TRIFERIC AVNU Solution for injection Ref.[10336] Active ingredients:

Ferric pyrophosphate citrate exposure-response relationships and the time course of pharmacodynamics response are unknown.

Drug interaction Studies

In vitro studies showed that ferric pyrophosphate citrate did not impact the pharmacodynamics of unfractionated heparin or low molecular weight heparin.

Following administration of ferric pyrophosphate citrate 6.75 mg via a 3-hour intravenous infusion at a rate of 1.5 mg/hr (6.5 mg delivered), the total plasma iron and transferrin bound iron exposure values are provided in Table 2.

Table 2. Total Plasma Iron and Transferrin Bound Iron Exposure Parameters after Intravenous Administration of Ferric Pyrophosphate Citrate via the Pre-dialyzer and Post-dialyzer Infusion Line during Hemodialysis:

* N=17 for pre-dialyzer and N=16 for post-dialyzer

Studies examining the carcinogenic potential of ferric pyrophosphate citrate have not been conducted.

Ferric pyrophosphate citrate was clastogenic in the in vitro chromosomal aberration assay in CHO cells in the presence of metabolic activation. Ferric pyrophosphate citrate was not mutagenic in the in vitro bacterial reverse mutation (Ames) test or clastogenic in the in vitro chromosomal aberration assay in CHO cells in the absence of metabolic activation or in the in vivo mouse micronucleus assay.

In a combined male and female fertility study in rats, ferric pyrophosphate citrate was administered intravenously over one hour three times per week at doses of up to 40 mg/kg. No adverse effects on fertility or reproduction were noted.

The efficacy of Triferic AVNU has been established based on adequate and well-controlled adult studies of ferric pyrophosphate citrate in iron replacement in patients with hemodialysis-dependent chronic kidney disease (HDD-CKD). Below is a display of the results of the adequate and well-controlled studies of ferric pyrophosphate citrate in this condition.

The efficacy of ferric pyrophosphate citrate in patients with HDD-CKD was assessed in two randomized, single blind, placebo-controlled clinical trials. Patients with hemoglobin of 9 g/dL to 12 g/dL with TSAT >20% and serum ferritin concentrations >200 mcg/L were enrolled. Patients were to remain in randomized treatment until pre-specified hemoglobin or ferritin criteria were met, indicating the need for a change in anemia management or if they completed 48 weeks. Ferric pyrophosphate citrate was added to bicarbonate concentrate with a final concentration of 110 mcg iron/L in the dialysate and was administered 3 or 4 times per week during hemodialysis. Most patients were receiving stable dose of erythropoiesis stimulating agents (ESAs) at baseline. After randomization, patients ESA doses were not to be changed.

In CRUISE 1 (NCT01320202), the mean age of patients was 58 years (range 23 to 89); 68% were male, 55% were Caucasian, 32% were African American, and 13% were other races.

In CRUISE 2 (NCT01322347), the mean age of patients was 58 years (range 20 to 89); 59% were male, 54% were Caucasian, 40% were African American, and 6% were other races.

Efficacy was assessed by the mean change in hemoglobin from baseline to the end-of-treatment period (average hemoglobin of the last one-sixth (1/6th) of the time in the randomized treatment period). About 18% of patientscompleted the planned 48 week treatment duration.

Table 3 shows the mean changes in hemoglobin (Hgb) and iron parameters in each treatment group from baseline to the end-of-treatment period for the ITT population.

Table 3. Changes from Baseline to end of Treatment in Hemoglobin, Ferritin, Reticulocyte Hgb (CHr) and Transferrin Saturation (TSAT):

* p<0.05