in India. Insufficient published data to support off-label paediatric dosing recommendations. Any use in children with heart failure should be under paediatric cardiology specialist supervision only, guided by institutional protocols.

RENAL ADJUSTMENT

eGFR (mL/min/1.73 m²)	Recommendation
≥ 60	No dose adjustment required; standard dosing
30–59	Start at 50 mg twice daily; titrate cautiously based on tolerability; monitor renal function and potassium within 1–2 weeks
< 30 (not on dialysis)	Limited data; use with extreme caution under specialist supervision; start at 50 mg twice daily if initiated; close monitoring of renal function, potassium, and blood pressure essential
End-stage renal disease / Haemodialysis	Not recommended; no adequate data available

Note: Sacubitril’s active metabolite (LBQ657) and valsartan both undergo partial renal excretion. Accumulation of LBQ657 occurs in renal impairment, increasing the risk of hypotension and adverse effects.

HEPATIC ADJUSTMENT

Child-Pugh Class	Recommendation
A (Mild)	No dose adjustment required
B (Moderate)	Initiate at 50 mg twice daily; titrate cautiously with close monitoring of liver function, blood pressure, and tolerability; area under curve of valsartan approximately doubled
C (Severe)	Not recommended; no safety or efficacy data available; avoid use

CONTRAINDICATIONS

Known hypersensitivity to sacubitril, valsartan, or any excipient of the formulation
History of angioedema associated with prior ACE inhibitor or ARB therapy
Concomitant use with any ACE inhibitor — a minimum 36-hour washout is mandatory before initiating sacubitril/valsartan after discontinuation of an ACE inhibitor (and vice versa)
Concomitant use with aliskiren in patients with diabetes mellitus or in patients with eGFR < 60 mL/min/1.73 m²
Second and third trimesters of pregnancy
Severe hepatic impairment (Child-Pugh C)
Hereditary or idiopathic angioedema

CAUTIONS

Systolic blood pressure < 100 mmHg at baseline (increased risk of symptomatic hypotension; consider starting at 50 mg BD and titrate slowly)
Volume- or salt-depleted patients (correct dehydration and optimise diuretic doses before initiation)
Renal artery stenosis (bilateral or stenosis in a solitary kidney)
Pre-existing renal impairment (eGFR < 60 mL/min/1.73 m²) — monitor renal function closely
Hyperkalaemia (K⁺ > 5.0 mEq/L at baseline — correct before initiating; avoid or use cautiously with potassium-sparing agents)
Concomitant use with an MRA (spironolactone/eplerenone) — combination is part of standard GDMT but requires potassium monitoring
History of angioedema of any cause (even if not ACE inhibitor/ARB-related — increased vigilance required)
Patients of Black African descent (higher background risk of angioedema with RAAS-acting drugs)
Aortic or mitral stenosis, hypertrophic obstructive cardiomyopathy
Sacubitril inhibits neprilysin which degrades amyloid-beta — theoretical concern regarding cerebral amyloid accumulation with long-term use; clinical significance remains unestablished (PERSPECTIVE trial showed no significant cognitive decline over 3 years)

PREGNANCY

Parameter	Detail
Overall safety	Contraindicated — Risk Category D; acts on the RAAS (valsartan component) and is associated with fetal toxicity including renal dysgenesis, oligohydramnios, skull ossification defects, pulmonary hypoplasia, and neonatal death when used in the second and third trimesters
First trimester	Should be avoided; discontinue immediately upon confirmation of pregnancy and switch to a safer alternative
Preferred alternatives in Indian obstetric practice	Methyldopa (first line for chronic hypertension/heart failure in pregnancy); labetalol; hydralazine with nitrate for acute heart failure management in pregnancy
When it may be used	Should not be used at any stage of pregnancy
Monitoring if inadvertently exposed	Serial ultrasonography for amniotic fluid volume, fetal renal function, limb contractures, and skull ossification; neonatal assessment for hypotension, hyperkalaemia, oliguria, and renal failure

LACTATION

Parameter	Detail
Compatibility with breastfeeding	Not recommended; unknown whether sacubitril, its active metabolite LBQ657, or valsartan is excreted in human breast milk (demonstrated in animal milk)
Expected drug levels in milk	Unknown in humans
Preferred alternatives	For heart failure management during lactation — hydralazine plus nitrate combination, or beta-blockers (carvedilol, metoprolol succinate); consult cardiologist and neonatologist
Monitoring in infant	If exposure occurs, monitor infant for hypotension (lethargy, poor feeding, excessive sleepiness), decreased urine output, and poor weight gain

ELDERLY

Recommended starting dose: 50 mg twice daily (irrespective of prior ACE inhibitor/ARB dose), unless the patient is well-established on high-dose RAAS blockade and normotensive
Titration: Slower titration recommended — increase dose every 3–4 weeks rather than every 2 weeks; guided by blood pressure tolerability and renal function
Extra risks: Greater susceptibility to symptomatic hypotension (especially in combination with diuretics); age-related decline in renal reserve increases risk of acute kidney injury; increased fall risk secondary to hypotension and dizziness; elderly patients constitute a significant proportion of HFrEF patients and should not be denied ARNI therapy solely on the basis of age if tolerated

MAJOR DRUG INTERACTIONS

Interacting Drug/Class	Effect / Mechanism	Action
ACE inhibitors (e.g., enalapril, ramipril, lisinopril)	Sacubitril inhibits neprilysin which degrades bradykinin; ACE inhibitors also increase bradykinin → combined use dramatically increases angioedema risk	Absolutely contraindicated concurrently; mandatory 36-hour washout in both directions
Aliskiren (in diabetic or renally impaired patients)	Triple RAAS blockade → markedly increased risk of hyperkalaemia, hypotension, and renal failure	Contraindicated in patients with diabetes or eGFR < 60; avoid combination in all patients if possible
Potassium-sparing diuretics (spironolactone, eplerenone, amiloride, triamterene)	Additive hyperkalaemia risk (RAAS blockade by both ARNI and MRA)	When MRA is part of GDMT, combination is acceptable but requires potassium monitoring within 1 week and periodically thereafter; hold if K⁺ > 5.4 mEq/L
Lithium	ARBs reduce renal lithium clearance → elevated serum lithium and toxicity risk	Monitor lithium levels closely if combination is unavoidable; consider alternative mood stabiliser or alternative antihypertensive
Potassium supplements	Additive hyperkalaemia	Avoid unless documented hypokalaemia; monitor K⁺ closely

MODERATE DRUG INTERACTIONS

Interacting Drug/Class	Effect	Action
NSAIDs (including COX-2 inhibitors, commonly used in Indian practice for musculoskeletal complaints)	Attenuation of antihypertensive effect; increased risk of acute kidney injury and hyperkalaemia, especially in volume-depleted or elderly patients	Avoid prolonged concurrent use; if short-term NSAID is required, monitor BP, renal function, and potassium
Thiazide or loop diuretics	Enhanced hypotensive effect; risk of volume depletion and pre-renal azotaemia	Optimise diuretic dose before initiating ARNI; reduce diuretic if symptomatic hypotension occurs; this is not a reason to withhold ARNI
SGLT2 inhibitors (dapagliflozin, empagliflozin)	Additive blood pressure lowering and natriuresis; combination is part of recommended GDMT	Monitor BP and volume status; slight increase in risk of hypotension and dehydration; generally well tolerated
Trimethoprim / co-trimoxazole	Trimethoprim acts as potassium-sparing diuretic → additive hyperkalaemia risk	Check serum potassium during concurrent use, particularly in elderly or renally impaired patients
Statins (atorvastatin specifically)	Sacubitril may increase AUC of atorvastatin by up to 1.3-fold via OATP1B1/1B3 inhibition	Usually clinically insignificant; no routine dose adjustment needed; be aware if high-dose statin adverse effects emerge
Sildenafil and other PDE5 inhibitors	Additive hypotensive effect	Use with caution; advise patients regarding positional hypotension; relevant in patients using PDE5 inhibitors for pulmonary hypertension as a comorbidity
Metformin	Sacubitril may increase levels of metformin via inhibition of OAT3 transporter	Monitor for metformin-related gastrointestinal adverse effects; clinical significance is minor at usual metformin doses

COMMON ADVERSE EFFECTS

Hypotension (most frequent; dose-related)
Dizziness
Hyperkalaemia (K⁺ > 5.4 mEq/L)
Cough (less frequent than with ACE inhibitors)
Renal impairment (rise in serum creatinine)
Fatigue / asthenia
Nausea, diarrhoea
Headache

SERIOUS ADVERSE EFFECTS

Angioedema: Rare but potentially life-threatening; involves face, lips, tongue, larynx, or intestinal mucosa — discontinue immediately, manage airway, administer adrenaline if needed; do not re-challenge; higher incidence in patients of Black African descent
Severe hypotension / shock: Particularly in volume-depleted patients or those on high-dose diuretics; may require intravenous fluid resuscitation and temporary discontinuation
Acute renal failure: Especially in bilateral renal artery stenosis, severe volume depletion, or concomitant nephrotoxic drug use; requires immediate evaluation and possible discontinuation
Severe hyperkalaemia (K⁺ > 6.0 mEq/L): May cause cardiac arrhythmias; requires urgent treatment and drug discontinuation or dose reduction
Hepatotoxicity: Rare; reported elevations in liver enzymes; monitor if symptoms suggestive of hepatic injury arise

MONITORING REQUIREMENTS

Timing	Parameters
Baseline (before initiation)	Blood pressure (supine and standing if possible), serum creatinine, eGFR, serum potassium, sodium, liver function tests, NT-proBNP (not BNP — see clinical notes), LVEF documentation, NYHA functional class, volume status assessment
1–2 weeks after initiation or each dose change	Blood pressure (including orthostatic assessment), serum creatinine, eGFR, serum potassium
Long-term (every 3–6 months for stable patients)	Blood pressure, renal function (creatinine, eGFR), serum potassium, sodium, NT-proBNP, NYHA class reassessment, LVEF (echocardiography at 3–6 months and then as clinically indicated)
Situational	Recheck renal function and potassium during intercurrent illness (dehydration, vomiting, diarrhoea, fever), addition of interacting drugs (NSAID, MRA, diuretic dose change), or symptoms of hypotension; monitor for angioedema signs at every visit

Important: BNP is a neprilysin substrate and will be elevated by sacubitril; it is therefore unreliable for monitoring HF status during treatment. Always use NT-proBNP for heart failure monitoring in patients on ARNI therapy.

BRANDS AVAILABLE IN INDIA

Entresto (Novartis) — originator brand
Sacuval (Sun Pharma)
Arniva (Cipla)
Sacubitril V (Glenmark)
Vymada (USV)
Lupinep V (Lupin)

(Brand availability may vary by region; verify current market availability before prescribing)

PRICE RANGE (INR)

Strength	Approximate Price per Tablet (INR)
50 mg	₹25–60 (generic) to ₹70–90 (originator)
100 mg	₹45–100 (generic) to ₹110–150 (originator)
200 mg	₹80–160 (generic) to ₹180–220 (originator)

Not listed on NLEM (National List of Essential Medicines); not NPPA price-controlled
Multiple Indian generics now available, making ARNI therapy more affordable than at the time of initial launch
Government supply: not routinely stocked in most government hospital formularies; availability varies by institution
Monthly cost for target dose (200 mg BD): approximately ₹4,800–13,200 depending on brand — this remains a practical barrier for many Indian patients

CLINICAL PEARLS

36-hour washout from ACE inhibitors is non-negotiable. This is the single most critical safety point — concurrent use or inadequate washout significantly increases angioedema risk. No washout is needed when switching from an ARB.
Use NT-proBNP, not BNP, for monitoring. Sacubitril inhibits neprilysin, which degrades BNP. BNP levels will be elevated and unreliable. NT-proBNP is not a neprilysin substrate and remains a valid monitoring biomarker.
Do not let perfect be the enemy of good — partial dose is better than no ARNI. If a patient cannot tolerate 200 mg BD, maintaining them on 50 mg or 100 mg BD still provides clinical benefit. Down-titrate rather than discontinue.
Initiate before discharge in hospitalised HFrEF patients. Evidence supports in-hospital initiation (PIONEER-HF trial) once the patient is haemodynamically stable; this improves long-term adherence and outcomes compared with waiting for outpatient initiation.
Hypotension management before reducing ARNI dose: First reduce or remove other vasodilators (amlodipine, nitrates, alpha-blockers) and optimise diuretic dosing. Separate timing of ARNI from other BP-lowering agents. Only reduce ARNI dose as a last resort.
Cost remains a barrier in Indian practice. With multiple Indian generic options now available, monthly costs have reduced substantially. Discuss affordability with the patient and consider generic substitution to improve long-term adherence.

VERSION

RxIndia v0.2 — 01 Mar 2026

REFERENCES

CDSCO (Central Drugs Standard Control Organisation) — product approval and prescribing information
Indian Pharmacopoeia
API Textbook of Medicine — Heart Failure management chapter
AIIMS Treatment Guidelines — Cardiology protocols for HFrEF
Goodman & Gilman’s The Pharmacological Basis of Therapeutics — ARNI pharmacology
Harrison’s Principles of Internal Medicine — Heart failure management
NLEM 2022 (for confirmation of non-inclusion)
PARADIGM-HF trial (McMurray JJV et al., NEJM 2014) — primary efficacy evidence
PARAGON-HF trial (Solomon SD et al., NEJM 2019) — evidence basis for HFmrEF off-label indication
PIONEER-HF trial (Velazquez EJ et al., NEJM 2019) — in-hospital initiation evidence

Angiotensin Receptor-Neprilysin Inhibitor (ARNI)

Medication Registry

Sacubitril + Valsartan

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