Vymada - Sacubitril & Valsartan (ARNI) For Heart Failure

Vymada Tablet (ARNI: Angiotensin Receptor Neprilysin Inhibitor) is an anti-hypertensive drug used in combination with Sacubitril & Valsartan to reduce the risk of cardiovascular events in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.

1. . VYMADA Sacubitril & Valsartan (ARNI : Angiotensin Receptor Neprilysin Inhibitor) By: Dr. Sunny Kumar Gupta Clinical Pharmacologist, HCG Cancer Hospital, Bangalore Pharm.D (Doctor Of Pharmacy)

2. . General description: Vymada Tablet is an anti-hypertensive drug used in combination with Sacubitril & Valsartan to reduce the risk of cardiovascular events in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction. It is usually administered in conjunction with other heart failure therapies , and other heart conditions in place of an ACE inhibitor or other ARB . According to guidelines of ACC/AHA/HFSA Guideline for the Management of Heart Failure, patients with NYHA Stage II-IV HFrEF tolerating ACE-inhibitor or ARB, replacement with ARNI is recommended to improved morbidity and mortality. Do not prescribe ARNI therapy concomitantly with ACE-inhibitors or within 36 hours of last dose of an ACE-inhibitor. Do not prescribe ARNI therapy to patients with prior angioedema It is used to treat a type of long-term heart failure in adults This type of heart failure occurs when the heart is weak and cannot pump enough blood to the lungs and the rest of the body. It was approved under the FDA's priority review process for use in heart failure on July 7, 2015 . As per PARADIGM-HF Trials, reduces risk of hospitalization rate by 21%, all CV death by 20%, all cause mortality by 16%, worsening of heart by 21% when compared with Enalapril.

3. . MOA:- (ARNI: Angiotensin Receptor Neprilysin Inhibitor) Sacubitril's active metabolite, LBQ657 inhibits neprilysin , a neutral endopeptidase that would typically cleave natiuretic peptides, which includes: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and c-type natriuretic peptide (CNP). ANP and BNP are released under atrial and ventricle stress, which activate downstream receptors leading to vasodilation, natriuresis and diuresis. Under normal conditions, neprilysin breaks down other vasodilating peptides and also vasoconstrictors such as angiotensin I and II, endothelin-1 and peptide amyloid beta-protein. Therefore, the inhibition of neprilysin leads to reduced breakdown and increased concentration of endogenous natriuretic peptides in addition to increased levels of vasoconstricting hormones such as angiotensin II. (However, when combined with valsartan, would result in blocking of angiotensin II to its receptor, preventing the vasoconstrictive effects and resulting in a decrease in vascular resistance and blood pressure.) Cardiovascular and renal effects of sacubitril is a result of the increased levels of peptides that are normally degraded by neprilysin .

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5. . Indications:- Heart Failure Indicated to reduce the risk of cardiovascular death and hospitalization for heart failure (HF) in patients with chronic heart failure (CHF) (NYHA class II-IV) and reduced ejection fraction Recommended starting dose: 49 mg/51 mg PO BID Target maintenance dose: After 2-4 weeks, double the dose to the target maintenance dose of 97 mg/103 mg PO BID as tolerated

6. . Dosage Modifications Patients not taking an ACE inhibitor or other ARB, or previously taking a low dose of these agents when initiating treatment:- Reduce starting dose to 24 mg/26 mg BID Double the dose every 2-4 weeks to target maintenance dose of 97 mg/103 mg BID as tolerated Renal impairment:- Mild-to-moderate ( eGFR ≥30 mL/min/1.73 m²) : No starting dose adjustment required Severe ( eGFR <30 mL/min/1.73 m²) : Reduce starting dose to 24 mg/26 mg BID; double the dose every 2-4 weeks to target maintenance dose of 97 mg/103 mg BID as tolerated Hepatic impairment:- Mild: No starting dose adjustment required Moderate: Reduce starting dose to 24 mg/26 mg BID; double the dose every 2-4 weeks to target maintenance dose of 97 mg/103 mg BID as tolerated Severe: Not recommended

7. Pharmacokinetics:- Absorption Absolute bioavailability Sacubitril: ≥60% Valsartan in Entresto is more bioavailable than the valsartan in other marketed tablet formulations; 26 mg, 51 mg, and 103 mg of valsartan in Entresto is equivalent to 40 mg, 80 mg, and 160 mg of valsartan in other marketed tablet formulations, respectively Steady-state Reached in 3 days At steady state, sacubitril and valsartan do not accumulate significantly, whereas LBQ657 accumulates by 1.6-fold Peak plasma concentration Sacubitril: 0.5 hr LBQ657: 2 hr Valsartan: 1.5 hr

8. Pharmacokinetics:- Distribution Protein bound Sacubitril: 94-97% LBQ657: 94-97%; LBQ657 crosses the blood-brain barrier to a limited extent (0.28%) Valsartan: 94-97% Vd Sacubitril: 103 L Valsartan: 75 L Metabolism Sacubitril is a prodrug that is metabolized by esterases to the active metabolite LBQ657 LBQ657 is not further metabolized to a significant extent Valsartan is minimally metabolized; only about 20% of the dose is recovered as metabolites; a hydroxyl metabolite has been identified in plasma at low concentrations (<10%)

9. Pharmacokinetics:- Elimination Half-life Sacubitril: 1.4 hr LBQ657: 11.5 hr Valsartan: 9.9 hr Excretion Sacubitril: 52-68% (primarily as LBQ657) in urine; 37-48% (primarily as LBQ657) in feces Valsartan: 13% in urine; 86% in feces It is available in oral form, in 50mg ( 24/26mg), 100mg (49/51mg ) & 200mg(97/103mg). Price: Rs1043per 14 Tablets ( vymada 50mg) : Rs2122per 28 Tablets ( vymada 100mg) : Rs1311per 14 Tablets ( vymada 200mg)

10. ADR:- >10% Hypotension (18%) Hyperkalemia (12%) 1-10% Cough (9%) Dizziness (6%) Orthostasis (2.1%) Falls (1.9%) <1% Angioedema, all patients (0.5%); in black patients (2.4%) Hypersensitivity (rash, pruritus, anaphylaxis ) Increases creatinine

11. . Dosing Considerations Contraindicated with concomitant use of an ACE inhibitor; if switching from an ACE inhibitor to sacubitril /valsartan, allow a washout period of 36 hr between administration of the 2 drugs Usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB Contraindications Hypersensitivity to any component History of angioedema related to previous ACE inhibitor or ARB therapy Coadministration of neprilysin inhibitors ( eg , sacubitril ) with ACE inhibitors may increase angioedema risk; do not administer ACE inhibitors within 36 hour of switching to or from sacubitril /valsartan. Concomitant use with aliskiren ( direct renin inhibitors) in patients with diabetes

12. . Cautions:- 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. Not for use in patients with hereditary angioedema; observe for signs and symptoms of angioedema; if angioedema occurs, discontinue drug immediately, provide appropriate therapy, and monitor for airway compromise. Sacubitril/valsartan lowers blood pressure and may cause symptomatic hypotension; patients who are volume-depleted or salt-depleted, or those taking diuretics, are at greater risk. Monitor renal function and potassium levels in susceptible patients ( eg , diabetes, hypoaldosteronism , high-potassium diet, renal artery stenosis); dosage reduction or interruption may be required.

13. . Pregnancy Discontinue as soon as pregnancy detected; during the second and third trimesters of pregnancy, resulting oligohydramnios may cause fetal injury ( eg , hypotension, neonatal skull hypoplasia, anuria, reversible and irreversible renal failure) and death Neonates with a history of in utero exposure: Direct attention toward support of blood pressure and renal perfusion; exchange transfusions or dialysis may be required Lactation Unknown if distributed in human breast milk; not recommended Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.

14. . T h a n k Y o u ! !