Pharmacology Update

Conivaptan Injection (Vaprisol®)

By William T. Elliott, MD, FACP, and James Chan, PhD, PharmD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationships to this field of study.

The FDA has approved the first of a new class of agents, the vaptans. Conivaptan, the first arginine vasopressin receptor antagonist, is approved for the management of serious sodium/water imbalance. It will be marketed by Astellas Pharma US, Inc as Vaprisol®.

Indications

Conivaptan is indicated for the treatment of euvolemic hyponatremia (eg, syndrome of inappropriate secretion of antidiuretic hormone, or in the setting of hypothyroidism, adrenal insufficiency, pulmonary disorder, etc) in hospitalized patients.1

Dosage

The recommended initial loading dose is 20 mg administered intravenously over 30 minutes followed by 20 mg infused over 24 hours. Conivaptan may be given for an additional 1 to 3 days at 20 mg daily. If the desired increase in serum sodium is not achieved, the drug may be given at a daily dose of 40 mg.

Potential Advantages

Conivaptan provides a new approach for the treatment of hyponatremia. As an arginine vasopressin receptor antagonist it promotes free-water excretion while maintaining levels of sodium and other electrolytes (aquaresis).

Potential Disadvantages

Conivaptan should not be administered with potent CYP450 3A4 inhibitors. Side effects include dehydration, hyperglycemia, hypoglycemia, hypokalemia, hypomagnesemia, and infusion site reactions. Other adverse events include thirst, headache, vomiting, peripheral edema, pollakiuria, diarrhea, polyuria, and phlebitis. It is currently not approved for use in congestive heart failure.1

Comments

Conivaptan is a non-peptide, dual V1A and V2, arginine vasopressin receptor antagonist. Antagonism of the V1A receptor reverses vasoconstrictive effects, increases cardiac output, reduces peripheral resistance, and reduces mean arterial blood pressure. At the V2 receptor, free water excretion is promoted without loss of sodium and other electrolytes.2 In animal models, conivaptan showed similar aquaretic effects to 100 mg/kg of furosemide without urinary excretion of electrolytes.3 In a randomized, double-blind, placebo-controlled study in hospitalized patients with mild-to-moderate euvolemic hyponatremia (n = 56), conivaptan treatment resulted in significant improvement in serum sodium with the first day of treatment.1 A dose of 40 mg following a 20 mg infusion produced an increase in sodium levels of at least 4 mEq/L in 52% of patients and 6 mEq/L or normalization in 39% after 2 days.3 Sixty seven percent (67%) had an increase of 6 mEq/L or normalization after 4 day. The mean change after 2 days was 5.7 mEq/L. In patients with advanced heart failure, conivaptan produces favorable changes in hemodynamics and urine output without affecting blood pressure or heart rate.5

Clinical Implications

Current management of euvolemic hyponatremia includes hypertonic saline with a loop diuretic, fluid restriction, or demeclocycline. These therapeutic options are not ideal and all have limitations. An arginine vasopressin antagonist and aquaretic, such as conivaptan, provides a new therapeutic option.

References

1. Vaprisol Product Information.

2. Goldsmith SR. Current treatments and novel pharmacologic treatments for hyponatremia in congestive heart failure. Am J Cardiol. 2005;95(9A):14B-23B.

3. Yatsu T, et al. Pharmacological profile of YM087, a novel nonpeptide dual vasopressin V1A and V2 receptor antagonist, in dogs. Eur J Pharmacol. 1997;321: 225-230.

4. www.centerwatch.com/patient/drugs/dru890.html. Accessed 1/26/06.

5. Udelson JE, et al. Acute hemodynamic effects of conivaptan, a dual V1A and V2 vasopressin receptor antagonist, in patients with advanced heart failure. Circulation. 2001;104:2417-2423.