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Treatment with SAMSCA® (tolvaptan)

SAMSCA is indicated for 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

Our patient selection guide can help you identify appropriate patients for SAMSCA therapy.

Important steps in the treatment of patients with hyponatremia is to determine whether their disease is acute (defined as duration of <48 hours) or chronic (defined as duration of ≥48 hours),1 and to take into account the rate of serum sodium correction.2 The risk of hyponatremia-associated complications then must be balanced against the risk of serum sodium correction. Factors that should be considered before treating include the rapidity of onset of hyponatremia; degree, duration, and symptomatology of hyponatremia; and the presence or absence of risk factors for neurologic complications.1

Treatment of Acute vs Chronic Hyponatremia

Because of the different effects of acute versus chronic hyponatremia on the brain, the treatment strategy for each will differ. Tap on the disease states below to see treatment options.

Patients requiring an urgent need to raise serum sodium to prevent or treat serious neurological symptoms should not be treated with SAMSCA.

Limit duration of therapy to 30 days.

Acute Symptomatic Hyponatremia  
Acute Asymptomatic Hyponatremia  
Chronic Symptomatic Hyponatremia  
Chronic Asymptomatic Hyponatremia  

Effects of hyponatremia on the brain and adaptive responses

The brain’s adaptation process during hyponatremia may be associated with the rare but serious consequence of osmotic demyelination syndrome (ODS) if the rate of correction of sodium is too-rapid. ODS can develop 1 to several days after aggressive treatment of hyponatremia (e.g., too-rapid correction), even with water restriction alone.3

Adapted from Adrogué HJ, Madias NE. Hyponatremia. N Engl J Med. 2000;342(21):1581-1589. Copyright © 2000 Massachusetts Medical Society. All rights reserved.

  1. Hypotonic hyponatremia results in water entering the brain.3
  2. Water gain leads to cerebral edema, intracranial hypertension, and a risk of brain injury.3
  3. Within hours, however, solutes exit the brain tissues, inducing loss of water.3
  4. This loss of water relieves the swelling of the brain. This adaptation process helps explain why even patients with severe hyponatremia may have few symptoms if the condition develops slowly.3
  5. Rapid correction of the hypotonic state can lead to shrinkage of the brain. Shrinkage of the brain leads to demyelination of pontine and extrapontine neurons, which can cause neurologic dysfunction in the form of quadriplegia, pseudobulbar palsy, seizures, coma, or even death. Patients with potassium depletion and malnutrition are at increased risk of this complication.3

Expert recommendations to avoid ODS in the management of hyponatremia

Experts advise that correction should be of an appropriate rate to reverse the manifestation of hypotonicity, but not to impose a risk of ODS.3 According to the expert panel recommendations for treating hyponatremia, the rate of correction of hyponatremia should be limited to <10 to 12 mEq/L in 24 hours and <18 mEq/L in 48 hours.2,3

As always, physicians must use their clinical judgment when treating patients with hyponatremia.

INDICATION and IMPORTANT SAFETY INFORMATION for SAMSCA® (tolvaptan)

INDICATION:

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

IMPORTANT SAFETY INFORMATION:

WARNING: INITIATE AND RE-INITIATE IN A HOSPITAL AND MONITOR SERUM SODIUM

  • 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

WARNING: NOT FOR USE FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)

  • 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 (www.fda.gov/medwatch).

Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING.

 

 

References:

1
Douglas I. Hyponatremia: why it matters, how it presents, how we can manage it. Cleve Clin J Med. 2006;73(suppl 3):S4-S12.
2
Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013;126(10 suppl 1):S1-S4.
3
Adrogué HJ, Madias NE. Hyponatremia. N Engl J Med. 2000;342(21):1581-1589.