When to start tolvaptan (vasopressin receptor antagonist) in patients with hyponatremia?

From the Guidelines

Tolvaptan should be initiated in patients with moderate to severe hyponatremia (serum sodium <125 mEq/L) who are symptomatic and have euvolemic or hypervolemic hyponatremia, particularly in the setting of SIADH (Syndrome of Inappropriate Antidiuretic Hormone secretion) or heart failure, as evidenced by the most recent and highest quality study 1.

Key Considerations for Tolvaptan Initiation

• The treatment typically begins with a low dose of 15 mg once daily, taken in the morning, with potential titration to 30-60 mg daily based on sodium response.
• Tolvaptan should be started in a hospital setting with close monitoring of serum sodium levels, aiming for a correction rate not exceeding 8-12 mEq/L in the first 24 hours and 18 mEq/L in the first 48 hours to prevent osmotic demyelination syndrome, as recommended by the guidelines 1.
• Patients should have unrestricted access to water but avoid excessive fluid intake.

Important Contraindications and Precautions

• Tolvaptan is contraindicated in patients who need urgent sodium correction, those with anuria, hypovolemic hyponatremia, or liver disease, due to the risk of adverse effects such as dehydration, hypernatremia, and renal impairment 1.
• The medication works by selectively blocking vasopressin V2 receptors in the kidney, promoting water excretion without affecting sodium and potassium excretion, thus addressing the underlying pathophysiology of inappropriate water retention seen in conditions like SIADH.

Monitoring and Safety

• Close monitoring of serum sodium levels is crucial to avoid excessive correction and prevent complications such as osmotic demyelination syndrome.
• Patients should be monitored for signs of dehydration, hypernatremia, and renal impairment, and the dose of tolvaptan should be adjusted accordingly.
• The use of tolvaptan in patients with liver disease requires caution, and monthly liver function tests are recommended in some cases 1.

From the FDA Drug Label

Tolvaptan tablets are a selective vasopressin V 2-receptor antagonist indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia [serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction], including patients with heart failure and Syndrome of Inappropriate Antidiuretic Hormone (SIADH) Limitations of Use: Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with tolvaptan tablets

Tolvaptan should be started in patients with hyponatremia when the following conditions are met:

• Serum sodium <125 mEq/L
• Symptomatic hyponatremia that has resisted correction with fluid restriction
• Patients have hypervolemic or euvolemic hyponatremia, including those with heart failure and SIADH However, tolvaptan should not be started in patients who:
• Require urgent intervention to raise serum sodium to prevent or treat serious neurological symptoms
• Have hypovolemic hyponatremia
• Are unable to respond appropriately to thirst
• Have anuria
• Have a history of hypersensitivity to tolvaptan
• Are taking strong CYP3A inhibitors
• Have autosomal dominant polycystic kidney disease (ADPKD) outside of the FDA-approved REMS 2

From the Research

Indications for Tolvaptan in Hyponatremia

• Tolvaptan, a vasopressin receptor antagonist, is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia, including patients with heart failure, liver disease, and syndrome of inappropriate antidiuretic hormone secretion (SIADH) 3, 4, 5.
• The treatment should be initiated in patients with serum sodium levels less than 125 mEq/L or in those with less marked symptomatic hyponatremia that has resisted correction with fluid restriction 4.
• Tolvaptan is effective in increasing serum sodium levels in patients with hyponatremia, including those with heart failure and liver disease, and can be used for long-term treatment 3, 4, 6.

Patient Selection

• Patients with hypovolemic hyponatremia, anuric patients, and those who cannot sense or respond to thirst should not be treated with tolvaptan 3.
• Fluid restriction should be avoided during the first 24 hours of treatment with tolvaptan to prevent overly rapid correction of hyponatremia 3.
• Tolvaptan should not be used in patients requiring urgent intervention to raise serum sodium acutely, such as those with severe symptomatic hyponatremia (e.g., seizures, coma) 7.

Clinical Evidence

• Clinical trials have demonstrated the efficacy and safety of tolvaptan in patients with hyponatremia, including those with heart failure and liver disease 3, 4, 6.
• The SALT trials showed that tolvaptan treatment rapidly and effectively resolved hyponatremia in patients with hypervolemic and euvolemic hyponatremia, including those with cirrhosis and heart failure 3.
• A study comparing tolvaptan with furosemide-based diuretic regimens in patients hospitalized for heart failure with hyponatremia found that tolvaptan was associated with similar diuresis and improvements in serum sodium levels 6.