VAPRISOL DEXTROSE IN PLASTIC CONTAINER (Page 4 of 5)

13 NONCLINICAL TOXICOLOGY

13.1 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).

14 CLINICAL STUDIES

14.1 Hyponatremia

The effect on serum sodium of VAPRISOL was demonstrated in a double-blind, placebo-controlled, randomized, multicenter study conducted in 84 patients with euvolemic (N=56) or hypervolemic (N=28) hyponatremia (serum sodium 115 -130 mEq/L) from a variety of underlying causes (malignant or nonmalignant diseases of the central nervous system, lung, or abdomen; congestive heart failure; hypertension; myocardial infarction; diabetes; osteoarthritis; or idiopathic). Study participants were randomized to receive either placebo IV (N=29), VAPRISOL 40 mg/day IV (N=29), or VAPRISOL 80 mg/day IV (N=26). Daily fluid intake was restricted to 2 liters. VAPRISOL or placebo was administered as a continuous infusion following a 30 minute IV loading dose on the first treatment day and patients were treated for 4 days. Serum or plasma sodium concentrations were assessed pre-dose (Hour 0) and at 4, 6, 10, and 24 hours post-dose on all treatment days.

Mean serum sodium concentration was 123.3 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.

Figure 2. Mean (SE) Change from Baseline in Sodium Concentrations with VAPRISOL 40 mg/day

Figure 2
(click image for full-size original)

Following treatment with 40 mg/day of VAPRISOL, the mean change from baseline in serum sodium concentration at the end of 2 days of treatment with VAPRISOL was 5.3 mEq/L (mean concentration 128.6 mEq/L). At the end of the 4-day treatment period, the mean change from baseline was 6.5 mEq/L (mean concentration 129.8 mEq/L). In addition, after 2 days and 4 days of treatment with VAPRISOL, 41% (after 2 days) and 69% (after 4 days) of patients achieved a ≥ 6 mEq/L increase in serum sodium concentration or a normal serum sodium of ≥ 135 mEq/L. Although 80 mg/day was also studied, it was not significantly more effective than 40 mg/day and was associated with a higher incidence of infusion site reactions and a higher rate of discontinuations for adverse events [see Adverse Reactions (6.1)]. Additional efficacy data are summarized in Table 2.

Table 2. Efficacy Outcomes of Treatment with VAPRISOL 40 mg/day
Efficacy Variable Placebo (N=29) VAPRISOL 40 mg/day ( N=29)

*: P ≤ 0.001 vs placebo

‡: efficacy variables were assessed on Day 2 of a 4-day treatment period

Day 2‡ Day 4 Day 2‡ Day 4
Baseline adjusted serum Na+ AUC over duration of treatment (mEq·hr/L)Mean (SD)LS Mean ± SE 6.2 (81.8)3.8 ± 26.9 61.4 (242.3)12.9 ± 61.2 205.9 (171.6)205.6 ± 26.6* 500.8 (365.5)490.9 ± 56.8*
Number of patients (%) and median event time (h) from first dose of study medication to a confirmed ≥ 4 mEq/L increase from Baseline in serum Na+ , [95% CI] 2 (7%)Not estimableNot estimable 9 (31%)Not estimableNot estimable 22 (76%)23.7* [10, 2] 23 (79%)23.7* [10, 2]
Serum Na+ (mEq/L)Baseline mean (SD)Mean (SD) at end of treatment Change from Baseline to end of treatmentMean change (SD)LS Mean change ± SE 124.3 (4.1)124.5 (4.7)0.2 (2.5)0.1 ± 0.7 124.3 (4.1)125.8 (4.9)1.5 (4.6)0.8 ± 0.8 123.3 (4.7)128.6 (5.9)5.3 (4.4)5.2 ± 0.7* 123.3 (4.7)129.8 (4.8)6.5 (4.4)6.3 ± 0.7*
Number (%) of patients who obtained a confirmed ≥ 6 mEq/L increase from Baseline in serum Na+ or a normal serum Na+ concentration ≥ 135 mEq/L during treatment 0 (0) 6 (21%) 12 (41%)* 20 (69%)*

The aquaretic effect of VAPRISOL is shown in Figure 3. VAPRISOL produced a baseline-corrected cumulative increase in effective water clearance of over 3800 mL compared to approximately 1300 mL with placebo by Day 4.

Figure 3. Baseline-Corrected Mean (SE) Cumulative Effective Water Clearance (EWC)

Figure 3
(click image for full-size original)

Equation
, where V is urine volume (mL/d), UNa is urine sodium concentration, UK is urine potassium concentration, PNa is plasma/serum sodium concentration, and PK is plasma/serum potassium concentration.

The effect on serum sodium of VAPRISOL (administered as a 20 or 40 mg/day IV continuous infusion for 4 days following a 30 minute IV infusion of a 20 mg loading dose on the first treatment day) was also evaluated in an open-label study of 251 patients with euvolemic or hypervolemic hyponatremia. The results are shown in Table 3.

Table 3. Efficacy Outcomes of Treatment with VAPRISOL 20 or 40 mg/day
Primary Efficacy Endpoint 20 mg/day N=37 40 mg/day N=214
Baseline adjusted serum Na+ AUC over duration of treatment (mEq·hr/L) Mean (SD) 753.8 (429.9) 689.2 (417.3)
Secondary Efficacy Endpoints
Number of patients (%)and median event time (h) from first dose of study medication to a confirmed ≥ 4 mEq/L increase from Baseline in serum Na+ , [95% CI] 29 (78%)23.8[12.0, 36.0] 178 (83%)24.4 [24.0, 35.8]
Total time (h) from first dose of study medication to end of treatment in which patients had a confirmed ≥ 4 mEq/L increase in serum Na+ from Baseline Mean (SD) 60.6 (35.2) 59.5 (33.2)
Serum Na+ (mEq/L)Baseline mean (SD)Mean (SD) at end of treatmentMean Change (SD) from Baseline to End of TreatmentMean (SD) at Follow-up Day 11Mean Change (SD) from Baseline to Follow-up Day 11Mean (SD) at Follow-up Day 34Mean Change (SD) from Baseline to Follow-up Day 34 122.5 (5.2)131.8 (3.9)9.4 (5.3)129.9 (6.2)7.1 (8.2)134.3 (4.5)11.5 (7.3) 123.8 (4.6)132.5 (4.6)8.8 (5.4)131.8 (5.8)8.0 (6.5)134.3 (5.2)10.7 (6.7)
Number (%) of patients who obtained a confirmed ≥ 6 mEq/L increase from Baseline in serum Na+ or a normal serum Na+ concentration ≥135 mEq/L during treatment 26 (70%)154 (72%)

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2022. All Rights Reserved.