Is Tolvaptan contraindicated in patients with clinically significant liver disease or hepatic impairment (e.g., active hepatitis, cirrhosis, Child‑Pugh class B or C, or liver enzymes >3 × upper limit of normal)?

Tolvaptan and Liver Disease: Contraindications and Precautions

Tolvaptan is contraindicated in patients with underlying liver disease according to the FDA label, and should be avoided in patients with clinically significant hepatic impairment including cirrhosis. 1

Absolute Contraindications

The FDA explicitly states to avoid tolvaptan use in patients with underlying liver disease. 1 This represents the strongest regulatory guidance and should be followed in clinical practice, particularly given the drug's well-documented hepatotoxicity risk.

Context-Dependent Use in Cirrhosis

Despite the FDA contraindication for underlying liver disease, there is a notable exception for short-term use in cirrhosis-related hyponatremia:

• For hyponatremia treatment in cirrhosis: Tolvaptan has been approved in the USA for management of severe hypervolemic hyponatremia associated with cirrhosis and ascites, but treatment duration must be limited to 30 days maximum. 2, 1

• Dose adjustment required: Patients with uncompensated liver cirrhosis require 50% of the standard dose because metabolism is approximately 60% slower. 3

• Enhanced monitoring: The European Association for the Study of the Liver recommends starting with 15 mg once daily with careful clinical monitoring and frequent sodium assessment, always initiated in the hospital. 3

The ADPKD Exception and Hepatotoxicity Risk

For autosomal dominant polycystic kidney disease (ADPKD), tolvaptan carries significant hepatotoxicity risk that necessitates strict exclusion of pre-existing liver disease:

• Incidence of liver injury: 4.4-5.6% of ADPKD patients develop alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations ≥3× upper limit of normal (ULN) versus 1.0-1.2% with placebo. 4, 5

• Timing of injury: Hepatocellular injury typically occurs between 3-18 months after starting tolvaptan, with most cases occurring within the first 18 months. 6, 4, 7

• Reversibility: Liver enzyme elevations are generally reversible, resolving within 1-4 months after tolvaptan cessation. 6, 7

Mandatory Monitoring Protocol for ADPKD

KDIGO 2025 guidelines mandate the following monitoring schedule 6:

• Monthly liver function tests (AST, ALT, bilirubin) for the first 18 months
• Every 3 months thereafter until drug discontinuation
• Within 48-72 hours if ALT or AST increases to >2× ULN or >2× baseline

When to Hold or Discontinue Tolvaptan

Immediate action required when 6:

• AST or ALT increases to ≥3× ULN
• AST or ALT increases to >2× baseline (even if <2× ULN)
• Multiple signs/symptoms of liver injury appear: fatigue, nausea, vomiting, anorexia, right upper quadrant pain, fever, rash, jaundice, pruritus, or ascites

Permanent discontinuation required unless 6:

• Another explanation for liver injury is identified AND
• The injury has completely resolved

Clinical Pitfalls to Avoid

• Do not use tolvaptan in patients with baseline liver enzyme elevations >3× ULN - this represents pre-existing liver disease and is a contraindication. 1

• Do not rechallenge after significant liver injury - Per the U.S. FDA label, tolvaptan should not be restarted in patients who had signs/symptoms of hepatic injury or transaminase levels >3× ULN unless another explanation accounts for the injury. 6

• Limited rechallenge data: While one study showed successful rechallenge in some patients with mild elevations (<3× ULN), 30 of 38 rechallenged patients experienced recurrent enzyme elevations. 8, 4

• No Hy's Law cases in recent trials: Despite frequent transaminase elevations, no cases meeting Hy's Law criteria (ALT >3× ULN plus total bilirubin >2× ULN) occurred in the REPRISE trial or long-term extension studies, suggesting that with proper monitoring, severe irreversible injury can be prevented. 4, 5

Special Considerations for Cirrhosis

When tolvaptan is used for hyponatremia in cirrhosis despite the underlying liver disease contraindication:

• 30-day maximum duration to minimize hepatotoxicity risk 1
• Hospital initiation required with close monitoring 3
• Long-term use shows increased mortality in cirrhosis patients, reinforcing the need for short-term use only 9
• Consider alternative strategies such as fluid restriction (1.0-1.5 L/day) or albumin administration for recurrent hyponatremia after discontinuation 9