Vaprisol^®
(conivaptan hydrochloride injection)

VAPRISOL^® (conivaptan hydrochloride injection) is a nonpeptide, dual antagonist of arginine vasopressin (AVP) V_1A and V₂ receptors.

Conivaptan hydrochloride is chemically [1,1’-biphenyl]-2-carboxamide, N-[4-[(4,5-dihydro-2-methylimidazo[4,5-d][1]benzazepin-6(1H)-yl)carbonyl]phenyl]-, monohydrochloride having a molecular weight of 535.04 and molecular formula C₃₂H₂₆N₄O₂•HCl . The structural formula of conivaptan hydrochloride is:

Conivaptan hydrochloride is a white to off-white or pale orange-white powder that is very slightly soluble in water (0.15 mg/mL at 23° C). Conivaptan hydrochloride injection is supplied as a sterile liquid in an ampule. Each ampule will deliver 20 mg conivaptan hydrochloride, 1.2 g propylene glycol, 0.4 g ethanol and Water for Injection, q.s. Lactic acid is added for pH adjustment to 3.0.

Conivaptan hydrochloride is a dual AVP antagonist with nanomolar affinity for human V_1A 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. The pharmacodynamic effects of conivaptan hydrochloride include increased free water excretion (i.e., effective water clearance [EWC]) generally accompanied by increased net fluid loss, increased urine output, and decreased urine osmolality. Studies in animal models of hyponatremia showed that conivaptan hydrochloride prevented the occurrence of hyponatremia-related physical signs in rats with the syndrome of inappropriate antidiuretic hormone secretion.

The pharmacokinetics of conivaptan have been characterized in healthy subjects, special populations and patients following both oral and intravenous dosing regimens. The pharmacokinetics of conivaptan following intravenous infusion (40 mg/day to 80 mg/day) and oral administration are non-linear, and inhibition by conivaptan of its own metabolism seems to be the major factor for the non-linearity. The intersubject variability of conivaptan pharmacokinetics is high (94% CV in CL).

The pharmacokinetics of conivaptan and its metabolites were characterized in healthy male subjects administered conivaptan hydrochloride as a 20 mg loading dose (infused over 30 minutes) followed by a continuous infusion of 40 mg/day for 3 days. Mean C_max for conivaptan was 619 ng/mL and occurred at the end of the loading dose. Plasma concentrations reached a minimum at approximately 12 hours after start of the loading dose, then gradually increased over the duration of the infusion to a mean concentration of 188 ng/mL at the end of the infusion. The mean terminal elimination half-life after conivaptan infusion was 5.0 hours, and the mean clearance was 15.2 L/h.

In an open-label safety and efficacy study, the pharmacokinetics of conivaptan were characterized in hypervolemic or euvolemic hyponatremia patients (ages 51-89 years) receiving conivaptan hydrochloride as a 20 mg loading dose (infused over 30 minutes) followed by a continuous infusion of 20 or 40 mg/day for 4 days. The median plasma conivaptan concentrations are shown in Figure 1 and pharmacokinetic parameters are summarized in Table 1.

(see CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions)

In a double-blind, placebo-controlled, randomized, multicenter study, 56 patients with euvolemic hyponatremia (serum sodium 115 -130 mEq/L) due to a variety of underlying causes (malignant or nonmalignant diseases of the central nervous system, lung, or abdomen; hypertension; myocardial infarction; diabetes; osteoarthritis; or idiopathic) were treated for 4 days with VAPRISOL or placebo. All patients received standard care for hyponatremia, primarily fluid restriction (daily fluid intake restricted to less than or equal to 2.0 liters). Study participants were randomized to receive either placebo IV (N=21), or VAPRISOL 40 mg/day IV (N=18), or VAPRISOL 80 mg/day IV (N=17). VAPRISOL was administered as a continuous infusion following a 30 minute IV infusion of a 20 mg loading dose on the first treatment day. Serum or plasma sodium concentrations were assessed at predose (Hour 0) and at 4, 6, 10, and 24 hours post dose on all treatment days. Mean serum sodium concentration was 124.0 mEq/L at study entry.

The mean change in serum sodium concentration from baseline over the 4 day treatment period is shown in Figure 2.

Following treatment with 40 mg/day of intravenous VAPRISOL, 83% of patients achieved an increase of ≥4 mEq/L in serum sodium concentration. The mean change from baseline in serum sodium concentration at the end of 2 days of treatment with VAPRISOL was 5.8 mEq/L (mean concentration 129.4 mEq/L). At the end of the 4 day treatment period, the mean change from baseline was 6.4 mEq/L (mean concentration 130.0 mEq/L). In addition, after 2 days and 4 days of treatment with VAPRISOL, 39% (after 2 days) and 67% (after 4 days) of patients achieved a ≥6 mEq/L increase in serum sodium concentration or a normal serum sodium of ≥135 mEq/L. Additional efficacy data are summarized in Table 3.

The aquaretic effect of VAPRISOL is shown in Figure 3. Conivaptan produced a baseline-corrected cumulative increase in effective water clearance of over 2900 mL compared to approximately 1800 mL with placebo by day 4.

In an open-label study in patients with euvolemic hyponatremia, 104 patients were treated for 4 days with VAPRISOL 20 or 40 mg/day IV as a continuous infusion following a 30 minute IV infusion of a 20 mg loading dose on the first treatment day. The results are shown in Table 4.

The safety and effectiveness of VAPRISOL for the treatment of congestive heart failure has not been established.

VAPRISOL is indicated for the treatment of euvolemic hyponatremia (e.g., the syndrome of inappropriate secretion of antidiuretic hormone, or in the setting of hypothyroidism, adrenal insufficiency, pulmonary disorders, etc.) in hospitalized patients.

VAPRISOL is not indicated for the treatment of patients with congestive heart failure. (See PRECAUTIONS )

VAPRISOL is contraindicated in patients with hypovolemic hyponatremia and in those who have hypersensitivity to any of its components.

The coadministration of VAPRISOL with potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, clarithromycin, ritonavir, and indinavir, is contraindicated. (See PRECAUTIONS: Drug Interactions for details and other important considerations)

The safety of VAPRISOL in hyponatremic patients with underlying congestive heart failure has not been established.

An overly rapid increase in serum sodium concentration (>12 mEq/L/24 hours) may result in serious sequelae. In controlled clinical trials of VAPRISOL, about 9% of patients who received VAPRISOL in doses of 20-40 mg/day IV met laboratory criteria for overly rapid correction of serum sodium, but none of these patients had permanent neurologic sequelae. Although not observed in the clinical studies with VAPRISOL, osmotic demyelination syndrome has been reported following rapid correction of low serum sodium concentrations. 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. If the serum sodium concentration continues to rise, VAPRISOL should not be resumed. If hyponatremia persists or recurs (after initial discontinuation of VAPRISOL for an undesirably rapid rate of rise of serum sodium concentration), and the patient has had no evidence of neurologic sequelae of rapid rise in serum sodium, VAPRISOL may be resumed at a reduced dose.

The use of VAPRISOL in patients with hepatic impairment (including ascites, cirrhosis, or portal hypertension) has not been systematically evaluated.

Increased systemic exposures after oral administration of conivaptan have been seen in patients with stable cirrhosis and moderate hepatic impairment. Intravenous VAPRISOL resulted in higher conivaptan exposure than did oral conivaptan, in study subjects without hepatic function impairment. Caution should be used when administering VAPRISOL to patients with hepatic 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 AUC for conivaptan was up to 80% higher after a single oral dose and 35% higher with repeated oral dosing in patients with renal impairment (CLcr< 60 mL/min/1.73 m²) as compared to those with normal renal function. Intravenous VAPRISOL resulted in higher conivaptan exposure than did oral conivaptan, in study subjects without renal function impairment. Caution should be used when administering VAPRISOL to patients with renal impairment.

Conivaptan may cause significant injection site reactions, even with proper dilution and infusion rates (see ADVERSE REACTIONS ). Conivaptan must only be administered when properly prepared and diluted (see Preparation) via large veins, and the infusion site should be rotated every 24 hours (see DOSAGE AND ADMINISTRATION).

(see CLINICAL PHARMACOLOGY: Drug-Drug Interactions)

Standard lifetime (104 week) carcinogenicity bioassays were conducted in mice and rats. Mice were given oral doses of 3, 10 or 30 mg/kg/day in males and 1, 3 or 10 mg/kg/day in females by gavage. Rats were given oral doses of 0.3, 1, 3 or 10 mg/kg/day in males and 1, 3, 10 or 30 mg/kg/day in females by gavage. No increased incidence of tumors was observed at doses up to 30 mg/kg/day in mice (6 times human systemic exposure of an IV bolus of 20 mg on day 1 followed by IV infusion 40 mg/day for 3 days based on AUC comparison) or rats (2 times human systemic exposure of an IV bolus of 20 mg on day 1 followed by IV infusion 40 mg/day for 3 days based on AUC comparison).

Conivaptan was not mutagenic or clastogenic with or without metabolic activation in the Ames test with Salmonella typhimurium and Escherichia coli, in human peripheral blood lymphocytes, or in vivo rat micronucleus assay.

In fertility studies after 4 weeks treatment by intravenous bolus at 0.5, 1.25 or 2.5 mg/kg/day, male fertility was unaffected. However, in females given IV bolus conivaptan 15 days before mating through gestation day 7 there was prolonged diestrus, decreased fertility and increased pre- and post-implantation loss at 2.5 mg/kg/day (systemic exposures less than the therapeutic dose).

The safety and effectiveness of VAPRISOL in pediatric patients have not been studied.

In clinical studies of intravenous VAPRISOL administered as a 20 mg IV loading dose followed by 40 mg/day IV for 2 to 4 days, 52% of participants were greater than or equal to 65 years of age and 34% were greater than or equal to 75 years of age. In general, the adverse event profile in elderly patients was similar to that seen in the general study population.

The most common adverse reactions reported with VAPRISOL administration were infusion site reactions. In studies in patients and healthy volunteers, infusion site reactions occurred in 52.5% of subjects treated with VAPRISOL 40 mg/day compared to 3.3% in the placebo group. The majority of the reactions were mild and did not lead to discontinuation of drug. However, some serious infusion site reactions did occur, and infusion site reactions were the most common type of adverse event leading to discontinuation of VAPRISOL. (See  DOSAGE AND ADMINISTRATION)

The adverse reactions presented in Table 5 are derived from 72 healthy volunteers and 111 patients with euvolemic hyponatremia who received VAPRISOL 20 mg IV as a loading dose followed by 40 mg/day IV for 2 to 4 days and from 40 healthy volunteers and 21 patients with euvolemic hyponatremia who received placebo. The adverse reactions occurred in at least 2% of patients treated with VAPRISOL and at a higher incidence for VAPRISOL-treated patients than for placebo-treated patients.

The safety of VAPRISOL in hyponatremic patients with underlying congestive heart failure has not been established.

VAPRISOL does not have known potential for psychogenic drug abuse and/or dependence.

Although no data on overdosage in humans are available, VAPRISOL has been administered as a 20 mg loading dose on Day 1 followed by continuous infusion of 80 mg/day for 4 days in hyponatremia patients and up to 120 mg/day for 2 days in CHF patients. No new toxicities were identified at these higher doses, but adverse events related to the pharmacologic activity of VAPRISOL, e.g. hypotension and thirst, occurred more frequently at these higher doses.

In case of overdose, based on expected exaggerated pharmacological activity, symptomatic treatment with frequent monitoring of vital signs and close observation of the patient is recommended.

VAPRISOL is for intravenous use only.

Administration of VAPRISOL through large veins and change of the infusion site every 24 hours are recommended to minimize the risk of vascular irritation.

VAPRISOL therapy should begin with a loading dose of 20 mg IV 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. If serum sodium is not rising at the desired rate, VAPRISOL may be titrated upward to a dose of 40 mg daily, again administered in a continuous intravenous infusion.

The total duration of infusion of VAPRISOL (after the loading dose) should not exceed four days.

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 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 PRECAUTIONS: Overly Rapid Correction of Serum Sodium)

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.

Store at 25° C (77° F); excursions permitted to 15 - 30° C (59 - 86° F), controlled room temperature (in accordance with USP). Do not store below 15° C (59° F). Ampules should be stored in their cardboard container protected from light until ready for use.

VAPRISOL^® (conivaptan hydrochloride injection) is supplied in 4 mL clear glass, one-point cut ampules. Each ampule contains 20 mg conivaptan hydrochloride.

10 ampules/carton (NDC 0469-1601-04)

Rx only

Marketed by:

Astellas Pharma US, Inc.

Deerfield, IL 60015-2548

Manufactured by:

Astellas Tokai Co., Ltd. Yaizu Plant

Shizuoka, 425-0072, Japan

May 2006