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
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
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
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.
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
Use in patients with severe renal impairment (CLcr < 30 mL/min) is
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The authors make no claims of the accuracy of the information contained herein; and these suggested doses are not a substitute for clinical
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