Jynarque (tolvaptan)

The following drug information is obtained from various newswires, published medical journal articles, and medical conference presentations.

Company:

Approval Status:

Approved April 2018

Specific Treatments:

autosomal dominant polycystic kidney disease

Therapeutic Areas

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General Information

Jynarque (tolvaptan) is a selective vasopressin V2-receptor antagonist.

Jynarque is specifically indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease.

Jynarque is supplied as a tablet for oral administration. The recommended initial dose is 60 mg orally per day as 45 mg taken on waking and 15 mg taken 8 hours later. Titrate to 60 mg plus 30 mg then to 90 mg plus 30 mg per day if tolerated with at least weekly intervals between titrations. Patients may down-titrate based on tolerability.

Clinical Results

FDA Approval

The FDA approval of Jynarque was based on two pivotal trials, lasting one year and three years, respectively. In the one-year REPRISE study, the primary endpoint was the treatment difference in the change of eGFR from pretreatment baseline to post-treatment follow-up, annualized by dividing by each subject’s treatment duration. In the randomized period, the change of eGFR from pretreatment baseline to post-treatment follow-up was −2.3 mL/min/1.73 m2/year with tolvaptan as compared with −3.6 mL/min/1.73 m2/year with placebo, corresponding to a treatment effect of 1.3 mL/min/1.73 m2/year (p <0.0001). In the three-year TEMPO 3:4 study, tolvaptan reduced the rate of decline in eGFR by 1.0 mL /min /1.73m2 /year as compared to placebo in patients with earlier stages of ADPKD. In the extension trial, eGFR differences produced by the third year of the TEMPO 3:4 trial were maintained over the next 2 years of Jynarque treatment. The primary endpoint in TEMPO 3:4 study was the intergroup difference for rate of change of total kidney volume (TKV) normalized as a percentage. The trial met its pre-specified primary endpoint of 3-year change in TKV (p<0.0001). 

Side Effects

Adverse effects associated with the use of Jynarque may include, but are not limited to, the following: 

  • thirst
  • polyuria
  • nocturia
  • pollakiuria
  • polydipsia

The Jynarque label comes with the following Black Box Warning:

Jynarque (tolvaptan) can cause serious and potentially fatal liver injury. Acute liver failure requiring liver transplantation has been reported. Measure ALT, AST and bilirubin before initiating treatment, at 2 weeks and 4 weeks after initiation, then monthly for the first 18 months and every 3 months thereafter. Prompt action in response to laboratory abnormalities, signs, or symptoms indicative of hepatic injury can mitigate, but not eliminate, the risk of serious hepatotoxicity. Because of the risks of serious liver injury, Jynarque is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS).

Mechanism of Action

Jynarque (tolvaptan) is a selective vasopressin V2-receptor antagonist with an affinity for the V2-receptor that is 1.8 times that of native arginine vasopressin (AVP). Tolvaptan affinity for the V2-receptor is 29 times that for the V1a-receptor. Decreased binding of vasopressin to the V2-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.

Additional Information

For additional information regarding Jynarque or autosomal dominant polycystic kidney disease, please visit https://www.jynarque.com/