Using Tolvaptan to Treat Hyponatremia: Results from a Post-authorization Pharmacovigilance Study

Abstract

Introduction: Hyponatremia is a common condition of varying etiology among hospitalized patients and is associated with adverse outcomes. Treatment to normalize serum sodium is advisable. Tolvaptan received European Union marketing authorization for hyponatremia secondary to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Post-marketing pharmacovigilance activities were required to characterize the safety profile of tolvaptan more fully in this population, which is often elderly with a high burden of comorbid illness.

Methods: This was a prospective, observational, multinational, post-authorization pharmacovigilance study (NCT01228682) in seven European countries. Hospitalized patients were enrolled who received tolvaptan for hyponatremia associated with SIADH and consented to data collection. Tolvaptan was initiated and assessments performed at physician discretion per local standards of care. To reflect actual clinical practice, no assessments or procedures were required outside the standard of care. Patients who continued to receive long-term tolvaptan following hospital discharge and provided consent received follow-up from their community physicians.

Results: A total of 252 patients (mean age 70.6 years) enrolled. Mean tolvaptan treatment duration was 139.4 days, median 18.5 (range 1-1130) days; most frequent dose was 15 mg/day (used in 75% of patients). Serum sodium increased from baseline (mean 123.2 mmol/l) during treatment week 1 and remained stable during follow-up, with little difference across doses of 7.5, 15, and 30 mg/day. Hyponatremia symptoms (e.g., confusion, unsteady gait, lethargy) were present in 122/252 (48.4%) patients at pre-treatment baseline, decreasing to 46/252 (18.3%) during treatment. Sixty-two patients (24.6%; mean baseline serum sodium 120 mmol/l) experienced rapid correction of hyponatremia within 72 h. No osmotic demyelination syndrome occurred.

Conclusion: In clinical practice, tolvaptan improved serum sodium and decreased hyponatremia symptoms in hyponatremia secondary to SIADH. Serum sodium should be monitored during treatment to minimize risk of rapid correction.

Trial registration: Clinicaltrials.gov identifier NCT01228682.

Keywords: Hyponatremia; Pharmacovigilance; Post-authorization safety study (PASS); Syndrome of inappropriate secretion of antidiuretic hormone (SIADH); Tolvaptan.

© 2021. The Author(s).

Figures

Fig. 1

Mean (SD) change from baseline in serum sodium (mmol/l) in patients grouped by stable daily tolvaptan dose received. Patients who did not enter a stable treatment phase were grouped according to their most used dose. Data are not shown for patients who received tolvaptan 3.75 mg less than daily, 3.75 mg/day, 7.5 mg less than daily, 15 mg less than daily, 45 mg/day, or 60 mg/day as a stable daily dose, given the small numbers of patients receiving a specific dose within each category. BSL baseline, D day, M month, SD standard deviation, W week

Fig. 2

Hyponatremia symptoms occurring in ≥1% of patients at either baseline or at any time during tolvaptan treatment. Baseline includes any symptoms starting in the 31 days up to tolvaptan initiation. Percentages are shown for the total number of patients (N = 252)