Fexeric - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Fexeric 1 g film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 1 g of ferric citrate coordination complex (equivalent to 210 mg o ferric iron).

Excipients with known effect:

Each film-coated tablet contains sunset yellow FCF (E110) (0.99 mg) and Allura Red AC (E129) (0.70 mg).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet.

Peach-coloured, oval shaped, film-coated tablet, embossed with “KX52”. Tablets are 19 mm long, 7.2 mm thick and 10 mm wide.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Fexeric is indicated for the control of hyperphosphataemia in adult patients with chronic kidney disease (CKD).

4.2 Posology and method of administration

4.3 Contraindications■■■

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, intraveno 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.

4.5 Interaction with other medicinal products and other forms of interaction

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 me

ase aluminium absorption, aluminium-based compounds should be 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.

4.6 Fertility, pregnancy and lactation

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.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

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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.

Table 2: Adverse reactions observed during clinical studies in which Fexeric was administered in CKD ND patients.

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.

4.9 Overdose

No data are available regarding overdose of Fexeric in humans. In patients with CKD, the maximum dose studied was 12 g (12 tablets) of Fexeric per day.

Iron overdose is dangerous, particularly in children, and requires immediate attention. The symptoms of acute iron overdose include vomiting, diarrhoea, abdominal pain, irritability, and drowsiness. If someone is known or suspected to have accidentally or intentionally ingested an overdose of Fexeric, immediate medical attention should be sought.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for treatment of hyperkalemia and hyperphosphatemia ATC code: V03AE08

Mechanism of action

This medicine contains ferric citrate coordination complex as the active substance. The iron component reacts with dietary phosphate in the gastrointestinal (GI) tract and precipitates phosphate as ferric phosphate. This compound is insoluble and is excreted in the stool, reducing the amount of phosphate that is absorbed from the GI tract. By binding phosphate in the GI tract and decreasing absorption, Fexeric lowers the levels of serum phosphorus. Following absorption, citrate is converted into bicarbonate by the tissues.

Clinical efficacy

The ability of Fexeric to control serum phosphorus in CKD patients was principally evaluated in one long-term, pivotal Phase III trial (Study 304) in CKD 5D patients, and in one pivotal Phase II, 12 week, placebo-controlled trial (Study 204) in CKD ND patients with anaemia. Both studies were performed in North American and/or Asian patients.

As a secondary endpoint in dialysis patients, and a co-primary endpoint in non-dialysis patients, the ability of Fexeric to increase iron stores was also evaluated.

Effects on phosphorus homeostasis

In the pivotal dialysis study 304, following a 2-week washout period, 441 CKD 5D patients with hyperphosphatemia were randomised to receive Fexeric (n=292) or active control (sevelamer carbonate and/or calcium acetate; n=149) open-label for 52 weeks. The starting dose of Fexeric was 6 tablets/day (6 g/day), in divided doses with meals. The starting dose of active control was the patient's dose prior to the washout period.

The dose of phosphate binder was titrated as needed to maintain serum phosphorus levels between 3.5 and 5.5 mg/dl, to a maximum of 12 g/day. Non-inferiority to sevelamer carbonate was determined at Week 12. Following completion of the 52-week active-controlled period, patients were eligible to enter a 4-week placebo-controlled period in which they were re-randomized to receive Fexeric (n=96) or placebo (n=96).

After 12 weeks of treatment, the mean (± SD) change in serum phosphorus from baseline was –2.02 ± 2.0 mg/dl for Fexeric and –2.21 ± 2.18 mg/dl for sevelamer carbonate, demonstrating non-inferiority of Fexeric to sevelamer. During the overall 52-week active-controlled period, the decrease in serum phosphorus (approximately 2.0 mg/dl following up to a 2 week washout period) and the percentage of patients who achieved and maintained serum phosphorus < 5.5 mg/dl (approximately 62%) were comparable in both the Fexeric and the active control groups (Table 3). During the subsequent 4-week placebo-controlled period, the serum phosphorus levels remained stable in patients receiving Fexeric (mean decrease of 0.24 mg/dl), whereas patients receiving placebo had a mean increase of 1.79 mg/dl (p < 0.0001 for treatment difference).

In the pivotal non-dialysis study 204, a total of 148 CKD ND patients with hyperphosphatemia and iron deficiency anaemia received treatment with study drug; there were 141 patients in the intent-to-treat population (Fexeric: 72 patients; Placebo: 69 patients). The starting dose of Fexeric was 3 tablets a day (3 g/day) in divided doses with meals and was adjusted as needed to a maximum of 12 g/day in order to maintain serum phosphorus levels between 3.0 and 3.5 mg/dl.

During the 12-week treatment period, patients treated with Fexeric had a significant decrease in serum phosphorus, compared to the placebo group (p < 0.001 for treatment difference) (Table 3). Urinary phosphorus excretion and FGF-23 were also significantly decreased relative to baseline in the CKD ND patients treated with Fexeric compared to patients treated with placebo.

• §Primary endpoint in Study 304; Co-primary endpoint in Study 204.

• *Proportion of patients achieving serum phosphorus < 5.5 mg/dl in CKD 5D patients;

• **Proportion of patients achieving serum phosphorus < 4.0 mg/dl in CKD ND patients

5.2 Pharmacokinetic properties

Formal pharmacokinetic studies have not been performed due to the medicine's pre­dominantly localised primary mechanism of action in the GI tract.

Examination of serum iron storage parameters has shown that there is low systemic absorption of iron of approximately 1% from Fexeric.

5.3 Preclinical safety data

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The non clinical programme was based on 7 repeat dose toxicology studies in rats and dogs. The target organ for primary toxicity of ferric citrate is the GI tract, with evidence of mucosal erosion and acute to sub-acute inflammation of the GI tract in dogs at elevated doses. In iron replete dogs, microscopic and macroscopic findings in the liver were consistent with signs of iron accumulation.

Data on primary and secondary pharmacodynamics, safety pharmacology and pharmacokinetics of Fexeric were derived from the repeat dose toxicology studies, and did not reveal safety concerns for humans.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

6.2 Incompatibilities

6.3 Shelf life

6.5 Nature and contents of container

6.6 Special precautions for disposal

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1039/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION