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Efficacy of SAMSCA® (tolvaptan): Data from the pivotal clinical trials

SAMSCA significantly increased average daily serum sodium from baseline to Day 4 and baseline to Day 30, vs placebo (P<0.0001) in the SALT (Study of Ascending Levels of Tolvaptan in hyponatremia) trials

  • Primary end point was average daily AUC for change in serum sodium from baseline to Day 4 (tolvaptan [n=213], 4.0 mEq/L; placebo [n=203], 0.4 mEq/L [P<0.0001]) and baseline to Day 30 (tolvaptan [n=213], 6.2 mEq/L; placebo [n=203], 1.8 mEq/L [P<0.0001])

In the SALT (Study of Ascending Levels of Tolvaptan in hyponatremia) pivotal trials—two identical, 30-day, randomized, double-blind, placebo-controlled, multicenter studies—424 patients with euvolemic or hypervolemic hyponatremia (serum sodium <135 mEq/L) were treated for 30 days with tolvaptan or oral placebo, then followed for an additional 7 days after withdrawal. Primary end point from pivotal clinical trials was average daily AUC for change in serum sodium from baseline to Day 4 (tolvaptan, 4.0 mEq/L; placebo, 0.4 mEq/L, P<0.0001) and baseline to Day 30 (tolvaptan, 6.2 mEq/L; placebo, 1.8 mEq/L, P<0.0001). Mean change in serum sodium from baseline to 8 hours for tolvaptan, 2.5 mEq/L; placebo, -0.5 mEq/L. P<0.0001 (secondary end point). Starting dose was 15 mg, and was increased to 30 or 60 mg, if necessary. Within 7 days of discontinuation, serum sodium concentrations in tolvaptan-treated patients declined to placebo-like levels.

Compared with placebo, SAMSCA provided a statistically significant increase from baseline (P<0.0001) in serum sodium in patients with euvolemic or hypervolemic hyponatremia

  • Significant increase in as early as 8 hours (mean change from baseline, secondary endpoint)
  • Proven in two identical randomized, placebo-controlled, double-blind phase 3 studies (Study of Ascending Levels of Tolvaptan in hyponatremia 1 and 2)1
  • The mean increases in serum sodium during treatment initiation (first 24 hours) were 4.06 mEq/L for SAMSCA 15 mg and 0.33 mEq/L for placebo (baseline <135 mEq/L)2
Too-rapid correction of serum sodium (e.g., >12 mEq/L/24 hours) can cause serious neurologic sequelae, including osmotic demyelination syndrome (ODS).

SAMSCA significantly increased serum sodium in hyponatremic patients with heart failure

  • Demonstrated in the pooled subgroup analysis of SALT-1 and SALT-2



SAMSCA is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure and Syndrome of Inappropriate Antidiuretic Hormone (SIADH).

Important Limitations:

  • Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with SAMSCA
  • It has not been established that raising serum sodium with SAMSCA provides a symptomatic benefit to patients



  • SAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely.
  • Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable


  • Because of the risk of hepatotoxicity, tolvaptan should not be used for ADPKD outside of the FDA-approved REMS.

SAMSCA is contraindicated in the following conditions:

  • — Use in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) outside of FDA-approved REMS
  • — Urgent need to raise serum sodium acutely
  • — Inability of the patient to sense or appropriately respond to thirst
  • — Hypovolemic hyponatremia
  • — Concomitant use of strong CYP 3A inhibitors
  • — Anuric patients
  • — Hypersensitivity (e.g. anaphylactic shock, rash generalized) to tolvaptan or its components
  • Too Rapid Correction of Serum Sodium Can Cause Serious Neurologic Sequelae: During initiation and after titration monitor patients to assess serum sodium concentrations and neurologic status. Subjects with SIADH or very low baseline serum sodium concentrations may be at greater risk for too-rapid correction of serum sodium. In patients receiving SAMSCA who develop too rapid a rise in serum sodium, discontinue or interrupt treatment with SAMSCA and consider administration of hypotonic fluid. Fluid restriction during the first 24 hours with SAMSCA may increase the likelihood of overly-rapid correction of serum sodium, and should generally be avoided. Co-administration of diuretics also increases the risk of too rapid correction of serum sodium and such patients should undergo close monitoring of serum sodium.
  • Liver Injury: Tolvaptan can cause serious and potentially fatal liver injury. In clinical trials, cases of serious liver injury have been attributed to chronically administered tolvaptan in patients with ADPKD. Liver failure requiring transplantation has been reported in postmarketing experience with tolvaptan in ADPKD. Limit duration of therapy with SAMSCA to 30 days. Avoid use in patients with underlying liver disease, including cirrhosis, because the ability to recover may be impaired.
  • Dehydration and Hypovolemia: In patients who develop medically significant signs or symptoms of hypovolemia, discontinuation is recommended. Dehydration and hypovolemia can occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted
  • Co-administration with Hypertonic Saline: Not recommended
  • Other Drugs Affecting Exposure to SAMSCA:
  • CYP 3A Inhibitors: Do not use with strong inhibitors of CYP 3A; avoid concomitant use with moderate CYP 3A inhibitors
  • CYP 3A Inducers: Avoid concomitant use with CYP 3A inducers. If co-administered, the dose of SAMSCA may need to be increased
  • P-gp Inhibitors: The dose of SAMSCA may have to be reduced if co-administered with P-gp inhibitors
  • Hyperkalemia or Drugs that Increase Serum Potassium: Monitor serum potassium levels in patients with a serum potassium >5 mEq/L and in patients receiving drugs known to increase serum potassium levels

Adverse Reactions: The most common adverse reactions (SAMSCA incidence  ≥5% more than placebo, respectively): thirst (16% vs 5%), dry mouth (13% vs 4%), asthenia (9% vs 4%), constipation (7% vs 2%), pollakiuria or polyuria (11% vs 3%) and hyperglycemia (6% vs 1%)

Gastrointestinal Bleeding in Patients with Cirrhosis: In patients with cirrhosis in the hyponatremia trials, GI bleeding was reported in 10% of tolvaptan-treated patients vs 2% for placebo

Pregnancy and Nursing Mothers: SAMSCA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from SAMSCA, a decision should be made to discontinue nursing or SAMSCA, taking into consideration the importance of SAMSCA to the mother

To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 (





Schrier RW, Gross P, Gheorghiade M, et al; SALT Investigators. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. ​N Engl J Med. 2006;355(20):2099-2112.
Data on file. SAM-136. Otsuka America Pharmaceutical, Inc.
Data on file. SAM-135. Otsuka America Pharmaceutical, Inc.