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Usual Dosing (Adults)

CLINICAL PHARMACOLOGY
Mechanism of Action:
Conivaptan hydrochloride is a dual arginine vasopressin (AVP) antagonist with nanomolar affinity for human V1A and V2 receptors in vitro. The level of AVP in circulating blood is critical for the regulation of water and electrolyte balance and is usually elevated in both euvolemic and hypervolemic hyponatremia. The AVP effect is mediated through V2 receptors, which are functionally coupled to aquaporin channels in the apical membrane of the collecting ducts of the kidney. These receptors help to maintain plasma osmolality within the normal range. The predominant pharmacodynamic effect of conivaptan hydrochloride in the treatment of hyponatremia is through its V2 antagonism of AVP in the renal collecting ducts, an effect that results in aquaresis, or excretion of free water.

INDICATIONS AND USAGE
VAPRISOL® is indicated to raise serum sodium in hospitalized patients with euvolemic and hypervolemic hyponatremia.

Important Limitations: VAPRISOL has not been shown to be effective for the treatment of the signs and symptoms of heart failure and is not approved for this indication.
It has not been established that raising serum sodium with VAPRISOL provides a symptomatic benefit to patients.

DOSAGE AND ADMINISTRATION
General Dosing Information:
-VAPRISOL is for intravenous use only.
-VAPRISOL is for use in hospitalized patients only.
-Administer VAPRISOL through large veins and change of the infusion site every 24 hours to minimize the risk of vascular irritation.
-Initiate with a loading dose of 20 mg IV administered over 30 minutes.

Follow the loading dose with 20 mg of VAPRISOL administered in a continuous intravenous infusion over 24 hours. After the initial day of treatment, administer VAPRISOL for an additional 1 to 3 days in a continuous infusion of 20 mg/day. If serum sodium is not rising at the desired rate, VAPRISOL may be titrated upward to a dose of 40 mg daily, administered in a continuous intravenous infusion.

The total duration of infusion of VAPRISOL (after the loading dose) should not exceed four days. The maximum daily dose of VAPRISOL (after the loading dose) is 40 mg/day.

Patients receiving VAPRISOL must have frequent monitoring of serum sodium and volume status. An overly rapid rise in serum sodium (> 12 mEq/L/24 hours) may result in serious neurologic sequelae. For patients who develop an undesirably rapid rate of rise of serum sodium, VAPRISOL should be discontinued, and serum sodium and neurologic status should be carefully monitored. If the serum sodium continues to rise, VAPRISOL should not be resumed. If hyponatremia persists or recurs, and the patient has had no evidence of neurologic sequelae of rapid rise in serum sodium, VAPRISOL may be resumed at a reduced dose [see package insert for Warnings and Precautions (5.2)]. For patients who develop hypovolemia or hypotension while receiving VAPRISOL, VAPRISOL should be discontinued, and volume status and vital signs should be frequently monitored. Once the patient is again euvolemic and is no longer hypotensive, VAPRISOL may be resumed at a reduced dose if the patient remains hyponatremic.

Renal Dosing

dialysis Renal Impairment:
In patients with renal impairment (CLcr 30 - 60 mL/min or CLcr 10 - 29 mL/min), increases in exposure of 1.7-fold and 1.9-fold, respectively, were observed after oral administration of conivaptan.  Adjust the dose of VAPRISOL accordingly.

Because of the high incidence of infusion site phlebitis (which can reduce vascular access sites) and unlikely benefit, use in patients with severe renal impairment (CLcr<30 mL/min) is not recommended.

Use in Patients with Renal Impairment:
The effect of renal impairment on the elimination of conivaptan after intravenous administration has not been evaluated. However, following oral administration of conivaptan, the AUCs for conivaptan in patients with renal impairment (CLcr 30 - 60 mL/min or CLcr 10 - 29 mL/min) were 70% and 85% higher, respectively, after a single oral dose and 58% and 69% higher, respectively, with repeated oral dosing compared to patients with normal renal function.

In patients with moderate renal impairment (CLcr 30 - 60 mL/min), initiate VAPRISOL with a loading dose of 10 mg followed by a continuous infusion of 10 mg over 24 hours for 2 to a maximum of 4 days. If serum sodium is not rising at the desired rate, VAPRISOL may be titrated upward to 20 mg over 24 hours.

In patients with CLcr > 60 mL/min, dose adjustment is not necessary.

Use in patients with severe renal impairment (CLcr < 30 mL/min) is not recommended.

Hemodialysis

dialysis Use in patients with severe renal impairment (CLcr < 30 mL/min) is not recommended.

Reference(s)

National Institutes of Health, U.S. National Library of Medicine, DailyMed Database.
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Conivaptan