Tolvaptan

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). SAMSCA is a selective vasopressin V 2 -receptor antagonist 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). Limitations of Use: Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with SAMSCA.

Tolvaptan is a selective vasopressin V 2 -receptor antagonist with an affinity for the V 2 -receptor that is 1.8 times that of native arginine vasopressin (AVP). Tolvaptan affinity for the V 2 -receptor is 29 times greater than for the V 1a -receptor. When taken orally, 15 to 60 mg doses of tolvaptan antagonize the effect of vasopressin and cause an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and a resulting increase in serum sodium concentrations. Urinary excretion of sodium and potassium and plasma potassium concentrations are not significantly changed. Tolvaptan metabolites have no or weak antagonist activity for human V 2 -receptors compared with tolvaptan.

SAMSCA should be initiated and re-initiated in a hospital. The recommended starting dose is 15 mg once daily. Dosage may be increased at intervals ≥24 hr to 30 mg once daily, and to a maximum of 60 mg once daily as needed to raise serum sodium.

SAMSCA is contraindicated in the following conditions: Patients with autosomal dominant polycystic kidney disease (ADPKD) outside of FDA-approved REMS Unable to sense or respond to thirst Hypovolemic hyponatremia Taking strong CYP3A inhibitors Anuria Hypersensitivity (e.g., anaphylactic shock, rash generalized) to tolvaptan or any components of the product Use in patients with autosomal dominant polycystic kidney disease (ADPKD) outside of FDA-approved REMS. Patients who are unable to respond appropriately to thirst. Hypovolemic hyponatremia. Concomitant use of strong CYP3A inhibitors. Anuria. Hypersensitivity

Boxed 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. Liver injury: Limit treatment duration to 30 days. If hepatic injury is suspected, discontinue SAMSCA. Avoid use in patients with underlying liver disease. Dehydration and hypovolemia may require intervention. Avoid use with hypertonic saline. Avoid use with moderate to strong CYP3A inhibitors. Monitor serum potassium in patients with potassium >5 mEq/L or on drugs known to increase potassium. Urinary outflow obstruction: Urinary output must be secured

Most common adverse reactions (≥5% placebo) are thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria, and hyperglycemia ( www.fda.gov/medwatch ).

Avoid concomitant use with: Moderate CYP3A inhibitors. Strong CYP3A inducers. V 2 -receptor antagonists. Monitor serum potassium during concomitant therapy with: Angiotensin receptor blockers Angiotensin converting enzyme inhibitors Potassium sparing diuretics

Store at 25°C (77°F), excursions permitted between 15°C and 30°C (59°F to 86°F).