Valsartan: Valsartan is eliminated mainly as unchanged drug. A small portion of the drug is metabolized by CYP 2C9, and some weak inhibitory potential is observed in vitro. No clinically significant effects on CYP is expected or observed in clinical studies. Sacubitril: Sacubitril is a weak inhibitor of CYP 2C8, 2C9 and 2C19, but has no potential for inhibition or induction of other CYP enzymes.

Valsartan: Angiotensin II receptor antagonist. Sacubitril: Sacubitril is a neprilysin inhibitor.

Valsartan: Valsartan is used in the treatment of essential hypertension. It is administered orally. Sacubitril: Sacubitril is used in combination with other drugs for the treatment of symptomatic chronic heart failure. The combination is administered orally.

Valsartan: About 80 per cent of administered dose of valsartan is excreted in unchanged form. A small portion of the drug is metabolized by CYP 2C9 to the inactive metabolite 4-OH-valsartan (Nakashima 2005, SPC). It has a half- life of about 5-9 hours (drugbank). Valsartan has been shown not to inhibit human cytochrome P450 enzymes CYP1A, 2A6, 2C19, 2D6, 2E and 3A in vitro in concentrations up to 100µM. A weak and clinically insignificant inhibition of CYP 2C9 was seen (Taavitsainen 2000). In an in vivo study, no drug-drug interaction was observed upon co-administration of Valsartan/sacubitril with digoxin/warfarin in healthy subjects (Ayalasomayajula). Sacubitril: Sacubitril is biotransformed via ester hydrolysis to the active metabolite LBQ657, which is excreted in the urine and feces (Flaracos 2016). Sacubitril is a week in vitro inhibitor of CYP 2C8 and 2C19, and its metabolite, LBQ657, is a weak inhibitor of CYP 2C9. Sacubitril has no potential for inhibition of other CYP enzymes, or for induction of CYP enzymes (Flaracos 2016, SPC). In an in vivo study, no drug-drug interaction was observed upon co-administration of Valsartan/sacubitril with digoxin/warfarin in healthy subjects (Ayalasomayajula). According to the SPC no clinically meaningful drug-drug interaction was observed when the combination valsartan/sacubitril was co-administered with digoxin, warfarin, hydrochlorothiazide, amlodipine, omeprazole, carvedilol or a combination of levonorgestrel/ethinyl estradiol (SPC Enestro).

Valsartan: Uneventful use reported in 15 patients with acute porphyria.