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

Role of Vasopressin in 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

Synthesis, Release, and Action of Vasopressin

Vasopressin is a 9-amino-acid peptide that is synthesized in the nerve bodies in the supraoptic and paraventricular nuclei of the hypothalamus and is secreted from the posterior pituitary gland.¹

Secretion of vasopressin is normally stimulated by increased plasma osmolality via activation of osmoreceptors in the anterior hypothalamus and by decreased blood volume or pressure via activation of baroreceptors in the carotid sinus, aortic arch, cardiac atria, and pulmonary venous system.^1,2

The primary role of vasopressin, or antidiuretic hormone, is to control the body's water, electrolyte balance, and blood pressure, by influencing the water excretion by the kidney. Vasopressin contributes to homeostasis by promoting the reabsorption of fluid through the V₂ receptors, by binding to these receptors, causing the translocation of aquaporin-2 water channels to the apical membrane in the collecting duct of the kidney.^2,3

Vasopressin V2-receptor activation

Vasopressin V₂-receptor activation. The binding of vasopressin to the V₂-receptor stimulates a Gs-coupled protein that activates adenylyl cyclase, in turn causing production of cAMP to activate protein kinase A. This pathway increases the exocytosis of aquaporin water channel-containing vesicles and inhibits endocytosis of the vesicles, both resulting in increases in aquaporin 2 channel formation and apical membrane insertion. This allows an increase in the permeability of water from the collecting duct.⁴

Relationship of vasopressin to hyponatremia

Inappropriately elevated plasma levels of vasopressin increase water reabsorption and retention, which will disproportionately expand the plasma volume, thus resulting in dilutional hyponatremia.²

In patients with syndrome of inappropriate antidiuretic hormone (SIADH), vasopressin release is not fully suppressed, despite hypo-osmolality, owing to other causes, including ectopic production of vasopressin by some tumors. The persistence of vasopressin release due to nonosmotic hemodynamic stimuli is also predominantly responsible for water retention and hyponatremia with hypervolemia and edema-forming disorders, such as heart failure and cirrhosis.²

Physiology of water homeostasis

V₂-receptors control the antidiuretic effect of vasopressin from their position in the renal collecting tubules. Antagonizing these receptors can produce a solute-sparing water excretion.²

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References:

Verbalis JG. Disorders of body water homeostasis. Best Pract Res Clin Endocrinol Metab. 2003;17(4):471-503.
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.
Knoers NVAM. Hyperactive vasopressin receptors and disturbed water homeostasis. N Engl J Med. 2005;352(18):1847-1850.
Finley JJ, Konstam MA, Udelson JE. Arginine vasopressin antagonists for the treatment of heart failure and hyponatremia. Circulation. 2008;118(4):410-421.

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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