The European Commission Approves Samsca(TM) (tolvaptan), Europe’s First and Only Oral Vasopressin Antagonist for Hyponatraemia Secondary to Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

TOKYO, Japan and UXBRIDGE, England - Otsuka Pharmaceutical Co., Ltd. and Otsuka Pharmaceutical Europe Ltd. (OPEL) announced today that the European Commission has approved the Marketing Authorisation Application for the company’s oral once-daily medication Samsca(TM)(tolvaptan), a selective V2-vasopressin receptor antagonist, for the treatment of hyponatraemia secondary to syndrome of inappropriate antidiuretic hormone secretion (SIADH) in adults. Samsca is the first oral vasopressin receptor antagonist available in Europe.

“It is very welcome news to learn that a licence has been granted for the use of tolvaptan in the treatment of hyponatraemia due to SIADH,” said Prof. Chris Thompson, Professor of Endocrinology at Beaumont Hospital, Dublin. “Hyponatraemic patients are vulnerable to a vast array of symptoms and complications and the treatments available for the treatment of hyponatraemia have had limited efficacy or significant tolerability issues. Clinicians will be aware of the excellent safety record and efficacy of tolvaptan in published trial data and will welcome the availability of a therapeutic agent which specifically treats the underlying cause of hyponatraemia.”

Results from the SALT-1 and SALT-2 (Study of Ascending Levels of Tolvaptan in Hyponatraemia -1 and -2 ) trial programme showed that once-daily oral tolvaptan was effective in increasing serum sodium concentrations(1) in patients with SIADH.

Hyponatraemia is the most common electrolyte disorder encountered in hospitalised patients and is defined as serum sodium of < 135 mmol/L.(2) The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common cause of hyponatraemia.(2)

Vasopressin and the V2 receptor play a central role in maintaining plasma osmolality. In SIADH, the body retains excess water, thus reducing the plasma osmolality by diluting sodium and causing hyponatraemia. SIADH is associated with a multitude of causes; however, cancer, central nervous system disorders and certain medications are common triggers.(2) Current treatment options are limited and often challenging to use.

Samsca is a novel molecule designed to be an orally available antagonist of the vasopressin V2 receptor, which plays a role in the kidney’s regulation of fluid excretion. Samsca is designed to promote aquaresis, the excretion of electrolyte-free water.(3)

Detailed recommendations for use of this product will be described in the Summary of Product Characteristics (SmPC) which will be published in the European Public Assessment Report (EPAR); these will be available in all official European Languages.

About Hyponatraemia

Hyponatraemia, characterised by low concentrations of sodium in the blood, is a known predictor of poor outcome in patients with serious underlying illnesses.(1) Hyponatraemia has long been associated with neurological symptoms including in its worst forms seizure and coma, and in its mildest forms decreased concentration and memory.(4) Normal serum sodium is between 135 to 145 mmol/L, whereas patients diagnosed with hyponatraemia have sodium levels of less than 135 mmol/L.

About SIADH

SIADH is characterised by inappropriate antidiuresis.(2) Vasopressin helps regulate the amount of water in the body by controlling how much water is excreted by the kidneys.(2) Vasopressin activates the V2-receptors on the collecting ducts cells in the kidneys, stimulating the insertion of aquaporin-2 water channels and the reabsorption of water.(3) In SIADH the body retains excess water, thus reducing the plasma osmolality, diluting sodium and causing hyponatraemia.(2,6) Current treatments include fluid restriction, urea, demeclocycline and intravenous infusion of saline.(6)

About Samsca

Samsca works by removing free water (water without sodium and other electrolytes) - this is known as aquaresis.

This is different from diuresis, in which both sodium and water are released. Samsca offers a selective treatment for hyponatraemia in SIADH. The mechanism of action of Samsca selectively blocks the binding of vasopressin to the V2- receptors in the collecting duct of the kidney. If the V2-receptors are occupied by vasopressin and the patient continues drinking, this will result in water retention, dilution of plasma osmolality and hyponatraemia.. 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 are not directly affected (aquaresis) (3).

About Otsuka Pharmaceutical Co., Ltd.

Founded in 1964, Otsuka Pharmaceutical Co., Ltd. is a global healthcare company with the corporate philosophy: ‘Otsuka-people creating new products for better health worldwide.’ Otsuka researches, develops, manufactures and markets innovative and original products, with a focus on pharmaceutical products for the treatment of diseases and consumer products for the maintenance of everyday health. Otsuka is committed to being a corporation that creates global value, adhering to the high ethical standards required of a company involved in human health and life, maintaining a dynamic corporate culture, and working in harmony with local communities and the natural environment.

Otsuka Pharmaceutical Co., Ltd. is a wholly owned subsidiary of Otsuka Holdings Co., Ltd., the holding company for the Otsuka Group. The Otsuka Group comprises 153 companies and employs approximately 36,000 people in 23 countries and regions worldwide. Otsuka and its consolidated subsidiaries earned Yen955.9 billion (approx. US $9.7 billion*) in annual revenues in fiscal 2008.

* Exchange rate as of March 31, 2009.

For additional information, visit www.otsuka-global.com and www.otsuka-europe.com

1. Schrier RW, Gross P, Gheorghiade M et al. Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia. (SALT-1, SALT-2). NEJM. 2006; 355(20):2099-112

2. Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. NEJM. 2007;356:2064-2072

3. Miyazaki T, Fujiki H, et al. Tolvaptan, an orally active vasopressin V(2)-receptor antagonist-pharmacology and clinical trials. Cardiovascular Drug Reviews.2007;25(1):1-13

4. Renneboog B, Musch W, Vandemergel S et al.:Mild chronic hyponatremia is associated with falls, unsteadiness and attention deficits . Am J Med 119:71e1 - 71e8 , 2006

5. Gheorghiade M, Gottlieb SS, Udelson JE et al. Vasopressin V2 Receptor Blockade with Tolvaptan versus Fluid Restriction in the Treatment of Hyponatraemia. Am J Cardiol 2006; 97:1064-1067

6. Verbalis JG, Goldsmith SR, et al. Hyponatraemia treatment guidelines 2007: expert panel recommendations. Am J Med. 2007;120(11A):S1-S21

Date of preparation: August 2009

OPEL/0609/TOL/0051

Source: Otsuka Pharmaceutical Europe Ltd.

EUROPE, Ali Ross, Otsuka Pharmaceutical Europe Ltd., Tel: +44(0)7768-337128, aross at otsuka-europe.com; JAPAN, Masamitsu Kitada, Otsuka Pharmaceutical Co., Ltd., kitadams at otsuka.jp