TOLVAPTAN

12.1 Mechanism of Action Tolvaptan is a selective vasopressin V 2 -receptor antagonist with an affinity for the V 2 -receptor that is 1.8 times that of native arginine vasopressin (AVP). Tolvaptan affinity for the V 2 -receptor is 29 times that for the V 1a -receptor. Decreased binding of vasopressin to the V 2 -receptor in the kidney lowers adenylate cyclase activity resulting in a decrease in intracellular adenosine 3′, 5′-cyclic monophosphate (cAMP) concentrations. Decreased cAMP concentrations prevent aquaporin 2 containing vesicles from fusing with the plasma membrane, which in turn causes an increase in urine water excretion, an increase in free water clearance (aquaresis) and a decrease in urine osmolality. In human ADPKD cyst epithelial cells, tolvaptan inhibited AVP-stimulated in vitro cyst growth and chloride-dependent fluid secretion into cysts. In animal models, decreased cAMP concentrations were associated with decreases in the rate of growth of total kidney volume and the

Contraindications

• • 4 CONTRAINDICATIONS JYNARQUE is contraindicated in patients: With a history
• • anaphylaxis
• • rash) to tolvaptan or any component of the product [see Adverse Reactions (6) ] Uncorrected urinary outflow obstruction Anuria History of signs or symptoms of significant liver impairment or injury
• • does not include uncomplicated polycystic liver disease ( 4 ) Concomitant use of strong CYP3A inhibitors is contraindicated ( 4 ) Uncorrected abnormal blood sodium concentrations ( 4
• • 5.3 ) Unable to sense or respond to thirst ( 4 ) Hypovolemia ( 4 ) Hypersensitivity to tolvaptan or any of its components ( 4 ) Uncorrected urinary outflow obstruction ( 4 ) Anuria ( 4 )