Entresto 50 mg BID Dosing in CrCl 29 mL/min
Entresto 50 mg twice daily is appropriate and does not require dose reduction for a patient with creatinine clearance of 29 mL/min, though close monitoring for hyperkalemia and worsening renal function is essential.
Pharmacokinetic Evidence in Renal Impairment
The key consideration is that sacubitrilat (the active neprilysin inhibitor component) accumulates significantly in renal impairment, while sacubitril and valsartan exposures remain unchanged 1.
Specific Pharmacokinetic Changes at CrCl <30 mL/min:
- Sacubitrilat AUC increases 2.7-fold in severe renal impairment (CrCl <30 mL/min) 1
- Sacubitrilat Cmax increases by approximately 60% regardless of renal impairment severity 1
- Half-life extends from 12 hours to 38.5 hours in severe renal impairment 1
- Sacubitril and valsartan exposures remain unchanged across all degrees of renal impairment 1
Dosing Recommendation
No dose adjustment is required based on renal function alone 1. The standard starting dose of 24/26 mg or 49/51 mg twice daily can be used, with titration to the target dose of 97/103 mg twice daily as tolerated 2.
Rationale:
- Clinical trials demonstrating mortality benefit used twice-daily dosing without specific renal-based dose reductions 2
- The drug was generally well tolerated in patients with severe renal impairment despite increased sacubitrilat exposure 1
- Titration should occur every 2-4 weeks to achieve target doses that reduce cardiovascular mortality and heart failure hospitalizations 2
Critical Monitoring Requirements
Essential Laboratory Monitoring:
- Serum potassium levels - Check at baseline, within 1 week of initiation, and regularly thereafter due to valsartan's potassium-sparing effects
- Renal function (creatinine/eGFR) - Monitor closely as both components can affect kidney function
- Blood pressure - Hypotension risk increases with renal impairment
Common Pitfalls to Avoid:
- Do not underdose - Only 27% of patients achieve target doses within 6 months, leading to suboptimal outcomes 2
- Avoid concurrent nephrotoxic agents - NSAIDs should be avoided as they increase hyperkalemia risk 3
- Monitor for drug interactions - If patient is on statins (particularly atorvastatin), monitor creatine kinase closely as sacubitril inhibits statin excretion and can cause rhabdomyolysis 4
Special Considerations at CrCl 29 mL/min
This patient sits at the threshold between moderate and severe renal impairment, requiring heightened vigilance:
- Potassium management: Discontinue or reduce potassium supplements; check potassium within 3 days and at 1 week after initiation 3
- Volume status: Address any dehydration emergently as it can precipitate acute kidney injury 3
- Diuretic adjustment: May need to optimize loop diuretic dosing rather than thiazides, as thiazide efficacy decreases below CrCl 30 mL/min 3, 5
Contraindications and Cautions
Absolute contraindications (not related to renal function but important to verify):
- History of angioedema with ACE inhibitors or ARBs
- Concurrent ACE inhibitor use (requires 36-hour washout period)
- Pregnancy
The 50 mg BID dose (49/51 mg formulation) is a reasonable starting or maintenance dose for this patient, with the goal of uptitrating to 97/103 mg twice daily if blood pressure, potassium, and renal function remain stable 2.