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Study Shows Vasopressin Receptor Antagonist VAPRISOL(R) (Conivaptan Hydrochloride Injection) Significantly Increased Serum Sodium Concentration in Patients with Euvolemic & Hypervolemic Hyponatremia
Date:9/20/2007

- Phase III data published in the American Journal of Nephrology -

DEERFIELD, Ill., Sept. 20 /PRNewswire-FirstCall/ -- Astellas Pharma US, Inc. today announced that its Phase III data on VAPRISOL was published in the September issue of the American Journal of Nephrology. In this study, VAPRISOL showed a significant increase in serum sodium concentrations in patients with hyponatremia -- a potentially life-threatening condition that occurs when the body's sodium level falls below normal.

"This study demonstrated that VAPRISOL 40 mg/day significantly increased serum [Na+] in patients with euvolemic or hypervolemic hyponatremia," said Joseph G. Verbalis, M.D., at the Georgetown University Hospital. "VAPRISOL will likely address an important clinical need for euvolemic or hypervolemic hyponatremia in hospitalized patients."

VAPRISOL is the first in a new class of arginine vasopressin (AVP) receptor antagonists. VAPRISOL blocks both V1a and V2 vasopressin receptors, resulting in increased urine output without increased sodium loss. This effect, known as "aquaresis," increases serum sodium levels and helps to restore salt and water balance in patients with hyponatremia due to increased body water (dilutional hyponatremia).

VAPRISOL is approved by the U.S. Food and Drug Administration as a treatment for euvolemic and hypervolemic hyponatremia in hospitalized patients. VAPRISOL is not indicated for the treatment of congestive heart failure. It should only be used for the treatment of hyponatremia in patients with underlying heart failure when the expected benefit of raising serum sodium outweighs the increased risk of adverse events. The approved doses for VAPRISOL include 20 mg/day and 40 mg/day. The 80 mg/day dose used in this study is not an approved dose.

In the double-blind, multicenter study, 84 patients with serum sodium levels of 115 to <130 mEq/L were randomized to receive placebo or a 20-mg intravenous bolus of conivaptan, followed by continuous infusion of conivaptan 40 mg/day (n=29) or 80 mg/day (n=26) for four days.

The primary endpoint of the study was the change from baseline in serum sodium levels over the entire course of treatment (expressed as the "area under the curve," or AUC). Secondary endpoints included: time to reach a >/= 4 mEq/L increase in serum sodium levels; total time during which patients had a >/= 4 mEq/L increase in serum sodium levels; change in serum sodium levels at day four; and number of patients who achieved a >/= 6 mEq/L increase in serum sodium levels or a normal serum sodium concentration (>/= 135 mEq/L) over the course of the study.

Both doses of VAPRISOL significantly improved serum sodium levels relative to placebo, with a mean change in AUC of 490.9 (mEq/L)hr in the VAPRISOL 40 mg/day group, 716.6 (mEq/L)hr in the VAPRISOL 80 mg/day group, and 12.9 (mEq/L)hr in the placebo group (p=0.001). On average, VAPRISOL 40 mg/day and 80 mg/day produced a >/= 4 mEq/L increase in serum sodium levels within 23.7 hours and 23.4 hours, respectively. Over the course of the study, patients receiving VAPRISOL 40 mg/day, 80 mg/day, or placebo experienced increases in serum sodium of >/= 4 mEq/L for 53.2 hrs, 72.7 hrs, and 14.2 hrs, respectively (p<.001). At study's end, the mean change in serum sodium concentration was 6.3 mEq/L in patients who received VAPRISOL 40 mg/day and 9.4 mEq/L in those who received VAPRISOL 80 mg/day, compared with 0.8 mEq/L in patients who were given placebo (p<.001). Sixty-nine percent of VAPRISOL 40 mg/day patients (p<.001) and 88.5 percent of VAPRISOL 80 mg/day patients (p<.001) achieved a >/= 6 mEq/L increase in serum sodium levels or a normal serum sodium concentration (>/= 135 mEq/L) over the treatment period, compared with 20.7 percent of patients receiving placebo.

Several treatment-emergent adverse events were more common in VAPRISOL patients than in placebo patients, including injection site phlebitis, hypotension and renal dysfunction.

Adverse events were mild or moderate in severity, and there were no differences in the rates of clinically meaningful serious adverse events across the study groups. However, discontinuations due to AEs were highest among patients given conivaptan 80 mg/day and were largely attributed to local infusion-site reactions.

Note: These study results were presented at the 2004 annual meeting of the Heart Failure Society of America in Toronto.

About Hyponatremia

Hyponatremia often results from elevated levels of the hormone arginine vasopressin (AVP), which regulates water and salt balance in the body. It is the most common electrolyte disorder in clinical medicine and one of the most difficult to treat.

Syndrome of inappropriate antidiuretic hormone (SIADH), advanced kidney failure, hypothyroidism, cancer and chronic high blood pressure are common causes of hyponatremia. Dilutional hyponatremia, which includes euvolemic and hypervolemic hyponatremia, is the most common form of the condition, and occurs when retained water dilutes serum sodium content. Patients with hyponatremia are classified as hypervolemic if swelling of body tissues (edema) is present or euvolemic if there is an increase in total body water content without edema.(1,2)

About VAPRISOL

Discovered and developed by Astellas Pharma Inc. headquartered in Tokyo, Japan, VAPRISOL is a novel drug that blocks the activity of AVP, resulting in increased urine output without loss of valuable electrolytes such as sodium and potassium. This effect, known as "aquaresis," helps to increase serum sodium levels in patients with hyponatremia, a condition of low serum sodium concentration, due to increased body water (dilutional hyponatremia). VAPRISOL is the first AVP receptor antagonist with a demonstrated safety profile and that effectively promotes aquaresis which helps to restore salt and water balance in patients with euvolemic and hypervolemic hyponatremia.

VAPRISOL is indicated for the treatment of euvolemic and hypervolemic hyponatremia in hospitalized patients. VAPRISOL is not indicated for the treatment of congestive heart failure. It should only be used for the treatment of hyponatremia in patients with underlying heart failure when the expected benefit of raising serum sodium outweighs the increased risk of adverse events. VAPRISOL is contraindicated in patients with hypovolemic hyponatremia.

In addition, coadministration of VAPRISOL with potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, clarithromycin, ritonavir, and indinavir, is contraindicated.

Serum sodium, volume, and neurological status must be monitored frequently because VAPRISOL potentially can cause overly rapid correction of sodium leading to serious sequelae. The use of VAPRISOL in patients with hepatic impairment (including ascites, cirrhosis, or portal hypertension) or renal impairment has not been systematically evaluated. Use caution when administering VAPRISOL to these patients.

The most common adverse reactions reported were infusion site reactions (incidence of 73% and 63% for 20 mg/day and 40 mg/day respectively) which were also the most common type of adverse reaction leading to discontinuation of VAPRISOL.

Discontinuations from treatment due to infusion site reactions were more common among VAPRISOL-treated patients (3%) than among placebo-treated patients (0%). Other common adverse reactions were headaches (8%, 10%), hypokalemia (22%, 10%), orthostatic hypotension (14%, 6%), and pyrexia (11%, 5%) for VAPRISOL 20mg/day and 40mg/day, respectively.

Complete prescribing information for VAPRISOL can be accessed at http://www.VAPRISOL.com.

About Astellas

Astellas Pharma US, Inc., located in Deerfield, Illinois, is a U.S. affiliate of Tokyo-based Astellas Pharma Inc., Astellas is a pharmaceutical company dedicated to improving the health of people around the world through the provision of innovative and reliable pharmaceutical products. The organization is committed to becoming a global category leader in focused areas by combining outstanding R&D and marketing capabilities. In the US, Astellas markets products in the areas of Immunology, Urology, Anti-Infectives, Cardiovascular and Dermatology. For more information about Astellas Pharma US, Inc., please visit our website at http://www.astellas.com/us.

References:

1. Goh KP. Management of hyponatremia. Am Fam Physician. 2004;

69:2387-2394.

2. Vachharajani TJ, Zaman F, Abreo KD. Hyponatremia in critically ill

patients. J Intensive Care Med. 2003;18:3-8.


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SOURCE Astellas Pharma US, Inc.
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