Long-Term Experience of Tolvaptan

Abstract

In Canada, tolvaptan (JINARC) is approved for the treatment of adults with autosomal dominant polycystic kidney disease to slow the progression of kidney enlargement and kidney function decline. Safety data from the pivotal Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO 3:4) study suggested the potential for increased risk of liver injury with tolvaptan, which led to the establishment of the Canadian Hepatic Safety Monitoring and Distribution Programme in 2015. This review summarizes data regarding hepatic safety from clinical trials and presents data from established risk mitigation programs and real-world evidence. Data show that frequent liver function monitoring allows timely detection of drug-induced liver injury and prompt treatment interruption. To date, this approach has led to the absence of serious liver injury or liver failure in more than 2800 patients treated with tolvaptan in Canada over the past 10 years.

Introduction

Drug-related hepatotoxicity may be intrinsic or idiosyncratic.¹ Intrinsic hepatotoxicity is reproducible in animals, occurs dose dependently at sublethal doses, and can be influenced by environmental and genetic sensitivity factors. A well-known example of intrinsic drug-related hepatotoxicity is acetaminophen. By contrast, idiosyncratic hepatotoxicity occurs in a minority of patients, has a variable time of onset, shows no relationship with drug dose, and is not reproducible in animals.

Although there are currently no standard criteria to define drug-induced liver injury (DILI), the US Food and Drug Administration (FDA) suggests using a threshold of aminotransferases >3× upper limit of normal (ULN) as a reasonable indicator of severe liver injury during drug development.² Hy's Law, developed by the FDA in the setting of assessing a drug for its potential to causes severe DILI,³ states that a drug must be stopped immediately if specific criteria are met (>3× ULN of alanine aminotransferase [ALT] or aspartate aminotransferase [AST] and >2× ULN total bilirubin [TBIL]). In addition, a causality assessment must be conducted to exclude other possible causes of liver injury.^2,4 A single verified case of Hy's Law in a clinical trial can have severe regulatory consequences, including nonapproval or removal of a drug from the market. According to the FDA, tolvaptan (JINARC) is classified in the most severe category for its potential to cause DILI and for the severity of the possible toxicity.^5,6

Initial safety data from the phase 3 Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO 3:4) study⁷ identified a potential for increased risk of liver injury with tolvaptan. In Canada, tolvaptan is indicated to slow the progression of kidney enlargement and kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD).⁸ The Canadian product monograph for JINARC contains a Boxed Warning regarding the risk of idiosyncratic hepatic toxicity and states that the use of tolvaptan has led to idiosyncratic elevations of ALT and AST, rarely with concomitant elevation of TBIL. This led to the mandatory establishment of the Canadian Hepatic Safety Monitoring and Distribution (HSMD) programme.⁸

This in-depth review aims to describe the risk, classification, and incidence of tolvaptan-induced liver injury from published literature, the Canadian HSMD programme, other safety programs around the world, and the Global Tolvaptan Pharmacovigilance Safety Report.

Tolvaptan-Associated Liver Injury—Data from Pivotal Trials

The clinical trial program for tolvaptan for the treatment of ADPKD includes the pivotal TEMPO 3:4 study, the TEMPO 3:4 extension study TEMPO 4:4, the Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy (REPRISE) study, and an open-label long-term safety and tolerability study (Table 1).

Table 1.

Design and end points of studies included in the clinical trial program for tolvaptan

Study	Design	End Points
TEMPO 3:4 (NCT00428948)7	• Phase 3, multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of tolvaptan in patients with ADPKD • Included adult patients (18–50 yr of age) with early-stage ADPKD with TKV ≥750 ml and an estimated creatinine clearance of ≥60 ml/min • Patients were randomized in a 2:1 ratio to receive tolvaptan at the highest of three twice-daily dose regimens that the patient found tolerable, or placebo, for 3 yr; starting dose of tolvaptan was daily morning and afternoon doses of 45 and 15 mg, respectively, with weekly increases to 60 and 30 mg, and then to 90 and 30 mg, according to patient-reported tolerability • 961 patients were randomized to the tolvaptan group and 484 patients to the placebo group • ALT, AST, and TBIL measured at baseline, end of titration, and 3–4-mo intervals thereafter	• Primary end point: annual rate of change in TKV • Secondary end points: composite of time to clinical progression (defined as worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of decline in kidney function
TEMPO 4:4a (NCT01214421)11	• Open-label, long-term extension study that evaluated the efficacy and safety of tolvaptan for a further 2 yr in patients who completed TEMPO 3:4 • All patients received tolvaptan in daily split-dose regimens of 45/15, 60/30, or 90/30 mg as morning and afternoon doses, with titration up or down based on tolerability • 557 patients from the tolvaptan group (early-treatment group) and 314 patients from the placebo group (delayed-treatment group) of the TEMPO 3:4 study enrolled in the TEMPO 4:4 • ALT, AST, and TBIL were initially measured at open-label baseline and then every 3 mo thereafter. After the first round of hepatic adjudication during the study (2012) and the occurrence of a 3rd case of Hy's law, the frequency of liver monitoring increased to once monthly for 18 mo	• Primary end point: change in TKV from TEMPO 3:4 baseline to mo 24 in TEMPO 4:4 • Key secondary end points: eGFR from TEMPO 3:4 baseline to mo 24 in TEMPO 4:4, and TKV and eGFR slopes during TEMPO 4:4
REPRISE (NCT02160145)12	• Phase 3, multicenter, randomized withdrawal, double-blind, placebo-controlled trial that evaluated the efficacy and safety of tolvaptan in patients with more advanced ADPKD (late CKD of stage 2 to early stage 4), using more frequent monitoring for toxic liver effects • Included patients 18–55 yr of age with eGFR 25–65 ml/min per 1.73 m2, or patients 56–65 yr of age with eGFR 25–44 ml/min per 1.73 m2; patients in the older group were also required to have evidence of decline in eGFR >2.0 ml/min per 1.73 m2 per year • Patients randomized 1:1 to receive tolvaptan at the highest of two twice-daily dose regimens that the patient found tolerable (morning and afternoon doses of 60 and 30, or 90 and 30 mg) or placebo, for 2 yr • 683 patients randomized to the tolvaptan group and 687 patients to the placebo group; 681 and 685 patients, respectively, were included in the safety analysis • The frequency of liver tests monitoring was conducted on a monthly basis	• Primary end point: change in eGFR from baseline • Key secondary efficacy end point: slope of change in eGFR derived from the individual slopes for each patient, with adjustment for the duration of the observations and with interpolation to 1 yr • Secondary safety end point: overall hepatic safety monitoring that included adjudication by the HAC of all cases of elevations in ALT/AST >3× ULN, elevations in TBIL >2× ULN, and hepatic-related AEs that were serious or led to discontinuation of the trial regimen
Open-label long-term safety and tolerability study (NCT02251275)25	• Prospective, multinational, open-label study that evaluated the long-term safety of tolvaptan • Included 1803 patients who completed TEMPO 4:4, REPRISE, or other tolvaptan trials • Assessments included monthly LFT during the first 18 mo of treatment with tolvaptan and every 3 mo thereafter

ADPKD, autosomal dominant polycystic kidney disease; AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; HAC, Hepatic Adjudication Committee; LFT, liver function test; REPRISE, Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy; TBIL, total bilirubin; TEMPO, Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes; TKV, total kidney volume; ULN, upper limit of normal.

^aTolvaptan efficacy and safety in management of autosomal dominant polycystic kidney disease and its outcomes 4:4 ran from 2010 to 2016. The first round of hepatic adjudication took place in 2012, leading to protocol amendment for frequency of liver monitoring also in 2012.

TEMPO 3:4

In TEMPO 3:4, liver enzymes were measured every 3–4 months.⁷ Although overall, the rates of adverse events (AEs) were similar between the tolvaptan group (97.9%) and the placebo group (97.1%), a greater proportion of patients in the tolvaptan group experienced elevated liver enzyme levels (Table 2). An independent and blinded expert Hepatic Adjudication Committee (HAC) re-examined data from TEMPO 3:4 to assess the risk of hepatotoxicity with tolvaptan.⁹ Of 35 adjudicated cases, the HAC identified 17 patients as having a probable or high likelihood that a liver injury event was caused by the study medication (tolvaptan [n=16] compared with placebo [n=1]). The HAC confirmed that two of the probable cases in the tolvaptan group (2/957 [0.2%]) and zero in the placebo group (0/484 [0%]) met Hy's Law criteria. ALT levels in most patients who discontinued tolvaptan (14/35) returned to ≤3× ULN within 40 days, whereas ALT levels in patients who continued therapy (21/35) returned to ≤3× ULN within 120 days. Based on these results, the HAC suggested a potential signature pattern for the development of acute hepatocellular injury with onset between 3 and 18 months after starting tolvaptan therapy.

Table 2.

Hepatic-related adverse events and serious adverse events in the TEMPO 3:4 study

Eventa	Tolvaptan (n=958)	Placebo (n=484)
AEs occurring in ≥2% of patients in either group, No. (%)
ALT increased	42 (4.4)	5 (1.0)
AST increased	30 (3.1)	4 (0.8)
Serious AEs more common in the tolvaptan group, No. (%)
ALT increased	9 (0.9)	2 (0.4)
AST increased	9 (0.9)	2 (0.4)
Adjudication of hepatic events
Patients meeting Hy's Law criteria	2	0

AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TEMPO, Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes.

^aAlanine aminotransferase/aspartate aminotransferase increased was defined as >3× upper limit of normal.

Betts et al. conducted an analysis using individual patient-level data from TEMPO 3:4 to calculate the number needed to harm with tolvaptan versus placebo on the risk of liver function abnormalities.¹⁰ The analysis calculated that for every 100 patients treated with tolvaptan, 1.78 additional patients would experience ALT >3× ULN over 12 months and 2.51 additional patients would experience ALT >3× ULN over 24 months (Table 3). For ALT >5× ULN, and serious ALT or AST elevation (defined as life-threatening, requiring hospitalization, or resulting in persistent or significant disability/incapacity), <1 additional patient for every 100 patients treated with tolvaptan versus placebo would experience these liver abnormalities at 12 or 24 months. The authors concluded that with proper monitoring, the benefits of tolvaptan outweigh the harm for patients at risk of rapidly progressing ADPKD.

Table 3.

Number needed to harm for tolvaptan versus placebo over 12 and 24 months of treatment

Liver Function Abnormalities	NNH over 12 mo	NNH over 24 mo
ALT >3× ULN	• 56.2 • For every 100 patients treated with tolvaptan instead of placebo, 1.78 additional patients would experience ALT >3× ULN	• 39.8 • For every 100 patients treated with tolvaptan instead of placebo, 2.51 additional patients would experience ALT >3× ULN
ALT >5× ULN	• 136.5 • For every 100 patients treated with tolvaptan instead of placebo, <1 additional patient would experience ALT >5× ULN	• 136.5 • For every 100 patients treated with tolvaptan instead of placebo, <1 additional patient would experience ALT >5× ULN
Serious ALT or AST elevation	• 159.9 • For every 100 patients treated with tolvaptan instead of placebo, <1 additional patient would experience serious ALT or AST elevation	• 191.4 • For every 100 patients treated with tolvaptan instead of placebo, <1 additional patient would experience serious ALT or AST elevation

Source: Betts et al.¹⁰ ALT, alanine aminotransferase; AST, aspartate aminotransferase; NNH, number needed to harm; ULN, upper limit of normal.

TEMPO 4:4

In TEMPO 4:4, increased ALT or AST levels >3× ULN were reported in 2.5% (14/557) of patients in the early-treatment group and 3.8% (12/314) of patients in the delayed-treatment group.¹¹ One patient in the delayed-treatment group met criteria for Hy's Law and fully recovered after discontinuing tolvaptan. Adjudication of data from TEMPO 4:4 identified one patient who met Hy's Law criteria and 39 patients who experienced ALT/AST elevations >3× ULN with TBIL levels <2× ULN.⁹ Causality was assessed as probable or higher for the one patient meeting Hy's Law criteria and for nine of 39 patients. For the one patient meeting Hy's Law criteria, the event occurred 3 months after initiating tolvaptan treatment. After permanent discontinuation of tolvaptan, ALT and TBIL levels returned to normal with no chronic liver injury.

Data show no relationship between the dose of tolvaptan and the degree of liver injury in both TEMPO 3:4 and TEMPO 4:4.⁹ The variable latent period and the rarity and unpredictability of the injury are suggestive of an idiosyncratic reaction. The HAC concluded that hepatic injury with tolvaptan is a rare event with all the characteristics of an idiosyncratic reaction. They therefore recommended monthly monitoring of liver enzymes to further reduce the risk of liver injury in patients receiving long-term treatment with tolvaptan.

REPRISE

During the double-blind period, the rates of AEs were similar between the tolvaptan group (83.5%) and the placebo group (82.3%).¹² Monthly monitoring of liver enzymes to mitigate risk of liver injury was implemented. A greater proportion of patients in the tolvaptan group experienced elevated liver enzyme levels compared with those in the placebo group (Table 4). In all 38 (5.6%) patients in the tolvaptan group with ALT levels >3× ULN, the disruption/discontinuation of treatment led to liver enzyme levels returning to normal. There were no reports of persistent sequelae, and no patients reported concurrent elevations in TBIL >2× ULN. No cases met criteria for Hy's Law.

Table 4.

Hepatic-related adverse events and serious adverse events in the REPRISE study

Event	5-wk Single-Blind Tolvaptan Period (N=1491)	Tolvaptan (n=681)	Placebo (n=685)
Discontinuation of trial regimen due to AE, No. (%)
Because of event in one of five liver SMQsa	4 (0.3)	11 (1.6)	1 (0.1)
Clinically significant elevations in hepatic laboratory values and events in one of five liver-related SMQsa, No. (%)
Specific liver-related event
Any	23 (1.5)	74 (10.9)	36 (5.3)
Serious AE	8 (0.5)	31 (4.6)	4 (0.6)
Elevation in ALT levels
To >3× ULN	3 (0.2)	38 (5.6)	8 (1.2)
To >5× ULN	1 (0.1)	23 (3.4)	5 (0.7)
To >10× ULN	0	8 (1.2)	4 (0.6)

Source: Torres et al.¹² AE, adverse event; ALT, alanine aminotransferase; SMQ, standardized MedDRA query; ULN, upper limit of normal.

^aThe five liver-related standardized MedDRA queries included adverse events related to cholestasis and jaundice of hepatic origin; hepatic failure, fibrosis, cirrhosis, and other liver damage–related conditions; noninfectious hepatitis; liver-related investigations, signs, and symptoms; and liver-related coagulation and bleeding disturbances.

Clinical Pattern of Tolvaptan-Associated Liver Injury in Patients with ADPKD

After the publication of results from REPRISE and a long-term, open-label extension study of tolvaptan, an updated HAC analysis was conducted.⁴ In the four pivotal trials of tolvaptan in patients with ADPKD, tolvaptan exposure was extensive, with more than 2300 patients having at least 18 months of treatment. A total of 799 patients had ≥5 years of exposure and 86 patients had >10 years of exposure. More patients receiving tolvaptan exhibited elevated liver enzymes than patients receiving placebo. In all cases, elevated liver enzyme levels returned to normal within 4 months of interrupting or discontinuing treatment. No patient in REPRISE or the long-term extension study met criteria for Hy's Law.

Overall, 210 cases of elevated ALT met the criteria for adjudication (46 from TEMPO 3:4, 39 from TEMPO 4:4, 72 from REPRISE, and 53 from the long-term extension trial; Table 5).⁴ None of these were adjudicated as definite, and no events in REPRISE or the long-term extension study were adjudicated as highly likely. The temporal pattern of increased ALT level to >3× ULN was consistent across TEMPO 3:4 and REPRISE, occurring between 60 and 240 days after the initiation of tolvaptan and becoming less frequent after 240 days (Figure 1). No hepatic event observed after 18 months of treatment with tolvaptan was adjudicated as having more than a possible relationship with tolvaptan. These results suggest that monthly liver monitoring for the first 18 months of treatment and every 3 months thereafter were sufficient.

Table 5.

Adjudication results of hepatic events from the four pivotal trials of tolvaptan in autosomal dominant polycystic kidney disease

Causality Analysis	TEMPO 3:4	TEMPO 4:4	REPRISE	Long-Term Extension Trial	Total
Tolvaptan and placebo combined
Adjudicated	46	39	72	53	210
Definite	0	0	0	0	0
Highly likely	1	3	0	0	4
Probable	17	6	15	2	40
Possible	11	11	39	24	85
Unlikely	17	19	18	23	77
Insufficient data	0	0	0	4	4
Tolvaptan
Adjudicated	35	39	62	53	189
Definite	0	0	0	0	0
Highly likely	1	3	0	0	4
Probable	16	6	15	2	39
Possible	9	11	33	24	77
Unlikely	9	19	14	23	65
Insufficient data	0	0	0	4	4
Placebo
Adjudicated	11	0	10	0	21
Definite	0	0	0	0	0
Highly likely	0	0	0	0	0
Probable	1	0	0	0	1
Possible	2	0	6	0	8
Unlikely	8	0	4	0	12
Insufficient data	0	0	0	0	0

Source: Alpers et al.⁴ 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.

Figure 1.

Time to first elevation in ALT >3× ULN. In REPRISE (A) and long-term extension study (B). ALT, alanine aminotransferase; REPRISE, Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy; ULN, upper limit of normal. Source: Alpers et al.⁴

Canadian, American, and European Risk Mitigation Programs

Canadian Safety Programme

In Canada, tolvaptan is available for the treatment of patients with ADPKD only through a manufacturer and product-specific controlled HSMD programme conducted and maintained by, or for, the market authorization holder of JINARC.⁸ Enrollment in the HSMD programme requires a duly signed manufacturer and product-specific patient-prescriber agreement and requires patients to undergo mandatory liver enzyme tests. Patients are given access to tolvaptan only if liver enzyme results are below 3× ULN. The Canadian HSMD programme recommends that liver enzyme testing be conducted once monthly for the first 18 months of treatment and then every 3 months for another 12 months, followed by testing every 3–6 months thereafter until treatment cessation, to enable prompt detection and management of elevated liver enzymes to avoid tolvaptan-induced DILI.⁸ This monitoring ensures that patients undergo regular liver enzyme monitoring and that patients who show signs of liver damage are not able to continue using tolvaptan. Causes of elevated liver enzymes are not collected by the programme. The goals of the Canadian HSMD programme are to minimize the risk of liver injury associated with tolvaptan, inform health care providers and patients about the serious risk and safe use conditions for tolvaptan, ensure appropriate patient selection for treatment with tolvaptan, and document appropriate laboratory monitoring of potential liver enzyme elevation while on treatment with tolvaptan (Table 6).⁸ As of May 31, 2024, 3280 patients have enrolled in the program and 2847 have received at least one dose of tolvaptan. ALT or AST elevations >3× ULN have been reported in 3.5% of patients, with a median and mean time to first event of 12.5 and 22.3 months, respectively (range, 1–81 months; cutoff April 10, 2024). Most events (63%) occurred in the first 18 months of treatment (Figure 2). Causes of liver enzyme elevations are not collected for the programme; therefore, it is unknown whether elevations are attributable to tolvaptan or other hepatic insults. These real-world data are consistent with data from pivotal clinical trials of tolvaptan.

Table 6.

The Canadian hepatic safety monitoring and distribution program for the use of tolvaptan in patients with autosomal dominant polycystic kidney disease

Suggested Measures to Mitigate the Risk of Liver Injury with the Use of Tolvaptan for the Treatment of ADPKD

• Blood testing for hepatic transaminases and TBIL is required before initiation • Monitoring of hepatic transaminases must be continued monthly for 18 mo, every 3 mo for the next 12 mo, and every 3–6 mo thereafter • At the onset of symptoms or signs consistent with hepatic injury, or if abnormal ALT or AST increases are detected, tolvaptan administration must be immediately interrupted and repeat liver tests, i.e., ALT, AST, TBIL, ALP, must be obtained as soon as possible, ideally within 48–72 h • Testing should continue at an increased frequency until symptoms/signs/laboratory abnormalities stabilize or resolve, at which point cautious reinitiation of tolvaptan may be considered • Guidelines for permanent discontinuation include:  • ALT or AST >8× ULN  • ALT or AST >5× ULN, for more than 2 wk  • ALT or AST >3× ULN, and TBIL >2× ULN or INR >1.5  • ALT or AST >3× ULN, with persistent symptoms of hepatic injury • Once a patient has been permanently discontinued from receiving tolvaptan, treatment must never be restarted

Source: JINARC Product Monograph. Available at https://jinarcmonograph.ca/. ADPKD, autosomal dominant polycystic kidney disease; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, international normalized ratio; TBIL, total bilirubin; ULN, upper limit of normal.

Figure 2.

Time to first reported ALT or AST elevation >3× ULN for patients with ADPKD treated with tolvaptan in Canada. ADPKD, autosomal dominant polycystic kidney disease; AST, aspartate aminotransferase. Source: Otsuka Canada Pharmaceutical Inc. Data on file.

The HSMD programme has been effective at preventing tolvaptan-induced DILI. No cases of clinical liver failure related to DILI have been reported. Eleven patients met criteria for permanent discontinuation over the years and were added to a permanent discontinuation list, thus ensuring that these patients never restart tolvaptan inadvertently. In addition, 15.6% (203/1299) of patients treated with tolvaptan for more than 18 months continue to undergo monthly liver enzyme measurements, per physician preference, instead of being monitored every 3–6 months as per the HSMD programme requirement. These Canadian real-world data also show that elevated liver enzymes have been detected as long as 81 months after tolvaptan initiation, suggesting the need for ongoing and permanent monitoring via a HSMD program regardless of how long a patient has been on therapy.

American Safety Program (Risk Evaluation Mitigation Strategy)

An analysis was conducted using Risk Evaluation Mitigation Strategy (REMS) data collected between May 14, 2018, and February 23, 2023, (5 years) for US patients (n=10,879) who were tolvaptan naïve and initiated treatment in the postmarketing setting.¹³ Tolvaptan exposure was >12 months for 45% of patients and >18 months for 35% of patients. Comparison of possible severe DILI incidence in the REMS and tolvaptan clinical trials (TEMPO 3:4, TEMPO 4:4, REPRISE, and the long-term extension trial) showed that the incidence of severe DILI was lower in the REMS data (0.8%; 82/10,879) than observed in clinical trials (5.5%; 151/2743). This difference may be due to differences in frequency of liver enzyme testing. In the REMS cohort, liver enzyme testing was conducted once monthly for the first 18 months of treatment, per product label. By contrast, liver function testing in TEMPO 3:4 and part of TEMPO 4:4 was conducted every 3–4 months. Therefore, it may have taken longer to detect and manage liver injury before the current testing schedule was mandated. Four of 82 patients with possible severe DILI were confirmed to have developed events suggestive of serious and potentially fatal liver injury. All four patients recovered after tolvaptan was discontinued. These events occurred 2–5 months after tolvaptan initiation. In two of these occurrences, no liver enzyme testing had been performed at 49 and 64 days.¹⁴ The absence of liver transplants or fatalities attributable to tolvaptan-related DILI in the REMS support the effectiveness of the liver safety precautions required by the tolvaptan prescribing label to promptly detect and manage possible liver AEs. No specific risk factors for tolvaptan-related DILI have been identified from patient demographics, medical history, or concomitant medication.¹³

European Safety Program

As of April 15, 2022, 2185 patients have been screened for eligibility and 2118 patients have been enrolled in European Safety Program, for a mean tolvaptan exposure of 631.3 days (approximately 21 months).¹⁵ Seventy-five (3.6%) patients experienced ALT or AST ≥3× ULN. In ten cases, further confirmation from the investigational sites was needed. The remaining 65 (3.1%) patients had confirmed transaminase elevations ≥3× ULN, similar to what was seen in clinical trials (TEMPO 3:4 and REPRISE). No cases of Hy's Law, no deaths due to liver injury, and no tolvaptan-related liver transplantation were reported. Most patients with ALT or AST ≥3× ULN experienced the elevation within the first 18 months of treatment and 1% experienced the elevation after 18 months. Tolvaptan treatment was interrupted or withdrawn as recommended per labeling in 59 of 65 (90.8%) patients with confirmed ALT or AST ≥3× ULN. At data cutoff, 66 of 84 events had resolved, seven were resolving, six were not resolved, and the outcome of five events was not reported. Treatment with tolvaptan was reinitiated in 27 patients who had interrupted treatment, and 20 of these patients were able to continue tolvaptan for more than 6 months after reinitiation. The interim results of this postmarketing safety study were consistent with those observed in tolvaptan clinical trials. The results also show that the risk of liver enzyme abnormality is the highest in the first 18 months after starting treatment, consistent with earlier findings. Finally, similar to Canadian and American real-world data, the absence of severe liver injury in European data indicates that liver enzyme testing once monthly for the first 18 months of treatment, and every 3 months thereafter, allows prompt detection and management of liver enzyme elevations and helps avoid severe cases of tolvaptan-induced DILI.

Other Safety Programs, Real-World Evidence, and Published Case Reports

Other safety programs for tolvaptan in patients with ADPKD from Australia,¹⁶ Japan,^17,18 and Korea¹⁹ are summarized in Table 7. The authors acknowledge the existence of additional published real-world evidence (RWE) and multiple published case reports of adverse hepatic safety events in patients receiving tolvaptan. However, a comprehensive summary of all published RWE and case reports is beyond the scope of this review.

Table 7.

Australian, Japanese, and Korean risk mitigation programs and real-world evidence for tolvaptan in autosomal dominant polycystic kidney disease

Country and Program	Safety Program Summary and RWE
Australia (IMADJIN)16	• Real-world data on hepatic safety were collected in patients treated with tolvaptan for ADPKD through the IMADJIN program. While treating clinicians were able to review detailed reports for patient's LFTs, the IMADJIN data set only collected data on the outcome of the results (normal or abnormal and tolvaptan treatment decision continue or discontinue); thus no further quantitative data are available • After a median follow-up of 12.0 mo, the estimated 12-mo persistence of treatment was 76.7% • Overall, 14% of patients reported a hepatic abnormality at some point • The rate of hepatic AEs was not related to tolvaptan dose, nor were AEs related to the length of time for tolvaptan treatment • Hepatic toxicity events were observed 3 mo after tolvaptan initiation and were less prevalent over time • Hepatic AEs, defined as abnormal LFTs resulting in tolvaptan discontinuation, were observed in 2.1% of patients
Japan (SLOW-PKD)17,18	• Postmarketing surveillance has been conducted by the SLOW-PKD study • ALT increase of >30 and >90 IU/L were observed in 38.3% and 8.6% of patients, respectively • Overall, 262 patients (15.7%) experienced hepatic AEs • Of 1492 patients that had ALT <30 IU/L at baseline, 6.1% (91/1492) of patients experienced ALT ≥3× ULN (defined as>90 and ≤240 IU/L) and 2.5% (38/1492) experienced ALT >8× ULN (defined as>240 IU/L) • Most cases of increased ALT >3× ULN occurred 3–14 mo after starting treatment with tolvaptan, with approximately 20% observed after 15 mo • Two deaths occurred during the reporting period that were considered as having a causal relationship to treatment with tolvaptan. One female patient was found to have a liver tumor after 7 mo; at surgery, the tumor could not be removed. One 51-yr-old female developed a cyst infection after 5 mo and subsequently developed disseminated intravascular coagulation and liver/renal impairment
Korea (ESSENTIAL)19	• The ESSENTIAL study is a multicenter, single-arm, open-label, phase 4 clinical trial designed to assess the safety of tolvaptan among Korean patients aged 19–50 yr with ADPKD with CKD stage 1–3 • A total of 117 patients were included in the analysis. The mean duration of treatment with tolvaptan was 1.7±0.6 yr, and the average dose was 94.4±24.1 mg/d • ALT elevations were observed in 22.2% (26/117) of patients and AST elevations were observed in 14.5% (17/117) of patients • The two most common AEs were DILI and aquaresis-related events • There were 17 cases of DILI (14.5%); most of these occurred within 18 mo of starting tolvaptan • A total of 8 (6.8%) patients discontinued tolvaptan treatment because of an AE. Of them, five patients discontinued because of a hepatic AE. Liver enzymes returned to normal after tolvaptan discontinuation

ADPKD, autosomal dominant polycystic kidney disease; AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DILI, drug-induced liver injury; LFT, liver function test; PKD, polycystic kidney disease; RWE, real-world evidence; ULN, upper limit of normal.

Worldwide Pharmacovigilance Data: Tolvaptan Periodic Safety Update Report

The periodic safety update report (PSUR) for tolvaptan is an aggregated document containing safety information from all sources that covers all forms of tolvaptan and for all indications (Table 8) around the world.²⁰ The latest version of the PSUR, generated by the marketing authorization holder, covers the period from May 19, 2021, to May 18, 2024, with an estimated exposure for all indications and forms of tolvaptan in this period of 597,199 patient-years. It has been identified that liver injury is an identified risk in patients with ADPKD treated with tolvaptan. The global safety database was searched for cases involving tolvaptan use in ADPKD indication and preferred terms (PTs) in the following Standardized MedDRA Queries (SMQs):

• Cholestasis and jaundice of hepatic origin SMQ (narrow).

• Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions SMQ (narrow).

• Hepatitis, noninfectious SMQ (narrow; this search includes the PT Hepatitis acute).

• Liver related investigations, signs and symptoms SMQ (narrow).

• Liver-related coagulation and bleeding disturbances SMQ (narrow). Events from the search strategy will be further referred to as hepatic events.

Table 8.

Indications for tolvaptan

Country or Region	Indications
Canada	1) To slow the progression of kidney enlargement and kidney function decline in patients with ADPKD 2) Treatment of clinically important, non-hypovolemic. hyponatremia (e.g., serum sodium < 130 mEq/L, or symptomatic hyponatremia)
EU/EEA	1) Treatment of adult patients with hyponatremia secondary to SIADH 2) To slow the progression of cyst development and renal insufficiency of ADPKD in adults with CKD stage 1–4 at initiation of treatment with evidence of rapidly progressing disease
Outside the EU/EEA (including US)	1) Treatment of clinically significant hypervolemic and euvolemic hyponatremia (or clinically important, nonhypovolemic hyponatremia) 2) Treatment of hyponatremia secondary to SIADH in adult patients 3) Treatment of volume overload in heart failure when adequate response is not obtained with other diuretics (e.g., loop diuretics) 4) Treatment of body fluid retention in hepatic cirrhosis when adequate response is not obtained with other diuretics (e.g., loop diuretics) 5) ADPKD

ADPKD, autosomal dominant polycystic kidney disease; EEA, European Economic Area; EU, European Union; SIADH, syndrome of inappropriate antidiuretic hormone secretion; US, the United States.

For the reporting period and ADPKD indication, there were 1892 reported cases, including 2519 hepatic events. The most frequently reported PT was ALT increased (545 events). The estimated exposure in the 3-year period specifically in ADPKD was 120,281 patient-years. The latest PSUR did not identify any new data altering the current understanding of the risk of liver injury with tolvaptan. The latest safety data are consistent with those of previous reporting periods and did not identify a significant increase in frequency, severity, or relatedness of risk of liver injury during the reporting period.

Cases with events of liver injury of special interest, such as liver transplantation or encephalopathy, or which met one of the following criteria, were selected to be assessed by an external HAC:

• ALT or AST >8× ULN.

• ALT or AST >5× ULN for more than 2 weeks.

• ALT or AST>3 × ULN and (TBIL >2× ULN or international normalized ratio >1.5).

• ALT or AST >3× ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).

• Patients with abnormal transaminase levels at baseline, ALT or AST >2× ULN, or a doubling of baseline of the highest abnormal baseline liver enzyme result.

Overall, 91 postmarketing cases met the criteria for adjudication by the HAC.

Liver safety data from tolvaptan clinical trials with data cutoff for latest report (February 23, 2024) show that no new Hy's Law cases have occurred, with a total of 29,732 cases exposed to tolvaptan for 6 months. The new data indicate an estimated risk of acute liver failure of 1:42,474 based on treatment for 6 months due to tolvaptan treatment in patients with ADPKD.²⁰

Conclusions

This review shows that in clinical trials, postmarket surveillance data, and real-world data of tolvaptan-treated patients, most cases of tolvaptan-related DILI occurred in the first 18 months of drug exposure. However, some cases of increased liver enzymes do occur after 18 months, confirming the necessity for ongoing and permanent liver enzyme monitoring while on tolvaptan treatment. Because tolvaptan has been associated with severe idiosyncratic liver injury, a risk mitigation program is essential to prevent liver failure and death. To date, European (European Renal Association, ERA 2022)²¹ and international (Kidney Disease Improving Global Outcomes 2025)²² guidelines recommend testing liver enzymes every month for the first 18 months of tolvaptan therapy, followed by testing every 3 months until cessation of the drug. Practical guidance published by US nephrologists recommends testing liver enzymes every 2 weeks for the first month and then monthly for months 2–18, followed by testing every 3 months thereafter.²³ In Canada, per HSMD programme recommendations, liver enzyme testing is conducted once monthly for the first 18 months of treatment and then every 3 months for a further 12 months, followed by testing every 3–6 months thereafter for the duration of treatment, to mitigate this risk.⁸

Frequent monitoring is essential for timely detection of abnormal liver enzymes and prompt treatment interruption because most patients recover within a few months of cessation of the drug. Although the estimated risk of acute liver failure is very low at 1:42,474,²⁰ the risk exists, as evidenced by the published case of a Japanese woman who underwent transplantation after acute liver injury while on tolvaptan.²⁴ This case supports advocating for strong adherence to safety monitoring programs and prompt discontinuation of tolvaptan if liver enzyme elevation is seen to avoid liver failure. In addition to this case report, data presented in this review confirm the necessity of routine blood testing and controlled drug distribution as an effective tool to avoid severe DILI. Canadian data specifically show that in more than 2800 treated patients over a period of 10 years, and with such a system in place, there is a decreased risk of DILI and most importantly no cases of liver failure related to DILI have been reported.

Thus, the Canadian HSMD programme has proven to be very effective in decreasing the risk of liver failure, permanent liver damage, or the inadvertent reinitiation of tolvaptan for permanently discontinued patients. As there are still relatively few data on the safety of long-term tolvaptan treatment, we suggest that it is necessary to continue long-term RWE studies and safety programs, such as the HSMD programme, to collect these data.

In clinical practice, the use of tolvaptan with concurrent mandatory monitoring by the HSMD programme, such as is in place in Canada, means that patients are at a negligible risk of liver failure. Although the concern for liver injury, first identified in the TEMPO 3:4 study, remains, these data show that it is greatly attenuated by the current measures in place, allowing the safe and effective use of tolvaptan. Monitoring programs such as the Canadian HSMD programme protect patients from potential harm, while ensuring they have access to the only approved therapy to slow ADPKD progression.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/KN9/B189.

Author Contributions

Writing – original draft: Ahsan Alam, Pierre Antoine Brown, Suzy Bubolic, Annick Laplante.

Writing – review & editing: Ahsan Alam, Pierre Antoine Brown, Suzy Bubolic, Thomas Jaeger, Annick Laplante.

Funding

Medical writing support was funded by Otsuka Canada Pharmaceutical Inc.