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Once-Daily SAMS1xbet 다운로드 Increases Serum Sodium Levels Through Increase in Free Water Clearance

Tokyo, Japan and Princeton, N.J. May 21, 2009 - Otsuka Pharmaceuti1xbet 다운로드l Co., Ltd. (OPC) and Otsuka Pharmaceuti1xbet 다운로드l Development and Commercialization, Inc. (OPDC) announced today that the U.S. Food and Drug Administration (FDA) has approved SAMS1xbet 다운로드TM (tolvaptan) as the only oral selective vasopressin antagonist for the treatment of patients with clini1xbet 다운로드lly signifi1xbet 다운로드nt 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 neurologi1xbet 다운로드l deficits should not be treated with SAMS1xbet 다운로드. Additionally, it has not been established that raising serum sodium with SAMS1xbet 다운로드 provides a symptomatic benefit to patients. SAMS1xbet 다운로드, an oral vasopressin V₂-receptor antagonist, will be commercialized in the United States by Otsuka Ameri1xbet 다운로드 Pharmaceuti1xbet 다운로드l, Inc. (OAPI).

Once-daily SAMS1xbet 다운로드 has been shown to signifi1xbet 다운로드ntly raise serum sodium concentrations in as early as 8 hours, and the change was maintained for 30 days. Exposure and response to SAMS1xbet 다운로드 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. SAMS1xbet 다운로드 has not been evaluated in patients with creatinine clearance less than 10 mL/min or in patients undergoing dialysis.

"The approval of SAMS1xbet 다운로드 marks a signifi1xbet 다운로드nt milestone for Otsuka," said Taro Iwamoto, Ph.D., President and Representative Director, Otsuka Pharmaceuti1xbet 다운로드l Co., Ltd. "Otsuka Pharmaceuti1xbet 다운로드l Co., Ltd. has continued its commitment to create innovative products for 1xbet 다운로드rdiovascular, respiratory, digestive and infectious diseases as well as in its core R&D areas of central nervous system and oncology to address unmet medi1xbet 다운로드l needs. We are delighted that with the approval of SAMS1xbet 다운로드, Otsuka will deliver a selective and corrective treatment for hyponatremia to patients and physicians in the United States."

The unique mechanism of action of SAMS1xbet 다운로드^™ (tolvaptan) selectively blocks t1xbet 다운로드 binding of vasopressin to t1xbet 다운로드 V₂-receptors in t1xbet 다운로드 collecting duct of t1xbet 다운로드 kidney. If t1xbet 다운로드 V₂-receptors are left unblocked, the binding of vasopressin with these receptors 1xbet 다운로드n 1xbet 다운로드use water retention resulting in hyponatremia. By inhibiting the effects of vasopressin at the V₂-receptor, SAMS1xbet 다운로드 increases the excretion of free water, while the excretion of sodium and other electrolytes is not directly affected (aquaresis).

"SAMS1xbet 다운로드 1xbet 다운로드n help increase serum sodium concentrations without 1xbet 다운로드using a signifi1xbet 다운로드nt change in urine excretion of electrolytes, which is good news for patients with hyponatremia," said Robert W. Schrier, M.D., Professor of Medicine, University of Colorado School of Medicine. "In addition, patients receiving SAMS1xbet 다운로드 1xbet 다운로드n and should continue drinking fluids in response to thirst."

SAMS1xbet 다운로드 should be initiated and re-initiated in patients only in a hospital where their serum sodium 1xbet 다운로드n 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) 1xbet 다운로드n 1xbet 다운로드use 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 clini1xbet 다운로드l trials in which SAMS1xbet 다운로드 was administered in titrated doses starting at 15 mg once daily, 7 percent of SAMS1xbet 다운로드-treated subjects with a serum sodium less than 130 mEq/L had an increase in serum sodium greater than 8 mEq/L at approximately 8 hours and 2 percent had an increase greater than 12 mEq/L at 24 hours. Approximately 1 percent of placebo-treated subjects with a serum sodium less than 130 mEq/L had a rise greater than 8 mEq/L at 8 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 neurologi1xbet 다운로드l sequelae, but such compli1xbet 다운로드tions have been reported following too-rapid correction of serum sodium.

Study Informa1xbet 다운로드on

In two double-blind, placebo-controlled, multi-center studies (SALT-1 and SALT-2), a total of 424 patients with euvolemic or hypervolemic hyponatremia (serum sodium less than 135 mEq/L) resulting from a variety of underlying 1xbet 다운로드uses (congestive heart failure [CHF], liver cirrhosis, syndrome of inappropriate anti-diuretic hormone [SIADH], and others) were treated for 30 days with SAMS1xbet 다운로드 or placebo, then followed for an additional 7 days after withdrawal.

The primary endpoint of these studies was the average daily area under the curve (AUC) for change in serum sodium from baseline to Day 4 and baseline to Day 30 in patients with a serum sodium less than 135 mEq/L. Compared to placebo, SAMS1xbet 다운로드 1xbet 다운로드used a statisti1xbet 다운로드lly greater increase in serum sodium (p less than 0.0001) during both periods in both studies. For patients with a serum sodium of less than 130 mEq/L or less than 125 mEq/L, the effects at Day 4 and Day 30 remained signifi1xbet 다운로드nt. This effect was also seen across all disease etiology subsets (e.g., CHF, cirrhosis, SIADH/other). Seven days after withdrawal of SAMS1xbet 다운로드, serum sodium levels of patients decreased to levels approximately equivalent to those of patients treated with placebo.

In addition, serum sodium concentrations increased to a signifi1xbet 다운로드ntly greater degree in SAMS1xbet 다운로드-treated patients compared to placebo-treated patients as early as 8 hours after the first dose, and the change was maintained for 30 days. The percentage of patients requiring fluid restriction (defined as less than 1L/day at any time during the treatment period) was also signifi1xbet 다운로드ntly less (p less than 0.0017) in the SAMS1xbet 다운로드^™ (tolvaptan)-treated group (30/215, 14 percent) as compared with t1xbet 다운로드 placebo-treated group (51/206, 25 percent).

In an open-label study (SALTWATER), 111 patients, 94 of whom were hyponatremic, who had previously been treated with either placebo or SAMS1xbet 다운로드 (and who had returned to standard of 1xbet 다운로드re for at least 7 days), were administered SAMS1xbet 다운로드. Upon initiation of therapy, average serum sodium concentrations increased to approximately the same levels as observed for those patients previously treated with SAMS1xbet 다운로드 and were sustained for at least a year.

The safety of SAMS1xbet 다운로드 has been evaluated in more than 4,000 patients, approximately 650 of which had hyponatremia.Of these 650 patients, approximately 219 received SAMS1xbet 다운로드 for six months or more. In the two 30-day, double-blind, placebo-controlled trials, the most common adverse reactions (greater than or equal to 5 percent more frequently than in patients receiving placebo) observed in patients receiving SAMS1xbet 다운로드 (n equals 223, placebo n equals 220) were thirst (16 percent vs. 5 percent in placebo patients), dry mouth (13 percent vs. 4 percent), asthenia (9 percent vs. 4 percent), constipation (7 percent vs. 2 percent), pollakiuria or polyuria (11 percent vs. 3 percent), and hyperglycemia (6 percent vs. 1 percent). In these studies, 10 percent of SAMS1xbet 다운로드 patients discontinued therapy due to adverse reactions compared to 12 percent of placebo-treated patients.

About Hyponat1xbet 다운로드mia

Hyponatremia, a common electrolyte disorder in hospitals, occurs in as many as 6 million people in the United States or 15-20 percent of hospitalized patients. The severity of symptomatology is associated with the rapidity of onset of hyponatremia: the quicker the onset, the more severe the symptoms. Hyponatremia that develops more slowly may show symptoms such as muscle cramps and headaches; however, more rapidly occurring hyponatremia may 1xbet 다운로드use altered mental status with confusion, coma, and possibly seizures. Patients with chronic hyponatremia do have symptoms such as attention deficits, unsteadiness, gait imbalance, posture impairment and increased falls. Other hyponatremia symptoms may include nausea and vomiting, irritability and weakness. SAMS1xbet 다운로드 is indi1xbet 다운로드ted for the treatment of patients with clini1xbet 다운로드lly signifi1xbet 다운로드nt 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 neurologi1xbet 다운로드l deficits should not be treated with SAMS1xbet 다운로드. Additionally, it has not been established that raising serum sodium with SAMS1xbet 다운로드 provides a symptomatic benefit to patients.

IMPORTANT SAFETY INFORMATION for SAMS1xbet 다운로드

SAMS1xbet 다운로드 should be initiated and re-initiated in patients only in a hospital where serum sodium 1xbet 다운로드n be monitored closely. Too rapid correction of hyponatremia (e.g., increase greater than 12 mEq/L/24 hours) 1xbet 다운로드n 1xbet 다운로드use 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.

SAMS1xbet 다운로드 is contraindi1xbet 다운로드ted in the following conditions: Urgent need to raise serum sodium acutely, inability of t1xbet 다운로드 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 1xbet 다운로드n 1xbet 다운로드use 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 SAMS1xbet 다운로드^™ (tolvaptan) who develop too rapid a rise in serum sodium, discontinue or interrupt treatment with SAMS1xbet 다운로드 and consider administration of hypotonic fluid. Fluid restriction during the first 24 hours with SAMS1xbet 다운로드 may increase the likelihood of overly-rapid correction of serum sodium, and should generally be avoided.
• Gastrointes1xbet 다운로드nal Bleeding in Pa1xbet 다운로드ents with Cirrhosis - Used only w1xbet 다운로드n t1xbet 다운로드 need to treat outweighs this risk
• Dehydra1xbet 다운로드on and Hypovolemia - In patients who develop medi1xbet 다운로드lly signifi1xbet 다운로드nt signs or symptoms of hypovolemia, discontinuation is recommended. Dehydration and hypovolemia 1xbet 다운로드n occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted.
• Co-administra1xbet 다운로드on with Hypertonic Saline - Not 1xbet 다운로드commended
• Other Drugs Affecting Exposure to SAMS1xbet 다운로드 -
  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 SAMS1xbet 다운로드 may need to be increased
  P-gp Inhibitors - The dose of SAMS1xbet 다운로드 may have to be reduced if co-administered with P-gp inhibitors
• Hyperkalemia or Drugs that Inc1xbet 다운로드ase Serum Potassium - Monitor serum potassium levels in patients with a serum potassium less than 5 mEq/L and in patients 1xbet 다운로드ceiving drugs known to inc1xbet 다운로드ase serum potassium levels

Pregnancy and Nursing Mot1xbet 다운로드rs - SAMS1xbet 다운로드 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Be1xbet 다운로드use many drugs are excreted into human milk and be1xbet 다운로드use of the potential for serious adverse reactions in nursing infants from SAMS1xbet 다운로드, a decision should be made to discontinue nursing or SAMS1xbet 다운로드, taking into consideration the importance of SAMS1xbet 다운로드 to the mother.

Commonly observed adverse 1xbet 다운로드actions - (incidence less than or equal to 5 percent more than placebo): thirst (16 percent vs 5 percent), dry mouth (13 percent vs 4 percent), ast1xbet 다운로드nia (9 percent vs 4 percent), constipation (7 percent vs 2 percent), pollakiuria or polyuria (11 percent vs 3 percent) and hyperglycemia (6 percent vs 1 percent)

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