FETCROJA 1g powder for concentrate infusion solution medication leaflet

Fetcroja 1 g powder for concentrate for solution for infusion

Each vial contains cefiderocol sulfate tosylate equivalent to 1 g of cefiderocol.

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

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion (powder for concentrate).

White to off-white powder.

Fetcroja is indicated for the treatment of infections due to aerobic Gram-negative organisms in adultswith limited treatment options (see sections 4.2, pct. 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 optionsonly after consultation with a physician with appropriate experience in the management of infectiousdiseases.

Table 1 Recommended dose of Fetcroja1 for patients with a creatinine clearance (CrCL)≥ 90 mL/min2

Renal function Dose Frequency Duration oftreatment

Normal renal function 2 g Every 8 hours Duration in(CrCL ≥90 to < 120 mL/min) accordance with thesite of infection3

Augmented renal clearance 2 g Every 6 hours Duration in(CrCL ≥ 120 mL/min) accordance with thesite of infection31To be used in combination with antibacterial agents active against anaerobic pathogens and/or Gram-positivepathogens 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 infectionsthe 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 berequired.

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 1.5 g Every 8 hours(CrCL ≥30 to < 60 mL/min)

Severe renal impairment 1 g Every 8 hours(CrCL ≥15 to < 30 mL/min)

End stage renal disease 0.75 g Every 12 hours(CrCL < 15 mL/min)

Patient with intermittent haemodialysis2 0.75 g Every 12 hours1As calculated using the Cockcroft-Gault formula.2As cefiderocol is removed by haemodialysis, administer cefiderocol at the earliest possible time aftercompletion of haemodialysis on haemodialysis days.

No dose adjustment is required in patients with hepatic impairment (see section 5.2).

No dosage adjustment is required (see section 5.2).

The safety and efficacy of Fetcroja in children below 18 years of age has not yet been established. Nodata are available.

Fetcroja is administered by intravenous infusion over 3 hours.

For instructions on reconstitution and dilution of the medicinal product before administration, seesection 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 isrecommended to adequately flush intravenous lines between administration of different medicinalproducts.

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).

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-lactamantibacterial medicinal products may also be hypersensitive to cefiderocol. Before initiating therapywith 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 andadequate emergency measures must be initiated.

Clostridioides difficile-associated diarrhoea

Clostridioides difficile-associated diarrhoea (CDAD) has been reported with cefiderocol (see section4.8). The condition can range in severity from mild diarrhoea to fatal colitis and should be consideredin 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 theadministration of specific treatment for Clostridioides difficile should be considered. Medicinalproducts that inhibit peristalsis should not be given.

Cephalosporins have been implicated in triggering seizures. Patients with known seizure disordersshould continue anticonvulsant therapy. Patients who develop focal tremors, myoclonus, or seizuresshould be evaluated neurologically and placed on anticonvulsant therapy if not already instituted. Ifnecessary, 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-associatedpneumonia (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 whohave limited treatment options is based on pharmacokinetic-pharmacodynamic analyses forcefiderocol and on limited clinical data from a randomized clinical trial in which 80 patients weretreated with cefiderocol and 38 patients were treated with best available therapy for infections causedby 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 bestavailable therapy (BAT) in a randomised, open-label trial in critically-ill patients with infectionsknown 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 throughend-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 therewas an association between mortality and infection with Acinetobacter spp., which accounted for themajority 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 areknown 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 requireinterruption of treatment or other appropriate measures.

Renal function monitoring

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

Drug/laboratory test interactions

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

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 recommendedmaximum daily dietary intake. The total daily dose (2 g administered 3 times a day) of sodium fromcefiderocol therapy is 2.1 g, just greater than the WHO recommend daily maximum of 2 g sodium foran adult.

When reconstituted in 100 mL of 5% dextrose injection each 2 g dose of cefiderocol provides15.28 mmol (352 mg) of sodium. The total daily sodium dose (2 g administered 3 times a day) fromcefiderocol 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 areanticipated between cefiderocol and substrates, inhibitors or inducers of cytochrome P450 enzymes(CYPs) or transporters (see section 5.2).

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

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

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

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

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

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). Frequencycategories 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 theavailable data). Within each System Organ Class, undesirable effects are presented in order ofdecreasing seriousness.

Table 3 Tabulated list of adverse reactions

System organ Common Uncommon Not knownclass(≥1/100 to <1/10) (≥1/1,000 to <1/100)

Infections and Candidiasis including oralinfestations candidiasis, vulvovaginalcandidiasis, candiduria andcandida infection,

Clostridioides difficile colitis includingpseudomembranous colitisand Clostridioides difficileinfection

Blood and Neutropenialymphaticsystemdisorders

Immune System Hypersensitivity

Disorders including skin reactionsand Pruritus

Respiratory, Coughthoracic andmediastinaldisorders

Gastrointestinal Diarrhoea, Nausea,disorders Vomiting

Skin and Rash including rashsubcutaneous macular, rash maculo-tissue disorders papular, rash erythematousand drug eruption

Renal and Chromaturiaurinarydisorders:

General Infusion site reactiondisorders and including infusionadministration site pain, injection sitesite conditions pain, infusion siteerythema and injection sitephlebitis

Investigations Alanine aminotransferase Blood urea increasedincreased, Gamma-glutamyltransferaseincreased, Aspartateaminotransferaseincreased, Hepaticfunction abnormalincluding liver functiontest increased, hepaticenzyme increased,transaminases increasedand liver function testabnormal, Bloodcreatinine increased

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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 generalsupportive treatment should be considered.

Approximately 60% of cefiderocol is removed by a 3- to 4-hour haemodialysis session.

Pharmacotherapeutic group: Antibacterials for systemic use, other beta-lactam antibacterials. ATCcode: J01DI04

Cefiderocol is a siderophore cephalosporin. In addition to passive diffusion through outer membraneporin 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 siderophoreuptake systems. Cefiderocol subsequently binds to penicillin binding proteins (PBPs), inhibitingbacterial peptidoglycan cell wall synthesis which leads to cell lysis and death.

Mechanisms of bacterial resistance that may lead to resistance to cefiderocol include mutant oracquired PBPs; beta-lactamase enzymes with ability to hydrolyse cefiderocol; mutations affectingregulation of bacterial iron uptake; mutations in siderophore transport proteins; overexpression ofnative bacterial siderophores.

The in vitro antibacterial activity effect of cefiderocol against normally susceptible species is notaffected 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 byporin 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 intrinsicresistance.

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 beenestablished by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) forcefiderocol and are listed here: https://www.ema.europa.eu/documents/other/minimum-inhibitory-concentration-mic-breakpoints_en.xlsx

The time that unbound plasma concentrations of cefiderocol exceeds the minimum inhibitoryconcentration (%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 theabsence 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

In vitro studies indicate that the following species are not susceptible to cefiderocol:

Aerobic Gram-positive organisms

Anaerobic organisms

The European Medicines Agency has deferred the obligation to submit the results of studies with

Fetcroja in one or more subsets of the paediatric population in the treatment of infections due toaerobic Gram-negative bacteria (see section 4.2 for information on paediatric use).

After multiple dose administration of cefiderocol, there is no accumulation of cefiderocol administeredevery 8 hours in healthy adult subjects with normal renal function.

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 healthyadult 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.

After administration of a single 1 g dose of [14C]-labelled cefiderocol infused over 1 hour, cefiderocolaccounted 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 for4.7% of the plasma AUC for total radioactivity, while other more minor metabolites each accountedfor < 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 thepharmacokinetics of midazolam (a CYP3A substrate), furosemide (a OAT1 and OAT3 substrate) ormetformin (a OCT1, OCT2, and MATE2-K substrate). Co-administration with 2 g doses ofcefiderocol given every 8 hours increased rosuvastatin (a OATP1B3 substrate) AUC by 21%, whichwas considered not to be clinically meaningful.

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.

Cefiderocol is primarily eliminated by the kidneys. After administration of a single 1 g dose of [14C]-labelled cefiderocol infused over 1 hour, the amount of total radioactivity excreted in urine was 98.6%of the administered dose, with 2.8% of the administered dose excreted in faeces. The amount ofunchanged cefiderocol excreted in urine was 90.6% of the administered dose.

Cefiderocol exhibits linear pharmacokinetics within the dose range of 100 mg to 4000 mg.

In a population pharmacokinetic analysis, no clinically relevant effect on the pharmacokinetics ofcefiderocol was observed with respect to age, gender or race.

Pharmacokinetic studies have not been performed with cefiderocol in infants and children under 18years of age (see section 4.2).

The pharmacokinetics of cefiderocol after administration of a single 1 g dose was assessed in subjectswith mild renal impairment (n=8, estimated glomerular filtration rate [eGFR] of 60 to < 90mL/min/1.73 m2), moderate renal impairment (n=7, eGFR 30 to < 60 mL/min/1.73 m2), severe renalimpairment (n=6, eGFR less than 30 mL/min/1.73 m2), end-stage renal disease (ESRD) requiringhaemodialysis (n=8), and healthy subjects with normal renal function (n=8, estimated creatinineclearance of at least 90 mL/min). The geometric mean ratios (GMR; mild, moderate, severe or ESRDwithout haemodialysis/normal renal function) and 90% confidence intervals (CI) for the AUC ofcefiderocol were 1.0 (0.8, 1.3), 1.5 (1.2, 1.9), 2.5 (2.0, 3.3) and 4.1 (3.3, pct. 5.2), respectively.

Approximately 60% of Fetcroja was removed by a 3- to 4-hour haemodialysis session.

The recommended dose adjustments in subjects with varying degrees of renal impairment are expectedto provide comparable exposures to subjects with normal renal function or mild renal impairment (seesection 4.2).

Patients with augmented renal clearance

Simulations using the population PK model demonstrated that the recommended dose adjustment for

ARC provide exposures, including %T>MIC, of Fetcroja comparable to those in patients with normalrenal function.

Hepatic impairment is not expected to alter the elimination of Fetcroja as hepaticmetabolism/excretion represent a minor pathway of elimination of Fetcroja.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, or genotoxicity. Carcinogenicity studies with cefiderocol have not been conducted.

Cefiderocol was negative for mutagenicity in an in vitro reverse mutation test with bacteria and in thein vitro HPRT gene mutation assay in human cells. Positive findings were seen in an in vitrochromosomal aberration test in cultured TK6 cells and an in vitro mouse lymphoma assay (MLA).

There was no evidence of in vivo genotoxicity (rat micronucleus assay and comet assay in rats).

Cefiderocol had no impairment of fertility and early embryonic development in rats treated withcefiderocol intravenously up to 1000 mg/kg/day corresponding to a margin to clinical exposure of 0.8.

There was no evidence of teratogenicity or embryotoxicity in rats or mice that received 1000mg/kg/day or 2000 mg/kg/day respectively corresponding to margins to clinical exposure of 0.9and 1.3

Cefiderocol had no adverse effects on growth and development, including neurobehavioural functionin juvenile rats that received 1000 mg/kg/day subcutaneously during postnatal day (PND)7 to PND27,or 600 mg/kg/day intravenously from PND28 to PND48.

Sucrose

Sodium chloride

Sodium hydroxide (pH adjustment)

This medicinal product must not be mixed with other medicinal products except those mentioned insection 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 isrecommended to adequately flush intravenous lines between administration of different medicinalproducts.

Powder3 years.

Stability of reconstituted solution in the vial

Chemical and physical in-use stability after reconstitution has been demonstrated for 1 hour at 25°C.

From a microbiological point of view, unless the method of opening/reconstitution precludes the riskof microbial contamination, the reconstituted product should be used immediately. If not usedimmediately, in-use storage times and conditions are the responsibility of the user and should not bemore than 1 hour at 25°C.

Stability of the diluted solution in the infusion bag

Chemical, microbiological and physical in-use stability after dilution has been demonstrated for 6hours at 25°C and for 24 hours at 2 to 8°C protected from light, followed by 6 hours at 25°C.

From a microbiological point of view, diluted products should be used immediately. If not usedimmediately, in-use storage times and conditions are the responsibility of the user and would normallynot be longer than 6 hours at 25°C or 24 hours at 2 to 8°C protected from light, followed by 6 hours at25°C, unless dilution has taken place in controlled and validated aseptic conditions. The 6-hour periodat 25°C should be inclusive of the product administration period of 3 hours (see section 4.2). If storingthe infusion solution in the refrigerator, the infusion bag should be removed and allowed to reachroom temperature prior to use.

For preparation of solution for administration, see section 6.6.

Store in a refrigerator (2°C - 8°C)

Store in the original carton in order to protect from light.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

14 mL vial (Type I clear glass vial), chlorobutyl elastomeric stopper, and aluminum seal with a plasticflip-off cap. The vials are packed in a cardboard carton.

Pack size of 10 vials.

Each vial is for single use only.

The powder should be reconstituted with 10 mL of either sodium chloride 9 mg/ml (0.9%) solution forinjection or 5% dextrose injection taken from the 100 mL bags that will be used to prepare the finalinfusion solution and should be gently shaken to dissolve. The vial(s) should be allowed to stand untilthe foaming generated on the surface has disappeared (typically within 2 minutes). The final volumeof the reconstituted solution in the vial will be approximately 11.2 mL (caution: the reconstitutedsolution is not for direct injection).

To prepare the required doses, the appropriate volume of reconstituted solution should be withdrawnfrom the vial according to Table 4. Add the withdrawn volume to the infusion bag containing theremainder of the 100 mL of sodium chloride 9 mg/ml (0.9%) solution for injection, or 5% dextroseinjection, inspect the resulting diluted drug product solution in the infusion bag visually for particulatematter and discoloration prior to use. Do not use discoloured solutions or solutions with visibleparticles.

Table 4 Preparation of cefiderocol doses

Cefideroco Number of 1 g Volume to withdraw Total volume of cefiderocoll dose cefiderocol vials to be from reconstituted solution required for furtherreconstituted vial(s) dilution in at least 100 mL of0.9% sodium chlorideinjection or 5% dextroseinjection2 g 2 vials 11.2 mL (entire 22.4 mLcontents) from bothvials1.5 g 2 vials 11.2 mL (entire 16.8 mLcontents) from first vial

AND 5.6 mL fromsecond vial1 g 1 vial 11.2 mL (entire 11.2 mLcontents)0.75 g 1 vial 8.4 mL 8.4 mL

Standard aseptic techniques should be used for solution preparation and administration.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Shionogi B.V.

Herengracht 464,1017CA Amsterdam

Netherlands

EU/1/20/1434/001

Date of first authorisation: 23 april 2020

Date of latest renewal:

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.