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

Pathophysiology of Hyponatremia in Heart Failure

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

O’Connell—hyponatremia in heart failure video

Hyponatremia in Heart Failure
– Patient Case Video
John O'Connell, MD

Vasopressin
Joseph G. Verbalis, MD

The role of arterial underfilling

The pathophysiology of heart failure and its relationship to hyponatremia is complex, as depicted in the figure below. Individuals who have heart failure with increased total blood volume and increased extracellular water retain both sodium and water despite having normal kidney function. Arterial underfilling has been proposed as the unifying etiology for this contradiction in volume states.¹

In heart failure, the decrease in effective arterial filling leads to a decrease in baroceptor stretch, a mechanism that mediates vasopressin release. The baroceptor-stretch response and subsequent vasopressin release is more potent than the neurohumoral hypo-osmotic inhibition of vasopressin release and overrides vasopressin inhibition.¹

Mechanism of neurohumoral activation

Adapted from Schrier, Am J Med, 2006.¹

The role of the RAAS and vasopressin release

The renin-angiotensin-aldosterone system (RAAS) and nonosmotic release of vasopressin are stimulated by the increase in sympathetic tone that results from the decrease in arterial baroceptor stretch in heart failure, as shown in the figure below. The excess of angiotensin II in heart failure causes systemic and arteriolar vasoconstriction, an increase in aldosterone concentration, and increased thirst, which further exacerbates dilutional hyponatremia.¹ The angiotensin and sympathetic pathways increase systemic vascular resistance and promote increased arterial filling.

The stimulation of vasopressin release activates the movement of aquaporin-2 water channels to the apical membrane of the collecting duct where passive water resorption occurs. Aldosterone causes sodium resorption and also acts at the collecting duct.¹

RAAS and vasopressin release

Adapted from Schrier, Am J Med, 2006.¹

In patients with heart failure, there is a decrease in transport of sodium and water to the collecting duct. This process is caused by arterial underfilling, which impairs the kidney's ability to excrete dilute urine.^1,2

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References:

Schrier RW. Water and sodium retention in edematous disorders: role of vasopressin and aldosterone. Am J Med. 2006;119(7, suppl 1):S47-S53.
Sica DA. Sodium and water retention in heart failure and diuretic therapy: basic mechanisms. Cleve Clin J Med. 2006;(73, suppl 2):S2-S7.

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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