As recommended in product labeling, liver enzyme monitoring is needed during the first 18 months of tolvaptan therapy and every 3 months thereafter, according to a retrospective analysis of safety data from prospective clinical trials of the drug when used for treating autosomal dominant polycystic kidney disease.
Among more than 2,900 tolvaptan-treated participants — including more than 2,300 with at least 18 months of drug exposure — twice-daily, split-dose regimens showed the following frequencies of liver enzyme level increases detected during recommended regular monitoring: “In the placebo-controlled REPRISE trial, more tolvaptan- than placebo-treated participants (38 of 681 [5.6%] vs 8 of 685 [1.2%]) experienced alanine aminotransferase level increases to >3× the upper limit of normal (ULN), similar to TEMPO 3:4 (40 of 957 [4.4%] vs 5 of 484 [1.0%]). No participant in REPRISE or the long-term extension experienced concurrent alanine aminotransferase level increases to >3× ULN and total bilirubin increases to >2× ULN (‘Hy’s Law’ laboratory criteria). Based on the expanded dataset, liver enzyme increases most often occurred within 18 months after tolvaptan initiation and were less frequent thereafter. Increased levels returned to normal or near normal after treatment interruption or discontinuation. Thirty-eight patients were rechallenged with tolvaptan after the initial drug-induced liver injury episode, with return of liver enzyme level increases in 30; 1 additional participant showed a clinical ‘adaptation’ after the initial episode, with resolution of the enzyme level increases despite continuation of tolvaptan.”