Otsuka Pharmaceutical Co, Ltd (OPC) and Otsuka Pharmaceutical Development and Commercialisation Inc (OPDC) announced that the US Food and Drug Administration (FDA) has approved Samsca (tolvaptan) as the only oral selective vasopressin antagonist for the treatment of patients with clinically significant hypervolemic and euvolemic hyponatremia (serum sodium less than 125 mEq/L, or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction) including patients with heart failure, cirrhosis and the syndrome of inappropriate anti-diuretic hormone (SIADH).

Patients requiring urgent treatment to raise serum sodium to prevent or to treat serious neurological deficits should not be treated with Samsca. Additionally, it has not been established that raising serum sodium with Samsca provides a symptomatic benefit to patients. Samsca, an oral vasopressin V2-receptor antagonist, will be commercialized in the United States by Otsuka America Pharmaceutical, Inc (OAPI).

Once-daily Samsca has been shown to significantly raise serum sodium concentrations in as early as eight hours, and the change was maintained for 30 days. Exposure and response to Samsca are similar in patients with a creatinine clearance of 10-79 mL/min and in patients without renal impairment; thus no dosage adjustment is necessary. Samsca has not been evaluated in patients with creatinine clearance less than 10 mL/min or in patients undergoing dialysis.

"The approval of Samsca marks a significant milestone for Otsuka," said Taro Iwamoto, Otsuka's president and representative director. "Otsuka has continued its commitment to create innovative products for cardiovascular, respiratory, digestive and infectious diseases as well as in its core R&D areas of central nervous system and oncology to address unmet medical needs. We are delighted that with the approval of SAMSCA, Otsuka will deliver a selective and corrective treatment for hyponatremia to patients and physicians in the United States."

The unique mechanism of action of Samsca (tolvaptan) selectively blocks the binding of vasopressin to the V2-receptors in the collecting duct of the kidney. If the V2-receptors are left unblocked, the binding of vasopressin with these receptors can cause water retention resulting in hyponatremia. By inhibiting the effects of vasopressin at the V2-receptor, Samsca increases the excretion of free water, while the excretion of sodium and other electrolytes is not directly affected (aquaresis).

"Samsca can help increase serum sodium concentrations without causing a significant change in urine excretion of electrolytes, which is good news for patients with hyponatremia," said Robert W Schrier, professor of Medicine, University of Colorado School of Medicine. "In addition, patients receiving Samsca can and should continue drinking fluids in response to thirst."

Samsca should be initiated and re-initiated in patients only in a hospital where their serum sodium can be monitored closely due to the risk of overly rapid correction of hyponatremia. Too rapid correction of hyponatremia (e.g., increase greater than 12 mEq/L/24 hours) can cause osmotic demyelination syndrome (ODS), resulting in dysarthria (difficulty speaking), mutism, dysphagia (trouble swallowing), lethargy, affective changes (mood changes), spastic quadraparesis (involuntary muscle weakness), seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. In controlled clinical trials in which Samsca was administered in titrated doses starting at 15 mg once daily, 7 per cent of Samsca-treated subjects with a serum sodium less than 130 mEq/L had an increase in serum sodium greater than 8 mEq/L at approximately eight hours and 2 per cent had an increase greater than 12 mEq/L at 24 hours. Approximately 1 per cent of placebo-treated subjects with a serum sodium less than 130 mEq/L had a rise greater than 8 mEq/L at eight hours and no patient had a rise greater than 12 mEq/L/24 hours. None of the patients in these studies had evidence of osmotic demyelination syndrome or related neurological sequelae, but such complications have been reported following too-rapid correction of serum sodium.