FEXERIC Film-coated tablet Ref.[49917] Active ingredients: Ferric citrate

Monitoring iron parameters

Increases in ferritin and transferrin saturation (TSAT) are observed with Fexeric use. This medicine should be used only in the absence of iron overload syndromes and with caution if serum ferritin rises above 500 ng/ml. Fexeric should be temporarily discontinued if serum ferritin exceeds 800 ng/ml. Significantly elevated ferritin levels were observed particularly when concomitant intravenous iron was used.

All patients receiving this medicine require at least quarterly monitoring of serum iron storage parameters (serum ferritin and TSAT). Serum ferritin and TSAT levels increase after intravenous iron administration; hence, blood samples for measurement of iron storage parameters should be obtained at a time appropriate to reflect the patient’s iron status after intravenous iron dosing taking into account the product used, the amount of iron given and the frequency of dosing, but a minimum of 7 days after intravenous iron dosing.

Patients treated with Fexeric should not receive concomitant treatment with other oral iron preparations.

Reductions in intravenous iron and erythropoiesis-stimulating agent (ESA) use with this medicine have been observed. Therefore, patients may need reduction in, or discontinuation of, intravenous iron and/or ESAs.

Inflammatory bowel disease

Patients with active, symptomatic inflammatory bowel disease were excluded from clinical trials. Fexeric should only be used in these patients following careful assessment of benefit/risk.

General

Each 1 g film-coated tablet contains sunset yellow FCF (E110) (0.99 mg) and Allura Red AC (E129) (0.70 mg) which may cause allergic reaction.

Effects of other medicinal products on Fexeric

Results from subgroup analyses in the pivotal clinical study in dialysis patients show that the concomitant use of frequently co-prescribed medications in CKD patients (fluoroquinolones, tetracyclines, proton pump inhibitors, thyroid hormones, sertraline, Vitamin D, warfarin, acetylsalicylic acid) do not affect the efficacy of Fexeric with respect to its ability to lower serum phosphorus.

Effects of Fexeric on other medicinal products

Since citrate is known to increase aluminium absorption, aluminium-based compounds should be avoided while patients receive Fexeric.

Treatment with Fexeric may lead to elevations in iron stores, particularly in patients receiving concomitant intravenous iron therapy. Patients with elevated ferritin levels receiving intravenous iron may require a reduction in dose or discontinuation of intravenous iron therapy.

Reductions in ESA use with Fexeric have been observed. Therefore, patients may need a reduction in the dose of ESAs.

In drug-drug interaction studies in healthy male and female subjects, Fexeric decreased the bioavailability of concomitantly administered ciprofloxacin (as measured by the area under the curve [AUC]) by approximately 45%. However, there was no interaction when Fexeric and ciprofloxacin were taken 2 hours apart. Consequently, ciprofloxacin should not be taken at the same time, but at least 2 hours before or after Fexeric. Fexeric did not alter the bioavailability of the following medicinal products when concomitantly administered: clopidogrel, digoxin, diltiazem, glimepiride, losartan.

From in vitro studies, certain antibiotic (doxycycline, cefdinir), anticonvulsant (valproate sodium), antidepressant (sertraline HCl), bisphosphonate (alendronate sodium), anti-parkinsonian (levodopa) and immunosuppressant (methotrexate) medications showed the potential to interact with Fexeric: any of these or other medicinal products that have the potential to interact with Fexeric, should be taken at least 2 hours before or after Fexeric.

Since iron-based preparations are known to reduce the absorption of levothyroxine (thyroxine), physicians should consider monitoring suitable markers or clinical signs of efficacy if these medicinal products are concomitantly administered with Fexeric.

Although the potential for interactions with medicinal products seems low, for concomitant treatment with products with a narrow therapeutic window, the clinical effect/adverse events should be monitored on initiation or dose adjustment of Fexeric or the concomitant product.

Pregnancy and women of childbearing potential

There are no data regarding the use of ferric citrate coordination complex in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Fexeric is not recommended during pregnancy and in women of childbearing potential not using contraceptive methods.

Breast-feeding

It is not known whether ferric citrate coordination complex/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Fexeric therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

No data are available on the potential influence of Fexeric on fertility.

Fexeric has no influence on the ability to drive and use machines.

Summary of the safety profile

The most commonly reported adverse reactions in dialysis-dependent chronic kidney disease (CKD 5D) patients during treatment were discoloured faeces and diarrhoea occurring in 18% and 13% of patients, respectively. These adverse reactions are characteristic of iron-containing medicinal products and abated with time with continued dosing. All serious adverse reactions were gastrointestinal in nature (abdominal pain, constipation, diarrhoea, gastritis, gastritis erosive, and haematemesis). These serious adverse reactions were uncommon (less than 1 case of each per 100 patients) and were each reported in 0.2% (1/557) of CKD 5D patients who received Fexeric.

The most commonly reported adverse reactions in non-dialysis dependent CKD (CKD ND) patients during treatment were discoloured faeces, constipation and diarrhoea occurring in 27%, 13% and 11% of patients, respectively. None of the reported serious events in Study 204 were considered to be possibly related to Fexeric. In the remaining non-dialysis studies, a total of 3 serious adverse reactions reported in 2 patients were gastrointestinal in nature (gastrointestinal ulcer, gastric polyps and colonic polyps).

Increases in ferritin and TSAT above safety thresholds are observed with Fexeric use.

Tabulated list of adverse reactions

The safety of Fexeric for the treatment of hyperphosphataemia has been investigated in 18 clinical trials involving a total of 1388 CKD 5D patients with treatment duration of up to 2 years and 145 CKD ND patients with treatment duration of 12 weeks to 1 year.

In CKD 5D patients, the primary evaluation of safety is based on the integrated analysis of data from 4 studies involving 557 CKD 5D patients treated with Fexeric for up to 1 year. In CKD ND patients, the primary evaluation of safety is based on data from the pivotal study (Study 204), where 75 patients were treated with Fexeric for 12 weeks. Adverse reactions reported in CKD 5D and CKD ND patients are presented in Tables 1 and 2, respectively. Frequencies of adverse reactions are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); and very rare (<1/10,000).

Table 1. Adverse reactions observed during clinical studies in which Fexeric was administered in CKD 5D patients on haemodialysis or peritoneal dialysis:

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.