Sacubitril + Valsartan

Oral
Chronic heart failure

Patient with systolic blood pressure 100-110 mmHg: Initially, 24 mg/26 mg tab bid.

Patient not currently or previously taking low doses of ACE inhibitors or ARB: 24 mg/26 mg bid, double the dose as tolerated every 2-4 weeks. Maintenance: 97 mg/103 mg bid.

Patient previously taking moderate to high dose of ACE inhibitors or ARB: 49 mg/51 mg bid, double the dose as tolerated every 2-4 weeks. Maintenance: 97 mg/103 mg bid.

Moderate (eGFR 30-60 mL/min/1.73 m²) and severe (eGFR <30 mL/min/1.73 m²): Initially, 24 mg/26 mg bid.

Moderate (Child-Pugh class B): Initially, 24 mg/26 mg bid. Severe (Child-Pugh class C): Contraindicated.

May be taken with or without food.

Hypersensitivity or history of angioedema, biliary cirrhosis, cholestasis. Concomitant use or use within 36 hours of ACE inhibitors or Angiotensin II Receptor Blockers (ARBs). Concomitant use with aliskiren-containing products in patients with diabetes mellitus. Severe hepatic impairment (Child-Pugh class C). Pregnancy.

Patient with risk factors for hypotension (e.g. salt- or volume depletion, MI); aortic/mitral stenosis, risk factors for renal failure (e.g. diabetes mellitus, hypoaldosteronism). Moderate to severe renal and moderate hepatic impairment (Child-Pugh class B). Lactation.

Significant: Hypotension, hyperkalaemia, decreased renal function.
Blood and lymphatic system disorders: Anaemia.
Gastrointestinal disorders: Diarrhoea, nausea, gastritis.
General disorders and administration site conditions: Fatigue, asthenia.
Investigations: Increased serum creatinine.
Metabolism and nutrition disorders: Hypokalaemia, hypoglycaemia.
Nervous system disorders: Dizziness, headache, vertigo.
Renal and urinary disorders: Renal failure.
Respiratory, thoracic and mediastinal disorders: Cough.
Vascular disorders: Orthostatic hypotension, syncope.
Potentially Fatal: Angioedema.

This drug may cause dizziness or fatigue, if affected, do not drive or operate machinery.

Monitor K levels at baseline and periodically thereafter, blood pressure, LFT, renal function (e.g. serum creatinine, BUN). Correct hyperkalaemia, volume and Na depletion prior to initiation of treatment.

Additive hypotensive effect with sildenafil and other PDE5 inhibitors. Increased risk of acute renal failure with NSAID(s). Increased serum concentration with rifampicin, ciclosporin, ritonavir. May reduce serum concentration of metformin.
Sacubitril: May increase serum concentration of OATP1B1, OATP1B3 substrates (e.g. atorvastatin). Increased concentration of statins.
Valsartan: May increase serum lithium concentration and toxicity. Increased risk of hyperkalaemia with potassium-sparing diuretics (e.g. triamterene), mineralocorticoid antagonists (e.g. spironolactone), K supplements, or other K-containing salt substitutes (e.g. heparin).
Potentially Fatal: Increased risk of angioedema with ACE inhibitors/ARBs. Increased risk of hypotension, hyperkalaemia, and acute renal failure with aliskiren in patients with diabetes mellitus.

Description:
Mechanism of Action: Sacubitril is a prodrug of sacubitrilat (LBQ-657) which inhibits neprilysin, a neutral endopeptidase (NEP), leading to increased levels of endogenous vasoactive peptides including natriuretic peptides, bradykinin and adrenomedullin.
Valsartan is an angiotensin II type 1 (AT₁) receptor blocker. It antagonizes AT₁-induced vasoconstriction, aldosterone, catecholamine and arginine vasopressin release, water intake, and hypertrophic response.
Pharmacokinetics:
Absorption: Sacubitril: Absolute bioavailability: >60%. Time to peak plasma concentration: Approx 0.5-1 hour (sacubitril); 2 hours (LBQ657).
Valsartan: Rapidly absorbed from the gastrointestinal tract. Bioavailability: Approx 23% (tab); approx 39% (solution). Time to peak plasma concentration: 1.5 hours.
Distribution: Sacubitril: LBQ657 crosses the blood brain barrier to limited extent (0.28%). Volume of distribution: 103 L. Plasma protein binding: 94-97%.
Valsartan: Volume of distribution: 75 L. Plasma protein binding: 94-97%.
Metabolism: Sacubitril: Metabolised by esterases to active metabolite, LBQ657.
Valsartan: Minimally metabolised (approx 20%; <10% as hydroxyl metabolite).
Excretion: Sacubitril: Via urine (approx 52-68%, primarily as LBQ657); faeces (37-48%, primarily as LBQ657). Elimination half-life: 1.4 hours (sacubitril); 11.5 hours (LBQ657).
Valsartan: Mainly via faeces (86%); urine (approx 13%). Elimination half-life: Approx 9.9 hours.

Source: National Center for Biotechnology Information. PubChem Database. Sacubitril, CID=9811834, https://pubchem.ncbi.nlm.nih.gov/compound/Sacubitril (accessed on Jan. 23, 2020)

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 60846, Valsartan. https://pubchem.ncbi.nlm.nih.gov/compound/Valsartan. Accessed Oct. 25, 2023.

Store at 25°C. Protect from moisture.

Thuốc đối kháng thụ thể angiotensin II / Các loại thuốc tim mạch khác

C09DX04 - valsartan and sacubitril ; Belongs to the class of angiotensin II receptor blockers (ARBs), other combinations. Used in the treatment of cardiovascular disease.

Anon. Sacubitril and Valsartan. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 05/02/2018.

Buckingham R (ed). Sacubitril. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com . Accessed 05/02/2018.

Buckingham R (ed). Valsartan. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 05/02/2018.

Entresto Film Coated Tablet (Novartis Pharmaceuticals Corporation). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 05/02/2018.

Joint Formulary Committee. Valsartan with Sacubitril. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 05/02/2018.