General Information

Samsca (tolvaptan) is a non-peptide vasopressin V(2)-receptor

antagonist. Vasopressin is a naturally occurring hormone produced primarily in the posterior pituitary gland but also to a smaller extent in the peripheral tissues, including the heart. The levels of vasopressin are elevated in heart failure and in some forms of hypertension.

Vasopressin seems to have vasoconstrictor and renal fluid retaining properties which may be detrimental when subjects are exposed to chronically elevated levels, as occurs in heart failure.
Samsca is specifically 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, cirrhosis, and Syndrome of Inappropriate Antidiuretic Hormone (SIADH).

Samsca is supplied as a tablet fro oral adminitration. The recommended initial dose of the drug is 15 mg administered once daily without regard to meals. The dose should be increased to 30 mg once daily, after at least 24 hours, to a maximum of 60 mg once daily, as needed to achieve the desired level of serum sodium. During initiation and titration, changes in serum electrolytes and volume should be frequently monitored.

Co-Administration The co-administration of tolvaptan with moderate CYP 3A inhibitors should be avoided, as this causes a marked (5-fold) increase in exposure to CYP 3A. Co-administration of tolvaptan with potent CYP 3A inducers reduces tolvaptan plasma concentrations by 85%. Therefore, the expected clinical effects may not be observed. Co-administration of tolvaptan with inhibitors of P-gp (e.g., cyclosporine) may necessitate a decrease in tolvaptan dose as tolvaptan is a substrate of P-gp.

Clinical Results
FDA Approval
The FDA approval of Samsca was based on the results of several clinical studies.
Hyponatremia
SALT-1 and SALT-2
These double-blind, placebo-controlled, multi-center studies enrolled 424 subjects with euvolemic or hypervolemic hyponatremia (serum sodium < 135 mEq/L) resulting from a variety of underlying causes. The subjects were treated for 30 days with tolvaptan, at an initial oral dose of 15 mg once daily, or placebo, then followed for an additional 7 days after withdrawal.

The dose of tolvaptan could be increased at 24 hour intervals to 30 mg once daily, then to 60 mg once daily, until either the maximum dose of 60 mg or normonatremia (serum sodium > 135 mEq/L) was reached. Serum sodium concentrations were determined at 8 hours after study drug initiation and daily up to 72 hours. The primary endpoint for these studies was the average daily 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

, tolvaptan caused a statistically greater increase in serum sodium (p< 0.0001) during both periods in both studies. For subjects with a serum sodium of <130 mEq/L or < 125 mEq/L, the effects at Day 4 and Day 30 remained significant. In subjects with hyponatremia (defined as <135 mEq/L), serum sodium concentration increased to a significantly greater degree in the tolvaptan-treated arm compared to the placebo arm as early as 8 hours after the first dose, and the change was maintained for 30 days.

The percentage of subjects requiring fluid restriction (defined as <1 L/day at any time during the treatment period) was also significantly less (p<0.0017) in the tolvaptan-treated group (14%) as compared with the placebo-treated group ( 25%). Within 7 days of tolvaptan discontinuation, serum sodium concentrations in tolvaptan-treated arm declined to levels similar to those of the placebo arm.

SALTWATER
This open label study enrolled 111 subjects, 94 of whom were hyponatremic (serum sodium <135 mEq/L), previously on tolvaptan or placebo therapy. The subjects received tolvaptan as a titrated regimen (15 to 60 mg once daily) after having returned to standard care for at least 7 days. By this time, their baseline mean serum sodium concentration had fallen to between their original baseline and post-placebo therapy level. Upon initiation of therapy, average serum sodium concentrations increased to approximately the same levels as observed for those previously treated with tolvaptan, and were sustained for at least a year (p-value< 0.0001).

Heart Failure
A double-blind, placebo-controlled study, dubbed EVEREST, enrolled 4,133 subjects with worsening heart failure. The subjects were randomized to tolvaptan or placebo as an adjunct to standard of care. Long-term tolvaptan treatment (mean duration of treatment of 0.75 years) had no demonstrated effect, either favorable or unfavorable, on all-cause mortality or the combined endpoint of CV mortality or subsequent hospitalization for worsening heart failure.

Ongoing Study Commitments
• Otsuka has agreed to conduct a pediatric study in patients aged 6 to 17 years to obtain pharmacokinetic data pertinent to pediatric dosing of tolvaptan.

Final Protocol Submission: by November 20, 2010>
Study Completion Date: by May 20, 2014
Final Report Submission: by November 20, 2014
• Otsuka has agreed to conduct a study to assess the effectiveness and safety of tolvaptan in the treatment of clinically significant hypervolemic and euvolemic hyponatremia in pediatric patients aged 6 to 17.

Final Protocol Submission: by November 20, 2010
Study Completion Date: by May 20, 2014
Final Report Submission: by November 20, 2014
Side Effects
Adverse events associated with the use of Samsca may include, but are not limited to, the following:

• Thirst
• Dry mouth
• Asthenia
• Constipation
• Pollakiuria
• Polyuria

• Hyperglycemia

Mechanism of Action

Samsca (tolvaptan) is a non-peptide vasopressin V(2)-receptor antagonist. Vasopressin is a naturally occuring hormone produced primarily in the posterior pituitary gland but also to a smaller externt in the peripheral tissues, including the heart. 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.

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