no effects with regard to minimum inhibitory concentration (MIC):
vancomycin, cefazolin, ampicillin, ampicillin/flucoxacillin, ceftazidime, gentamicin, and amphotericin.
13. NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Icodextrin did not demonstrate evidence of genotoxicity potential in in vitro bacterial cell reverse mutation assay(Ames test); in vitro mammalian cell chromosomal aberration assay (CHO cell assay); and in the in vivo micronucleus assay in mice. Long-term animal studies to eva luate the carcinogenic potential of EXTRANEAL or
icodextrin have not been conducted. Icodextrin is derived from maltodextrin, a common food ingredient.
A fertility study in rats where males and females were treated for four and two weeks, respectively, prior to mating
and until day 17 of gestation at up to 1.5 g/kg/day (1/3 the human exposure on a mg/m2
basis) revealed slightly low
epididymal weights in parental males in the high dose group as compared to Control. Toxicological significance of
this finding was not evident as no other reproductive organs were affected and all males were of proven fertility. The
study demonstrated no effects of treatment with icodextrin on mating performance, fertility, litter response, embryofetal
survival, or fetal growth and development.
14. CLINICAL STUDIES
EXTRANEAL has demonstrated efficacy as a peritoneal dialysis solution in clinical trials of approximately 480
patients studied with end-stage renal disease (ESRD).
14.1 Ultrafiltration, Urea and Creatinine ClearanceIn the active-controlled trials of one to six months in duration, described below, EXTRANEAL used once-daily for
the long dwell in either continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD)therapy resulted in higher net ultrafiltration than 1.5% and 2.5% dextrose solutions, and higher creatinine and ureanitrogen clearances than 2.5% dextrose. Net ultrafiltration was similar to 4.25% dextrose across all patients in thesestudies. Effects were generally similar in CAPD and APD.
In an additional randomized, multicenter, active-controlled two-week study in high average/high transporter APDpatients, EXTRANEAL used once daily for the long dwell produced higher net ultrafiltration compared to 4.25%dextrose. Mean creatinine and urea nitrogen clearances were also greater with EXTRANEAL and ultrafiltration
efficiency was improved.
In 175 CAPD patients randomized to EXTRANEAL (N=90) or 2.5% dextrose solution (N=85) for the 8-15 hourovernight dwell for one month, mean net ultrafiltration for the overnight dwell was significantly greater in theEXTRANEAL group at weeks 2 and 4 (Figure 1). Mean creatinine and urea nitrogen clearances were also greater
with EXTRANEAL (Figure1).
Figure 1 - Mean Net Ultrafiltration, Mean Creatinine and Urea Nitrogen Clearance for the Overnight Dwell
In another study of 39 APD patients randomized to EXTRANEAL or 2.5% dextrose solution for the long, daytime
dwell (10-17 hours) for three months, the net ultrafiltration reported during the treatment period was (mean ± SD)
278 ± 192 mL for the EXTRANEAL group and -138 ± 352 mL for the dextrose group (p<0.001). Mean creatinine
and urea nitrogen clearances were significantly greater for EXTRANEAL than 2.5% dextrose at weeks 6 and 12
(p<0.001).
In a six-month study in CAPD patients comparing EXTRANE |
