Tolvaptan

Tolvaptan, sold under the brand name Samsca among others, is an aquaretic drug that functions as a selective, competitive vasopressin receptor 2 (V2) antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca.[8] Tolvaptan, as Jynarque, was granted approval for medical use in the United States in April 2018.[9]

Tolvaptan
Clinical data
Trade namesSamsca, Jinarc, Jynarque, others
Other namesOPC-41061
AHFS/Drugs.comMonograph
MedlinePlusa609033
License data
Pregnancy
category
  • UK: Contraindicated
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityUnknown (40% absorbed)
Protein binding99%
MetabolismLiver (CYP3A4-mediated)[7]
Elimination half-life12 hours (terminal)
Identifiers
IUPAC name
  • N-(4-{[(5R)-7-Chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl}-3-methylphenyl)-2-methylbenzamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.219.212
Chemical and physical data
FormulaC26H25ClN2O3
Molar mass448.95 g·mol−1
3D model (JSmol)
SMILES
  • Cc1ccccc1C(=O)Nc2cc(C)c(cc2)C(=O)N3c4ccc(Cl)cc4[C@H](O)CCC3
InChI
  • InChI=1S/C26H25ClN2O3/c1-16-6-3-4-7-20(16)25(31)28-19-10-11-21(17(2)14-19)26(32)29-13-5-8-24(30)22-15-18(27)9-12-23(22)29/h3-4,6-7,9-12,14-15,24,30H,5,8,13H2,1-2H3,(H,28,31) Y
  • Key:GYHCTFXIZSNGJT-UHFFFAOYSA-N Y
 NY (what is this?)  (verify)

The U.S. Food and Drug Administration (FDA) granted tolvaptan a fast track designation for clinical trials investigating its use for the treatment of polycystic kidney disease.[10] The FDA granted Jynarque an orphan drug designation in April 2012, for the treatment of autosomal dominant polycystic kidney disease.[11]

Tolvaptan is available as a generic medication.[12]

Medical uses

Tolvaptan (Samsca) is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia.[13]

Tolvaptan (Jynarque) is indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD).[14]

Tolvaptan phosphate is a prodrug of tolvaptan, developed for intravenous administration. Tolvaptan phosphate is converted into the active drug tolvaptan in the human body following administration.[15]

Side effects

The FDA has determined that tolvaptan should not be used for longer than 30 days and should not be used in patients with underlying liver disease because it can cause liver injury, potentially leading to liver failure.[16] When using to treat hyponatremia, it may cause too rapid correction of hyponatremia resulting in fatal osmotic demyelination syndrome.[17]

Pharmacology

Tolvaptan is a selective vasopressin V2 receptor antagonist.[13][14]

Chemistry

Tolvaptan is a racemate, a 1:1 mixture of the following two enantiomers:[18]

Enantiomers of tolvaptan

(R)-Tolvaptan
CAS number: 331947-66-1
(S)-Tolvaptan
CAS number: 331947-44-5

References
  1. "Samsca 15 mg tablets - Summary of Product Characteristics (SmPC)". (emc). Retrieved 14 December 2020.
  2. "Jinarc 15 mg tablets - Summary of Product Characteristics (SmPC)". (emc). 21 April 2020. Retrieved 14 December 2020.
  3. "Jynarque- tolvaptan kit Jynarque- tolvaptan tablet". DailyMed. 31 March 2020. Retrieved 14 December 2020.
  4. "Samsca- tolvaptan tablet". DailyMed. 26 October 2020. Retrieved 14 December 2020.
  5. "Samsca EPAR". European Medicines Agency (EMA). Retrieved 14 December 2020.
  6. "Jinarc EPAR". European Medicines Agency (EMA). Retrieved 14 December 2020.
  7. Shoaf S, Elizari M, Wang Z, et al. (2005). "Tolvaptan administration does not affect steady state amiodarone concentrations in patients with cardiac arrhythmias". J Cardiovasc Pharmacol Ther. 10 (3): 165–71. doi:10.1177/107424840501000304. PMID 16211205. S2CID 39158242.
  8. "Drug Approval Package: Samsca (Tolvaptan) Tablets NDA #022275". U.S. Food and Drug Administration (FDA). 21 July 2009. Retrieved 15 August 2020. Lay summary (PDF). {{cite web}}: Cite uses deprecated parameter |lay-url= (help)
  9. "Drug Approval Package: Jynarque (tolvaptan)". U.S. Food and Drug Administration (FDA). 8 June 2018. Retrieved 15 August 2020.
  10. "Otsuka Maryland Research Institute, Inc. Granted Fast Track Designation For Tolvaptan In PKD". Medical News Today. Healthline Media UK Ltd. Retrieved 6 December 2018.
  11. "Tolvaptan Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). 6 April 2012. Retrieved 15 August 2020.
  12. "Drugs@FDA: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 15 August 2020.
  13. "Samsca- tolvaptan tablet". DailyMed. 28 May 2019. Retrieved 15 August 2020.
  14. "Jynarque- tolvaptan kit Jynarque- tolvaptan tablet". DailyMed. 31 March 2020. Retrieved 15 August 2020.
  15. "Otsuka Obtains Approval in Japan for SAMTASU® for I.V. Infusion, a V2 -Receptor Antagonist for the Treatment of Cardiac Edema" (Press release). March 28, 2022. Retrieved June 11, 2022.
  16. "U.S. Food and Drug Administration." Samsca (Tolvaptan): Drug Safety Communication. N.p., 30 Apr. 2013. Web. 1 June 2014. <http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm350185.htm>
  17. Goodman & Gilman's the pharmacological basis of therapeutics. Brunton, Laurence L, Knollmann, Björn C, Hilal-Dandan, Randa (Thirteenth ed.). New York. 5 December 2017. ISBN 9781259584732. OCLC 994570810.{{cite book}}: CS1 maint: others (link)
  18. Rote Liste Service GmbH (Hrsg.): Rote Liste 2017 - Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte). Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, ISBN 978-3-946057-10-9, S. 222.

Further reading
  • "Tolvaptan". Drug Information Portal. U.S. National Library of Medicine.
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