What is the maximum approved dose of Entresto (sacubitril/valsartan)?

Maximum Dose of Entresto

The maximum approved dose of Entresto (sacubitril/valsartan) is 97 mg sacubitril/103 mg valsartan taken twice daily, for a total daily dose of 194 mg sacubitril and 206 mg valsartan. 1

Standard Dosing for Adults

• Target maintenance dose: 97/103 mg twice daily 2, 1
• Starting dose: 49/51 mg twice daily for most patients 1
• Titration schedule: Double the dose after 2-4 weeks to reach the target maintenance dose of 97/103 mg twice daily, as tolerated 1

This target dose of 97/103 mg twice daily represents the maximum therapeutic dose studied in major clinical trials and is the FDA-approved maximum for heart failure treatment 2, 1.

Dose Adjustments Requiring Lower Starting Doses

While the maximum dose remains 97/103 mg twice daily, certain patient populations require starting at a lower dose (24/26 mg twice daily) with subsequent titration to the maximum tolerated dose 3:

Severe Renal Impairment

• Patients with eGFR <30 mL/min/1.73 m² should start at 24/26 mg twice daily 3, 1
• Titrate upward every 2-4 weeks toward the target maximum of 97/103 mg twice daily as tolerated 1

Moderate Hepatic Impairment

• Patients with Child-Pugh B classification should start at 24/26 mg twice daily 3, 1
• Titrate to the maximum dose of 97/103 mg twice daily as tolerated 1
• Severe hepatic impairment (Child-Pugh C) is a contraindication 3, 1

ACE Inhibitor/ARB Naïve Patients

• Patients not currently taking an ACE inhibitor or ARB, or those on low doses, should start at 24/26 mg twice daily 1
• Titrate every 2-4 weeks to reach the maximum dose of 97/103 mg twice daily 1

Pediatric Maximum Dosing

For pediatric patients ≥1 year old weighing ≥50 kg, the maximum dose is identical to adults: 97/103 mg twice daily 1. For children <50 kg, weight-based dosing applies with a maximum of 3.1 mg/kg twice daily 1.

Clinical Context and Evidence

The 2022 AHA/ACC/HFSA guidelines confirm that the target dose achieved in the landmark PARADIGM-HF trial was 182 mg sacubitril and 193 mg valsartan total daily (equivalent to approximately 91/96.5 mg twice daily), which is close to but slightly below the maximum approved dose 2. This demonstrates that the maximum dose of 97/103 mg twice daily is both safe and represents the optimal therapeutic target.

Important caveat: In real-world practice, only 27.2% of patients achieve the maximum 200 mg (97/103 mg) twice daily dose within 6 months, with slower uptitration, hypotension, and patient factors limiting dose escalation 4. However, the goal remains to reach the maximum tolerated dose up to 97/103 mg twice daily, as higher doses show greater NT-proBNP reduction compared to lower doses 5.

Safety Considerations at Maximum Dose

• Hypotension is the most common dose-limiting side effect, particularly at the maximum dose 6, 7
• A 36-hour washout period is mandatory when switching from an ACE inhibitor to avoid angioedema risk 1
• Monitor blood pressure, electrolytes, and renal function closely during uptitration to maximum dose 3