Tolvaptan (Samsca): Vasopressin receptor antagonist approved for the treatment of clinically significant hypervolemic and euvolemic hyponatremia

Tolvaptan is an oral selective vasopressin V₂-receptor antagonist that causes increased urine water excretion, thus leading to increased free water clearance (aquaresis), decreased urine osmolality, and increased serum sodium concentrations. This agent was approved on May 19, 2009, for the treatment of patients with 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 (HF), cirrhosis, and syndrome of inappropriate antidiuretic hormone (SIADH).

Efficacy. The efficacy of tolvaptan for the treatment of hyponatremia was assessed in 2 double-blind, placebo-controlled, multicenter studies. Patients were randomized to treatment with either tolvaptan (n=223) or placebo (n=220) for 30 days and were followed for 7 days after treatment withdrawal. Tolvaptan was initiated at a dose of 15 mg once/d; the dose could be increased at 24-hour intervals to 30 mg once/d and then to 60 mg once/d until normonatremia (serum sodium >135 mEq/L) was reached. The primary end point was the average daily area under the curve (AUC) for change in serum sodium from baseline to Day 4 and from baseline to Day 30. Tolvaptan treatment was associated with a significantly greater increase in serum sodium versus placebo (P<.0001) during both periods across the 2 studies. This effect was significant in patients with serum sodium <130 mEq/L or <125 mEq/L; a significant improvement was also observed across patient subgroups (eg, patients with cirrhosis or SIADH). In an open-label study, patients previously treated with tolvaptan or placebo were re-treated after they had returned to standard care for ≥7 days. Re-initiation of tolvaptan therapy led to serum sodium concentration increases similar to those observed during previous tolvaptan treatment; these increased levels were sustained for ≥1 year.

Safety. If correction of hyponatremia occurs too rapidly, osmotic demyelination can occur, potentially resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, or death. Patients should be carefully monitored during treatment to assess serum sodium concentrations and neurologic status. In clinical trials, tolvaptan-treated patients with cirrhosis were more likely than placebo-treated patients to experience gastrointestinal bleeding. Dehydration and hypovolemia can occur in tolvaptan-treated patients, especially in those who are being treated with diuretics or are fluid-restricted. Tolvaptan therapy should be interrupted or discontinued in patients showing signs or symptoms of hypovolemia. Tolvaptan treatment could lead to increased serum potassium; levels should be monitored after initiation of treatment in patients with serum potassium >5 mEq/L and in those who are receiving drugs known to increase serum potassium levels. The most common adverse events associated with tolvaptan treatment include thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria, and hyperglycemia.

Dosing. Tolvaptan should be initiated at a dose of 15 mg administered once/d without regard to meals. After ≥24 hours, the dose should be increased to 30 mg once/d; the dose can then be increased to a maximum of 60 mg once/d as needed. Tolvaptan therapy should be initiated (or re-initiated) in the hospital so that healthcare professionals can evaluate therapeutic response, as too-rapid correction of hyponatremia can lead to osmotic demyelination. During initiation and titration of therapy, healthcare professionals should frequently monitor patients for changes in serum electrolytes and volume. Fluid restriction should be avoided during the first 24 hours of therapy. After treatment discontinuation, patients should be advised to resume fluid restriction, and healthcare professionals should monitor patients for changes in serum sodium and volume status.