Entresto ® (sacubitril & valsartan) Manufacturer: Novartis Pharmaceuticals Corporation FDA Approval...

Entresto® (sacubitril & valsartan)

Manufacturer: Novartis Pharmaceuticals Corporation

FDA Approval Date: July 7 2015

Entresto® - sacubitril/valsartan

Clinical Application

• Indications:• Neprilysin inhibitor and angiotensin II

receptor blocker combination to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction

• Place in therapy:• Patient who have progressed in severity of

their heart failure on optimum ACE inhibitor therapy



• Contraindications • Hypersensitivity to any component

• History of angioedema related to previous ACE inhibitor or ARB therapy

• Concomitant use with ACE inhibitors

• Concomitant use with aliskiren in patients with diabetes



• Warnings & precautions • Observe for signs and symptoms of

angioedema and hypotension

• Monitor renal function and potassium in susceptible patients



• Pregnancy – contraindicated

• Lactation – not recommended


Drug Facts

• Pharmacology:• Sacubitril – prodrug metabolized to

active metabolite (LBQ657), which inhibits neprilysin

• Neprilisyn – neutral endopeptidase • Leads to increase in level of peptides,

including natriuretic peptides • Valsartan – blocks the angiotensin II

type-1 (AT1) receptor


Drug Facts

• Pharmacokinetics:

A Time to peak: 0.5 hrs Time to peak of metabolite: 2 hrs

D Protein binding – 94-97% Vd: 103 L

MMetabolized by esterases to active metaboliteMajor metabolite is not metabolized

ET1/2 sacubitril: 1.4 hrs T1/2 metabolite: 11.5 hrs


Drug Interactions

• Drug Interactions – Object Drugs: • Object drugs are affected by “the

reviewed drug”

• List ( ##%) if available

• Ex: ASA (100%)

Precipitant Object Nature of interaction Entresto* Furosemide,

levonorgestrel, HCTZ, metformin

Decrease AUC and Cmax

Entresto* Atorvastatin Increase AUC and Cmax Entresto ACE-I Increased risk of

angioedema Entresto Aliskiren Dual RAAS blockade Entresto Potassium-sparing

diuretics, ACE-IIncreased risk of hyperkalemia

NSAID Entresto Decreased renal function Entresto Lithium Increased concentrations


Adverse Effects

Side effect Entresto Enalapril

Angioedema 0.5% 0.2%

Hypotension 18% 12%

Impaired renal function 6% 5%

Hyperkalemia 12% 14%

Cough 9% 13%


Monitoring Parameters

• Efficacy Monitoring:• Blood pressure at each visit and dose

titration

• Toxicity Monitoring:• Serum electrolytes (K+)

• SCr


Prescription Information

• Dosing: initial • Previous ACE-I or ARB – 49/51 mg bid

• No ACE-I or ARB or low doses – 24/26 mg bid

• Dosing: target • Titrate after 2-4 weeks to 97/103 mg bid as

tolerated by the patient



• Renal impairment • Mild-moderate – no dose adjustment

• Severe – 24/26 mg bid (initial)

• Hepatic impairment • Mild – no adjustment

• Moderate (Child-Pugh B) – 24/26 mg bid (initial)

• Severe impairment – not recommended



• If switching from ACE-I to Entresto, 36 hour washout period is recommended

• Cost – Source: NY Times; Accessed 8/21/15• $4,500/year

• Novartis offers free 30-day supply and $10 co-pay cards


Literature Review

PARADIGM-HF

•Purpose: To compare the combination of sacubitril/valsartan with enalapril in patients who have HFrEF

•Design: randomized, double-blind, phase 3 trial

• 1043 sites in 47 countries

McMurray JJV, et al. N Engl J Med. 2014;371(11): 993-1004


Literature Review

• Inclusion Criteria

• Exclusion Criteria


Inclusion Criteria Exclusion Criteria

• Age >18 years

• NYHA class II-IV

• Ejection fraction <40% (amended to <35%)

• BNP >150 pg/mL or pro-BNP >600 pg/mL

• Treatment with ACE-I or ARB

• Symptomatic hypotension

• SBP <100 mg

• eGFR <30 ml/min/1.73 m2 or eGFR >25%

• Serum K+ >5.2 mEq/L

• Hx of angioedema or unacceptable side effects during receipt of ACE-I or ARB


Literature Review• Intervention: LCZ696 200 mg bid vs.

enalapril 10 mg bid

• Primary endpoint: composite of death from cardiovascular causes or a first hospitalization for HF

• Secondary endpoint: • Time to death from any cause• Change from baseline to 8 months in clinical

summary score (KCCQ) • Time to new onset atrial fibrillation • Time to first occurrence of a decline in renal

functionMcMurray JJV, et al. N Engl J Med. 2014;371(11): 993-1004


Literature Review

• Baseline characteristics


Entresto (N=4187) Enalapril (N=4212)

Age 63.8 63.8

Female 879 (21.0%) 953 (22.6%)

White 2763 (66.0%) 2781 (66.0%)

Medical History:•HTN•Afib•Hospitalization for HF•MI •Pretrial use of ACE-I •Pretrial use of ARB

2969 (70.9%)1517 (36.2%) 2607 (62.3%)1818 (43.4%) 3266 (78.0%) 929 (22.2%)

2971 (70.5)1574 (37.4%) 2667 (63.3%) 1816 (43.1%)3266 (77.5%) 963 (22.9%)

Treatment at randomization:•Diuretic •Beta-blocker•Mineralocorticoid antagonist

3363 (80.3%) 3899 (93.1%) 2271 (54.2%)

3375 (80.1%) 3912 (92.9%) 2400 (57.0%)

NYHA class II 2998 (71.6%) 2921 (69.3%)


Literature Review

• Results


Entresto (N=4187)

Enalapril (N=4212)

HR or Difference (95% CI)

P-value

Composite outcome 914 (21.8)1117 (26.5)

0.80 (0.73-0.87) <0.001

Death from cardio-vascular causes 558 (13.3) 693 (16.5) 0.80 (0.71-0.89) <0.001

1st hospitalization for worsening HF 537 (12.8) 658 (15.6) 0.79 (0.71-0.89) <0.001

Death from any cause 711 (17.0) 835 (19.8) 0.84 (0.76-0.93) <0.001

Change in KCCQ clinical summary

score at 8 mo-2.99 -4.63 1.64 (0.63-2.65) 0.001

New-onset afib 84 (3.1) 83 (3.1) 0.97 (0.72-1.31) 0.83

Decline in renal fxn 94 (2.2) 108 (2.6) 0.86 (0.65-1.13) 0.28


Literature Review

• Safety endpoints


Entresto (N=4187)

Enalapril (N=4212)

P-value

Hypotension

Symptomatic 588 (14.0) 388 (9.2) <0.001Symptomatic w/ SBP <90

mmHg 112 (2.7) 59 (1.4) <0.001

SCr > 2.5 mg/dl 139 (3.3) 188 (4.5) 0.007

Serum K >6.0 mmol/L 181 (4.3) 236 (5.6) 0.007

Cough 474 (11.3) 601 (14.3) <0.001


Literature Review

• Conclusions• Entresto’s dual inhibition was more

effective in reducing the risk of death from cardiovascular causes or hospitalization for HF than ACE inhibition with enalapril

• The only significant side effect was symptomatic hypotension, though this did not increase the rate of discontinuation


Entresto™ - sacubitril/valsartan

Summary

• Entresto™ inhibits neprilysin and angiotensin receptors

• Indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction

• Initial dose is based on receipt of ACE-I or ARB therapy prior to initiation

• Avoid use in combination with an ACE-I or in patients with a history of angioedema

• Most common side effect is hypotension


References1. Entresto [sacubitril and valsartan] package insert.

Novartis Pharmaceutical Corporation. July 2015.

2. McMurray, J, et al. PARADIGM-HF Study. New England Journal of Medicine. 2014;371;11:993-1004.

3. Pollack, A. The New York Times Website. F.D.A. Approves Heart Drug Entresto Said to Cut Death Risk by 20%. http://www.nytimes.com/2015/07/08/business/international/fda-approves-heart-drug-entresto-after-promising-trial-results.html. Published July 7, 2015. Accessed August 21, 2015.

Entresto ® (sacubitril & valsartan) Manufacturer: Novartis Pharmaceuticals Corporation FDA Approval...

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