FETCROJA Powder for concentrate for solution for infusion Ref.[27921] Active ingredients: Cefiderocol

Hypersensitivity reactions

Hypersensitivity has been reported with cefiderocol (see sections 4.3 and 4.8).

Patients who have a history of hypersensitivity to carbapenems, penicillins or other beta-lactam antibacterial medicinal products may also be hypersensitive to cefiderocol. Before initiating therapy with Fetcroja, careful inquiry should be made concerning previous hypersensitivity reactions to beta-lactam antibiotics (see section 4.3).

If a severe allergic reaction occurs, treatment with Fetcroja must be discontinued immediately and adequate emergency measures must be initiated.

Clostridioides difficile-associated diarrhoea

Clostridioides difficile-associated diarrhoea (CDAD) has been reported with cefiderocol (see section 4.8). The condition can range in severity from mild diarrhoea to fatal colitis and should be considered in patients who present with diarrhoea during or subsequent to the administration of cefiderocol. Discontinuation of therapy with cefiderocol and the use of supportive measures together with the administration of specific treatment for Clostridioides difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

Seizure

Cephalosporins have been implicated in triggering seizures. Patients with known seizure disorders should continue anticonvulsant therapy. Patients who develop focal tremors, myoclonus, or seizures should be evaluated neurologically and placed on anticonvulsant therapy if not already instituted. If necessary, the dose of cefiderocol should be adjusted based on renal function (see section 4.2). Alternatively, cefiderocol should be discontinued.

Limitations of the clinical data

In clinical trials, cefiderocol has only been used to treat patients with the following types of infection: complicated urinary tract infections (cUTI); hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), healthcare-associated pneumonia (HCAP); sepsis and patients with bacteraemia (some with no identified primary focus of infection).

The use of cefiderocol to treat patients with infections due to Gram-negative aerobic pathogens who have limited treatment options is based on pharmacokinetic-pharmacodynamic analyses for cefiderocol and on limited clinical data from a randomized clinical trial in which 80 patients were treated with Fetcroja and 38 patients were treated with best available therapy for infections caused by carbapenem-resistant organisms.

All-cause mortality in patients with infections due to carbapenem-resistant Gram-negative bacteria

A higher all-cause mortality rate was observed in patients treated with cefiderocol as compared to best available therapy (BAT) in a randomised, open-label trial in critically-ill patients with infections known or suspected to be due to carbapenem-resistant Gram-negative bacteria. The higher day 28 all-cause mortality rate with cefiderocol occurred in patients treated for nosocomial pneumonia, bacteraemia and/or sepsis [25/101 (24.8%) vs. 9/49 (18.4%) with BAT; treatment difference 6.4%, 95% CI (-8.6, 19.2)]. All-cause mortality remained higher in patients treated with cefiderocol through end-of-study [34/101 (33.7%) vs. 9/49 (18.4%) with BAT; treatment difference 15.3%, 95% CI (-0.2, 28.6)]. The cause of the increase in mortality has not been established. In the cefiderocol group there was an association between mortality and infection with Acinetobacter spp., which accounted for the majority of infections due to non-fermenters. In contrast, mortality was not higher in cefiderocol vs. BAT patients with infections due to other non-fermenters.

Spectrum of activity of cefiderocol

Cefiderocol has little or no activity against the majority of Gram-positive organisms and anaerobes (see section 5.1). Additional antibacterial medicinal products should be used when these pathogens are known or suspected to be contributing to the infectious process.

Non-susceptible organisms

The use of cefiderocol may result in the overgrowth of non-susceptible organisms, which may require interruption of treatment or other appropriate measures.

Renal function monitoring

Renal function should be monitored regularly as dose adjustment may be needed during the course of therapy.

Drug/laboratory test interactions

Cefiderocol may result in false-positive results in urine dipstick tests (urine protein, ketones, or occult blood). Alternative methods of testing should be used by the clinical laboratories to confirm positive tests.

Antiglobulin test (Coombs test) seroconversion

A positive direct or indirect Coombs test may develop during treatment with cefiderocol.

Controlled sodium diet

Each 1 g vial contains 7.64 mmol of sodium (approximately 176 mg).

Each 2 g dose of cefiderocol, when reconstituted with 100 mL of 0.9% sodium chloride injection, provides 30.67 mmol (705 mg) of sodium and is approximately 35% of the WHO adult recommended maximum daily dietary intake. The total daily dose (2 g administered 3 times a day) of sodium from cefiderocol therapy is 2.1 g, just greater than the WHO recommend daily maximum of 2 g sodium for an adult.

When reconstituted in 100 mL of 5% dextrose injection each 2 g dose of cefiderocol provides 15.28 mmol (352 mg) of sodium. The total daily sodium dose (2 g administered 3 times a day) from cefiderocol reconstituted in 5% dextrose injection is 1,056 mg which is approximately 53% of the WHO adult recommended maximum daily dietary intake of 2 g sodium.

Based on in vitro studies and two phase 1 clinical studies no significant drug-drug interactions are anticipated between cefiderocol and substrates, inhibitors or inducers of cytochrome P450 enzymes (CYPs) or transporters (see section 5.2).

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of cefiderocol sodium in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Fetcroja during pregnancy.

Breast-feeding

It is unknown whether Fetcroja/metabolites are excreted in human milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Fetcroja therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

The effect of cefiderocol on fertility in humans has not been studied. Based on preclinical data, from a study with sub-clinical exposure, there is no evidence that Fetcroja has an effect on male or female fertility (see section 5.3).

Fetcroja has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most common adverse reactions were diarrhoea (8.2%), vomiting (3.6%), nausea (3.3%) and cough (2%).

Tabulated list of adverse reactions

The following adverse reactions have been reported with cefiderocol during clinical studies (Table 3). Adverse reactions are classified according to frequency and System Organ Class (SOC). Frequency categories are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each System Organ Class, undesirable effects are presented in order of decreasing seriousness.

Table 3. Tabulated list of adverse reactions:

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.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

If treatment with a combination of another medicinal product and Fetcroja is unavoidable, administration should not occur in the same syringe or in the same infusion solution. It is recommended to adequately flush intravenous lines between administration of different medicinal products.