サクビトリル

This chemical does not meet GHS hazard criteria for 50% (1 of 2) of reports.

Warning

H317 (50%): May cause an allergic skin reaction [Warning Sensitization, Skin]；H319 (50%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]

P261, P264+P265, P272, P280, P302+P352, P305+P351+P338, P321, P333+P317, P337+P317, P362+P364, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 2 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.；Reported as not meeting GHS hazard criteria per 1 of 2 reports by companies.；There is 1 notification provided by 1 of 2 reports by companies with hazard statement code(s).；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

The large prospective, placebo-controlled trials of sacubitril-valsartan in patients with heart failure usually did not mention or list ALT elevations or severe hepatic adverse events or deaths. In the FDA clinical review of data from these trials, elevations in ALT or AST were said to arise in 1.3% of patients on sacubitril-valsartan but a similar portion of those on enalapril [1.0%], and all elevations were judged to be unrelated to therapy and likely due to congestive liver disease due to heart failure. A single case of jaundice with aminotransferase elevations occurred, but in a patient who had stopped combination therapy because of worsening renal dysfunction and who was experiencing acute decompensated heart failure. Since approval and more widespread use of sacubitril-valsartan there have been at least two reports of acute liver injury attributed to its use. Both cases were relatively mild and resolved rapidly once the drug was stopped. Whether the injury was due to sacubitril or valsartan (or an interaction of both) was not clear. Valsartan, like other commonly used angiotensin receptor blockers, is known to be a rare cause of acute liver injury. The contribution of the underlying heart failure and possible congestive hepatopathy is also an issue. The reported cases did not have a liver biopsy and were not rechallenged with the drug which might have clarified the causality.；Likelihood score: D (possible rare cause of clinically apparent liver injury, which may be due to valsartan rather than sacubitril).

n a 7-day valsartan-controlled study in patients with reduced ejection fraction (HFrEF), administration of sacubitril + valsartan (Entresto) resulted in a significant non-sustained increase in natriuresis, increased urine cGMP, and decreased plasma MR-proANP and NT-proBNP compared to valsartan. In a 21-day study in HFrEF patients, it significantly increased urine ANP and cGMP and plasma cGMP, and decreased plasma NT-proBNP, aldosterone and endothelin-1. In clinical studies, this combination had no effect on QTc interval.

Sacubitril's active metabolite, LBQ657 inhibits neprilysin, a neutral endopeptidase that would typically cleave natiuretic peptides, which includes: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and c-type natriuretic peptide (CNP). ANP and BNP are released under atrial and ventricle stress, which activate downstream receptors leading to vasodilation, natriuresis and diuresis. Under normal conditions, neprilysin breaks down other vasodilating peptides and also vasoconstrictors such as angiotensin I and II, endothelin-1 and peptide amyloid beta-protein. Therefore, the inhibition of neprilysin leads to reduced breakdown and increased concentration of endogenous natriuretic peptides in addition to increased levels of vasoconstricting hormones such as angiotensin II. (However, when combined with valsartan, would result in blocking of angiotensin II to its receptor, preventing the vasoconstrictive effects and resulting in a decrease in vascular resistance and blood pressure.) Cardiovascular and renal effects of sacubitril is a result of the increased levels of peptides that are normally degraded by neprilysin.