Frequently Asked Questions

A: Hyponatremia is characterized by abnormally low sodium levels in the plasma and is usually defined by a serum sodium concentration of less than 135 mEq/L.¹

A: Estimates on the prevalence of hyponatremia vary but range as high as 30% of hospitalized patients and 18% of nursing home residents aged 60 years or older.^1-3 Hyponatremia frequently goes undiagnosed—in one study of hospitalized patients, only one-third of severe hyponatremia cases (serum [Na⁺] ≤115 mEq/L) were properly identified.⁴

A: Hyponatremia can occur in any patient, but it is more common in the elderly and in patients with certain underlying conditions, including congestive heart failure (CHF), cirrhosis, syndrome of inappropriate antidiuretic hormone (SIADH), severe hypothyroidism, adrenal insufficiency, and pulmonary disorders.^5,6

A: It is important to address hyponatremia because untreated or suboptimally treated hyponatremia increases the risk of morbidity and mortality.^2,7,8 Hyponatremia is the most common form of fluid and electrolyte imbalance seen in hospitalized patients.⁶ It is frequently secondary to other serious conditions such as congestive heart failure (CHF), cirrhosis, syndrome of inappropriate antidiuretic hormone (SIADH), severe hypothyroidism, adrenal insufficiency, and pulmonary disorders.^5,6

A: Many patients with hyponatremia appear to be asymptomatic, particularly when the decline in serum sodium concentration is mild or occurs over a long period of time.^1,6,9 However, a recent study revealed an increase in falls and impairments in gait and attention in patients with hyponatremia that was thought to be asymptomatic.⁹ In patients with more severe or more rapid declines in serum sodium, serious neurological symptoms can occur, including hallucinations, seizures, and coma.⁶ Nonneurological symptoms can include fatigue, thirst, and nausea.⁶

A: AVP, also known as antidiuretic hormone (ADH), is the key regulator of salt and water balance in the body, which is accomplished via the interaction of AVP with the V₂ receptors in the kidneys.^5,10-12 AVP is elevated in a number of disease states, leading to retention of water by the kidneys, which, in turn, can contribute to the development of hyponatremia.^5,12,13

A: Vaprisol is the first in a newer class of agents for the treatment of hyponatremia, the AVP receptor antagonists.¹⁴ Vaprisol blocks both V_1A and V₂ receptors.¹⁴ By blocking V₂ receptors, Vaprisol causes the excretion of free water, or aquaresis, which results in increased urine output in patients with euvolemic or hypervolemic hyponatremia.¹⁴

A: The level of arginine vasopressin (AVP) circulating in the blood is critical for the regulation of water and electrolyte balance.¹⁰ The AVP level is frequently elevated in patients with euvolemic or hypervolemic hyponatremia.¹⁵ The predominant effect of Vaprisol occurs through antagonism of the V₂ receptors in the kidneys, which results in aquaresis—the electrolyte-sparing excretion of free water.¹⁴ The clinical significance of V_1A receptor inhibition is still unknown.

A: Vaprisol is different from other treatments for hyponatremia because it targets arginine vasopressin (AVP), the key regulator of salt and water balance in the body.^10,14 No other class of therapy for hyponatremia directly addresses the effects of elevated AVP in this way.² Vaprisol has demonstrated its ability to raise serum sodium concentration in patients with euvolemic or hypervolemic hyponatremia.¹⁴

A: Aquaresis involves the excretion of free water without the loss of electrolytes, such as sodium and potassium, thus helping to correct serum sodium concentration in patients with hyponatremia.¹³ During diuresis, the excretion of water is accompanied by the loss of sodium and other necessary electrolytes.¹³

A: At present, there are no outcome data for Vaprisol. However, studies are currently being conducted that may provide this information in the near future.

A: In an open-label study, the increases in serum sodium concentration seen in patients receiving Vaprisol were maintained for up to 30 days post treatment.¹⁴ However, the impact of Vaprisol on maintenance of serum sodium concentration is not known.

A: In a randomized, double-blind, placebo-controlled trial of patients with euvolemic or hypervolemic hyponatremia, Vaprisol increased serum sodium by 6.5 mEq/L at the end of treatment (96 hours), compared with 1.5 mEq/L for placebo.¹⁴ In this study, 69% of patients receiving Vaprisol achieved a ≥6 mEq/L increase in serum sodium concentration by the end of treatment, compared with 21% of patients receiving placebo.¹⁴

A: Continued improvement in serum sodium concentration was observed when Vaprisol was administered over 2 to 4 days,¹⁴ and no clinical studies have been conducted with solely a 1-day treatment regimen. Keep in mind, however, that Vaprisol administration should be discontinued if a patient develops an undesirably rapid rise in serum sodium concentration.

A: Vaprisol is for intravenous use only and should be administered through large veins, with a change in the infusion site every 24 hours. Vaprisol therapy should begin with a loading dose of 20 mg administered over 30 minutes. The loading dose should be followed by 20 mg of Vaprisol administered in a continuous intravenous infusion over 24 hours. Following the initial day of treatment, Vaprisol is to be administered for an additional 1 to 3 days in a continuous infusion of 20 mg/day.
Titration: If the serum sodium concentration is not rising at the desired rate, Vaprisol may be titrated up to a dose of 40 mg daily, administered as a continuous infusion.

A: Yes. The use of diuretics was not excluded in clinical trials conducted with Vaprisol.¹⁶ In addition, no drug interactions were observed with furosemide.¹⁴

A: No. While Vaprisol should be administered through a large vein, it does not require the use of a dedicated central line.

A: In clinical studies of Vaprisol, 89% (20 mg/day regimen) and 60% (40 mg/day regimen) of patients were at least 65 years of age, and 60% (20 mg/day regimen) and 40% (40 mg/day regimen) were at least 75 years of age.¹⁴ The adverse events profile in geriatric patients was similar to that seen in the general study population.¹⁴

A: Vaprisol Premixed in 5% Dextrose contains the same active ingredient as the Vaprisol Ampule but comes in a ready-to-use container that requires no measuring or mixing. In addition, Vaprisol Premixed in 5% Dextrose contains no propylene glycol or ethanol, which are components in the ampule formulation. Vaprisol Premixed in 5% Dextrose has a shelf life of 24 months—6 months longer than the ampule formulation, allowing for longer storage of the product.

A: Vaprisol Premixed in 5% Dextrose is a clear, colorless, sterile, nonpyrogenic solution of conivaptan hydrochloride in dextrose. The 100-mL, single-use, premixed formulation of Vaprisol comes in an INTRAVIA^® Container, a product of Baxter Healthcare Corporation, containing 20 mg of conivaptan hydrochloride in 5% dextrose solution. Lactic acid, USP is added for pH adjustment to pH 3.4 to 3.8.

INTRAVIA is a registered trademark of Baxter International, Inc.

A: Clinical trials were not required for the approval of the premixed formulation. The premixed formulation was designed to allow the same dosage regimen as the ampule formulation. The target concentration of conivaptan hydrochloride in the premixed formulation was chosen to match the concentration that is administered after dilution of the Vaprisol Ampule in 100 mL 5% dextrose injection. Therefore, Vaprisol Premixed in 5% Dextrose requires no further dilution prior to administration.

A: There is no difference in dosage between Vaprisol Premixed in 5% Dextrose and the Vaprisol Ampule. However, there are differences with respect to preparation and administration.

Ampule
Loading Dose
Withdraw 4 mL (20 mg) of Vaprisol (4 mL of conivaptan hydrochloride injection) and add to an infusion bag containing 100 mL of 5% Dextrose Injection, USP. Gently invert the bag several times to ensure complete mixing of the solution. The contents of the IV bag should be administered over 30 minutes.

Continuous Infusion
To prepare a continuous IV infusion containing 20 mg conivaptan hydrochloride, withdraw 4 mL (20 mg) from a single ampule of Vaprisol and dilute into an IV bag containing 250 mL of 5% Dextrose Injection, USP. Gently invert the bag several times to ensure complete mixing of the solution. The contents of the IV bag should be administered over 24 hours.

To prepare a continuous IV infusion containing 40 mg conivaptan hydrochloride, withdraw 4 mL (20 mg) from each of two ampules of Vaprisol (8 mL [40 mg] of conivaptan hydrochloride injection) and dilute into an IV bag containing 250 mL of 5% Dextrose Injection, USP. Gently invert the bag several times to ensure complete mixing of the solution. The contents of the IV bag should be administered over 24 hours.

Premixed
Loading Dose
Administer 20 mg/100 mL Vaprisol flexible plastic container over 30 minutes.

Continuous Infusion
For patients requiring 20 mg conivaptan hydrochloride injection per day, administer one 20 mg/100 mL Vaprisol flexible plastic container over 24 hours.

For patients requiring 40 mg conivaptan hydrochloride injection per day, administer two consecutive 20 mg/100 mL Vaprisol flexible plastic containers over 24 hours.

Note, the total volume of a 20 mg continuous infusion will decrease from 250 mL/day for the ampule formulation to 100 mL/day for the premixed formulation.

A: Vaprisol is contraindicated in patients with hypovolemic hyponatremia. The coadministration of Vaprisol with potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, clarithromycin, ritonavir, and indinavir, is contraindicated. Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products.

A: There are no precautions specific to Vaprisol Premixed in 5% Dextrose. As with the Vaprisol Ampule, the use of Vaprisol in patients with hepatic impairment (including ascites, cirrhosis, or portal hypertension) or renal impairment has not been systematically evaluated. Vaprisol is not indicated for the treatment of congestive heart failure. It should only be used in the treatment of hyponatremia associated with congestive heart failure if the benefit of increasing serum sodium outweighs the risk of adverse events associated with Vaprisol use in the patient population. Serum sodium concentration and neurologic status should be monitored appropriately during Vaprisol administration, and Vaprisol administration should be discontinued if the patient develops an undesirably rapid rate of rise of serum sodium.

A: Vaprisol was reformulated with several improvements in mind. Vaprisol Premixed in 5% Dextrose:

• Is ready to use and requires no measuring or mixing
• Contains no propylene glycol or ethanol
• Has a shelf life of 24 months

A: No. The Vaprisol Ampule will be discontinued upon availability of Vaprisol Premixed in 5% Dextrose.

A: No. The FDA did not require additional clinical data for approval of Vaprisol Premixed in 5% Dextrose.