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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Last Update: March 24, 2014.



Tolvaptan is a vasopressin 2 receptor antagonist which is used for short term treatment of severe hyponatremia in patients with heart failure, cirrhosis or syndrome of inappropriate secretion of antidiuretic hormone (SIADH). It has been used experimentally to prevention progression of disease in autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan recently has been implicated in causing serum aminotransferase elevations as well as clinically apprent acute liver injury during long term use.


Tolvaptan (tol vap' tan) is a vasopressin 2 receptor antagonist (vaptan) that is used for treatment of hyponatremia caused by elevated levels of arginine vasopressin (also known as antidiuretic hormone: ADH), commonly found in patients with inappropriate ADH syndrome (SIADH) or with fluid overload from heart failure or cirrhosis. Vasopressin acts on type 2 receptors in the distal renal tubules causing reabsorption of free water, without electrolytes. Inappropriate secretion of vasopressin (as occurs in some paraneoplastic syndromes) is associated with retention of water and dilutional hyponatremia that can be symptomatic and even fatal. In controlled clinical trials, tolvaptan given for 28 days resulted in an increase in serum sodium and diuresis in patients with hypervolemic hyponatremia, in patients with cirrhosis and heart failure, and euvolemic hyponatremia in patients with SIADH. Tolvaptan was approved for use in the United States in 2009 and current indications are for short term therapy of patients with hypervolemic or euvolemic hyponatremia due to SIADH, congestive heart failure or cirrhosis. Tolvaptan has also been used experimentally to prevent progression of disease in patients with autosomal dominant polycystic kidney disease (ADPKD), but has not been approved for this use in the United States. Tolvaptan is available in tablets of 15 and 30 mg under the brand name Samsca. The recommended dose is 15 mg initially, titrating up to a maximum of 60 mg once daily, but limiting therapy to 30 days. Common side effects include excessive thirst, dry mouth and urinary frequency. Rare, but more serious side effects include hypernatremia and osmotic demyelination injury.


In prelicensure clinical trials, tolvaptan was not implicated in causing serum enzyme elevations or clinically apparent liver injury. However, instances of worsening of hepatic failure and complications of portal hypertension were reported in a small proportion of patients with cirrhosis treated with tolvaptan. These complications included variceal hemorrhage, hepatic encephalopathy and worsening of jaundice. In many trials, however, the frequency of these complications was not significantly greater than in placebo treated controls. More recently, in large registration trials of long term therapy in patients with ADPKD, serum aminotransferase elevations occurred in 4% to 5% of patients on tolvaptan, compared to only 1% of controls. Furthermore, clinically apparent liver injury occurred in approximately 0.1% of treated patients. The time to onset of illness ranged from 3 to 7 months (Case 1), but occasionally arose during long term therapy (Case 2: after 3 years of intermittent use). The clinical presentation was with the insidious development of fatigue, nausea and abdominal pain followed by dark urine, jaundice and pruritus. The pattern of serum enzyme elevations was typically hepatocellular or mixed, and liver biopsy showed an acute hepatitis with mild cholestasis. All patients recovered after stopping therapy, generally within 1 to 3 months of stopping therapy without evidence of residual injury. Immunoallergic features and autoantibodies were not found. Rapid recurrence on rechallenge was demonstrated in several patients with marked serum enzyme elevations during therapy, but patients with jaundice were not reexposed. The frequency of clinically apparent liver injury during therapy was one reason for the lack of formal approval of long term tolvaptan therapy for ADPKD.

Mechanism of Injury

Tolvaptan is metabolized by the microsomal P450 drug metabolizing enzyme CYP 3A4 and liver injury may be the result of its activation to a toxic intermediate. Inhibitors of CYP 3A4 (such as ketoconazole) can raise levels of tolvaptan and should be avoided.

Outcome and Management

The hepatic injury caused by tolvaptan is usually reversible with stopping the medication. Tolvaptan has not been linked to cases of acute liver failure, chronic hepatitis, prolonged cholestasis or vanishing bile duct syndrome. Rechallenge usually causes recurrence and should be avoided. There is no information on possible cross sensitivity to liver injury among various vasopressin 2 receptor antagonists, such as satavaptan, lixivaptan or conivaptan.

Drug Class: Diuretics, Vasopressin Antagonists


Case 1. Acute hepatitis with jaundice attributed to tolvaptan therapy.

[Modified from: Clinical review. Tolvaptan; NDA 204441: Case 04251-731-2738]

A 45 year old woman with autosomal dominant polycystic kidney disease (ADPKD) developed mild symptoms of fatigue, abdominal pain, anorexia and nausea approximately 5 months after starting tolvaptan as a part of a controlled trial of this agent in ADPKD. She had no previous history of liver disease, alcohol use, or risk factors for viral hepatitis or drug allergies. Her liver tests had been normal before treatment and again 4 months after starting tolvaptan. Her other medical conditions included renal insufficiency, recurrent urinary tract infections, hypertension and osteoarthritis. Other medications included atenolol, impidapril and olmesartan, all of which she had taken chronically. Tolvaptan was continued and she was monitored more frequently. Tests for viral hepatitis and other causes of liver disease were said to be negative. Her symptoms improved for a few days, but then worsened as did serum enzyme abnormalities and serum bilirubin (Table). Tolvaptan was stopped approximately 6 weeks after onset of symptoms. Nevertheless, serum bilirubin levels continued to rise and peaked at 7.6 mg/dL 11 days after stopping tolvaptan. Subsequently, symptoms resolved and serum enzymes fell into the normal range within the next two months.

Key Points

Medication:Tolvaptan (120 mg daily)
Pattern:Hepatocellular (R=16.2)
Severity:Moderate (hospitalized)
Latency:4 months
Recovery:2 months after stopping
Other medications:Atenolol, impidapril, olmesartan

Laboratory Values

Time After StartingTime After StoppingALT (U/L)Alk P (U/L)GGT (U/L)Bilirubin (mg/dL)Other
PrePre16140.4Tolvaptan started
123 daysPre46196310.5
166 daysPre5703582740.5Symptomatic
190 daysPre1592151990.6
202 days08823383231.4Tolvaptan stopped
207 days5 days8093162444.1
213 days11 days5983252067.6
222 days22 days2002401892.0
232 days32 days571701241.8
249 days49 days30621.1
Normal Values<35<350<50<1.2


This patient developed symptoms and serum enzyme elevations 4 months after starting tolvaptan. The medication was continued and, after improving temporarily, she developed further symptoms and jaundice. No other cause of the abnormalities was found and all liver tests fell into the normal range within two months of stopping.

Case 2. Acute hepatitis with jaundice attributed to tolvaptan therapy.

[Modified from: Clinical review. Tolvaptan; NDA 204441: Case 08271-468-4301]

A 44 year old woman with autosomal dominant polycystic kidney disease (ADPKD) participating in an experimental study of tolvaptan was found to have serum enzyme elevations at a routine 3 month study visit. She reported having mild and transient nausea and abdominal pain during the previous several weeks, but denied jaundice or dark urine. She had no previous history of liver disease or drug allergies. Her liver tests had been repeatedly normal in the past including during a three year period of taking placebo as a participant in a randomized controlled trial of tolvaptan. Tests were also normal just before starting open-label tolvaptan therapy (Table). She did not drink alcohol and had no risk factors for viral hepatitis. Her other medical conditions included renal insufficiency, recurrent urinary tract infections, hypertension and osteoarthritis. Other medications included perindopril, an antihypertensive, angiotensin converting enzyme (ACE) inhibitor available in Europe. Tolvaptan was stopped promptly, and she was admitted for evaluation and monitoring. During the ensuing weeks she developed more persistent symptoms of fatigue, nausea and anorexia followed by dark urine and jaundice. Tests for hepatitis A, B, C and E and mononucleosis were negative as were antinuclear and smooth muscle antibodies. Abdominal ultrasound and magnetic resonance imaging demonstrated multiple kidney and hepatic cysts, but no evidence of biliary obstruction or hepatic masses. A liver biopsy showed a cholestatic hepatitis with focal necrosis consistent with drug induced liver injury. In follow up, her symptoms resolved and liver tests were improved when she was seen 3 months after initial onset. During long term follow up, however, she continued to have mild elevations in serum aminotransferase levels (< twice ULN).

Key Points

Medication:Tolvaptan (120 mg daily)
Pattern:Hepatocellular (R=~15, using GGT)
Severity:Moderate (hospitalized)
Latency:3 months
Recovery:3 months
Other medications:Perindopril

Laboratory Values

Time After StartingTime After StoppingALT (U/L)GGT (U/L)Bilirubin (mg/dL)Other
PrePre12160.4Tolvaptan started
89 days012431220.8Tolvaptan stopped
98 days8 days10981901.2Symptomatic
108 days18 days17422089.6
4 months1 month74616410.2Liver biopsy
6 months3 months59630.6
7 months4 months59540.6
Normal Values<35<50<1.2


This patient developed a moderately severe acute hepatitis 90 days after starting tolvaptan in an experimental, open-label, rollover trial of this agent given long term in patients with symptomatic autosomal dominant polycystic kidney disease. The injury was detected during a routine visit and tolvaptan was promptly stopped. However, she developed symptoms and jaundice over the ensuing weeks with serum bilirubin rising to a peak of 10.2 mg/dL. A liver biopsy showed a cholestatic hepatitis without extensive necrosis. She was symptomatic for several weeks but eventually recovered, although she continued to have mild serum ALT and AST elevations in subsequent follow up. This was one of three cases of acute liver injury with jaundice that arose during the clinical development of tolvaptan as therapy for ADPKD.



Tolvaptan – Samsca®


Diuretics, Vasopressin Antagonists


Product labeling at DailyMed, National Library of Medicine, NIH


Tolvaptan Chemical Structure


References updated: 24 March 2014

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    (Expert review of hepatotoxicity published in 1999 before the availability of tolvaptan or conivaptan).
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    (Textbook of pharmacology and therapeutics; arginine vasopressin 2 receptors antagonists are aquaretics and nonpeptide inhibitors include conivaptan, tolvaptan, lixivaptan and mozavaptan).
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    (Controlled trial of tolvaptan [15 mg daily] vs placebo for 7 days in 110 patients with heart failure and fluid overload; side effects included thirst, constipation, urinary frequency and fatigue; ALT elevations and clinically apparent liver injury were not mentioned).
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    (Among 51 patients with congestive heart failure and fluid overload treated with tolvaptan for 7-14 days, ALT levels were increased in 6%, but no patient had a serious liver related adverse event).
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    (Analysis of two 3-year studies of tolvaptan in 63 patients with polycystic kidney disease; ALT elevations occurred in 2 patients [3.2%]; no details given).
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    (Systematic review of vaptans identified 12 controlled trials in a total of 2266 patients with cirrhosis and ascites; therapy had no effect on mortality or rates of variceal hemorrhage; no mention of ALT elevations or other liver complications).
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    (Analysis of 2061 patients with heart failure enrolled in placebo arm of tolvaptan trials found that liver test abnormalities were frequent with ALT elevations in 21%, Alk P in 23% and bilirubin in 26%, but most elevations were mild and improved with therapy of heart failure).
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    (Among 40 patients with cirrhosis and intractable ascites treated with tolvaptan [3.75 or 7.5 mg daily for 7 days], adverse events included hepatic encephalopathy in 4 [10%], but no specifics given).
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    (40 year old man with cirrhosis and hypervolemic hyponatremia had marked transient diuresis [from <50 to 800 mL/hr] after a single dose of tolvaptan, paracentesis and albumin infusions).
  • Cárdenas A, Ginès P, Marotta P, Czerwiec F, Oyuang J, Guevara M, Afdhal NH. Tolvaptan, an oral vasopressin antagonist, in the treatment of hyponatremia in cirrhosis. J Hepatol 2012; 56: 571-8. [PubMed: 22027579]
    (Subanalysis of trials reported by Schrier [2006] limited to patients with cirrhosis treated with tolvaptan [n=63] vs placebo [n=57] for 30 days; serious liver related adverse events occurred in 3 and deaths from liver disease in 2 tolvaptan treated subjects; gastrointestinal bleeding occurred in 6 [10%] tolvaptan- vs 1 [2%] placebo-treated patients).
  • Sakaida I, Kawazoe S, Kajimura K, Saito T, Okuse C, Takaguchi K, Okada M, et al; ASCITES-DOUBLEBLIND Study Group. Tolvaptan for improvement of hepatic edema: A phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Hepatol Res 2013. [Epub ahead of print] [PubMed: 23551935]
    (Controlled trial of 7 days of tolvaptan vs placebo in 162 patients with cirrhosis and ascites found slight increase in serum sodium [1.2 vs -0.7] and decrease in body weight [-1.9 vs-0.4 kg] and ascites with tolvaptan therapy; "No marked abnormalities were clinically observed in clinical laboratory tests").
  • Yu C, Sharma N, Saab S. Hyponatremia: clinical associations, prognosis, and treatment in cirrhosis. Exp Clin Transplant 2013; 11: 3-11. [PubMed: 23387536]
    (Review of the management of hyponatremia in cirrhosis states that the effect of vaptans is dose dependent, starts 1-2 hours after administration, lasts for 4-12 hours, and is lost within a week of withdrawal, suggesting that continuous or long term therapy is needed).
  • Abhyankar A, Robson SC, Tapper EB, Bonder A. Letter in response to the recently published review: hyponatremia in cirrhosis and end-stage liver disease-treatment with the vasopressin v2-receptor antagonist tolvaptan. Dig Dis Sci 2013; 58: 889-90. [PubMed: 23371016]
    (Summary of experience in treating 9 patients with cirrhosis and hyponatremia using oral tolvaptan for periods ranging from 9 days to 2 years; the major "patient issues" were intense thirst and high cost; no mention of liver related side effects).
  • Yakushijin K, Yamamoto K, Kurata K, Miyata Y, Kakiuchi S, Tomioka H, Kawamori-Iwamoto Y, et al. Tolvaptan as an alternative treatment for refractory fluid retention associated with sinusoidal obstruction syndrome after allogeneic stem cell transplantation. Int J Hematol 2013; 97: 284-6. [PubMed: 23297121]
    (42 year old man with lymphoma developed sinusoidal obstruction syndrome 3 weeks after allogenic hematopoietic cell transplantation [with myeloablation with busulfan and cyclophosphamide] and was given two days of tolvaptan for ascites and fluid overload followed by rise of serum sodium to 159 mEq/L; patient ultimately died of hepatic and multiorgan failure).


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