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What is hyponatremia?

Hyponatremia is a condition in which there is an excess of body water relative to body sodium1

Often defined as serum sodium concentration < 135 mEq/L

[Na+] < 135 mEq/L

Hyponatremia may be depletional, or dilutional2,3

  • Depletional hyponatremia results from body electrolyte losses that are in excess of body water losses3
  • Dilutional hyponatremia results from retained water and is often associated with an excessive secretion of vasopressin2,3

Hypotonic hyponatremia is classified into 3 main categories

These categories are based on the initial assessment of the patient's volume status, medical history, urine osmolality, and sodium concentration.1,3

The 3 main categories with their volume status are illustrated below.
Hyponatremia
Category
Total Body Water Total Body Sodium Extracellular Fluid Edema
Hypovolemic Reduced Reduced Reduced Absent
Euvolemic Increased Unchanged Increased Absent
Hypervolemic Increased Increased Greatly Increased Present
The figure below provides a guide for classifying hyponatremia into categories.

Types of Hyponatremia

Based on assessment of volume status, medical history, and urine osmolality and sodium concentrations, hyponatremia can be classified as hypovolemic, euvolemic, or hypervolemic. Douglas I. Hyponatremia: why it matters, how it presents, how we can manage it. Cleve Clin J Med. 2006;73(suppl 3):S4-S12. Reprinted with permission. Copyright © 2006 Cleveland Clinic. All rights reserved.

Prevalence of Hyponatremia

In the United States, the estimated prevalence of hyponatremia ranges from 3.16 million to 6.07 million persons.5

Risk Factors

Certain medical conditions and medications have the potential to increase the risk of hyponatremia.2,6

Signs & Symptoms

Patients who experience hyponatremia may exhibit clinical manifestations that are largely related to central nervous system dysfunction. Signs and symptoms are important to recognize.2,7

It has not been established that raising serum sodium with SAMSCA® (tolvaptan) provides a symptomatic benefit to patients

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 hepatoxicity, 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
Adrogué HJ. Consequences of inadequate management of hyponatremia. Am J Nephrol. 2005;25(3):240-249.
3
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.
4
Han D-S, Cho B-S. Therapeutic approach to hyponatremia. Nephron. 2002;92(suppl 1):9-13.
5
Boscoe A, Paramore C, Verbalis JG. Cost of illness of hyponatremia in the United States. Cost Eff Resource Alloc. 2006;4:10.
6
Liamis G, Milionis H, Elisaf M. A review of drug-induced hyponatremia. Am J Kidney Dis. 2008;52(1):144-153.
7
Adrogué HJ, Madias NE. Hyponatremia. N Engl J Med. 2000;342(21):1581-1589.