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Congestive Heart Failure

The number of heart failure patients with hypervolemic hyponatremia who have been treated with intravenous VAPRISOL is too small to establish safety in patients with underlying congestive heart failure. (See ADVERSE REACTIONS)

Overly Rapid Correction of Serum Sodium

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.

Hepatic Impairment

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.

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 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.

Injection Site Reactions

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)

Carcinogenesis, Mutagenesis, Impairment of Fertility

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).

Pregnancy

Pregnancy Category C

Conivaptan has been shown to have adverse effects on the fetus when given to animals during pregnancy at systemic exposures less than those achieved at a therapeutic dose based on AUC comparisons. There are no adequate and well-controlled studies in pregnant women. VAPRISOL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The patient should be apprised of the potential hazard to the fetus. Conivaptan crosses the placenta and is found in fetal tissue in rats. Fetal tissue levels were <10% of maternal plasma concentrations while placental levels were 2.2-fold higher than maternal plasma concentrations indicating that conivaptan can be transferred to the fetus. Conivaptan that is taken up by fetal tissue is slowly cleared, suggesting that fetal accumulation is possible. Milk levels were up to 3 times higher than maternal plasma levels following an intravenous dose of 1 mg/kg (systemic exposures less than therapeutic based on AUC comparisons).

In female rats given an intravenous bolus dose of 0.5, 1.25 or 2.5 mg/kg/day conivaptan hydrochloride before mating and continuing through gestation day 7, prolonged diestrus, decreased fertility and increased pre- and post-natal implantation loss occurred at 2.5 mg/kg/day (systemic exposures less than the therapeutic dose).

In pregnant rats given intravenous doses of 0.5, 1.25 or 2.5 mg/kg/day from gestation day 7 through 17 (organogenesis), no significant maternal or fetal effects were observed at systemic exposures less than therapeutic exposure based on AUC comparisons.

Pregnant rats were administered intravenous conivaptan hydrochloride at a dose of 2.5 mg/kg/day (systemic exposures less than therapeutic based on AUC) from gestation day 7 through lactation day 20 (weaning), and the pups showed decreased neonatal viability, weaning indices, delayed growth and physical development (including sexual maturation), and delayed reflex development. No discernible changes were seen in pups from dams administered conivaptan hydrochloride at 0.5 or 1.25 mg/kg/day from this same period. No maternal adverse effects were seen with conivaptan hydrochloride administration (0.5, 1.25, or 2.5 mg/kg/day from gestation day 7 through lactation day 20; systemic exposures less than therapeutic dose based on AUC comparisons).

In pregnant rabbits given intravenous doses of 3, 6 or 12 mg/kg/day from gestation day 6 through 18 (organogenesis) there were no fetal findings; however, maternal toxicity was observed in all groups (systemic exposures less than the therapeutic dose).

In bolus intravenous postnatal rat studies, decreased neonatal viability, decreased weaning indices, delayed growth/physical development and delayed sexual maturation of offspring were observed at 2.5 mg/kg/day (systemic exposures less than the therapeutic dose).

Labor and Delivery

The effect of conivaptan on labor and delivery in humans has not been studied. Conivaptan hydrochloride delayed delivery in rats dosed orally at 10 mg/kg/day by oral gavage (systemic exposures equivalent to the therapeutic dose based on AUC comparisons). Administration of conivaptan hydrochloride at 2.5 mg/kg/day intravenously increased peripartum pup mortality (systemic exposures were less than the therapeutic dose based on AUC comparisons). These effects may be associated with conivaptan activity on oxytocin receptors in the rat. The relevance to humans is unclear.

Lactating Women

It is not known whether conivaptan is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when VAPRISOL is administered to a lactating woman. Conivaptan is excreted in milk and detected in neonates when given by intravenous administration to lactating rats. Milk levels of conivaptan in rats reached maximal levels at 1 hour post dose following intravenous administrations and were up to 3 times greater than maternal plasma levels. Administration of conivaptan hydrochloride at 2.5 mg/kg/day intravenously increased peripartum pup mortality; systemic exposures were less than the therapeutic dose based on AUC comparisons.

Pediatric Use

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

Geriatric Use

In clinical studies of intravenous VAPRISOL administered as a 20 mg IV loading dose followed by 20 mg/day or 40 mg/day IV for 2 to 4 days, 89% (20 mg/day regimen) and 60% (40 mg/day regimen) of participants were greater than or equal to 65 years of age and 60% (20 mg/day regimen) and 40% (40 mg/day regimen) 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.

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