Schedule H

Oral

• Film-coated tablets (fixed-dose combination):

• Sacubitril 24 mg + Valsartan 26 mg

• Sacubitril 49 mg + Valsartan 51 mg

• Sacubitril 97 mg + Valsartan 103 mg

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Chronic Heart Failure with Reduced Ejection Fraction (HFrEF) — NYHA Class II–IV

Dosing by Patient Category:

Patient Category Starting Dose Titration Usual Maintenance Dose Maximum Dose

Standard patients (on prior ACEI/ARB at moderate-high dose) 49/51 mg twice daily Double dose every 2–4 weeks if tolerated (SBP ≥100 mmHg, K⁺ <5.4 mmol/L, stable renal function) 97/103 mg twice daily 97/103 mg twice daily

ACEI/ARB-naïve, elderly (>75 yrs), or eGFR <30 mL/min/1.73m² 24/26 mg twice daily Double dose every 2–4 weeks as tolerated 97/103 mg twice daily 97/103 mg twice daily

Patients with symptomatic hypotension or low-dose prior ACEI/ARB 24/26 mg twice daily Titrate cautiously with close BP monitoring 97/103 mg twice daily 97/103 mg twice daily

Critical Clinical Notes:

• Mandatory 36-hour washout period after stopping any ACEI before initiating sacubitril/valsartan (to prevent angioedema)

• Must not be used concurrently with any ACEI or other ARBs

• Continue concomitant beta-blockers, MRAs, and SGLT2 inhibitors as part of guideline-directed medical therapy

• Do not up-titrate if SBP <100 mmHg, serum K⁺ >5.4 mmol/L, or worsening renal function

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

Indication Dose Duration Notes Evidence Basis

Heart Failure with Preserved Ejection Fraction (HFpEF) — OFF-LABEL Starting dose: 24/26 mg or 49/51 mg twice daily; Titration: as tolerated; Maximum: 97/103 mg twice daily Long-term Specialist (cardiologist) supervision only; consider in symptomatic patients with elevated natriuretic peptides PARAGON-HF trial showed modest benefit in subgroups; not standard Indian practice

Post-myocardial infarction with LV systolic dysfunction — OFF-LABEL Starting dose: 24/26 mg twice daily; Titration: gradual as tolerated Long-term Specialist supervision only; limited Indian experience PARADISE-MI trial; international data only

PAEDIATRIC DOSING (Specialist Only)

Primary Indications (Approved / Standard in India)

NOT APPROVED for paediatric use in India

• Safety and efficacy not established in patients below 18 years of age

• No approved paediatric indications in Indian regulatory guidelines

Secondary Indications – Paediatrics (Off-label, if any)

Not applicable.

Age Restriction Statement:

Use is not recommended in individuals below 18 years of age. Any use in paediatric patients should only occur within clinical trial settings or under specialist paediatric cardiology supervision.

Degree of Impairment Recommendation

Mild (Child-Pugh A) No dose adjustment required

Moderate (Child-Pugh B) Start at 24/26 mg twice daily; titrate very cautiously with close hepatic monitoring

Severe (Child-Pugh C) Contraindicated

History of angioedema related to prior ACEI or ARB use

• Concomitant use with any ACE inhibitor (requires 36-hour washout period)

• Concomitant use with aliskiren in patients with diabetes mellitus

• Pregnancy (all trimesters)

• Severe hepatic impairment (Child-Pugh C)

• Known hypersensitivity to sacubitril, valsartan, or any excipient

• Symptomatic hypotension (especially in volume-depleted, elderly, or those on high-dose diuretics)

• Hyperkalaemia (particularly with concurrent MRAs, potassium supplements, or renal impairment)

• Renal impairment (monitor serum creatinine regularly)

• Significant aortic or mitral stenosis

• Hepatic dysfunction (even mild to moderate)

• Black patients (potentially increased angioedema risk)

• Bilateral renal artery stenosis

• Not adequately studied in valvular heart failure

Aspect Details

Risk Category Contraindicated in all trimesters

Fetal Risks Renal failure, oligohydramnios, skull hypoplasia, limb contractures, pulmonary hypoplasia

Action if Pregnancy Detected Discontinue immediately

Preferred Alternatives Hydralazine + nitrates; beta-blockers (labetalol, metoprolol); digoxin

Monitoring Serial ultrasound for amniotic fluid if inadvertent exposure occurred

Aspect Details

Compatibility Not recommended during breastfeeding

Excretion in Milk Unknown for both sacubitril and valsartan

Preferred Alternatives Hydralazine, nitrates, or beta-blockers with established lactation safety (metoprolol, labetalol)

Infant Monitoring Observe for hypotension, poor feeding, lethargy if inadvertent exposure

• Start at lower dose (24/26 mg BID), especially if:

– Age >75 years

– Frail or volume-depleted

– On multiple antihypertensives

• Slower titration recommended (every 4 weeks rather than 2 weeks)

• Increased hypotension risk — monitor BP closely, especially postural

• Monitor renal function and potassium more frequently

• Higher risk of falls secondary to dizziness/hypotension

Interacting Drug Effect/Risk Management

ACE inhibitors Markedly increased angioedema risk Contraindicated; mandatory 36-hour washout before starting

Aliskiren (in diabetics) Increased risk of hyperkalaemia, hypotension, renal impairment Contraindicated

Potassium-sparing diuretics (spironolactone, eplerenone, amiloride) Increased hyperkalaemia risk Monitor potassium closely; reduce dose if K⁺ >5.5 mmol/L

Potassium supplements Additive hyperkalaemia Avoid unless treating documented hypokalaemia

NSAIDs (including COX-2 inhibitors) Increased renal impairment, hyperkalaemia, reduced antihypertensive effect Avoid chronic use; if essential, monitor renal function and K⁺

Lithium Increased lithium toxicity Avoid combination; if unavoidable, monitor lithium levels frequently

Interacting Drug Effect/Risk Management

Loop/thiazide diuretics Potentiates hypotension Monitor BP closely during initiation and dose changes

Other antihypertensives (CCBs, alpha-blockers) Additive BP lowering Monitor for symptomatic hypotension

Metformin Potential for lactic acidosis if renal function worsens Monitor renal function periodically

Statins (CYP3A4/OATP substrates) Minor interaction; potential for increased statin exposure Generally safe; monitor for myopathy at high statin doses

Sildenafil/tadalafil Additive hypotension Use with caution; counsel patient about symptoms

• Hypotension (symptomatic)

• Hyperkalaemia

• Dizziness

• Cough (less frequent than with ACE inhibitors)

• Renal function deterioration

• Headache

• Fatigue

• Nausea

• Diarrhoea

Adverse Effect Clinical Action

Angioedema (face, lips, tongue, larynx) Discontinue immediately; emergency airway management; higher risk in Black patients or prior ACEI angioedema

Severe hypotension Withhold dose; IV fluids if needed; dose reduction on rechallenge

Acute kidney injury Hold drug; evaluate for other causes; consider nephrology referral

Severe hyperkalaemia (K⁺ >6.0 mmol/L) Withhold drug; treat hyperkalaemia; cardiology/nephrology input

Hepatotoxicity (rare) Discontinue; hepatology referral

Phase Parameters Frequency

Baseline BP, serum creatinine, eGFR, serum potassium, LFTs (if hepatic disease suspected) Before initiation

After initiation/dose change Serum potassium, serum creatinine, BP Within 1–2 weeks

Long-term BP, renal function, potassium Every 1–2 months; more frequent if on MRAs or with renal impairment

Clinical Symptoms of hypotension, dizziness, angioedema Every visit

• Vymada® (Novartis)

• Azmarda® (Cipla)

• Nepribio® (Macleods)

• Sacubidil-V® (Dr Reddy's)

• Corsac-V® (Lupin)

• Sacuval® (Sun Pharma)

• Other branded generics available

Strength Approximate Price per Tablet

24/26 mg ₹35–55

49/51 mg ₹60–90

97/103 mg ₹110–150

• Not under NPPA price control as of latest NLEM

• Prices vary by brand and region

• Mandatory ACEI washout: Always ensure 36-hour gap after stopping any ACEI before starting sacubitril/valsartan to prevent life-threatening angioedema

• Quadruple therapy in HFrEF: Use as part of guideline-directed medical therapy alongside beta-blocker, MRA, and SGLT2 inhibitor for optimal mortality benefit

• Start low in high-risk patients: Use 24/26 mg BID in elderly, hypotensive, ACEI/ARB-naïve, or renally impaired patients

• Hold titration thresholds: Do not uptitrate if SBP <100 mmHg, K⁺ >5.5 mmol/L, or eGFR declining

• Superior to ACEI: Reduces mortality and HF hospitalisation more than enalapril in HFrEF (PARADIGM-HF evidence applied in Indian practice)

• Not a direct ARB substitute: Do not simply switch from ARB for hypertension — indication is specifically symptomatic heart failure with reduced EF

sacubitril; sacubitril/valsartan; ARNI; heart failure; HFrEF; neprilysin inhibitor; hyperkalaemia caution; renal monitoring; Schedule H; cardiology

RxIndia v1.0 — 12 May 2025

1. • CDSCO approved product labelling (Sacubitril/Valsartan FDC)

• AIIMS Pharmacology Drug Formulary

• API Textbook of Medicine (India)

• ICMR Heart Failure Guidelines

• NFI 2021

• PARADIGM-HF trial (evidence basis for HFrEF indication)

• PARAGON-HF trial (referenced for off-label HFpEF use)

• Indian Heart Failure Registry publications