Additional assessments of JYNARQUE across multiple subgroups

Study 206: Retrospective analysis: long-term effects of JYNARQUE
 

STUDY DESIGN AND LIMITATIONS

STUDY 206 - Long-term treatment effects1

WATCH VIDEO: JYNARQUE INSIGHTS - LONG TERM DATA

A 5.5-year retrospective, pooled analysis in patients with ADPKD to evaluate the long-term treatment effects of JYNARQUE on kidney function and kidney volume

STUDY 206 was a pooled, longitudinal analysis of data from 8 JYNARQUE clinical trials and 5 studies without JYNARQUE (natural history or standard of care) in subjects with ADPKD. To control for heterogeneity in disease characteristics between JYNARQUE and SOC treatment groups, analysis populations were matched for baseline demographic and disease characteristics.

The primary objective was to assess the longer-term effects of tolvaptan on kidney function (measured by the rate of decline in eGFR) and total kidney volume (TKV).

Limitations of the pooled analysis

  • Differences between treatment groups may have affected the outcomes
    • Use of matching and multiple regression adjustment for the relative comparison helped to reduce this bias, but residual confounding possibly still exists
  • Patients enrolled at different times and in clinical studies may have had differences in characteristics or lifestyle factors not reflected in baseline characteristics
  • Subjects who did not perform well may have dropped off earlier, especially among observational studies. Therefore, observations after 5.5 years of follow-up were excluded to reduce potential bias caused by informative missingness

Video: Insights into the long-term data for JYNARQUE
• Duration: 15 minutes, 46 seconds

 

PRIMARY OBJECTIVE: CHANGE IN KIDNEY FUNCTION

Change in kidney function1

Estimated change from theoretical baseline eGFR, Graph
Estimated change from theoretical baseline eGFR, Graph
Matched analysis showed JYNARQUE slowed annualized eGFR decline1

 

STUDY 206 SOURCE STUDIES

 

See data on the long-term effects of JYNARQUE.

 

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PRIMARY OBJECTIVE: ESTIMATED TKV

Estimated TKV (% of baseline) at Years 1, 3, and 51

Estimated TKV at Years 1, 3, and 5, Chart
Estimated TKV at Years 1, 3, and 5, Chart
Estimated TKV at Years 1, 3, and 5 was smaller with JYNARQUE than with SOC1

*Percentage change from baseline.

STUDY 206 SOURCE STUDIES

 

See data on the long-term effects of JYNARQUE.

 

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SECONDARY OBJECTIVE: IMPACT OF TREATMENT GAPS

A secondary objective of Study 206 was to analyze this group of patients to understand the impact of JYNARQUE treatment gaps on disease progression1

Impact of the JYNARQUE treatment gap on disease progression1

 

Estimated rate of eGFR decline and Estimated rate of TKV growth
Estimated rate of eGFR decline and Estimated rate of TKV growth
Impact of the JYNARQUE treatment gap showed direct effect in slowing the rates of eGFR and TKV growth1

 

  • Off-treatment days were primarily due to the gap between JYNARQUE titration/run-in period for subjects on placebo in REPRISE and resumption of JYNARQUE at the start of the long-term safety trial
  • Median off-treatment gap was 55 days

 

 

ADPKD=autosomal dominant polycystic kidney disease; CI=confidence interval; eGFR=estimated glomerular filtration rate; SOC=standard of care; TKV=total kidney volume.

 

Post-hoc analysis:
Patients with 
<25 eGFR

 

The effects of JYNARQUE® (tolvaptan) in patients with baseline eGFR of 15 to 29 mL/min/1.73 m2 were retrospectively investigated in a post hoc analysis2

Understanding the use of JYNARQUE in patients with CKD stage 4

  • Although JYNARQUE slowed eGFR decline in subjects with ADPKD in the TEMPO 3:4 and REPRISE trials, the effects of JYNARQUE in subjects with eGFR of 15 to 24 mL/min/1.73 m2 were not investigated in clinical trials REPRISE and TEMPO 3:4
  • The full Prescribing Information for JYNARQUE does not specify a lower eGFR limit for eligible patients, but use of the medication is contraindicated in patients with anuria

Study design

  • A post-hoc analysis retrospectively investigated eGFR decline in patients from the REPRISE trial who at the time of enrollment in an open-label extension (OLE) trial had a baseline eGFR of 15 to 29 mL/min/1.73 m2
    • The analysis included data from the first 12 months of JYNARQUE therapy during the OLE
  • Cohort included patients with eGFR decline with placebo in REPRISE and JYNARQUE in OLE with eGFR of 15 to 29 mL/min/1.73 m2

Patient subsets

  • Subset 1 (n=148) received placebo in REPRISE and began JYNARQUE in OLE*
  • Subset 2 (n=148) received JYNARQUE in REPRISE and in OLE and matched to REPRISE in placebo-treated subjects

Annualized eGFR slopes were compared within the subsets.

*Patients served as self-controls.

Comparative mean annualized eGFR slope2

 

LS mean annualized change in eGFR, Graph
LS mean annualized change in eGFR, Graph

JYNARQUE decreased the rate of eGFR decline in late-stage ADPKD patients in a post-hoc analysis2

 

  • Treatment effect was maintained in REPRISE JYNARQUE subjects continuing JYNARQUE in OLE
  • Initiating or maintaining JYNARQUE therapy delayed eGFR decline in subjects with baseline eGFR of 15 to 29 mL/min/1.73 m2

Although these data support the use of JYNARQUE in patients with more severe impairments in kidney function, expert opinion notes that patients with higher eGFR will benefit the most from therapy.3,4

 

 

See data on the effects of JYNARQUE in patients with late-stage CKD.

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ADPKD=autosomal dominant polycystic kidney disease; CKD=Chronic Kidney Disease; CKD-EPI=Chronic Kidney Disease Epidemiology Collaboration; eGFR=estimated glomerular filtration rate; LS=least squares; OLE=open-label extension.

 

Treatment in 
younger patients 
(18-35 years)

The clinical impact of JYNARQUE vs placebo in younger subjects (aged 18-35) was retrospectively assessed from a pooled database5

Primary objective:

  • Assess treatment effect of JYNARQUE compared with standard of care (SOC)* alone on the annual rate of change of kidney function decline (eGFR) for up to 5.5 years

Rationale:

  • Previous data among patients aged 18-35 years with ADPKD were limited to 3 years of follow-up in the TEMPO 3:4 study
Limited data exist on the long-term effect of treatment with JYNARQUE on kidney function among patients aged 18–35 years. Linking patient data from multiple clinical trials and observational studies increases the duration of follow-up and facilitates evaluation of the long-term treatment effect of JYNARQUE.

Study overview5

A pooled database consisting of existing data from clinical trials and observational studies was used for the analysis (tolvaptan: n=2928; SOC: n=4189). Data from patients participating in multiple studies were linked longitudinally to maximize the duration of follow-up (5.5 years).

The analysis comprised 3 steps:

  1. MATCH patients 1:1 from the JYNARQUE and SOC cohorts to minimize confounding
  2. ESTIMATE the effects of JYNARQUE vs SOC on kidney function decline over 5.5 years of follow-up†
  3. EXTRAPOLATE predicted kidney function decline to 35 years‡

Patient characteristics of the matched cohort5

CKD stage characteristics5

CKD Stage Characteristics, Chart
CKD Stage Characteristics, Chart

*SOC in the following trials was: OVERTURE, patients were controlled for blood pressure (BP); CRISP was noninterventional; and in HALT-PKD, patients received an angiotensin-converting enzyme inhibitor (ACEi) with or without an angiotensin receptor blocker (ARB) with standard BP control.

†The annual rate of change of eGFR was estimated using a mixed model that included time (continuous), treatment, baseline eGFR, time-by-treatment interaction, and patient-specific slopes and intercepts with an unstructured variance-covariance matrix.

‡Extrapolations of predicted eGFR values for up to 35 years were performed assuming the same relationship as in the first 5.5 years and a baseline eGFR of 93 mL/min/1.73 m2.

Impact of JYNARQUE treatment in younger patients

Estimated annual rate of change in eGFR (ml/min/1.73 m2)§

Reduction in declines vs SOC, Chart

Estimated eGFR change from baseline over time

Cumulative reduction in decline of eGFR (JYNARQUE - SOC)5

young-patients-years
young-patients-years
Treatment in younger patients (18-35 years) with JYNARQUE may produce notable differences in
the rate of change in eGFR over time.

§Change from baseline eGFR was estimated based on the theoretical baseline value estimated from the mixed model. Positive values of the difference indicate slower rates of decline in eGFR for the JYNARQUE cohort (values shown reflect eGFR for JYNARQUE – eGFR for SOC).

Predicted impact on time to ESKD

Extrapolation of predicted effects of JYNARQUE on eGFR out to 35 years5

Mixed modelII

Predicted Delay in ESKD, JYNARQUE vs SOC, Graph
Predicted Delay in ESKD, JYNARQUE vs SOC, Graph

The extrapolations were performed using a mixed model that assumed patients had a baseline eGFR of 93 mL/min/1.73 m2 and assumed maintenance of the same relationship as observed in the first 5.5 years.

Extrapolations based on the Irazabal equation (Sensitivity Analysis)

Predicted Delay in ESKD Based on Irazabal Equation, JYNARQUE vs SOC, Graph
Predicted Delay in ESKD Based on Irazabal Equation, JYNARQUE vs SOC, Graph

The prediction intervals for the estimates were wide, indicating large variability. Therefore, these projections need to be interpreted with caution.

JYNARQUE decreased the rate of eGFR decline in younger patients (18-35 years) in a post-hoc analysis

IIExtrapolations were based on the mixed model including treatment, time, treatment-by-time interaction, and baseline eGFR for a patient with baseline eGFR of 93 mL/min/1.73 m2. 95% prediction intervals were based on the empirical best linear unbiased predictor.

Extrapolations for SOC were based on the Irazabal equation for a predicted mean based on the sample means/proportions of the matched analysis set. The coefficients of the treatment (-3.90) and time-by-treatment interaction (1.69) terms estimated from the mixed model were added to predict the eGFR means for JYNARQUE.

See the clinical impact of JYNARQUE in younger patients

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ADPKD=autosomal dominant polycystic kidney disease; CKD=chronic kidney disease; CRISP=Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease; eGFR=estimated glomerular filtration rate; ESKD=end-stage kidney disease; HALT-PKD=HALT Progression of Polycystic Kidney Disease; OVERTURE=Observational Study in Patients with Autosomal Dominant Polycystic Kidney Disease; 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.

 

Post-hoc analysis:
Patients >55 years

 

The clinical benefit of JYNARQUE in patients aged >55 years was retrospectively investigated from a pooled database7

Understanding the impact of JYNARQUE on patients >55 years from the pivotal trials7,8

In REPRISE subgroup analyses, a treatment effect of JYNARQUE was not observed in patients older than 55 years (N=200). These results, however, should be viewed in context of the relatively slow progression of disease observed in placebo-treated older patients (2.34 mL/min/1.73 m2 decline vs 4.60 mL/min/1.73 m2 among patients aged ≤55 years) and the relatively short duration of follow-up

-There is no upper age limit within the Full Prescribing Information for JYNARQUE

-US expert opinion suggests that therapy with JYNARQUE may be continued until reaching the need for kidney replacement therapy regardless of age4

Study overview7

This post-hoc pooled subgroup analysis aimed to assess the longer-term effect of JYNARQUE compared with SOC on kidney function in older patients (aged >55 years) with ADPKD with CKD Stages 3 and 4:

  • Pooled database was constructed with data from 11 studies
  • Data across studies were linked longitudinally to allow longer-term follow-up
  • Subjects on JYNARQUE were matched 1:1 with subjects on SOC based on baseline CKD stage, sex, age and eGFR
  • The annual rate of change in eGFR was estimated using CKD-EPI*

Subjects who were randomized to JYNARQUE from REPRISE (n=95) were matched 1:1 with SOC subjects (n=53 from HALT-PKD and n=42 from OVERTURE):

  • Mean age - 60.2 years
  • Age range - 56 to 65 years
  • CKD Stage 3 - 69%
  • CKD Stage 4 - 31%

Mean duration of JYNARQUE with a mean gap of 29 days between REPRISE and the extension study: 2.4 years

*Estimation was done using a mixed model that included treatment, time, baseline eGFR, and time-by-treatment interaction.

Estimated annual rate of eGFR change in the matched analysis set7

Estimated annual rate of eGFR change in the matched analysis set, Graph
Estimated annual rate of eGFR change in the matched analysis set, Graph

The annual rate of change of eGFR was estimated using a mixed model that included treatment, time, baseline eGFR, and time-by-treatment interaction as fixed effects and subject-specific intercept and slope (for time) as random effects with an unstructured variance-covariance matrix. Data after 5.5 years were excluded.

JYNARQUE  decreased the rate of eGFR decline in patients >55 years in a post hoc analysis7

 

Evaluate the risk-to-benefit profile in older patients treated with JYNARQUE.

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ADPKD=autosomal dominant polycystic kidney disease; CI=confidence interval; CKD=chronic kidney disease; CKD-EPI=Chronic Kidney Disease Epidemiology Collaboration; eGFR=estimated glomerular filtration rate; HALT-PKD=HALT Progression of Polycystic Kidney Disease; OVERTURE=Observational Study in Patients With Autosomal Dominant Polycystic Kidney Disease; SOC=standard of care.

 

Predictive modeling: Impact on delaying 
time to ESKD

In the absence of clinical data, the expected but still unproven benefit of JYNARQUE to delay ESKD has been modeled by several investigators

To date, no outcomes-driven clinical trials have been conducted to document the impact of JYNARQUE on time to ESKD

 

PREDICTION MODEL IN DELAYING TIME TO ESKD:

Based on TEMPO 3:4 and REPRISE data4

Chebib et al prediction model overview

  • Results of the TEMPO 3:4 and REPRISE trials were extrapolated to estimate the potential benefit of JYNARQUE treatment in delaying the need for renal replacement therapy
  • The model assumed that all patients exhibit similar declines in eGFR over time as they progress to ESKD
  • Based on available data, the effect of JYNARQUE was predicted to be sustained and cumulative

 

TEMPO 3:4: Predicted impact of JYNARQUE in delaying ESKD*

TEMPO 3:4: Predicted impact of JYNARQUE® in delaying ESKD, Graph
TEMPO 3:4: Predicted impact of JYNARQUE® in delaying ESKD, Graph

 

Predictions based on TEMPO 3:4 may underestimate the long-term treatment effect because the impact of therapy on eGFR decline was less than that observed in REPRISE in patients with more advanced disease

*These extrapolations are made using the average decline in eGFR seen with placebo (3.7 mL/min per year) and tolvaptan (2.72 mL/min per year) in the TEMPO 3:4 trial.

 

REPRISE: Predicted impact of JYNARQUE in delaying ESKD†

REPRISE: Predicted impact of JYNARQUE® in delaying ESKD, Graph
REPRISE: Predicted impact of JYNARQUE® in delaying ESKD, Graph

 

†These extrapolations are made using the average decline in eGFR seen with placebo (3.61 mL/min per year) and tolvaptan (2.34 mL/min per year) in the REPRISE trial.

JYNARQUE is predicted to delay ESKD by a greater number of years if therapy is initiated in patients with more preserved renal function4

 

†These extrapolations are made using the average decline in eGFR seen with placebo (3.61 mL/min per year) and tolvaptan (2.34 mL/min per year) in the REPRISE trial.

 

See predicted impact of JYNARQUE in delaying time
to ESKD in patients with ADPKD.

 

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PREDICTION MODEL IN DELAYING TIME TO ESKD:

Based on TEMPO 3:4 data according to baseline CKD stage9

Bennett et al prediction model overview

 

  • The effect of JYNARQUE on ADPKD progression was modeled by applying a constant treatment effect to the rate of renal function decline, consistent with that observed in the TEMPO 3:4 trial
  • Following validation, the ADPKD Outcomes Model (ADPKD-OM) was used to estimate the potential long-term renal benefits of JYNARQUE therapy in hypothetical ADPKD cohorts

—The ADPKD-OM represents a tool to predict natural disease progression and long-term outcomes in ADPKD patients, based on readily available and/or measurable clinical characteristics

  • The effect of JYNARQUE therapy on ADPKD progression was added to the ADPKD-OM by applying a constant reduction to the rate of renal function (eGFR) decline predicted for an untreated patient
  • Consistent with TEMPO 3:4 observations, the natural rate of eGFR decline was reduced by 26.4% when using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation

 

Predicted trajectory of CKD progression in modeled ADPKD patients treated with JYNARQUE compared with natural history9

Predicted trajectory of CKD progression, Graph

 

Projected impact of JYNARQUE is greater when introduced in the earlier stages of CKD9

 

  • The estimated delay to ESKD is predicted to be greatest among patients with CKD Stage 1 at baseline (6.6 years) compared with CKD Stage 2 (4.7 years) and CKD Stage 3 (2.7 years)
  • When the effect of tolvaptan on eGFR decline was restricted to Mayo subclasses lC-lE, the ADPKD-OM predicted an additional delay to ESKD of approximately one-third of a year, when eGFR was measured by CKD-EPI (4.3 years versus 4.0 years)

 

See predicted impact of JYNARQUE in delaying time to ESKD
in patients with ADPKD.

 

 

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PREDICTION MODEL IN DELAYING TIME TO ESKD:

Based on TEMPO 3:4 data by differentiation of Mayo subclass level and CKD stage10

Mader et al prediction model overview

  • The TEMPO 3:4 treatment effect differentiated by the Mayo subclass level was applied to predict the time to ESKD
  • The model applied a constant treatment effect to baseline natural history progression estimates as estimated via the Irazabal equation
  • In the base-case analysis, the annual absolute reduction in eGFR decline for JYNARQUE versus placebo of 1.20 mL/min/1.73 m2 from the TEMPO 3:4 trial was applied to predicted eGFR decline in the absence of treatment‡

‡The model applies the treatment effect for JYNARQUE at the subclass level regardless of CKD stage. 

 

Predicted impact of JYNARQUE by CKD stage and Mayo subclass on time to ESKD10

Predicted impact of JYNARQUE by CKD Stage, Chart
Predicted impact of JYNARQUE by CKD Stage, Chart

 

Results were consistent across CKD stages and Mayo subclasses10

 

See predicted impact of JYNARQUE in delaying time to ESKD
in patients with ADPKD.

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ADPKD=autosomal dominant polycystic kidney disease; CKD=chronic kidney disease; eGFR=estimated glomerular filtration rate; ESKD=end-stage kidney disease.

 

Real-world evidence
evaluating 
effectiveness

 

Examining the effectiveness of JYNARQUE in real-world clinical practice

A retrospective, non-interventional chart review study was conducted to evaluate the clinical impact of JYNARQUE in a real-world setting11

Study design and limitations1,6,11

  • Nephrologists (N=57) were recruited through a web-based survey to provide data from medical records of JYNARQUE-treated patients under their care (N=149)
  • The study period of chart review spanned from May 2019 to September 2022
  • Historical controls (patients not treated with JYNARQUE; N=959) were selected from the CRISP I and II, HALT-PKD Study A, and OVERTURE studies in the pooled ADPKD database 
  • eGFR was calculated using the CKD-EPI equation based on serum creatinine

Matched analysis-Set 1:

JYNARQUE (n=110) and historical controls (n=110)
  • Cases and controls were matched 1:1 on baseline age (±2 years), gender, and CKD stage (1, 2, 3a, 3b, 4, 5)
  • The comparison between cases and controls in the matched analysis used a mixed model with eGFR as the response variable

Matched analysis-Set 2:

JYNARQUE (n=98) and historical controls (n=98)
  • Additional analyses were performed wherein cases and controls were matched on baseline age (±2 years), gender, and eGFR (±5 mL/min/1.73 m2)

Limitations:

  • Nephrologists were selected via convenience sampling, potentially limiting the generalizability of the results
  • The medical records chosen may be from memorable patients or patients seen more recently; therefore, the selected patients may not be representative of the general ADPKD population
  • Patient data such as diagnoses and laboratory measurements collected from medical records may contain inaccuracies

Estimated annual rate of change in eGFR – Set 1

Estimated annual rate of change in eGFR by treatment in the matched analysis11

Annual Rate of Decline in eGFR – Set 1, Chart

Estimated eGFR over time11

Estimated eGFR, JYNARQUE vs Historic Controls – Set 1, Graph

Estimated annual rate of change in eGFR – Set 2

Estimated annual rate of change in eGFR by treatment in the matched analysis11

Annual Rate of Decline in eGFR – Set 2, Chart

Estimated eGFR over time11

Estimated eGFR, JYNARQUE vs Historical Controls – Set 2, Graph
JYNARQUE slowed the annual rate of decline of eGFR in a real-world setting compared
with matched historical controls11

Review the real-world evidence for JYNARQUE

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CKD=chronic kidney disease; CKD-EPI=Chronic Kidney Disease Epidemiology Collaboration; CRISP=Consortium for Radiologic Imaging Studies of PKD; eGFR=estimated glomerular filtration rate; HALT-PKD=HALT Progression of PKD; OVERTURE=Observational Study in Patients With Autosomal Dominant Polycystic Kidney Disease

Get safety information and discontinuation
rates from the JYNARQUE clinical trials

CLINICAL SAFETY PROFILE

  1. Zhou X, Davenport E, Ouyang J, et al. Pooled data analysis of the long-term treatment effects of tolvaptan in ADPKD. Kidney Int Rep. 2022;7(5):1037-1048.
  2. Torres VE, Gansevoort RT, Perrone RD, et al. Tolvaptan in ADPKD patients with very low kidney function. Kidney Int Rep. 2021;6(8):2171-2178.
  3. Chebib FT, Torres VE. Assessing risk of rapid progression in autosomal dominant polycystic kidney disease and special considerations for disease-modifying therapy. Am J Kidney Dis. 2021;78(2):282-292.
  4. Chebib FT, Perrone RD, Chapman AB, et al. A practical guide for treatment of rapidly progressive ADPKD with tolvaptan. J Am Soc Nephrol. 2018;29(10):2458-2470.
  5. Chebib FT, Dahl N, Zhou X, et al. Poster presented at: PKD Connect 2023; June 23-25, 2023; Denver, CO.
  6. Irazabal MV, Rangel LJ, Bergstralh EJ, et al. Imaging classification of autosomal dominant polycystic kidney disease: a simple model for selecting patients for clinical trials. J Am Soc Nephrol. 2015;26(1):160-172.
  7. Chebib FT, Zhou X, Garbinsky D, et al. Pooled data analysis of the long-term effect of tolvaptan in patients between 56 and 65 years with autosomal dominant polycystic kidney disease (ADPKD). Presented at: National Kidney Foundation Spring Clinical Meetings; Boston, MA. April 6–10, 2022. Abstract 350.
  8. Torres VE, Chapman AB, Devuyst O, et al; for the REPRISE Trial Investigators. Tolvaptan in later-stage autosomal dominant polycystic kidney disease. N Engl J Med. 2017;377(20):1930-1942.
  9. Bennett H, McEwan P, Hamilton K, O'Reilly K. Modelling the long-term benefits of tolvaptan therapy on renal function decline in autosomal dominant polycystic kidney disease: an exploratory analysis using the ADPKD outcomes model. BMC Nephrol. 2019;20(1):136.
  10. Mader G, Purser M, Mladsi D, Sanon M, Oberdhan D, Watnick T, Seliger S. Benefit of tolvaptan on time to end-stage renal disease (ESRD) for patients with rapidly progressing autosomal dominant polycystic kidney disease (ADPKD): a disease progression model. Poster presented at the 2020 National Kidney Foundation Spring Clinical Meeting; New Orleans, LA. March 25-29, 2022. Abstract.
  11. Perrone RD, Nunna S, Gandhi HK, et al. Poster presented at: ASN Kidney Week; November 1-5, 2023; Philadelphia, PA.

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.