Important safety information
Clinical use:
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ENTRESTO® should be administered in combination with other heart failure therapies, in place of an ACEi or ARB.
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ENTRESTO® should be initiated, and up-titration conducted, by a physician experienced with the treatment of heart failure.
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No dosage adjustment is required in patients over 65 years. However, ENTRESTO® has been studied in a limited number of patients above the age of 80 years. Caution is required in these patients.
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The safety and efficacy of ENTRESTO® in pediatric patients (<18 years of age) has not been established.
Contraindications:
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Recent symptomatic hypotension prior to initiation of treatment with ENTRESTO® (sacubitril/valsartan)
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Concomitant use with any drug formulation containing an ACEi, due to potential enhanced risk of angioedema. ENTRESTO® must not be administered until at least 36 hours have elapsed following discontinuation of ACEi therapy.
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Known history of angioedema related to previous ACEi or ARB therapy
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History of hereditary or idiopathic angioedema
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As for any formulation containing an ACEi or ARB, use of ENTRESTO® together with aliskiren-containing drugs is contraindicated in patients with diabetes mellitus, whether Type 1 or 2, or in patients with moderate to severe renal impairment, i.e., eGFR <60 mL/min/1.73 m2.
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Pregnant and nursing women
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Hypersensitivity to the active substances, sacubitril or valsartan, or to any of the excipients
Most serious warnings and precautions:
Use in pregnancy: When used in pregnancy, ARBs can cause injury to or even death of the developing fetus. When pregnancy is detected, ENTRESTO® should be discontinued as soon as possible.
Use of ACEi: ENTRESTO® must not be initiated until at least 36 hours have elapsed following discontinuation of ACEi therapy due to the risk of angioedema. If treatment with ENTRESTO® is stopped, ACEi therapy must not be initiated until 36 hours after the last dose of ENTRESTO®.
NT-proBNP monitoring: Due to the action of sacubitril on BNP levels, only NT-proBNP may be a suitable biomarker for the monitoring of heart failure patients treated with ENTRESTO®.
Use of medications known to raise serum potassium levels: Caution should be exercised when co-administering ENTRESTO® with medications known to raise serum potassium levels (e.g., potassium-sparing diuretics, potassium supplements).
Other relevant warnings and precautions:
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ENTRESTO® should not be administered with any other drug formulation containing an ARB.
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Caution when co-administering ENTRESTO® with direct renin inhibitors such as aliskiren.
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Angioedema: Caution is recommended in patients with a prior history of any angioedema and in black patients.
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Symptomatic hypotension: ENTRESTO® is not recommended in patients with systolic blood pressure <100 mmHg at the time of treatment initiation.
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Hyperkalemia: Measure serum potassium before instituting ENTRESTO®, and during treatment, as appropriate, taking into account the patient’s predisposition to develop hyperkalemia.
Patients with serum potassium >5.2 mmol/L prior to initiation of treatment with ENTRESTO® have not been studied. Careful monitoring of serum potassium is recommended in patients with severe renal impairment, diabetes mellitus, hypoaldosteronism, or a high potassium intake in their diet. -
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Decreases in renal function in susceptible individuals. Closely monitor serum creatinine, and down-titrate or interrupt ENTRESTO® in patients who develop a clinically significant decrease in renal function. Before initiation of therapy and during treatment, assess renal function, as appropriate.
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Caution in patients with renal artery stenosis, if ENTRESTO® is to be used. Careful monitoring of renal function should be carried out.
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Advising women of child-bearing potential to use contraception during treatment with ENTRESTO® and for one (1) week after their last dose.
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Nursing women: Because of the potential risk for adverse drug reactions in breastfed newborns, a decision should be made whether to abstain from breast-feeding or to discontinue ENTRESTO® while breast-feeding, taking into account the importance of ENTRESTO® to the mother.
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A starting dose of 24 mg sacubitril/26 mg valsartan twice daily is recommended in patients with moderate hepatic impairment (Child-Pugh B).
ENTRESTO® is not recommended in patients with severe hepatic impairment (Child-Pugh C). -
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ENTRESTO® is not recommended in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2).
For more information:
Please consult the Product Monograph at www.novartis.ca/EntrestoMonograph for important information relating to adverse reactions, drug interactions, and dosing information which have not been discussed in this piece. The Product Monograph is also available by calling 1-800-363-8883 or via medinfo.canada@novartis.com.
References:
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1.
ENTRESTO® Product Monograph. Novartis Pharmaceuticals Canada Inc. July 13, 2021.
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2.
Novartis Data on File – First and only. 2021.
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3.
McDonald M, et al. CCS/CHFS Heart Failure Guidelines Update: Defining a new pharmacologic standard of care for heart failure with reduced ejection fraction. Can J Cardiol 2021;37(4):531-546.
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4.
McMurray JJ, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.
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5.
Novartis Data on File – PARADIGM. 2020.
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6.
Packer M, McMurray JJ, Desai AS et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation 2015;131:54-61.
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Desai AS, McMurray JJ, Packer M et al. Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients. Eur Heart J 2015;36(30):1990-7.
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8.
Volpe M, et al. The natriuretic peptides system in the pathophysiology of heart failure: From the molecular basis to treatment. Clin Sci (Lond). 2016;130(2):57-77.
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9.
Fielitz J, et al. Neutral endopeptidase is activated in cardiomyocytes in human aortic valve stenosisand heart failure. Circulation. 2002;105:286-289.