ENTRESTO SPRINKLE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ENTRESTO SPRINKLE (ENTRESTO SPRINKLE).
Sacubitril inhibits neprilysin, increasing natriuretic peptides; valsartan antagonizes angiotensin II type 1 receptor, causing vasodilation and reduced aldosterone.
| Metabolism | Sacubitril is metabolized by esterases to active sacubitrilat; valsartan is primarily metabolized by CYP2C9. |
| Excretion | Renal excretion: sacubitrilat ~52-68% unchanged; valsartan ~13% unchanged and ~80% as metabolites in feces via biliary excretion; total clearance of sacubitril is 52% renal, 48% fecal; valsartan clearance is primarily biliary (feces) with minor renal. |
| Half-life | Terminal half-life: sacubitrilat ~11.5 hours; valsartan ~9.9 hours; in heart failure, effective half-life supports twice-daily dosing; accumulation minimal after steady state. |
| Protein binding | Sacubitrilat: ~94% bound to plasma proteins; valsartan: ~95% bound primarily to albumin. |
| Volume of Distribution | Sacubitril: 103 L (approx. 1.5 L/kg for 70 kg); valsartan: 17 L (approx. 0.24 L/kg); sacubitrilat distributes extensively into tissues; valsartan limited to extracellular fluid. |
| Bioavailability | Oral bioavailability: sacubitril ~60% (as prodrug); valsartan ~23% (low due to first-pass); food decreases peak concentration but not AUC; no IV formulation available. |
| Onset of Action | Oral: NT-proBNP reduction observed within 2 hours; hemodynamic effects (e.g., reduced PCWP) seen within 1-2 hours; maximal effect on natriuresis within 4 hours. |
| Duration of Action | Clinical effects persist for 12 hours with BID dosing; sustained reduction in NT-proBNP and blood pressure over 24 hours; duration matches dosing interval. |
Sacubitril/valsartan 24 mg/26 mg orally twice daily, doubled every 2-4 weeks to target 97 mg/103 mg twice daily.
| Dosage form | CAPSULE, PELLETS |
| Renal impairment | eGFR >=30 mL/min/1.73m2: no adjustment; eGFR 15-29 mL/min/1.73m2: initial dose 24 mg/26 mg twice daily; eGFR <15 mL/min/1.73m2: not recommended. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: initial dose 24 mg/26 mg twice daily; Child-Pugh C: not recommended. |
| Pediatric use | Weight >=50 kg: 49 mg/51 mg twice daily; weight 40-49 kg: 24 mg/26 mg twice daily; weight <40 kg: not established. |
| Geriatric use | No specific dose adjustment; consider lower initial dose due to age-related renal impairment; monitor renal function and blood pressure. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ENTRESTO SPRINKLE (ENTRESTO SPRINKLE).
| Breastfeeding | No human data on sacubitril or sacubitrilat excretion in breast milk; valsartan is excreted in animal milk. M/P ratio unknown. Risk of infant hypotension and renal impairment. Use is not recommended during breastfeeding. |
| Teratogenic Risk | Entresto (sacubitril/valsartan) is contraindicated in pregnancy due to direct renin-angiotensin system (RAS) blockade. Second and third trimester exposure causes oligohydramnios, fetal renal dysfunction, skull ossification defects, hypotension, and anuria. First trimester risk is uncertain but RAS inhibitors are generally avoided. No adequate human studies; animal studies show fetotoxicity. |
■ FDA Black Box 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.
| Serious Effects |
["Hypersensitivity to any component","History of angioedema with ACE inhibitors or ARBs","Concomitant ACE inhibitor use (within 36 hours)","Pregnancy","Hereditary or idiopathic angioedema"]
| Precautions | ["Hypotension","Renal impairment","Hyperkalemia","Angioedema","Hepatic impairment"] |
| Food/Dietary | Avoid high-potassium foods (e.g., bananas, oranges, potatoes, spinach, avocado, tomatoes, salt substitutes containing potassium chloride) to reduce risk of hyperkalemia. No significant food effect on absorption; can be taken with or without food. Avoid grapefruit juice as it may increase valsartan exposure. |
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| Fetal Monitoring | If inadvertent exposure occurs, monitor fetal ultrasound for amniotic fluid volume and renal function. Serial fetal assessments including growth scans. Monitor maternal blood pressure and renal function. Neonates exposed in utero should be observed for hypotension, oliguria, and hyperkalemia. |
| Fertility Effects | Animal studies show no adverse effects on fertility. RAS blockade in humans may theoretically affect reproductive function, but no specific human evidence for Entresto. |
| Clinical Pearls | ENTRESTO SPRINKLE (sacubitril/valsartan) is the first angiotensin receptor-neprilysin inhibitor (ARNI). It is indicated for heart failure with reduced ejection fraction (HFrEF) and for treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged ≥1 year. Initiate at 3.1 mg/3.2 mg twice daily in patients not currently taking an ACEi or ARB, but if switching from an ACEi, allow a 36-hour washout period to reduce risk of angioedema. Do not coadminister with ACEis; combination increases angioedema risk. Monitor blood pressure, renal function, and serum potassium. Dose adjustments needed for severe renal impairment (eGFR <30 mL/min/1.73 m²) or moderate hepatic impairment (Child-Pugh B). |
| Patient Advice | Take ENTRESTO SPRINKLE exactly as prescribed, twice daily, with or without food. · Do not take within 36 hours of any ACE inhibitor medicine. Do not take with aliskiren if you have diabetes. · If you miss a dose, take it as soon as you remember; if it is almost time for your next dose, skip the missed dose. Do not double the dose. · Common side effects include low blood pressure, dizziness, cough, and high potassium. Seek medical attention if you experience swelling of face, lips, tongue, or throat (angioedema) or trouble breathing. · This medicine can harm an unborn baby; use effective contraception during treatment and tell your doctor if you become pregnant. · Avoid potassium supplements or salt substitutes containing potassium unless directed by your doctor. · Keep the medicine in its original packet (blister) until use. If transferring from a container, use a spoon or other device to ensure correct dose. |