Due to the risks of liver injury, JYNARQUE® (tolvaptan)
is available only through a REMS Program

Insights into the JYNARQUE REMS Program • Duration: 14 minutes, 4 seconds

An evidence-based answer to a common clinical question about JYNARQUE:

Are there any data on drug-induced liver injury from the Risk Evaluation and Mitigation Strategy (REMS) Program?

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The JYNARQUE Risk Evaluation and Mitigation Strategy (REMS) Program makes monitoring your patients to HELP mitigaTe the risk of liver injury a top priority

The JYNARQUE REMS Program includes the following steps:

Prescribers first enroll in the JYNARQUE REMS Program, order baseline hepatic tests, and counsel their patients accordingly. Patients then enroll in the JYNARQUE REMS Program, where they are monitored at 2 weeks and 4 weeks after treatment initiation, then monthly for 18 months, and every 3 months thereafter. JYNARQUE is exclusively available through 3 REMS-certified pharmacies.

In clinical trials,

    Incidence of serious liver injury

    • 0.2% (3/1487) of JYNARQUE patients experienced serious hepatocellular injury (elevations of hepatic transaminases of at least 3 times ULN combined with elevated bilirubin at least 2 times the ULN) in a 3-year placebo-controlled trial and its open-label extension (in which patients’ liver tests were monitored every 4 months) compared to none of the placebo-treated patients

    Incidence of liver injury

    • 4.9% (80/1637) of JYNARQUE patients experienced ALT elevations >3 times the ULN at an increased frequency within the first 18 months after initiating treatment compared to 1.1 % (13/1166) of patients taking placebo in the two double-blind, placebo-controlled trials. ALT elevations usually resolved within 1 to 4 months after discontinuing treatment

    Patients should stop taking JYNARQUE and notify their HCP if they show signs or symptoms of liver injury.

    ALT=alanine aminotransferase; ULN=upper limit of normal.

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    Post-marketing liver safety was investigated in a retrospective analysis of the ongoing JYNARQUE REMS Program1

    • Retrospective interim analysis of adult patients with ADPKD who were JYNARQUE-naïve and started JYNARQUE in the post-marketing setting
    • Patients were monitored at 2 weeks and 4 weeks after treatment initiation, then monthly for 18 months, and every 3 months thereafter during treatment with JYNARQUE
    • REMS incidence rates were compared with those from JYNARQUE trials by calculating an incidence rate ratio (trials were: TEMPO 3:4, TEMPO 3:4 extension  [TEMPO 4:4], REPRISE, and long-term extension, which enrolled subjects from REPRISE, TEMPO 4:4, and previous JYNARQUE trials)
    • The analysis period was from the start of the program (May 14, 2018), which occurred immediately prior to tolvaptan commercialization (May 21, 2018), to the data cutoff date of February 23, 2022

    Number of REMS patients1

    Indirect comparison of DILI incidence in clinical trials vs REMS1†

    Risk of possible severe DILI does not appear to increase following treatment exposure beyond 12 months with continued liver enzyme monitoring. Conclusions about the timing of possible severe DILI are limited by the fact that approximately half of REMS patients had JYNARQUE exposure no longer than 12 months.

     

    Retrospective interim analysis from the REMS Program demonstrated a lower rate of possible severe drug-induced liver injury (DILI) compared with the JYNARQUE clinical trial population.1

     

    *In all 4 patients, liver enzymes normalized after JYNARQUE discontinuation.1

    †The comparison of incidence in the REMS and clinical trials (TEMPO 3:4, REPRISE, and their extension trials) was post hoc and indirect, using 2 separate datasets.1

     

    CI=confidence interval; IRR=incidence rate ratio; PY=patient year. REPRISE=Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy; TEMPO=Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes.

    DILI CLASSIFICATION CRITERIA

    Learn more about the JYNARQUE REMS
    Program post-marketing liver safety study.

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    1. Lioudis M, Nunna S, George V, et al. Post-marketing liver safety data from 4 years of the tolvaptan risk evaluation and mitigation strategy (REMS) in the treatment of autosomal dominant polycystic kidney disease (ADPKD). Poster presented at NKF Spring Clinical Meetings; April 11-15, 2023; Austin, TX.
    2. Risk Evaluation and Mitigation Strategies | REMS. US Food and Drug Administration website.
      https://www.fda.gov/drugs/drug-safety-and-availability/risk-evaluation-and-mitigation-strategies-rems. Accessed May 15, 2020.

    See results from the retrospective interim analysis of the JYNARQUE REMS program

    View Results

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    talking to patients about REMS

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    INDICATION and IMPORTANT SAFETY INFORMATION

    JYNARQUE is indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD).

    WARNING: RISK OF SERIOUS LIVER INJURY

    WARNING: RISK OF SERIOUS LIVER INJURY

    • JYNARQUE® (tolvaptan) can cause serious and potentially fatal liver injury. Acute liver failure requiring liver transplantation has been reported
    • Measure transaminases (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 Risk Evaluation and Mitigation Strategy program called the JYNARQUE REMS Program

    CONTRAINDICATIONS:

    • History, signs or symptoms of significant liver impairment or injury. This contraindication does not apply to uncomplicated polycystic liver disease
    • Taking strong CYP3A inhibitors
    • With uncorrected abnormal blood sodium concentrations
    • Unable to sense or respond to thirst
    • Hypovolemia
    • Hypersensitivity (e.g., anaphylaxis, rash) to JYNARQUE or any component of the product
    • Uncorrected urinary outflow obstruction
    • Anuria

    Serious Liver Injury: JYNARQUE can cause serious and potentially fatal liver injury. Acute liver failure requiring liver transplantation has been reported in the post-marketing ADPKD experience. Discontinuation in response to laboratory abnormalities or signs or symptoms of liver injury (such as fatigue, anorexia, nausea, right upper abdominal discomfort, vomiting, fever, rash, pruritus, icterus, dark urine or jaundice) can reduce the risk of severe hepatotoxicity. To reduce the risk of significant or irreversible liver injury, assess ALT, AST and bilirubin prior to initiating JYNARQUE, at 2 weeks and 4 weeks after initiation, then monthly for 18 months and every 3 months thereafter.

    Hypernatremia, Dehydration and Hypovolemia: JYNARQUE therapy increases free water clearance which can lead to dehydration, hypovolemia and hypernatremia. Instruct patients to drink water when thirsty, and throughout the day and night if awake. Monitor for weight loss, tachycardia and hypotension because they may signal dehydration. Ensure abnormalities in sodium concentrations are corrected before initiating therapy. If serum sodium increases above normal or the patient becomes hypovolemic or dehydrated and fluid intake cannot be increased, suspend JYNARQUE until serum sodium, hydration status and volume status parameters are within the normal range.

    Inhibitors of CYP3A: Concomitant use of JYNARQUE with drugs that are moderate or strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, indinavir/ritonavir, ritonavir, and conivaptan) increases tolvaptan exposure. Use with strong CYP3A inhibitors is contraindicated; dose reduction of JYNARQUE is recommended for patients taking moderate CYP3A inhibitors. Patients should avoid grapefruit juice beverages while taking JYNARQUE.

    Adverse Reactions: Most common observed adverse reactions with JYNARQUE (incidence >10% and at least twice that for placebo) were thirst, polyuria, nocturia, pollakiuria and polydipsia.

    Other Drug Interactions:

    • Strong CYP3A Inducers: Co-administration with strong CYP3A inducers reduces exposure to JYNARQUE. Avoid concomitant use of JYNARQUE with strong CYP3A inducers
    • V2-Receptor Agonist: Tolvaptan interferes with the V2-agonist activity of desmopressin (dDAVP). Avoid concomitant use of JYNARQUE with a V2-agonist

    Pregnancy and Lactation: Based on animal data, JYNARQUE may cause fetal harm. In general, JYNARQUE should be discontinued during pregnancy. Advise women not to breastfeed during treatment with JYNARQUE.

    To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch).

    Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING.