Dual blockade of the Renin-Angiotensin-Aldosterone System (RAAS): Entresto must not be administered with an ACE inhibitor due to the risk of angioedema. Entresto must not be initiated until 36 hours after taking the last dose of ACE inhibitor therapy. If treatment with Entresto is stopped, ACE inhibitor therapy must not be initiated until 36 hours after the last dose of Entresto (see Contraindications, Dosage & Administration and Interactions).
Caution is required while co-administering Entresto with direct renin inhibitors such as aliskiren (see Contraindications and Interactions). Entresto must not be administered with aliskiren in patients with Type 2 diabetes (see Contraindications).
Entresto should not be co-administered with an ARB due to the angiotensin II receptor blocking activity of Entresto (see Dosage & Administration and Interactions).
Hypotension: Cases of symptomatic hypotension have been reported in patients treated with Entresto during clinical trials. If hypotension occurs, dose adjustment of diuretics, concomitant antihypertensive drugs, and treatment of other causes of hypotension (e.g. hypovolemia) should be considered. If hypotension persists despite such measures, the dosage of Entresto should be reduced or the product should be temporarily discontinued (see Dosage & Administration). Permanent discontinuation of therapy is usually not required. Symptomatic hypotension is more likely to occur if the patient has been volume- depleted, e.g., by diuretic therapy, dietary salt restriction, diarrhea or vomiting. Sodium and/or volume depletion should be corrected before starting treatment with Entresto.
Impaired renal function: As for any drug that acts on the renin-angiotensin-aldosterone system, use of Entresto may be associated with decreased renal function. In PARADIGM-HF, the incidence of clinically relevant renal impairment was low and associated treatment discontinuation was observed less frequently in patients receiving Entresto (0.65%) compared to enalapril (1.28%). Down titration of Entresto should be considered in patients who develop a clinically significant decrease in renal function. Caution should be exercised when administering Entresto in patients with severe renal impairment (see Dosage & Administration and Pharmacology under Actions).
Hyperkalemia: As for any drug that acts on the renin-angiotensin-aldosterone system, use of Entresto may be associated with an increased risk of hyperkalemia. In PARADIGM-HF, the incidence of clinically relevant hyperkalemia was low, resulting in treatment discontinuation in 0.26% of Entresto treated patients compared to 0.35% of enalapril treated patients. Medications known to raise potassium levels (e.g. potassium-sparing diuretics, potassium supplements) should be used with caution when co-administered with Entresto. If clinically significant hyperkalemia occurs, measures such as reducing dietary potassium, or adjusting the dose of concomitant medications should be considered. Monitoring of serum potassium is recommended especially in patients with risk factors such as severe renal impairment, diabetes mellitus, hypoaldosteronism or receiving a high potassium diet (see Dosage & Administration).
Angioedema: Angioedema has been reported in patients treated with Entresto. If angioedema occurs, Entresto should be immediately discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. Entresto must not be re-administered. In cases of confirmed angioedema where swelling has been confined to the face and lips, the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms.
Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine/adrenaline solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly administered.
Patients with a prior history of angioedema were not studied. As they may be at higher risk for angioedema, caution is recommended if Entresto is used in these patients. Entresto must not be used in patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy, or in patients with hereditary angioedema (see Contraindications).
Black patients may have increased susceptibility to develop angioedema.
Patients with renal artery stenosis: Similar to other drugs that affect the renin-angiotensin-aldosterone system, Entresto may increase blood urea and serum creatinine levels in patients with bilateral or unilateral renal artery stenosis. Caution is required in patients with renal artery stenosis and monitoring of renal function is recommended.
Females of child-bearing potential (and contraceptive measures if applicable): Females patients of child-bearing potential should be advised about the consequences of exposure to Entresto during pregnancy and to use contraception during treatment with Entresto and for 1 week after their last dose.
Fertility: There are no available data on the effect of Entresto on human fertility. No impairment of fertility was demonstrated in studies with Entresto in male and female rats (see Pharmacology: Toxicology: Non-Clinical Safety Data under Actions).