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Vaprisol

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Vaprisol

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hyponatremia Associated with Heart Failure

The amount of safety data on the use of VAPRISOL in patients with hypervolemic hyponatremia associated with heart failure is limited. VAPRISOL should be used to raise serum sodium in such patients only after consideration of other treatment options [see ADVERSE REACTIONS].

Overly Rapid Correction of Serum Sodium

Osmotic demyelination syndrome is a risk associated with overly rapid correction of hyponatremia (i.e., > 12 mEq/L/24 hours). Osmotic demyelination results in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma or death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, use slower rates of correction. In controlled clinical trials of VAPRISOL, about 9% of patients who received VAPRISOL in doses of 20-40 mg/day IV had rises of serum sodium > 12 mEq/L/24 hours, but none of these patients had evidence of osmotic demyelination or permanent neurologic sequelae. 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 [see DOSAGE AND ADMINISTRATION].

Coadministration of VAPRISOL and Drugs Eliminated Primarily by CYP3A Mediated Metabolism

In clinical trials of oral conivaptan, two cases of rhabdomyolysis occurred in patients who were also receiving a CYP3A-metabolized HMG-CoA reductase inhibitor. Avoid concomitant use of VAPRISOL with drugs eliminated primarily by CYP3A-mediated metabolism. Subsequent treatment with CYP3A substrate drugs may be initiated no sooner than 1 week after the infusion of VAPRISOL is completed [see DRUG INTERACTIONS].

Coadministration of VAPRISOL and Digoxin

Coadministration of digoxin with oral conivaptan resulted in a 1.8-and 1.4-fold increase in digoxin Cmax and AUC, respectively. Monitor digoxin levels [see DRUG INTERACTIONS].

Infusion Site Reactions

Infusion site reactions are common and can include serious reactions, even with proper infusion rates [see ADVERSE REACTIONS]. Administer VAPRISOL via large veins, and rotate the infusion site every 24 hours [see DOSAGE AND ADMINISTRATION].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Standard lifetime (104 week) carcinogenicity bioassays were conducted in mice and rats. Male and female mice were given oral doses of conivaptan hydrochloride up to 30 mg/kg/day and 10 mg/kg/day, respectively, by gavage. Male and female rats were given oral doses of up to 10 mg/kg/day and 30 mg/kg/day, respectively, by gavage. There was no increased incidence of tumors associated with exposure to conivaptan in either species. The 30 mg/kg/day dosage regimen in male mice and female rats was shown to result in a systemic exposure (AUC) about twice the human systemic exposure from an IV bolus of 20 mg on day 1 followed by IV infusion of 40 mg/day for 3 days. The 10 mg/kg/day dosage regimen in female mice and male rats was shown to result in about one-fourth and one-half the human therapeutic exposure, respectively.

Conivaptan was not genotoxic in the bacterial reverse mutation assay, the in vitro human peripheral blood lymphocyte chromosomal aberration assay, or in vivo rat micronucleus assay. Fertility of male rats treated with conivaptan hydrochloride by IV bolus doses of up to 2.5 mg/kg/day for the 4 weeks preceding mating and throughout the mating period was unaffected. However, when female rats were given IV bolus conivaptan from 15 days before mating through gestation day 7, there was prolonged diestrus, decreased fertility (decreased numbers of corpora lutea and implantations) and increased post-implantation loss at 2.5 mg/kg/day (systemic exposure less than human exposure at the therapeutic dose).

Developmental Toxicity

When pregnant rats were given intravenous doses of conivaptan hydrochloride up to 2.5 mg/kg/day on gestation days 7 through 17 (systemic exposures less than human therapeutic exposure based on AUC comparisons), no significant maternal or fetal effects were observed. When pregnant rats received intravenous conivaptan hydrochloride at a dose of 2.5 mg/kg/day (systemic exposure less than human therapeutic exposure based on AUC comparison) from gestation day 7 through lactation day 20 (weaning), the pups showed decreased neonatal viability and weaning indices, decreased body weight, and delayed reflex and physical development (including sexual maturation). No discernible effects were seen in pups from dams administered conivaptan hydrochloride at 0.5 or 1.25 mg/kg/day during this same period. No maternal adverse effects of conivaptan were seen in this study. When pregnant rabbits were given intravenous doses of conivaptan hydrochloride up to 12 mg/kg/day on gestation days 6 through 18 (about twice the human therapeutic exposure) there were no fetal or maternal findings.

Use In Specific Populations

Pregnancy

Pregnancy Category C. Conivaptan has been shown to have adverse effects on the fetus when given to rats during pregnancy at systemic exposures less than those achieved at the human therapeutic dose based on AUC comparisons [see Nonclinical Toxicology]. There are no adequate and well-controlled studies of VAPRISOL use 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. Rat fetal tissue levels were < 10% of maternal plasma concentrations while placental levels were 2.2-fold higher than maternal plasma concentrations. Conivaptan that is taken up by fetal tissue is slowly cleared, suggesting that fetal accumulation is possible.

Labor and Delivery

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

Nursing Mothers

It is not known whether conivaptan is excreted in human milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from VAPRISOL, a decision should be made to discontinue nursing or VAPRISOL, taking into consideration the importance of VAPRISOL to the mother. 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 administration and were up to 3 times greater than maternal plasma levels following an intravenous dose of 1 mg/kg (systemic exposure less than human therapeutic exposure based on AUC comparison).

Pediatric Use

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

Geriatric Use

In clinical studies of 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.

Use in Patients with Hepatic Impairment

No clinically relevant increase in exposure was observed in subjects with mild hepatic impairment; therefore no dose adjustment of VAPRISOL is necessary. The exposure to VAPRISOL approximately doubles with moderate hepatic impairment. The impact of severe hepatic impairment on the exposure to conivaptan has not been studied [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Use in Patients with Renal Impairment

No clinically relevant increase in exposure was observed in subjects with mild and moderate renal impairment (CLcr 30 – 80 mL/min). No dose adjustment of VAPRISOL is necessary.

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 [see CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 2/28/2012
This monograph has been modified to include the generic and brand name in many instances.

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