Interactions : אינטראקציות

4.5     Interaction with other medicinal products and other forms of interaction
Interactions resulting in a contraindication

ACE inhibitors
The concomitant use of sacubitril/valsartan with ACE inhibitors is contraindicated, as the concomitant inhibition of neprilysin (NEP) and ACE may increase the risk of angioedema. Sacubitril/valsartan 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 sacubitril/valsartan (see sections 4.2 and 4.3).

Aliskiren
The concomitant use of sacubitril/valsartan with aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or in patients with renal impairment (eGFR <60 ml/min/1.73 m2) (see section 4.3). The combination of sacubitril/valsartan with direct renin inhibitors such as aliskiren is not recommended (see section 4.4). Combination of sacubitril/valsartan with aliskiren is potentially associated with a higher frequency of adverse reactions such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) (see sections 4.3 and 4.4).

Interactions resulting in concomitant use not being recommended

Sacubitril/valsartan contains valsartan, and therefore should not be co-administered with another ARB containing medicinal product (see section 4.4).

Interactions requiring precautions

OATP1B1 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 sacubitril/valsartan increased the Cmax of atorvastatin and its metabolites by up to 2-fold and AUC by up to 1.3-fold. Caution should be exercised when co-administering sacubitril/valsartan with statins. No clinically relevant interaction was observed when simvastatin and Entresto were co-administered.


ENT API JUL23 V3                                                              EU SmPC 05.2023 PDE5 inhibitors including sildenafil
Addition of a single dose of sildenafil to sacubitril/valsartan at steady state in patients with hypertension was associated with a significantly greater blood pressure reduction compared to administration of sacubitril/valsartan alone. Therefore, caution should be exercised when sildenafil or another PDE5 inhibitor is initiated in patients treated with sacubitril/valsartan.

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 sacubitril/valsartan is co-administered with these agents (see section 4.4).

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 sacubitril/valsartan 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 sacubitril/valsartan who are taking NSAIDs concomitantly (see section 4.4).

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 including sacubitril/valsartan . 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 sacubitril/valsartan and furosemide had no effect on the pharmacokinetics of sacubitril/valsartan 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 sacubitril/valsartan.

Nitrates, e.g. nitroglycerine
There was no interaction between sacubitril/valsartan and intravenously administered nitroglycerin with regard to blood pressure reduction. Co-administration of nitroglycerin and sacubitril/valsartan 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 sacubitril/valsartan 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 sacubitril/valsartan 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 sacubitril/valsartan with metformin reduced both Cmax and AUC of metformin by 23%. The clinical relevance of these findings is unknown. Therefore, when initiating therapy with sacubitril/valsartan in patients receiving metformin, the clinical status of the patient should be evaluated.


ENT API JUL23 V3                                                                EU SmPC 05.2023 No significant interaction

No clinically meaningful interaction was observed when sacubitril/valsartan was co-administered with digoxin, warfarin, hydrochlorothiazide, amlodipine, omeprazole, carvedilol or a combination of levonorgestrel/ethinyl estradiol.