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 Cirrhosis

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

Deitelzweig—hyponatremia in cirrhosis video

Hyponatremia in Cirrhosis
– Patient Case Video
Steve Deitelzweig, MD

Vasopressin
Joseph G. Verbalis, MD

Water retention and cirrhosis

The pathophysiology of hyponatremia in cirrhosis is multifactorial. On the simplest level, vasopressin is elevated in cirrhosis because metabolic clearance by the liver is impaired, correlating with disease severity.¹

In patients who have cirrhosis with ascites, liver and kidney function both are diminished. In addition, urine clearance after a water load provocation is reduced proportionally to the level of end-organ disease. Vasopressin also plays a role in water retention and is elevated along with norepinephrine, renin, and aldosterone in patients in whom water load excretion is significantly impaired.¹ This process represents a nonosmotic stimulus for vasopressin secretion.

Arterial underfilling and RAAS stimulation

As in patients with heart failure, another source of nonosmotic stimulation for vasopressin release is arterial underfilling, which leads to baroceptor-dependent stimulation of the renin-angiotensin-aldosterone system (RAAS).¹ The constant deployment of the RAAS, characteristic of late stages of cirrhosis, causes vasoconstriction. Decreased blood flow results in lack of water delivery to the kidney collecting ducts, causing increased water and sodium retention, and resulting in edema and ascites.¹

Effects of vasopressin in cirrhosis

Adapted from Gines, Hepatology, 2008.²

Patients with cirrhosis have a number of pathological conditions leading to hyponatremia. There is an impairment in the renal capacity to eliminate solute-free water, increased arterial vasodilatation, leading to arterial underfilling, and subsequent increases in levels of vasopressin.¹

The increase in vasopressin causes 2 distinct physiological responses: an increase in arterial vasoconstriction mediated by the systemic V₁-receptors, which increases arterial pressure; and an increase in tubular water resorption mediated by the kidney V₂-receptors, which leads to solute-free retention and hyponatremia.¹

A dilutional cause of hyponatremia

The major cause of hyponatremia in cirrhosis is dilutional. In other words, decreased delivery of water to the appropriate nephron segment results in decreased excretion. In patients with cirrhosis, increased proximal resorption of sodium and impaired delivery of sodium to the distal part of the glomerulus are responsible for an increase in aldosterone.¹

Renal water handling in cirrhosis

In some patients, the distal delivery of filtrate may be reduced because of a decrease in glomerular filtration rate and/or increased proximal resorption of solutes. The reduction in the distal delivery of filtrate may limit the rate of water excretion. The increased plasma levels of vasopressin enhance the water permeability of the collecting ducts and cause a marked resorption of water, which reduces urine volume. Highly concentrated urine is eliminated. Adapted from Gines, Hepatology, 2008.²

Thus several mechanisms are responsible for the hyponatremia seen in cirrhosis: vasopressin levels are elevated secondary to decreased liver degradative function, and the role of vasopressin is evoked by both osmotic and nonosmotic stimulation. Atrial underfilling and decreased solute delivery to the distal segment are both contributors to the hyponatremia associated with cirrhosis.

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References:

Gines P, Berl T, Bernardi M, et al. Hyponatremia in cirrhosis: from pathogenesis to treatment. Hepatology. 1998;28(3):851-864.
Gines P, Guevara M. Hyponatremia in cirrhosis: pathogenesis, clinical significance, and management. Hepatology. 2008;48(3):1002-1010.

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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