cefiderocol: prescribing information – dosing, contraindications, interactions, side effects

Fetcroja is indicated for the treatment of infections due to aerobic Gram-negative organisms in adults with limited treatment options (see sections 4.2, 4.4 and 5.1).

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

It is recommended that Fetcroja should be used to treat patients that have limited treatment options only after consultation with a physician with appropriate experience in the management of infectious diseases.

Posology

Table 1
Recommended dose of Fetcroja1 for patients with a creatinine clearance (CrCL)
≥ 90 mL/min2
Renal function
Dose
Frequency
Duration of treatment
Normal renal function
2 g
Every 8 hours
Duration in accordance with the site of infection3
(CrCL ≥ 90 to < 120 mL/min)
Augmented renal clearance
2 g
Every 6 hours
Duration in accordance with the site of infection3
(CrCL ≥ 120 mL/min)
1To be used in combination with antibacterial agents active against anaerobic pathogens and/or Gram-positive pathogens when these are known or suspected to be contributing to the infectious process.
2As calculated using the Cockcroft-Gault formula.
3e.g. for complicated urinary tract infections including pyelonephritis and complicated intra-abdominal infections the recommended treatment duration is 5 to 10 days. For hospital-acquired pneumonia including ventilator- associated pneumonia the recommended treatment duration is 7 to 14 days. Treatment up to 21 days may be

required.

Special populations

Renal impairment

Table 2
Recommended dose of Fetcroja for patients with a CrCl < 90 ml/min1
Renal function
Dose
Frequency
Mild renal impairment
2 g
Every 8 hours
(CrCL ≥ 60 to < 90 mL/min)
Moderate renal impairment

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypersensitivity to any cephalosporin antibacterial medicinal product.

Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of beta-lactam antibacterial agent (e.g. penicillins, monobactams or carbapenems).

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
System organ class
Common
Uncommon
Not known
(≥ 1/100 to < 1/10)
(≥ 1/1,000 to < 1/100)
Infections and infestations
Candidiasis including oral candidiasis, vulvovaginal candidiasis, candiduria and candida infection, Clostridioides difficile coli tis including pseudomembranous colitis and Clostridioides difficile infection Blood and lymphatic system disorders Neutropenia, Eosinophilia Immune System Disorders Hypersensitivity including skin reactions and Pruritus Respiratory, thoracic and Cough

System organ class
Common
Uncommon
Not known
(≥ 1/100 to < 1/10)
(≥ 1/1,000 to < 1/100) mediastinal disorders
Gastrointestinal disorders
Diarrhoea, Nausea,
Vomiting
Skin and subcutaneous tissue disorders
Rash including rash macular, rash maculo- papular, rash erythematous and drug eruption Hepatobiliary disorders Alanine aminotransferase increased, Gamma- glutamyltransferase increased, Aspartate aminotransferase increased, Hepatic function abnormal including liver function test increased, hepatic enzyme increased, transaminases increased and liver function test abnormal Renal and urinary disorders:
Blood creatinine increased
Blood urea increased
Chromaturia
General disorders and administration site conditions
Infusion site reaction including infusion site pain, injection site pain, infusion site erythema and injection site phlebitis 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.

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 cefiderocol 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.

There is no information on clinical signs and symptoms associated with an overdose of cefiderocol.
In the event of overdose, patients should be monitored and treatment discontinuation and general supportive treatment should be considered.
Approximately 60% of cefiderocol is removed by a 3- to 4-hour haemodialysis session.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antibacterials for systemic use, other beta-lactam antibacterials. ATC code: J01DI04 Mechanism of action Cefiderocol is a siderophore cephalosporin. In addition to passive diffusion through outer membrane porin channels, cefiderocol is able to bind to extracellular free iron via its siderophore side chain, allowing active transport into the periplasmic space of Gram-negative bacteria through siderophore uptake systems. Cefiderocol subsequently binds to penicillin binding proteins (PBPs), inhibiting bacterial peptidoglycan cell wall synthesis which leads to cell lysis and death.
Resistance
Mechanisms of bacterial resistance that may lead to resistance to cefiderocol include mutant or acquired PBPs; beta-lactamase enzymes with ability to hydrolyse cefiderocol; mutations affecting regulation of bacterial iron uptake; mutations in siderophore transport proteins; overexpression of native bacterial siderophores.
The in vitro antibacterial activity effect of cefiderocol against normally susceptible species is not affected by the majority of beta-lactamases, including metallo-enzymes. Due to the siderophore- mediated mode of cell entry, the in vitro activity of cefiderocol activity is generally less affected by porin loss or efflux-mediated resistance compared to many other beta-lactam agents.
Cefiderocol has little or no activity against Gram-positive or anaerobic bacteria due to intrinsic resistance.
Antibacterial activity in combination with other antibacterial agents
In vitro studies demonstrated no antagonism between cefiderocol and amikacin, ceftazidime/avibactam, ceftolozane/tazobactam, ciprofloxacin, clindamycin, colistin, daptomycin, linezolid, meropenem, metronidazole, tigecycline, or vancomycin.
Susceptibility testing breakpoints
MIC (minimum inhibitory concentration) interpretive criteria for susceptibility testing have been established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for cefiderocol and are listed here: https://www.ema.europa.eu/documents/other/minimum-inhibitory- concentration-mic-breakpoints_en.xlsx Pharmacokinetic/pharmacodynamic relationship The time that unbound plasma concentrations of cefiderocol exceeds the minimum inhibitory concentration (%fT>MIC) against the infecting organism has been shown to best correlate with efficacy.
Antibacterial activity against specific pathogens
In-vitro studies suggest that the following pathogens would be susceptible to cefiderocol in the absence of acquired mechanisms of resistance:
Aerobic Gram-negative organisms
Achromobacter spp.
Acinetobacter baumannii complex
Burkholderia cepacia complex
Citrobacter freundii complex

Citrobacter koseri
Escherichia coli
Enterobacter cloacae complex
Klebsiella (Enterobacter) aerogenes
Klebsiella pneumoniae
Klebsiella oxytoca
Morganella morganii
Proteus mirabilis
Proteus vulgaris
Providencia rettgeri
Serratia spp.
Pseudomonas aeruginosa
Serratia marcescens
Stenotrophomonas maltophilia

After multiple dose administration of cefiderocol, there is no accumulation of cefiderocol administered every 8 hours in healthy adult subjects with normal renal function.
Distribution
The binding of cefiderocol to human plasma proteins, primarily albumin, is in the range of 40 to 60%, the geometric mean (CV%) volume of distribution during the terminal phase of cefiderocol in healthy adult subjects (n = 43) after intravenous administration of a single 2 g dose of cefiderocol was 18.0 L (18.1%), similar to extracellular fluid volume.
Biotransformation
After administration of a single 1 g dose of [14C]-labelled cefiderocol infused over 1 hour, cefiderocol accounted for 92.3% of the plasma AUC for total radioactivity. The most predominant metabolite, pyrrolidine chlorobenzamide (PCBA, which is a degradation product of cefiderocol), accounted for 4.7% of the plasma AUC for total radioactivity, while other more minor metabolites each accounted for < 2% of the plasma AUC for total radioactivity.
Interaction with other medicinal products.
Co-administration with 2 g doses of cefiderocol given every 8 hours did not affect the pharmacokinetics of midazolam (a CYP3A substrate), furosemide (a OAT1 and OAT3 substrate) or metformin (a OCT1, OCT2, and MATE2-K substrate). Co-administration with 2 g doses of cefiderocol given every 8 hours increased rosuvastatin (a OATP1B3 substrate) AUC by 21%, which was considered not to be clinically meaningful.
Elimination
The terminal elimination half-life in healthy adult subjects was 2 to 3 hours. The geometric mean (%CV) of clearance of cefiderocol in healthy subjects is estimated to be 5.18 (17.2%) L/hr.