European Journal of Clinical Pharmacology

, Volume 72, Issue 10, pp 1177–1183 | Cite as

Risk factors for hypernatremia in patients with short- and long-term tolvaptan treatment

  • Keita Hirai
  • Tatsuki Shimomura
  • Hideaki Moriwaki
  • Hidetoshi Ishii
  • Takayuki Shimoshikiryo
  • Daiki Tsuji
  • Kazuyuki Inoue
  • Toshihiko Kadoiri
  • Kunihiko ItohEmail author



The long-term efficacy of tolvaptan, a vasopressin V2 receptor antagonist, has been reported. However, the safety of long-term treatment remains to be fully elucidated. We assessed the safety profile of tolvaptan with respect to hypernatremia.


This retrospective study included 371 patients treated with tolvaptan. Risk factors for hypernatremia (serum sodium concentration ≥147 mEq/L) were determined.


Hypernatremia occurred in 95 patients (25.6 %), of whom 71 (19.1 %) developed hypernatremia within 7 days of tolvaptan treatment (early onset). Stepwise logistic regression analysis demonstrated that baseline serum sodium ≥140 mEq/L, an initial tolvaptan dosage >7.5 mg, and a BUN/serum creatinine ratio ≥20 were independent risk factors for early onset of hypernatremia. Tolvaptan was prescribed for more than 7 days to 233 patients, of whom 123 were administrated tolvaptan for more than 1 month. Hypernatremia occurred in 24 of these patients (10.3 %) (late onset). Predictive factors for late onset of hypernatremia were an average daily dosage of tolvaptan >7.5 mg and age ≥75 years.


A daily dosage of 7.5 mg or less was recommended to prevent hypernatremia in short- as well as long-term tolvaptan treatment, and mainly elderly patients were at risk for hypernatremia.


Hypernatremia Tolvaptan Diuretics Heart failure Liver cirrhosis 


Authors’ contributions

Hirai K, Moriwaki H, Tsuji D, Inoue K, Kadoiri T and Itoh K designed and managed this study. Hirai K, Shimomura T, Moriwaki H, Ishii H, and Shimoshikiryo T collected the clinical data. Hirai K analyzed all data and wrote the manuscript. All authors read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

All authors declare that they had no support from any organization for the submitted work, no financial relationship with any organizations that might have an interest in the submitted work, and no other relationships or activities that could appear to have influenced the submitted work.

Ethical approval

This study was approved by the ethics committee of the Shizuoka General Hospital (Shizuoka, Japan).


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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Keita Hirai
    • 1
    • 2
  • Tatsuki Shimomura
    • 1
  • Hideaki Moriwaki
    • 3
  • Hidetoshi Ishii
    • 1
    • 4
  • Takayuki Shimoshikiryo
    • 1
  • Daiki Tsuji
    • 1
    • 2
  • Kazuyuki Inoue
    • 1
    • 2
  • Toshihiko Kadoiri
    • 4
  • Kunihiko Itoh
    • 1
    • 2
    Email author
  1. 1.Department of Clinical Pharmacology & Genetics, School of Pharmaceutical SciencesUniversity of ShizuokaShizuokaJapan
  2. 2.Laboratory of Clinical PharmacogenomicsShizuoka General HospitalShizuokaJapan
  3. 3.Department of CardiologyShizuoka General HospitalShizuokaJapan
  4. 4.Department of PharmacyShizuoka General HospitalShizuokaJapan

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