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. .
VYMADASacubitril & 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.

4. .

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

14. .
Thank You!!