Interactions Resulting in a Contraindication: ACE Inhibitors: The concomitant use of Entresto with ACE inhibitors is contraindicated, as the concomitant inhibition of neprilysin (NEP) and ACE may increase the risk of angioedema. Entresto must not be started until 36 hours after taking the last dose of ACE inhibitor therapy. ACE inhibitor therapy must not be started until 36 hours after the last dose of Entresto (see Dosage & Administration and Contraindications).
Aliskiren: The concomitant use of Entresto with aliskiren-containing products is contraindicated in patients with diabetes mellitus or in patients with renal impairment (eGFR <60 mL/min/1.73 m2) (see Contraindications). The combination of Entresto with direct renin inhibitors such as aliskiren is not recommended (see Precautions). Combination of Entresto with aliskiren is potentially associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) (see Contraindications and Precautions).
Interactions Resulting in Concomitant Use Not Being Recommended: Entresto contains valsartan, and therefore should not be co-administered with another ARB containing product (see Precautions).
Interactions Requiring Precautions: OAT1B1 and OATP1B3 Substrates, e.g. Statins: In vitro data indicate that sacubitril inhibits OATP1B1 and OATP1B3 transporters. Entresto may therefore increase the systemic exposure of OATP1B1 and OATP1B3 substrates such as statins. Co-administration of Entresto increased the Cmax of atorvastatin and its metabolites by up to 2-fold and AUC by up to 1.3-fold. Therefore, caution should be exercised when co-administering Entresto with statins.
PDE5 Inhibitors Including Sildenafil: Addition of a single dose of sildenafil to Entresto at steady state in patients with hypertension was associated with a significantly greater blood pressure reduction compared to administration of Entresto alone. Therefore, caution should be exercised when sildenafil or another PDE5 inhibitor is initiated in patients treated with Entresto.
Potassium: Concomitant use of potassium-sparing diuretics (triamterene, amiloride), mineralocorticoid antagonists (e.g. spironolactone, eplerenone), potassium supplements, salt substitutes containing potassium or other agents (such as heparin) may lead to increases in serum potassium, and to increases in serum creatinine. Monitoring of serum potassium is recommended if Entresto is co-administered with these agents (see Precautions).
Non-Steroidal Anti-Inflammatory Agents (NSAIDs), Including Selective Cyclooxygenase-2 (COX-2) Inhibitors: In elderly patients, volume-depleted patients (including those on diuretic therapy), or patients with compromised renal function, concomitant use of Entresto and NSAIDs may lead to an increased risk of worsening of renal function. Therefore, monitoring of renal function is recommended when initiating or modifying treatment in patients on Entresto who are taking NSAIDs concomitantly (see Precautions).
Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors or angiotensin II receptor antagonists. Interactions between Entresto and lithium have not been investigated. Therefore, this combination is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased further.
Furosemide: Co-administration of Entresto and furosemide had no effect on the pharmacokinetics of Entresto but reduced Cmax and AUC of furosemide by 50% and 28%, respectively. While there was no relevant change in urine volume, the urinary excretion of sodium was reduced within 4 hours and 24 hours after co-administration. The average daily dose of furosemide was unchanged from baseline until the end of the PARADIGM-HF study in patients treated with Entresto.
Nitrates, e.g. Nitroglycerine: There was no drug-drug interaction between Entresto and intravenously administered nitroglycerin with regard to blood pressure reduction. Co-administration of nitroglycerin and Entresto was associated with a treatment difference of 5 bpm in heart rate compared to the administration of nitroglycerine alone. A similar effect on the heart rate may occur when Entresto is co-administered with sublingual, oral or transdermal nitrates. In general no dose adjustment is required.
OATP and MRP2 Transporters: The active metabolite of sacubitril (LBQ657) and valsartan are OATP1B1, OATP1B3, OAT1 and OAT3 substrates; valsartan is also a MRP2 substrate. Therefore, co-administration of Entresto with inhibitors of OATP1B1, OATP1B3, OAT3 (e.g. rifampicin, ciclosporin), OAT1 (e.g. tenofovir, cidofovir) or MRP2 (e.g. ritonavir) may increase the systemic exposure of LBQ657 or valsartan. Appropriate care should be exercised when initiating or ending concomitant treatment with such medicinal products.
Metformin: Co-administration of Entresto with metformin reduced both Cmax and AUC of metformin by 23%. The clinical relevance of these findings is unknown. Therefore, when initiating therapy with Entresto in patients receiving metformin, the clinical status of the patient should be evaluated.
No Significant Interaction: No clinically meaningful drug-drug interaction was observed when Entresto was co-administered with digoxin, warfarin, hydrochlorothiazide, amlodipine, omeprazole, carvedilol or a combination of levonorgestrel/ethinyl estradiol.
CYP 450 Interactions: In vitro metabolism studies indicate that potential for CYP 450-based drug interactions is low since there is limited metabolism of Entresto via CYP450 enzymes. Entresto does not induce or inhibit CYP450 enzymes.