IMPORTANT SAFETY INFORMATIONU.S. FULL PRESCRIBING INFORMATION, including Boxed WARNING and Medication Guide

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. SAFETY INFORMATION CONTINUED BELOW

Samsca

Etiology and Pathogenesis of Hyponatremia

About Hyponatremia Prevalence and Prognosis Etiology and Pathogenesis Role of Vasopressin in Hyponatremia Hypervolemic Hyponatremia Pathophysiology of Hyponatremia in Heart Failure Pathophysiology of Hyponatremia in Cirrhosis Euvolemic Hyponatremia Pathophysiology of SIADH in Hyponatremia Management of Hyponatremia Acute vs Chronic Hyponatremia The Role of Vasopressin Receptor Antagonists

Types of Hyponatremia
Alpesh Amin, MD

Dilutional Hyponatremia: SIADH and Edematous States
Joseph G. Verbalis, MD

The 3 categories of hyponatremia

In general, hyponatremia can be described as an excess of body water relative to serum sodium levels, often identified as a serum sodium concentration <135 mEq/L. It is often associated with decreased serum osmolality resulting from changes in total body water, rather than from changes in body sodium content. These changes are often associated with thirst, vasopressin, and the kidney.¹

Hyponatremia may be depletional, resulting from electrolyte losses in excess of water (depletional hyponatremia), or dilutional, resulting from retained water (dilutional hyponatremia). Dilutional hyponatremia is often associated with an excessive secretion of vasopressin.²

Hypotonic hyponatremia is classified into 3 main categories: hypovolemic, euvolemic, or hypervolemic based on the initial assessment of the patient's volume status, medical history, urine osmolality, and sodium concentration.^1,3 This review focuses on euvolemic and hypervolemic hyponatremia.

SAMSCA is contraindicated in hypovolemic and depletional hyponatremia.

Based on assessment of volume status, medical history, and urine osmolality and sodium concentrations, hyponatremia can be classified as hypovolemic, euvolemic, or hypervolemic.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. Reprinted with permission. Copyright © 2006 Cleveland Clinic. All rights reserved.

Euvolemic hyponatremia

Euvolemic hyponatremia, a dilutional form of hyponatremia, occurs when the total serum sodium is normal or near normal, but the total body water is increased without clinically evident edema. The syndrome of inappropriate antidiuretic hormone (SIADH) is the most common cause of euvolemic hyponatremia. Patients with euvolemic hyponatremia have no signs of volume depletion or volume expansion.^1,3

Hypervolemic hyponatremia

Hypervolemic hyponatremia, a dilutional form of hyponatremia, occurs when there is an increase in total body water but a relatively smaller increase in the total serum sodium, so the available sodium is effectively diluted. There are 3 primary causes of hypervolemic hyponatremia: heart failure, cirrhosis of the liver, and renal disease. The clinical signs of hypervolemic hyponatremia include signs of volume expansion, such as the presence of clinically evident edema, ascites, and pulmonary edema.³

Volume status and dilutional hyponatremia

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References:

Douglas I. Hyponatremia: why it matters, how it presents, how we can manage it. Cleve Clin J Med. 2006;73(suppl 3):S4-S12.
Adrogué HJ. Consequences of inadequate management of hyponatremia. Am J Nephrol. 2005;25(3):240-249.
Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW, Sterns RH. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med. 2007;120(11, suppl 1):S1-S21.

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, cirrhosis, 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

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.

SAMSCA is contraindicated in the following conditions:

— 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

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.
Gastrointestinal Bleeding in Patients With Cirrhosis – Use in cirrhotic patients only when need to treat outweighs this risk
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

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.

Commonly observed 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%).

Please see U.S. FULL PRESCRIBING INFORMATION, including Boxed WARNING, and Medication Guide.

Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan.
Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850.
SAMSCA is a registered trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan.

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