Safety Profile
of Tolvaptan

For a full listing of adverse drug reactions, and recommendations for managing adverse drug reactions, please consult the LUPIN-TOLVAPTAN Product Monograph.

The adverse reaction profile of Tolvaptan was mainly based on three phase III clinical trials: TEMPO 3:4, TEMPO 4:4 and REPRISE.1†‡§

The total clinical safety database for Tolvaptan was comprised of approximately 3,226 adult patients who participated in single and multiple-dose trials in ADPKD and who had approximately 8,430 patient-years of exposure to Tolvaptan.1

Safety Data from TEMPO 3:41†

  • Most commonly reported adverse reactions, consistent with the pharmacologic activity of Tolvaptan were thirst, polyuria, nocturia, and pollakiuria occurring in approximately 55%, 38%, 29% and 23% of patients, respectively.
  • Most commonly reported SAEs that occurred more frequently in Tolvaptan patients compared to placebo patients, with ≥0.5% difference, included increased ALT (0.9% vs. 0.4%), increased AST (0.9% vs. 0.4%), chest pain (0.8% vs. 0.4%) and headache (0.5% vs. 0%).
  • Adverse events that led to discontinuation of Tolvaptan were reported for 15.0% of patients, compared to 4.3% of placebo-treated patients, and included polyuria, pollakiuria, nocturia, thirst, abnormal hepatic function, and fatigue.

Incidence of Treatment-Emergent Adverse Drug Reactions in at Least 3% of Tolvaptan Subjects and Greater than Placebo in TEMPO 3:41

Safety Data from REPRISE1§

In the single-blind Tolvaptan run-in phase:

  • Most frequently reported adverse reactions were polyuria (31.4%), thirst (28.2%), and nocturia (20.3%).
  • Most frequently reported SAEs were alanine aminotransferase increased (0.3%), polyuria (0.3%), and nocturia (0.2%).
  • 6.8% of patients discontinued Tolvaptan due to an adverse event which included polyuria, nocturia, thirst, fatigue and pollakiuria.

In the double-blind phase:

  • Most frequently reported adverse reactions were (Tolvaptan vs. placebo): polyuria (5.3% vs. 1.3%), nocturia (4.7% vs. 1.6%), blood creatinine increased (4.6% vs. 4.8%), thirst (3.8% vs. 1.9%), fatigue (3.5% vs. 0.6%), headache (2.3% vs. 1.6%), ALT increased (3.2% vs. 0.9%), and AST increased (2.2% vs. 1.2%).
  • Most commonly reported SAE that occurred more frequently in Tolvaptan patients compared to placebo patients, with ≥0.5% difference, included hepatic enzyme increased (1.6% vs. 0.1%) and ALT increased (1.2% vs. 0.0%).
  • Adverse events that led to discontinuation of Tolvaptan were reported for 9.5% of patients, compared to 2.2% of placebo-treated patients, and included hepatic enzyme increased, ALT increased, AST increased, liver function test increased, and pollakiuria.

Incidence of Treatment-Emergent Adverse Drug Reactions in at Least 3% of Tolvaptan Subjects and Greater than Placebo in REPRISE1

Hepatotoxicity

Tolvaptan has been associated with idiosyncratic drug-induced hepatocellular injury, as seen by elevations of serum ALT and AST, rarely associated with concomitant elevations of total bilirubin.1

TEMPO 3:41†

Elevation (>3 x ULN) of ALT was observed in 4.4% (42/958) of patients on Tolvaptan, and 1.0% (5/484) of patients on placebo, while elevation (>3 x ULN) of AST was observed in 3.1% (30/958) of patients on Tolvaptan and 0.8% (4/484) patients on placebo when monitoring for liver enzymes elevation was every 3-4 months.

Two (2/957, 0.2%) of these Tolvaptan treated-patients, as well as a third patient from an extension open-label trial, exhibited increases in hepatic enzymes (>3 x ULN) with concomitant elevations in total bilirubin (>2 x ULN).

REPRISE1§

In the single-blind Tolvaptan run-in phase, elevations (>3 x ULN) of ALT and AST were observed in 0.2% (3/1,478) and 0.2% (3/1,477) of patients on Tolvaptan, respectively.

Relative to the first double-blind, placebo-controlled trial, similar elevations (>3 x ULN) of ALT (5.6% (38/681) of patients on Tolvaptan and 1.2% (8/685) of patients on placebo) and AST (3.5% (24/681) of patients on Tolvaptan and 0.9% (6/685) of patients on placebo) were observed in the double-blind phase.

Monitoring for Hepatoxicity1

To mitigate the risk of significant and/or irreversible liver injury, blood testing for hepatic transaminases and total bilirubin is required:

  • prior to initiation of LUPIN-TOLVAPTAN,
  • then hepatic transaminases continuing monthly for 18 months,
  • every 3 months for the next 12 months, and then
  • at 3–6-month intervals thereafter during treatment with LUPIN-TOLVAPTAN.

Concurrent monitoring for symptoms that may indicate liver injury (such as fatigue, anorexia, nausea, right upper abdominal discomfort, vomiting, fever, rash, pruritus, icterus, dark urine or jaundice) is also warranted.

At the onset of symptoms or signs consistent with hepatic injury, or if abnormal ALT or AST increases are detected:

  • LUPIN-TOLVAPTAN administration must be immediately interrupted and repeat liver tests, i.e., ALT, AST, total bilirubin, alkaline phosphatase, must be obtained as soon as possible, ideally within 48-72 hours
  • Testing should continue at an increased frequency until symptoms/signs/laboratory abnormalities stabilize or resolve, at which point cautious re-initiation of LUPIN-TOLVAPTAN may be considered.

Permanent discontinuation from receiving Tolvaptan is a contraindication and so once a patient has been permanently discontinued from receiving Tolvaptan, treatment must never be restarted. The permanent discontinuation status of patients should be verified prior to initiation with Tolvaptan.

Other Adverse Drug Reactions

Co-administration with Anti-hypertensive Medications1

Among ADPKD patients taking anti-hypertensive medications, a higher incidence of dizziness, presyncope, and syncope was observed in patients treated with Tolvaptan, compared to those treated with placebo.

Increases in Serum Sodium1

TEMPO 3:4†

Overall incidence of hypernatremia, reported as an adverse event was 2.8% in patients treated with Tolvaptan, compared to 1.0% in placebo-treated patients.

REPRISE§

In the single-blind period, no incidence of hypernatremia was reported.

In the double-blind treatment period of REPRISE, 0.4% of hypernatremia were reported in the Tolvaptan group and 0% in the placebo group.

None of these events lead to Tolvaptan discontinuation.

Increases in Serum Uric Acid1

TEMPO 3:4†

Gout was observed in 2.9% (20/961) of patients on Tolvaptan and 1.4% (7/483) patients on placebo, with a higher incidence of the use of allopurinol (8.2% vs. 5.8%), benzbromarone (0.4% vs. 0.2%), and colchicine-containing medications (2.3% vs. 0.8%) to manage gout in patients on Tolvaptan, compared to patients on placebo, respectively.

REPRISE§

In the single-blind period, gout was reported in 0.5% (7/1,491).

Gout was observed in 3.1% (21/681) of patients on Tolvaptan and 2.9% (20/685) of patients on placebo in the double-blind placebo-controlled trial in ADPKD patients with late stage 2 to early stage 4 CKD.

Less Common Clinical Trial Adverse Drug Reactions <3%1

The following adverse reactions occurred in <3% of ADPKD patients treated with Tolvaptan and at a rate greater than placebo in the double-blind, placebo-controlled trial (n=961 Tolvaptan; n=483 placebo), and are not mentioned elsewhere in the labeling:

Metabolism and Nutrition Disorders: dehydration, hyperglycemia

Respiratory, Thoracic and Mediastinal Disorders: dyspnea

ADPKD=autosomal dominant polycystic kidney disease; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CKD=chronic kidney disease; SAE=serious adverse event; ULN=upper limit of normal.

† TEMPO 3:4 was a double-blind, 36-month, placebo-controlled, multi-center trial. The total daily dose of 60-120 mg Tolvaptan was evaluated for safety in 961 adult ADPKD patients, with approximately 2,335 patient-years of exposure to Tolvaptan. A total of 836 patients were treated with Tolvaptan for at least 1 year and 742 patients treated with Tolvaptan had at least 3 years of exposure.1

‡ TEMPO 4:4 was an open-label extension of TEMPO 3:4. Tolvaptan was evaluated for safety in 1,083 adult patients at a total daily dose of 60-120 mg, with approximately 3,281 patient-years of exposure to Tolvaptan. A total of 698 and 509 patients were treated with Tolvaptan for at least 1 year and at least 3 years, respectively.1

§ REPRISE was a double-blind, placebo-controlled, multi-center trial. Tolvaptan was evaluated for safety in 683 adult patients with approximately 612 patient-years of exposure to Tolvaptan at a daily divided dose of up to 90 mg/30 mg. A total of 577 patients were treated with Tolvaptan for at least 1 year. Patients who successfully completed the single-blind Tolvaptan run-in period were randomized to a double-blind phase. If an adverse event continued from the single- to double-blind period, it was considered treatment emergent in the double-blind treatment period only if the adverse event worsened, became more severe or serious, or led to discontinuation. All patients were monitored monthly for liver enzymes elevation.1

Reference: 1. LUPIN-TOLVAPTAN DRAFT Product Monograph. Lupin Pharma Canada Ltd. January 28, 2025.