entresto ® (sacubitril & valsartan) manufacturer: novartis pharmaceuticals corporation fda...
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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
Entresto® - sacubitril/valsartan
Clinical Application
• 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
Entresto® - sacubitril/valsartan
Clinical Application
• Warnings & precautions • Observe for signs and symptoms of
angioedema and hypotension
• Monitor renal function and potassium in susceptible patients
Entresto® - sacubitril/valsartan
Clinical Application
• Pregnancy – contraindicated
• Lactation – not recommended
Entresto® - sacubitril/valsartan
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
Entresto® - sacubitril/valsartan
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
Entresto® - sacubitril/valsartan
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
Entresto® - sacubitril/valsartan
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%
Entresto® - sacubitril/valsartan
Monitoring Parameters
• Efficacy Monitoring:• Blood pressure at each visit and dose
titration
• Toxicity Monitoring:• Serum electrolytes (K+)
• SCr
Entresto® - sacubitril/valsartan
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
Entresto® - sacubitril/valsartan
Prescription Information
• 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
Entresto® - sacubitril/valsartan
Prescription Information
• 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
Entresto® - sacubitril/valsartan
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
Entresto® - sacubitril/valsartan
Literature Review
• Inclusion Criteria
• Exclusion Criteria
McMurray JJV, et al. N Engl J Med. 2014;371(11): 993-1004
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
Entresto® - sacubitril/valsartan
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
Entresto® - sacubitril/valsartan
Literature Review
• Baseline characteristics
McMurray JJV, et al. N Engl J Med. 2014;371(11): 993-1004
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%)
Entresto® - sacubitril/valsartan
Literature Review
• Results
McMurray JJV, et al. N Engl J Med. 2014;371(11): 993-1004
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
Entresto® - sacubitril/valsartan
Literature Review
• Safety endpoints
McMurray JJV, et al. N Engl J Med. 2014;371(11): 993-1004
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
Entresto® - sacubitril/valsartan
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
McMurray JJV, et al. N Engl J Med. 2014;371(11): 993-1004
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
Entresto® - sacubitril/valsartan
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.