VAPRISOL DEXTROSE IN PLASTIC CONTAINER (Page 2 of 5)

7 DRUG INTERACTIONS

7.1 CYP3A Inhibitors and Substrates

Conivaptan is a sensitive substrate of CYP3A. Coadministration with strong CYP3A inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, ritonavir and indinavir) increases conivaptan exposure and is contraindicated [see Contraindications (4.2) and Clinical Pharmacology (12.3)].

Coadministration with CYP3A substrates results in increased exposure of the other drug. Avoid concomitant use with drugs eliminated primarily by CYP3A-mediated metabolism. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after the infusion of VAPRISOL is completed [see Clinical Pharmacology (12.3)].

7.2 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data with VAPRISOL in pregnant women to inform a drug-associated risk for major birth defects and miscarriage.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major malformations and miscarriage in clinically recognized pregnancies is 2-4%, and 15-20%, respectively.

Data

Animal Data

When pregnant rats were given intravenous 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 fetal or maternal effects were noted. However, when the same doses were administered to pregnant rats 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). These effects occurred only at the highest dose administered (2.5 mg/kg/day). No maternal adverse effects of conivaptan were seen in this study. When pregnant rabbits were administered intravenous doses of conivaptan hydrochloride up to 12 mg/kg/day on gestation days 6 through 18 (at about twice the human therapeutic exposure), there were no fetal or maternal findings.

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.

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).

8.2 Lactation

Risk Summary

There is no information regarding conivaptan or its metabolites in human milk, the effects of conivaptan on the breastfed infant, or the effects of conivaptan on milk production. Conivaptan is present in rat milk; however, due to species-specific differences in lactation physiology, the clinical relevance of these data are not clear [see Data]. Because of the potential for serious adverse reactions, including electrolyte abnormalities (e.g., hypernatremia), hypotension, and volume depletion in breastfed infants, advise a woman not to breastfeed during treatment with VAPRISOL.

Data

Milk levels of conivaptan in rats reached maximal levels at 1 hour following intravenous administration and were up to 3 times maternal plasma levels following an intravenous dose of 1 mg/kg (systemic exposure less than human therapeutic exposure based on AUC comparison).

8.3 Females and Males of Reproductive Potential

Infertility

Females

Based on findings of decreased fertility in female rats, conivaptan may impair fertility in females of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 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.

8.6 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 systemic exposure to unbound conivaptan doubled in subjects with moderate and severe hepatic impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

8.7 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 (12.3)].

10 OVERDOSAGE

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.

11 DESCRIPTION

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 C32 H26 N4 O2 ∙HCl. The structural formula of conivaptan hydrochloride is:

Structural Formula
(click image for full-size original)

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 premixed solution with dextrose in a flexible plastic container.

Each container contains a clear, colorless, sterile, non-pyrogenic solution of conivaptan hydrochloride in dextrose injection for intravenous use. Each 100 mL, single-use premixed INTRAVIA Container contains 20 mg of conivaptan hydrochloride and 5 g of Dextrose Hydrous, USP. Lactic Acid, USP is added for pH adjustment to pH 3.4 to 3.8. The flexible plastic container is fabricated from a specially designed multilayer plastic (PL 2408). Solutions in contact with the plastic container leach out certain of the chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials. The flexible container has a foil overwrap. Water can permeate the plastic into the overwrap, but the amount is insufficient to affect the premixed solution significantly.

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