Tolvaptan

Tolvaptan is a selective vasopressin V 2 -receptor antagonist with an affinity for the V 2 -receptor that is 1.8 times that of native arginine vasopressin (AVP). Tolvaptan affinity for the V 2 -receptor is 29 times that for the V 1a -receptor.

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

• JYNARQUE is contraindicated in patients: With a history, signs or symptoms of significant liver impairment or injury.contraindicated

Recommended dosage ( 2.1 ) Initial Dosage Titration Step Target Dosage 1st Dose 45 mg 1st Dose 60 mg 1st Dose 90 mg 2nd Dose (8 hours later) 15 mg 2nd Dose (8 hours later) 30 mg 2nd Dose (8 hours later) 30 mg Total Daily Dose 60 mg Total Daily Dose 90 mg Total Daily Dose 120 mg Dose adjustment is recommended for patients taking moderate CYP3A inhibitors ( 2.4 , 5.4 , 7.1 ) 2.1 Recommended Dosage The initial dosage for JYNARQUE 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. Encourage patients to drink enough water to avoid thirst or dehydration. 2.2 Monitoring To mitigate the risk of significant or irreversible liver injury, perform blood testing for ALT, AST and bilirubin prior to initiation of JYNARQUE, at 2 and 4 weeks after initiation, monthly for 18 months and every 3 months thereafter . Monitor for concurrent symptoms that may indicate liver injury [see Warnings and Precautions (5.1) ] . 2.3 Missed Doses If a dose of JYNARQUE is not taken at the scheduled time, take the next dose at its scheduled time. 2.4 Co-Administration with CYP3A Inhibitors CYP3A Inhibitors Concomitant use of strong CYP3A inhibitors is contraindicated [see Contraindications (4) and Warnings and Precautions (5.4) ] . In patients taking concomitant moderate CYP3A inhibitors, reduce the dose of JYNARQUE per Table 1.

Hypernatremia, dehydration and hypovolemia: May require intervention ( 5.3 ) 5.1 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. In a 3-year placebo-controlled trial and its open-label extension (in which patients' liver tests were monitored every 4 months), evidence of serious hepatocellular injury (elevations of hepatic transaminases of at least 3 times the upper limit of normal [ULN] combined with elevated bilirubin at least 2 times the ULN) occurred in 0.2% (3/1487) of tolvaptan-treated patients compared to none of the placebo-treated patients. To reduce the risk of significant or irreversible liver injury, assess ALT, AST and bilirubin prior to initiation of JYNARQUE, at 2 weeks and 4 weeks after initiation, then monthly for 18 months and every 3 months thereafter. At the onset of signs or symptoms consistent with hepatic injury or if ALT, AST, or bilirubin increase to >2 times ULN, immediately discontinue JYNARQUE, obtain repeat tests as soon as possible (within 48 to 72 hours), and continue testing as appropriate.

The following adverse reactions are discussed in more detail in other sections of the labeling: Serious Liver Injury [see Boxed Warning and Warnings and Precautions (5.1) ] Hypernatremia, Dehydration and Hypovolemia [see Warnings and Precautions (5.3) ] Drug Interactions with Inhibitors of CYP3A [see Warnings and Precautions (5.4) ] Most common observed adverse reactions with JYNARQUE (incidence >10% and at least twice that for placebo) were thirst, polyuria, nocturia, pollakiuria and polydipsia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. JYNARQUE has been studied in over 3000 patients with ADPKD. Long-term, placebo-controlled safety information of JYNARQUE in ADPKD is principally derived from two trials where 1,413 subjects received tolvaptan and 1,098 received placebo for at least 12 months across both studies. TEMPO 3:4: A Phase 3, Double-Blind, Placebo-Controlled, Randomized Trial in Early, Rapidly-Progressing ADPKD The TEMPO 3:4 (NCT00428948) trial employed a two-arm, 2:1 randomization to tolvaptan or placebo, titrated to a maximally-tolerated total daily dose of 60 to 120 mg. A total of 961 subjects with rapidly progressing ADPKD were randomized to JYNARQUE.

Pregnancy: May cause fetal harm ( 8.1 ) Lactation: Breastfeeding not recommended ( 8.2 ) 8.1 Pregnancy Risk Summary Available data with JYNARQUE use in pregnant women are insufficient to determine if there is a drug associated risk of adverse developmental outcomes. In embryo-fetal development studies, pregnant rats and rabbits received oral tolvaptan during organogenesis. At maternally non-toxic doses, tolvaptan did not cause any developmental toxicity in rats or in rabbits at exposures approximately 4- and 1-times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 90/30 mg. However, effects on embryo-fetal development occurred in both species at maternally toxic doses. In rats, reduced fetal weights and delayed fetal ossification occurred at 17 times the human exposure. In rabbits, increased abortions, embryo-fetal death, fetal microphthalmia, open eyelids, cleft palate, brachymelia and skeletal malformations occurred at approximately 3 times the human exposure (see Data ). Advise pregnant women of the potential risk to the fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage in the U.S.

Metabolism

In healthy subjects, the pharmacokinetics of tolvaptan after single doses of up to 480 mg and multiple doses up to 300 mg once daily have been studied. In ADPKD patients, single doses up to 120 mg and multiple split-doses up to 90/30 mg have been studied.

Single oral doses up to 480 mg (4 times the maximum recommended daily dose) and multiple doses up to 300 mg once daily for 5 days have been well tolerated in trials in healthy subjects. There is no specific antidote for tolvaptan intoxication. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: a rise in serum sodium concentration, polyuria, thirst, and dehydration/hypovolemia. No mortality was observed in rats or dogs following single oral doses of 2000 mg/kg (maximum feasible dose). A single oral dose of 2000 mg/kg was lethal in mice, and symptoms of toxicity in affected mice included decreased locomotor activity, staggering gait, tremor and hypothermia. In patients with suspected JYNARQUE overdosage, assessment of vital signs, electrolyte concentrations, ECG and fluid status is recommended. Continue replacement of water and electrolytes until aquaresis abates. Dialysis may not be effective in removing JYNARQUE because of its high binding affinity for human plasma protein (>98%).

• May 19, 2009NDANDA022275Otsuka
• Apr 23, 2018NDANDA204441Otsuka
• May 19, 2020ANDAANDA207605Apotex
• May 19, 2020ANDAANDA211891Alkem Labs Ltd
• Jul 16, 2021ANDAANDA205646Hetero Labs Ltd V
• Feb 15, 2022ANDAANDA206119Ph Health
• Jun 21, 2023ANDAANDA216949Msn
• Apr 23, 2025ANDAANDA216063Lupin

1. 1Death9977.2%
2. 2Thirst8606.2%
3. 3Off Label Use8506.1%
4. 4Renal Impairment8286.0%
5. 5Cardiac Failure8025.8%
6. 6Product Dose Omission Issue6524.7%
7. 7Wrong Technique In Product Usage Process5043.6%
8. 8Product Use In Unapproved Indication4903.5%
9. 9Underdose4803.5%
10. 10Dehydration4603.3%
11. 11Pollakiuria4533.3%
12. 12No Adverse Event4373.1%
13. 13Polyuria4343.1%
14. 14Blood Creatinine Increased4323.1%
15. 15Inappropriate Schedule Of Product Administration4283.1%

Recent PubMed references pinned to Tolvaptan as a MeSH major topic. Citations link to pubmed.ncbi.nlm.nih.gov.

• Tolvaptan for paraneoplastic SIADH in small cell lung cancer: a scoping review.
  Cancer treatment and research communications · 2026 · Cammann VL, Sheryl M, Fürst T, et al.
  PMID 42119219DOI 10.1016/j.ctarc.2026.101233
• TLR4 knockout ameliorates acute LPS-sensitized tolvaptan-induced idiosyncratic liver injury by disrupting drug metabolism, inflammation, and bile acid homeostasis.
  Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association · 2026 · Jiang X, Hu YX, Cheng BY, et al.
  PMID 42055275DOI 10.1016/j.fct.2026.116113
• Intravenous Tolvaptan Sodium Phosphate Can Fail to Improve Fluid Overload Due to Heart Failure in Patients With Chronic Kidney Disease: A Case Report.
  Pharmacology research & perspectives · 2026 · Uno T, Nakakura I, Ikeda A, et al.
  PMID 41992482DOI 10.1002/prp2.70252
• Increasing plasma sodium with Tolvaptan under regulated water intake: comparison with hypertonic saline.
  American journal of physiology. Renal physiology · 2026 · Sweis NW, Tuazon J, Cheema Y, et al.
  PMID 41886260DOI 10.1152/ajprenal.00049.2026
• The PKD Daily: Development and Content Validation of a Hybrid Diary for Tracking Urinary Events in Adults with Autosomal Dominant Polycystic Kidney Disease (ADPKD).
  Advances in therapy · 2026 · O'Connor M, Broderick L, Waldman LT, et al.
  PMID 41806278DOI 10.1007/s12325-026-03528-0
• Long-Term Tolvaptan Administration in Chinese Patients with Autosomal Dominant Polycystic Kidney Disease: A Retrospective Study in Real Clinical Practice.
  Kidney & blood pressure research · 2026 · Li M, Sun M, Cui S, et al.
  PMID 41774609DOI 10.1159/000550806
• Trajectories of Kidney Function in Autosomal Dominant Polycystic Kidney Disease Patients Treated with Tolvaptan.
  Medicina (Kaunas, Lithuania) · 2026 · Jankowska Z, Niemczyk M
  PMID 41597478DOI 10.3390/medicina62010194
• Relcovaptan: a promising therapeutic agent in traumatic spinal cord injury that acts by modulating newly identified transcriptional regulators of aquaporins compared to tolvaptan.
  Turkish journal of medical sciences · 2025 · Iş Ş, Ceman D, Iş M, et al.
  PMID 41509943DOI 10.55730/1300-0144.6097

The 10 most recently updated of 121 ClinicalTrials.gov registrations naming Tolvaptan as an intervention. Registration is not evidence of efficacy or safety — reference crosswalk only.

• Bempedoic Acid Therapy for Polycystic Kidney Disease
  Not yet recruiting · Phase 2 · Interventional · 120 enrolled · Kenneth Hallows
  NCT07282821updated 2026-05-01
• The German ADPKD Tolvaptan Treatment Registry
  Recruiting · Observational · 2,000 enrolled · University of Cologne
  NCT02497521updated 2026-04-30
• HYDROchlorothiazide to PROTECT Polycystic Kidney Disease Patients and Improve Their Quality of Life
  Recruiting · Phase 3 · Interventional · 300 enrolled · University Medical Center Groningen
  NCT05373264updated 2026-02-25
• A Study to See Iftolvaptan is Safe in Infants and Children Who at Enrollment Are 28 Days to Less Than 18 Years Old withAutosomal Recessive Polycystic Kidney Disease (ARPKD)
  Recruiting · Phase 3 · Interventional · 20 enrolled · Otsuka Pharmaceutical Development & Commercialization, Inc.
  NCT04782258updated 2026-02-17
• Probenecid (PB) to Treat Hereditary Nephrogenic Diabetes Insipidus (NDI), ADPKD Treated With Tolvaptan, and Severely Polyuric Patients With Previous Lithium Administration
  Completed · Phase 2 · Interventional · 36 enrolled · Mayo Clinic
  NCT05190744updated 2026-01-27
• Canadian Medical Assessment of JINARC™ Outcomes Registry
  Completed · Observational · 530 enrolled · Otsuka Canada Pharmaceutical Inc.
  NCT02925221updated 2026-01-07
• A Study to See if Tolvaptan Can Delay Dialysis in Infants and Children Who at Enrollment Are 28 Days to Less Than 12 Weeks Old With Autosomal Recessive Polycystic Kidney Disease (ARPKD)
  Withdrawn · Phase 3 · Interventional · 0 enrolled · Otsuka Pharmaceutical Development & Commercialization, Inc.
  NCT04786574updated 2025-12-24
• Post-Marketing Surveillance Study of Tolvaptan in Patients With ADPKD
  Completed · Observational · 1,802 enrolled · Otsuka Pharmaceutical Co., Ltd.
  NCT02847624updated 2025-12-10
• A Study of HRS-9057 in Patients With Heart Failure and Volume Overload
  Completed · Phase 1 · Interventional · 25 enrolled · Fujian Shengdi Pharmaceutical Co., Ltd.
  NCT06506994updated 2025-11-17
• Phase I Study Multi Dose of 7.5mg Tolvaptan in Health Male
  Completed · Phase 1 · Interventional · 12 enrolled · Otsuka Beijing Research Institute
  NCT07166887updated 2025-09-10

Frequently asked questions

How does Tolvaptan work?

Tolvaptan is a selective vasopressin V 2 -receptor antagonist with an affinity for the V 2 -receptor that is 1.8 times that of native arginine vasopressin (AVP). Tolvaptan affinity for the V 2 -receptor is 29 times that for the V 1a -receptor.

What is Tolvaptan used for?

According to FDA labeling, Tolvaptan carries indications including: JYNARQUE is indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD).. This is a reference summary of labeled uses, not medical advice or a treatment recommendation.

What class of drug is Tolvaptan?

Tolvaptan is classified as Vasopressin antagonists, Vasopressin V2 Receptor Antagonist, Cytochrome P450 3A Inhibitors, Vasopressin V2 Receptor Antagonists, Increased Diuresis.

What are the brand names for Tolvaptan?

Tolvaptan is marketed under brand names including Jynarque, Samsca.

What are the contraindications for Tolvaptan?

Tolvaptan labeling lists contraindications including: JYNARQUE is contraindicated in patients: With a history, signs or symptoms of significant liver impairment or injury.. Always consult the full prescribing information and a clinician.