Conivaptan hydrochloride injection (Vaprisol) is an arginine vasopressin ViA/V2‐receptor antagonist approved for the treatment of euvolemic or hypervolemic hyponatremia in hospitalized patients. Overly rapid increases in serum sodium concentration ([Na+]), regardless of treatment, may cause severe adverse neurological events. Reported here is an evaluation of the frequency of overly rapid serum [Na+] increases during clinical trials with conivaptan.
Conivaptan was evaluated in a randomized controlled trial (RCT) of 84 patients and in an open‐label study (OLS) of 251 patients, all with euvolemic or hypervolemic hyponatremia (serum [Na+]: from 115 to <130 mEq/L in RCT; ≤130 mEq/L in OLS). After infusion of a 20‐mg loading dose, conivaptan was given in a continuous 4‐day infusion of 40 or 80 mg/day in the RCT and 20 or 40 mg/day in the OLS. A serum [Na+] increase that was too fast or excessive — necessitating discontinuation or dose reduction — was defined in the study protocols as an increase > 12 mEq/L in 24 hours or > 24 mEq/L in total, an absolute serum [Na+] > 145 mEq/L, or in the RCT only, an increase that in the investigator's opinion occurred too quickly.
Of the 306 patients given conivaptan in the 2 trials combined, 15 (4.9%) experienced an overly rapid increase in serum [Na+]. In the RCT, 4 of 55 patients (7.3%) given conivaptan (2 given 40 mg/day and 2 given 80 mg/day), and none of the 29 patients given a placebo had a serum [Na+] increase that exceeded the protocol guidelines. Conivaptan was temporarily withheld and then resumed at a lower dose in 3 of these patients and discontinued in the fourth. In the OLS, serum [Na+] increased ≥12 mEq/L over 24 h in 11 patients (4.4%) (1 of 37 [2.7%] given 20 mg/d and 10 of 214 [4.7%] given 40 mg/d, mean ± SD increase = 14.7 ± 1.9 mEq/L), hours leading to discontinuation of study drug. No cases of osmotic demyelination syndrome were reported from patients who experienced an overly rapid increase in serum [Na+] in either study.
In these 2 clinical studies, an overly rapid serum [Na+] increase occurred in approximately 5% of patients who received conivaptan for the treatment of euvolemic or hypervolemic hyponatremia. These episodes were managed by discontinuing treatment or by temporarily withholding therapy and resuming it at a lower dose. Additional experience is needed in patients whose pretreatment serum [Na+] is very low.
R. H. Sterns, none; L. E. Wagoner, none; S. Rosansky, none; J. G. Verbalis, Astellas Pharma US, Inc., consultant fees, speaker fees, research funding; Otsuka Pharmaceutical Co., consultant fees; sanofi‐aventis, consultant fees; B. McNutt, Astellas Pharma US, Inc., employment.
To cite this abstract:Sterns R, Wagoner L, Rosansky S, Verbalis J, McNutt B. Low Incidence of Overly Rapid Serum Sodium Increase During Treatment of Euvolemic and Hypervolemic Hyponatremia with Conivaptan. Abstract published at Hospital Medicine 2008, April 3-5, San Diego, Calif. Abstract 75. Journal of Hospital Medicine. 2008; 3 (suppl 1). https://www.shmabstracts.com/abstract/low-incidence-of-overly-rapid-serum-sodium-increase-during-treatment-of-euvolemic-and-hypervolemic-hyponatremia-with-conivaptan/. Accessed September 22, 2019.