Vaprisol (conivaptan) is a non-peptide dual arginine vasopressin (AVP) V1A and V2 receptor antagonist. It is designed to inhibit the effects of AVP, also known as antidiuretic hormone, on receptors in the kidneys.
Vaprisol is specifically indicated for the treatment of hospitalized patients with euvolemic hyponatremia, or low serum sodium levels at normal water volumes, resulting from inappropriate or excessive secretion of AVP.
Vaprisol is supplied as a sterile liquid for IV infusion in clear, glass, one-point cut ampules. The recommended regimen of treatment is a loading dose of 20 mg of the drug delivered via 30 minute infusion, followed by an additional infusion of 20 mg continuously over 24 hours. Subsequent infusions should be administered every 1-3 days at 20 mg/day via continuous infusion. Dose may be titrated up to 40 mg/day if response is not sufficiently rapid.
Approval of Vaprisol was based on a double-blind, placebo-controlled, randomized, multicenter study, which enrolled 56 patients with euvolemic hyponatremia. Subjects received one of two doses of Vaprisol (40 mg/day or 80 mg/day) or placebo, in addition to current standard-of-care treatment for the condition (including fluid restriction). Vaprisol was administered in a 20 mg/30 minute administration on day 1, followed by continuous infusion at the trial dose. Trial data indicated that the 40 mg/day dose produced an increase in sodium levels of at least 4 mEq/L in 52% of patients, and of at least 6 mEq/L or normalization in 39% of subjects after 2 days and 67% after 4 days (mean change after 2 days: 5.8 mEq/L)
In addition, an open-label study of the drug enrolled 104 patients, who received 20 mg or 40 mg via continuous infusion Vaprisol daily (following a 20 mg/30 min loading dose) for 4 days. Baseline-adjusted serum sodium Area-Under-Curve was 1000.2 hr*mEq/L for the 20 mg daily dose, and 648.9 hr*mEq/L for the 40 mg daily dose (the primary efficacy measure). Secondary endpoints were also positive, with 90.9% of patients at the 20 mg/day dose and 82.8% of patients at the 40 mg/day dose achieving an increase in serum sodium levels of at least 4 mEq/L from baseline (median time to response 12.0 hours and 24.4 hours, respectively). This level of response was sustained for 78.2 and 59.7 hours of the treatment period, respectively.
The safety and efficacy of Vaprisol for the treatment of congestive heart failure has not been established.
Ongoing Study Commitments
Adverse events associated with the use of Vaprisol may include, but are not limited to, the following:
Close monitoring of serum sodium levels is required during treatment, as overly rapid increases in serum sodium levels (>12 mEq/L/24 hours) has been associated in previous studies with serious, potentially permanent sequelae, including osmotic demyelination syndrome.
In addition, several potential drug-drug interactions have been identified. First, Vaprisol is metabolized by the hepatic enzyme CYP3A4; co-administration drugs that inhibit this enzyme (including but not limited to ketoconazole, itraconazole, clarithromycin, ritonavir, and indinavir) may increase serum Vaprisol concentration and halflife, and should be avoided. Second, clinical studies indicated that the drug significantly increased maximum concentrations and serum halflife of the P-glycoprotein substrate digoxin, and levels of that drug should be closely monitored during Vaprisol therapy.
Finally, animal models indicated potential fetal toxicity risks associated with conivaptan administration at doses below those predicted to have clinical benefit. The drug has been shown to cross the placenta and may accumulate in fetal tissues. In rats, pups whose mothers received the drug while pregnant demonstrated decreased neonatal viability, weaning indices, delayed growth and physical development (including sexual maturation), and delayed reflex development. Studies have not been conducted in pregnant women to detail specific human toxicities, but pregnant patients should discuss potential risks with their doctors.
Vaprisol (conivaptan) is a non-peptide dual AVP V1A and V2 receptor antagonist. In the kidneys, AVP's activity (primarily at V2 receptors) inhibit aquaresis, or excretion of free water. By exerting antagonistic activity at both V1A and V2 receptors, the drug is designed to inhibit inappropriate/excessive AVP secretion, thereby increasing rates aquaresis. Increased water secretion is correlated with net fluid loss, increased urinary output, and decreased urinary osmolality.
Tang WH, Bhavnani S, Francis GS. Vasopressin receptor antagonists in the management of acute heart failure Expert Opinions on Investigational Drugs 2005 May;14(5):593-600
Tahara A, Tsukada J, Tomura Y, Kusayama T, Wada K, Ishii N, Taniguchi N, Suzuki T, Yatsu T, Uchida W, Shibasaki M. Effects of YM218, a nonpeptide vasopressin V1A receptor-selective antagonist, on human vasopressin and oxytocin receptors Pharmacologial Research 2005 Mar;51(3):275-81
Fernandez-Varo G, Ros J, Cejudo-Martin P, Cano C, Arroyo V, Rivera F, Rodes J, Jimenez W. Effect of the V1a/V2-AVP receptor antagonist, Conivaptan, on renal water metabolism and systemic hemodynamics in rats with cirrhosis and ascites. Journal of Hepatology 2003 Jun;38(6):755-61
For additional information regarding Vaprisol or euvolemic hyponatremia, please visit the Astellas web page.