Adult: Available preparations:
Sacubitril 24 mg and Valsartan 26 mg
Sacubitril 49 mg and Valsartan 51 mg
Sacubitril 97 mg and Valsartan 103 mg
In patient with reduced ejection fraction: Initially, 49 mg/51 mg bid. Dosage is individualised and may be increased after 2-4 weeks as tolerated to target maintenance dose of 97 mg/103 mg 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.
Renal Impairment
Moderate (eGFR 30-60 mL/min/1.73 m2) and severe (eGFR <30 mL/min/1.73 m2): Initially, 24 mg/26 mg bid.
Hepatic Impairment
Moderate (Child-Pugh class B): Initially, 24 mg/26 mg bid. Severe (Child-Pugh class C): Contraindicated.
Administration
May be taken with or without food.
Contraindications
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.
Special Precautions
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.
Adverse Reactions
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.
Patient Counseling Information
This drug may cause dizziness or fatigue, if affected, do not drive or operate machinery.
Monitoring Parameters
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.
Drug Interactions
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.
Action
Description: 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.
Chemical Structure
Sacubitril Source: National Center for Biotechnology Information. PubChem Database. Sacubitril, CID=9811834, https://pubchem.ncbi.nlm.nih.gov/compound/Sacubitril (accessed on Jan. 23, 2020)
Valsartan Source: National Center for Biotechnology Information. PubChem Database. Valsartan, CID=60846, https://pubchem.ncbi.nlm.nih.gov/compound/Valsartan (accessed on Jan. 20, 2020)
C09DX04 - valsartan and sacubitril ; Belongs to the class of angiotensin II receptor blockers (ARBs), other combinations. Used in the treatment of cardiovascular disease.
References
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.
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