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

Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after hemodialysis and until clinically stable.

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving parenteral iron products. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after hemodialysis until clinically stable. Personnel and therapies should be immediately available for the treatment of serious hypersensitivity reactions [see Adverse Reactions (6.1)].

Hypersensitivity reactions have been reported in 1 (0.3%) of 292 patients receiving ferric pyrophosphate citrate in two randomized clinical trials.

5.2 Iron Laboratory Testing

Determine iron status on pre-dialysis blood samples. Post-dialysis serum iron parameters may overestimate serum iron and transferrin saturation.

The following clinically significant adverse reactions are described below and elsewhere in the labeling:

• Hypersensitivity Reactions [see Warnings and Precautions (5.1)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.

The safety of ferric pyrophosphate citrate injection, for intravenous use, has been established based on adequate and well-controlled studies of ferric pyrophosphate citrate solution for hemodialysis [see Clinical Studies (14)]. Below is a display of the adverse reactions of ferric pyrophosphate citrate solution for hemodialysis in these adequate and well-controlled studies.

The safety of ferric pyrophosphate citrate solution for hemodialysis was evaluated in 292 patients in two randomized, placebo-controlled clinical trials (CRUISE 1 (NCT01320202) and CRUISE 2 (NCT01322347)) who were administered ferric pyrophosphate citrate solution for hemodialysis usefor periods of up to 1 year [see Clinical Studies (14)]. The mean total exposure in the randomized treatment period was 5 months. A total of 296 patients received placebo treatment for a similar time period. In the two studies, 64% were male and 54% were Caucasian. The median age of patients was 60 years (range, 20 to 89 years).

Adverse reactions occurring in 3% or greater of patients treated with ferric pyrophosphate citrate solution for hemodialysis use in the randomized clinical trials are listed in Table 1.

Table 1. Adverse Reactions Reported in Two Clinical Trials in at Least 3% of Patients Receiving Ferric Pyrophoshate Citrate Solution for Hmodialysis Use and at an Incidence at Least 1% Greater than Placebo:

Other Adverse Reactions

Less common adverse reactions occurring at a frequency of <3%:

• Hypersensitivity Reactions [see Warnings and Precautions (5.1)]

Adverse Reactions Leading to Treatment Discontinuation

In clinical trials, adverse reactions leading to treatment discontinuation include headache, asthenia, dizziness, constipation, nausea, hypersensitivity reactions, intradialytic hypotension, pruritis and pyrexia.

Risk Summary

There are no available data on Triferic AVNU use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, intravenous administration of ferric pyrophosphate citrate to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes at maternally toxic dose levels that were higher than the maximum theoretical amount of iron transferred to patients from Triferic AVNU (see Data).

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 birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

In a fertility and early embryonic development study in female rats, the maternally toxic ferric pyrophosphate citrate dose of 40 mg/kg administered three times per week by intravenous infusion was not toxic to the developing embryo.

In embryo-fetal developmental toxicity studies, ferric pyrophosphate citrate was administered during the period of organogenesis as a one-hour intravenous infusion to pregnant rats and rabbits. No maternal or developmental toxicity was observed at doses up to 30 mg/kg/day in rats and 20 mg/kg/day in rabbits. Maternally toxic doses affected embryo-fetal development, resulting in post-implantation loss due to early resorptions, abnormal placentae, decreased fetal body weight and fetal head and vertebral malformations at 90 mg/kg/day in rats and vertebral malformations at 40 mg/kg/day in rabbits.

A pre-and post-natal development study was conducted in pregnant rats with intravenous doses of ferric pyrophosphate citrate up to 90 mg/kg/day. The maternally toxic dose of 90 mg/kg/day resulted in reductions in the number of live offspring and lower offspring body weights. There were no adverse effects on survival of offspring at doses up to 30 mg/kg/day, or on behavior, sexual maturation or reproductive parameters of offspring at any dose level.

Risk Summary

There are no data on the presence of ferric pyrophosphate citrate in human milk, the effects on the breastfed child, or the effect on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Triferic AVNU and any potential adverse effects on the breastfed child from Triferic AVNU or from the underlying maternal condition.

Safety and effectiveness have not been established in pediatric patients.

In controlled clinical trials, 99 (29%) patients ≥65 years of age were treated with ferric pyrophosphate citrate. No overall differences in safety and efficacy were observed between older and younger patients in these trials [see Clinical Studies (14)].