SACUBITRIL AND VALSARTAN
Clinical safety rating: avoid
NSAIDs may diminish the antihypertensive effect Lithium levels may be increased Use in pregnancy can cause injury and death to the developing fetus.
Sacubitril inhibits neprilysin, increasing natriuretic peptides; Valsartan blocks angiotensin II type 1 receptor, reducing vasoconstriction and aldosterone release. Combined, they enhance vasodilation, decrease sympathetic activity, and reduce cardiac remodeling.
| Metabolism | Sacubitril is metabolized by esterases to active metabolite sacubitrilat; Valsartan is primarily metabolized by CYP2C9. |
| Excretion | Sacubitril is converted to sacubitrilat, which is primarily eliminated renally (52–68% as sacubitrilat) and via biliary/fecal routes (37–48% as metabolites). Valsartan is predominantly eliminated via biliary/fecal route (83%) with renal elimination accounting for 13%. |
| Half-life | Sacubitrilat terminal half-life is approximately 11.5 hours; valsartan terminal half-life is approximately 9.9 hours. Twice-daily dosing maintains therapeutic concentrations. |
| Protein binding | Sacubitrilat: 94–97% bound to plasma proteins; valsartan: 94–97% bound primarily to albumin. |
| Volume of Distribution | Sacubitrilat: Vd approximately 7–10 L (0.1 L/kg assuming 70 kg); valsartan: Vd approximately 17 L (0.24 L/kg). Vd does not suggest extensive tissue distribution. |
| Bioavailability | Oral bioavailability of sacubitril is ≥60%; valsartan bioavailability is ~23% (range 10–35%). Food reduces all exposure but not clinically relevant. |
| Onset of Action | Oral: Reduction in NT-proBNP observed within 2–4 hours; hemodynamic effects (e.g., reduction in systolic blood pressure) within 2 weeks of initiation. |
| Duration of Action | Duration of hemodynamic effect (e.g., blood pressure reduction) persists over the 12-hour dosing interval. Clinical benefit in heart failure is sustained with chronic therapy. |
| Molecular Weight | Sacubitril: 411.46 Da; Valsartan: 435.52 Da; Sacubitrilat: 429.47 Da |
Initial dose: 24 mg/26 mg (sacubitril 24 mg/valsartan 26 mg) orally twice daily, then double at 2- to 4-week intervals to target maintenance dose of 97 mg/103 mg twice daily.
| Dosage form | TABLET |
| Renal impairment | eGFR >=30 mL/min/1.73m2: No adjustment. eGFR 15-29 mL/min/1.73m2: Starting dose 24/26 mg twice daily; target dose 97/103 mg twice daily if tolerated. eGFR <15 mL/min/1.73m2: Not recommended. |
| Liver impairment | Child-Pugh A (mild): No adjustment. Child-Pugh B (moderate): Starting dose 24/26 mg twice daily. Child-Pugh C (severe): Not recommended. |
| Pediatric use | Weight ≥40 kg: 24/26 mg twice daily initially, titrate to 49/51 mg twice daily after 2-4 weeks, then to 97/103 mg twice daily as tolerated. Weight <40 kg: Not established. |
| Geriatric use | No specific dose adjustment based on age alone. Use caution due to higher risk of hypotension, renal impairment, and hyperkalemia; initiate at 24/26 mg twice daily and titrate slowly. |
| 1st trimester | Data limited; avoid use due to potential fetal renin-angiotensin system effects and unknown sacubitril effects. |
| 2nd trimester | Contraindicated: associated with fetal oligohydramnios, renal failure, and skull ossification defects from valsartan. |
| 3rd trimester | Contraindicated: high risk of fetal renal dysfunction, oligohydramnios, and neonatal hypotension. |
Clinical note
NSAIDs may diminish the antihypertensive effect Lithium levels may be increased Use in pregnancy can cause injury and death to the developing fetus.
| FDA category | Contraindicated |
| Placental transfer | Valsartan crosses the placenta; sacubitrilat (active metabolite) likely crosses based on molecular weight; evidence from animal studies. |
| Breastfeeding |
■ FDA Black Box Warning
WARNING: FETAL TOXICITY. Drugs acting directly on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as pregnancy is detected.
| Common Effects | heart failure |
| Serious Effects |
History of angioedema with ACE inhibitors or ARBsConcomitant use with ACE inhibitors (within 36 hours)Concomitant use with aliskiren in diabetes mellitusSevere hepatic impairment (Child-Pugh C)Pregnancy (second and third trimesters)
| Precautions | Angioedema (especially if prior ACE inhibitor-associated), Hypotension, Renal impairment, Hyperkalemia, Do not coadminister with ACE inhibitors (risk of angioedema), Monitor serum potassium and renal function |
| Food/Dietary | No specific food interactions. However, advise patients to avoid grapefruit juice as it may interact with valsartan metabolism, though evidence is weak. Moderate alcohol intake is generally acceptable but may exacerbate hypotension. Caution with high-potassium foods (bananas, oranges, spinach, potatoes) due to risk of hyperkalemia; monitor potassium levels. |
Loading safety data…
| No human data; both components likely excreted in milk; due to potential for infant renal and cardiovascular effects, advise against use. |
| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | First trimester: Possible risk. Second and third trimesters: Known to cause fetal renal dysfunction, oligohydramnios, skull ossification delay, and neonatal toxicity due to renin-angiotensin system blockade. Contraindicated in second and third trimesters. |
| Fetal Monitoring | Monitor fetal renal function via ultrasound, amniotic fluid index, and fetal growth. Monitor maternal blood pressure, renal function, and serum potassium. |
| Fertility Effects | No specific studies in humans. In animal studies, no adverse effects on fertility at clinically relevant doses. Possible indirect effects via renin-angiotensin system in males and females. |
| Clinical Pearls | Sacubitril/valsartan (Entresto) is a first-line therapy for heart failure with reduced ejection fraction (HFrEF). It should not be used concomitantly with ACE inhibitors or within 36 hours of the last ACE inhibitor dose due to risk of angioedema. Monitor blood pressure, renal function, and potassium levels. May cause hypotension, especially in volume-depleted patients. Contraindicated in history of angioedema. Adjust dose in severe renal impairment (eGFR <30 mL/min/1.73m²). Contains valsartan, an ARB; therefore, avoid combination with ARBs. Can be initiated after switching from ACEi or ARB. The recommended starting dose is 49/51 mg twice daily, titrated to 97/103 mg twice daily as tolerated. |
| Patient Advice | Take this medication exactly as prescribed, usually twice daily with or without food. · Do not take with ACE inhibitors or within 36 hours of stopping an ACE inhibitor. · Inform your doctor if you have a history of angioedema or kidney problems. · Watch for signs of angioedema (swelling of face, lips, tongue, throat; difficulty breathing) and seek emergency help if they occur. · Avoid potassium supplements and salt substitutes containing potassium without your doctor's approval. · Report dizziness, fainting, or feeling lightheaded, especially at the start of treatment. · Stay hydrated, but do not consume excessive fluids without medical advice. · Do not stop taking this medication abruptly; consult your doctor before discontinuing. · If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your regular schedule. Do not double the dose. · Keep a list of all your medications and share it with your healthcare provider. |