ZINFORO 600mg powder for concentrate infusion solution medication leaflet

Zinforo 600 mg powder for concentrate for solution for infusion

Each vial contains ceftaroline fosamil acetic acid solvate monohydrate equivalent to 600 mgceftaroline fosamil.

After reconstitution, 1 mL of the solution contains 30 mg of ceftaroline fosamil.

For the full list of excipients, see section 6.1.

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

A pale yellowish-white to light yellow powder.

Zinforo is indicated for the treatment of the following infections in neonates, infants, children,adolescents and adults (see sections 4.4 and 5.1):

- Complicated skin and soft tissue infections (cSSTI)

- Community-acquired pneumonia (CAP)

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

The recommended durations of treatment are 5-14 days for cSSTI and 5-7 days for CAP.

Table 1 Dosage in adults with normal renal function, creatinine clearance (CrCL)> 50 mL/min

Indications Posology Infusion time(mg/infusion) (minutes)/Frequency

Standard dosea

Complicated skin and soft tissue infections (cSSTI) 5 - 60b/every 12 hours

Community-acquired pneumonia (CAP)

Indications Posology Infusion time(mg/infusion) (minutes)/Frequency

High doseb600 mgcSSTI confirmed or suspected to be caused by S. 120/every 8 hoursaureus with an MIC = 2 mg/L or 4 mg/L toceftarolineca For patients with supranormal renal clearance receiving the standard dose, an infusion time of 60 minutesmay be preferable.

b Infusion times of less than 60 minutes and high dose recommendations are based on pharmacokinetic andpharmacodynamic analyses only. See sections 4.4 and 5.1.

c For treatment of S. aureus for which the ceftaroline MIC is ≤ 1 mg/L, the standard dose is recommended.

Table 2 Dosage in paediatric patients with normal renal function, creatinine clearance (CrCL)> 50 mL/min*

Indications Age group Posology Infusion time(mg/infusion) (minutes)/Frequency

Adolescents aged from 12

Standard dosea to < 18 years with 600 mg 5-60b/every 12 hoursbodyweight ≥ 33 kg

Adolescents aged from

Complicated skin and 12 years to < 18 years 12 mg/kg to asoft tissue infections bodyweight < 33 kg and maximum of 5-60b/every 8 hours(cSSTI) children ≥ 2 years to 400 mg< 12 years

Infants ≥ 2 months to8 mg/kg 5-60b/every 8 hours

Community-acquired < 2 yearspneumonia (CAP) Neonates from birth tob 6 mg/kg 60/every 8 hours< 2 months

High doseb Children and adolescents 12 mg/kg to aaged from ≥ 2 years to maximum of 120/every 8 hourscSSTI confirmed or < 18 years 600 mgsuspected to be caused by

S. aureus with an Infants ≥ 2 months to

MIC = 2 mg/L or 4 mg/L < 2 years 10 mg/kg 120/every 8 hoursto ceftarolineca For patients with supranormal renal clearance receiving the standard dose, an infusion time of 60 minutesmay be preferable.

b Infusion times of less than 60 minutes, neonatal and high dose recommendations are based onpharmacokinetic and pharmacodynamic analyses only. See sections 4.4 and 5.1.

c For treatment of S. aureus for which the ceftaroline MIC is ≤ 1 mg/L, the standard dose is recommended.

* Calculated using the Schwartz formula (in mL/min/1.73 m2) for paediatric patients.

No dosage adjustment is required for the elderly with creatinine clearance values > 50 mL/min (seesection 5.2).

The dose should be adjusted when creatinine clearance (CrCL) is ≤ 50 mL/min, as shown in

Tables 3 and 4 (see sections 4.9 and 5.2). The recommended durations of treatment are 5-14 days forcSSTI and 5-7 days for CAP.

Table 3 Dosage in adults with impaired renal function, creatinine clearance (CrCL)≤ 50 mL/min

Indications Creatinine clearance Posology Infusion time(mL/min)a (mg/infusion) (minutes)/Frequency

Standard dose> 30 to ≤ 50 400 mg

Complicated skin and softtissue infections(cSSTI) ≥ 15 to ≤ 30 300 mg 5-60c/every 12 hours

Community-acquired ESRD, including 200 mgpneumonia (CAP) haemodialysisb

High dosec > 30 to ≤ 50 400 mg≥ 15 to ≤ 30 300 mgcSSTI confirmed orsuspected to be caused by 120/every 8 hours

ESRD, including

S. aureus with an b 200 mghaemodialysis

MIC = 2 mg/L or 4 mg/Lto ceftarolineda Calculated using the Cockcroft-Gault formula for adults. Dose is based on CrCL. CrCL should be closelymonitored and the dose adjusted according to changing renal function.

b Ceftaroline is haemodialyzable; thus Zinforo should be administered after haemodialysis on haemodialysisdays.

c Infusion times of less than 60 minutes and high dose recommendations are based on pharmacokinetic andpharmacodynamic analyses only. See sections 4.4 and 5.1.

d For treatment of S. aureus for which the ceftaroline MIC is ≤ 1 mg/L, the standard dose is recommended.

Dose recommendations for neonates, infants and children and adolescents are based onpharmacokinetic (PK) modelling.

There is insufficient information to recommend dosage adjustments in adolescents aged from 12 to< 18 years with bodyweight < 33 kg and in children aged from 2 to 12 years with End-stage renaldisease (ESRD).

There is insufficient information to recommend dosage adjustments in paediatric patients < 2 yearswith moderate or severe renal impairment or ESRD.

Table 4 Dosage in paediatric patients with impaired renal function, creatinine clearance(CrCL) ≤ 50 mL/min

Indications Age group Creatinine Posology Infusion timeclearance (mg/infusion) (minutes)/Frequency(mL/min)a

Standard dose Adolescents aged > 30 to ≤ 50 400 mgfrom 12 to ≥ 15 to ≤ 30 300 mg< 18 years with ESRD, 5-60c/every 12 hours

Complicated skin bodyweight including 200 mgand soft tissue ≥ 33 kg haemodialysisbinfections 8 mg/kg to a(cSSTI) Adolescents aged > 30 to ≤ 50 maximum offrom 12 years to 300 mg< 18 yearsbodyweight 5-60c/every 8 hours

Community- 6 mg/kg to a< 33 kg andacquired ≥ 15 to ≤ 30 maximum ofchildren ≥ 2 yearspneumonia 200 mgto < 12 years(CAP)

Indications Age group Creatinine Posology Infusion timeclearance (mg/infusion) (minutes)/Frequency(mL/min)a

High dosec 10 mg/kg to a> 30 to ≤ 50 maximum ofcSSTI confirmed 400 mg

Children andor suspected toadolescents agedbe caused by S. 8 mg/kg to a 120/every 8 hoursfrom ≥2 years toaureus with an ≥ 15 to ≤ 30 maximum of< 18 years

MIC = 2 mg/L or 300 mg4 mg/L toceftarolineda Calculated using the Schwartz formula for paediatric patients (in mL/min/1.73 m2). Dose is based on CrCL.

CrCL should be closely monitored and the dose adjusted according to changing renal function.

b Ceftaroline is haemodialyzable; thus Zinforo should be administered after haemodialysis on haemodialysisdays.

c Infusion times of less than 60 minutes and high dose recommendations are based on pharmacokinetic andpharmacodynamic analyses only. See sections 4.4 and 5.1.

d For treatment of S. aureus for which the ceftaroline MIC is ≤ 1 mg/L, the standard dose is recommended.

No dosage adjustment is considered necessary in patients with hepatic impairment (see section 5.2).

Intravenous use. Zinforo is administered by intravenous infusion over 5 to 60 minutes for standarddose or 120 minutes for high dose (for cSSTI caused by S. aureus with MIC of 2 or 4 mg/L toceftaroline) in infusion volumes of 50 mL, 100 mL or 250 mL (see section 6.6). Infusion relatedreactions (such as phlebitis) can be managed by prolonging the infusion duration.

Infusion volumes for paediatric patients will vary according to the weight of the child. The infusionsolution concentration during preparation and administration should not exceed 12 mg/mL ceftarolinefosamil.

For instructions on reconstitution and dilution of the medicinal product before administration, seesection 6.6.

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

Hypersensitivity to the cephalosporin class of antibacterials.

Immediate and severe hypersensitivity (e.g. anaphylactic reaction) to any other type of beta-lactamantibacterial agent (e.g. penicillins or carbapenems).

Serious and occasionally fatal hypersensitivity reactions are possible (see sections 4.3 and 4.8).

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxicepidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), andacute generalised exanthematous pustulosis (AGEP) have been reported in association withbeta-lactam antibiotics (including cephalosporins) treatment.

Patients who have a history of hypersensitivity to cephalosporins, penicillins or other beta-lactamantibacterials may also be hypersensitive to ceftaroline fosamil. Ceftaroline should be used withcaution in patients with a history of non-severe hypersensitivity reactions to any other beta-lactamantibiotics (e.g. penicillins or carbapenems). If a severe allergic reaction or SCAR occurs duringtreatment with Zinforo, the medicinal product should be discontinued and appropriate measures taken.

With other beta-lactam antibiotics there have been reports of hypersensitivity reactions whichprogressed to Kounis syndrome (acute allergic coronary arteriospasm that can result in myocardialinfarction, see section 4.8).

Clostridium difficile-associated diarrhoea

Antibacterial-associated colitis and pseudomembranous colitis have been reported with ceftarolinefosamil and may range in severity from mild to life threatening. Therefore, it is important to considerthis diagnosis in patients who present with diarrhoea during or subsequent to the administration ofceftaroline fosamil (see section 4.8). In such circumstance, the discontinuation of therapy withceftaroline fosamil and the use of supportive measures together with the administration of specifictreatment for Clostridium difficile should be considered.

Non-susceptible organisms

Superinfections may occur during or following treatment with Zinforo.

Patients with pre-existing seizure disorder

Seizures have occurred in toxicology studies at 7-25 times human ceftaroline Cmax levels (seesection 5.3). Clinical study experience with ceftaroline fosamil in patients with pre-existing seizuredisorders is very limited. Therefore, Zinforo should be used with caution in this patient population.

Direct antiglobulin test (Coombs test) seroconversion and potential risk of haemolytic anaemia

The development of a positive direct antiglobulin test (DAGT) may occur during treatment withcephalosporins. The incidence of DAGT seroconversion in patients receiving ceftaroline fosamil was11.2% in the five pooled pivotal studies with administration every 12 hours (600 mg administered over60 minutes every 12 hours) and 32.3% in a study in patients receiving ceftaroline fosamil every8 hours (600 mg administered over 120 minutes every 8 hours), (see section 4.8). In clinical studiesthere was no evidence of haemolysis in patients who developed a positive DAGT on treatment.

However, the possibility that haemolytic anaemia may occur in association with cephalosporinsincluding Zinforo treatment cannot be ruled out. Patients experiencing anaemia during or aftertreatment with Zinforo should be investigated for this possibility.

Limitations of the clinical data

There is no experience with ceftaroline in the treatment of CAP in the following patient groups: theimmunocompromised, patients with severe sepsis/septic shock, severe underlying lung disease (e.g.cystic fibrosis, see section 5.2), those with PORT Risk Class V, and/or CAP requiring ventilation atpresentation, CAP due to methicillin-resistant S. aureus or patients requiring intensive care. Caution isadvised when treating such patients.

There is no experience with ceftaroline in the treatment of cSSTI in the following patient groups: theimmunocompromised, patients with severe sepsis/septic shock, necrotizing fasciitis, perirectal abscessand patients with third degree and extensive burns. There is limited experience in treating patients withdiabetic foot infections. Caution is advised when treating such patients.

There are limited clinical trial data on the use of ceftaroline to treat cSSTI caused by S. aureus with an

MIC of > 1 mg/L. The recommended dosages of Zinforo shown in Tables 1 to 4 for the treatment ofcSSTI caused by S. aureus with ceftaroline MIC of 2 or 4 mg/L are based on pharmacokinetic-pharmacodynamic modelling and simulation (see sections 4.2 and 5.1). Zinforo should not be used totreat cSSTI due to S. aureus for which the ceftaroline MIC is > 4 mg/L.

The recommended dosage of Zinforo shown in Table 2 for paediatric patients < 2 months of age arebased on pharmacokinetic-pharmacodynamic modelling and simulation.

Infusion times of less than 60 minutes are based on pharmacokinetic and pharmacodynamic analysesonly.

No clinical drug-drug interaction studies have been conducted with ceftaroline fosamil.

The interaction potential of ceftaroline or ceftaroline fosamil on medicinal products metabolised by

CYP450 enzymes is expected to be low since they are not inhibitors nor inducers of CYP450 enzymesin vitro. Ceftaroline or ceftaroline fosamil are not metabolised by CYP450 enzymes in vitro, thereforeco-administered CYP450 inducers or inhibitors are unlikely to influence the pharmacokinetics ofceftaroline.

Ceftaroline is neither a substrate, nor an inhibitor of renal uptake transporters (OCT2, OAT1, and

OAT3) in vitro. Therefore, interactions of ceftaroline with medicinal products that are substrates orinhibitors (e.g. probenecid) of these transporters would not be expected.

As with adults, the interaction potential is expected to be low in paediatrics.

There are no or limited amount of data from the use of ceftaroline fosamil in pregnant women. Animalstudies conducted in rat and rabbit do not indicate harmful effects with respect to reproductive toxicityat exposures similar to therapeutic concentrations. Following administration throughout pregnancy andlactation in the rat, there was no effect on pup birth weight or growth, although minor changes infoetal weight and delayed ossification of the interparietal bone were observed when ceftarolinefosamil was administered during organogenesis (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Zinforo during pregnancy unless theclinical condition of the woman requires treatment with an antibiotic with Zinforo’s antibacterialprofile.

It is unknown whether ceftaroline fosamil or ceftaroline is excreted in human milk. A risk to thenewborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feedingor to discontinue/abstain from Zinforo therapy taking into account the benefit of breast-feeding for thechild and the benefit of therapy for the woman.

The effects of ceftaroline fosamil on fertility on humans have not been studied. Animal studies withceftaroline fosamil do not indicate harmful effects with respect to fertility (see section 5.3).

Undesirable effects e.g. dizziness may occur and this may have an effect on the ability to drive and useof machines (see section 4.8).

The most common adverse reactions occurring in ≥ 3% of approximately 3242 patients treated with

Zinforo in clinical studies were diarrhoea, headache, nausea, and pruritus, and were generally mild ormoderate in severity. Clostridium difficile-associated disease (CDAD) and severe hypersensitivityreactions may also occur.

A greater incidence of rash in Asian patients (see below) and a greater incidence of DAGTseroconversion (see section 4.4) were observed in a study of adult patients with cSSTI conducted with

Zinforo 600 mg administered over 120 minutes every 8 hours.

The following adverse reactions have been identified during clinical trials and post-marketingexperience with Zinforo. Adverse reactions are classified according to System Organ Class andfrequency. Frequency categories are derived according to the following conventions: 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), not known (cannot be estimated from the available data).

Table 5 Frequency of adverse reactions by system organ class from clinical trials and post-marketing experience

System Very Common Uncommon Rare Not knownorgan class common

Infections and Clostridiuminfestations difficile colitis(see section 4.4)

Blood and Anaemia, Agranulocytosis*lymphatic leucopenia, , eosinophilia*system neutropenia*,disorders thrombocytopenia, prothrombintime (PT)prolonged,activated partialthromboplastintime (aPTT)prolonged,internationalnormalized ratio(INR) increased

Immune Rash, pruritus Anaphylaxis,system hypersensitivitydisorders (e.g. urticaria, lipand faceswelling) (seesections 4.3and 4.4)

Nervous Headache, Encephalopathy*,system dizziness +disorders

Vascular Phlebitisdisorders

Respiratory, Eosinophilicthoracic and pneumonia*mediastinaldisorders

System Very Common Uncommon Rare Not knownorgan class common

Gastrointestin Diarrhoea,al disorders nausea,vomiting,abdominalpain

Hepatobiliary Increaseddisorders transaminases

Renal and Blood creatinineurinary increaseddisorders

General Pyrexia,disorders and infusion siteadministration reactionssite (erythema,conditions phlebitis,pain)

Investigations Coombs

Direct Test

Positive(seesection 4.4)

* Adverse Drug Reaction (ADR) identified post-marketing.

+ Risk of encephalopathy is higher in patients with renal impairment in whom the dose of ceftaroline has not beenappropriately reduced (see sections 4.2 and 4.9).

Severe Cutaneous Adverse Reactions

SCARs (Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia andsystemic symptoms, acute generalised exanthematous pustulosis) have been reported with beta-lactamantibiotics, including cephalosporins (see section 4.4).

Kounis Syndrome

Acute coronary syndrome associated with an allergic reaction (Kounis syndrome) has been reportedwith other beta-lactam antibiotics.

Rash was observed at a common frequency in both the pooled Phase III studies in cSSTI withadministration of Zinforo every 12 hours (600 mg administered over 60 minutes every 12 hours) andthe study in cSSTI with administration every 8 hours (600 mg administered over 120 minutes every8 hours). However, the frequency of rash in the subgroup of Asian patients receiving Zinforo every8 hours was very common (18.5%).

The safety assessment in paediatric patients is based on the safety data from 2 trials in which227 patients aged from 2 months to 17 years with cSSTI or CAP received Zinforo. Overall, the safetyprofile in these 227 patients was similar to that observed in the adult population.

In addition, the safety assessment in neonates is based on the safety data from 2 trials in which34 patients (age range from birth to less than 60 days) received Zinforo; 23 of these patients receivedonly a single dose of Zinforo. Overall, the adverse events reported in these studies were consistentwith the known safety profile for Zinforo.

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.

Limited data in patients receiving higher than recommended Zinforo dosages show similar adversereactions as observed in the patients receiving recommended dosages. Treatment of overdose shouldfollow standard medical practice.

Relative overdosing could occur in patients with moderate renal impairment. Neurological sequelae,including encephalopathy, have been noted in cases where beta-lactam antibiotics (includingcephalosporins) have been given to patients with impaired renal function without reducing the dose(see section 4.2) .

Ceftaroline can be removed by haemodialysis; over a 4 hour dialysis period, approximately 74% of agiven dose was recovered in the dialysate.

Pharmacotherapeutic group: Antibacterials for systemic use, other cephalosporins and penems,

ATC code: J01DI02

The active moiety after Zinforo administration is ceftaroline.

Ceftaroline is a cephalosporin antibacterial with in vitro activity against Gram-positive and -negativebacteria. The bactericidal action of ceftaroline is mediated through binding to essential penicillin-binding proteins (PBPs) . Biochemical studies have shown that ceftaroline has high affinity for PBP2aof methicillin-resistant Staphylococcus aureus (MRSA) and PBP2x of penicillin non-susceptible

Streptococcus pneumoniae (PNSP) . As a result, minimum inhibitory concentrations (MICs) ofceftaroline against a proportion of these organisms tested fall into the susceptible range (see

Resistance section below) .

Ceftaroline is not active against strains of Enterobacterales producing extended-spectrum beta-lactamases (ESBLs) from the TEM, SHV or CTX-M families, serine carbapenemases (such as KPC) ,class B metallo-beta-lactamases or class C (AmpC) cephalosporinases. Organisms that express theseenzymes and which are therefore resistant to ceftaroline occur at very variable rates between countriesand between healthcare facilities within countries. If ceftaroline is commenced before susceptibilitytest results are available then local information on the risk of encountering organisms that expressthese enzymes should be taken into consideration. Resistance may also be mediated by bacterialimpermeability or drug efflux pump mechanisms. One or more of these mechanisms may co-exist in asingle bacterial isolate.

Interaction with other antibacterial agents

In vitro studies have not demonstrated any antagonism between ceftaroline in combination with othercommonly used antibacterial agents (e.g. amikacin, azithromycin, aztreonam, daptomycin,levofloxacin, linezolid, meropenem, tigecycline, and vancomycin) .

Susceptibility testing breakpoints

MIC (minimum inhibitory concentration) interpretive criteria for susceptibility testing have beenestablished by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) forceftaroline fosamil and are listed here: https://www.ema.europa.eu/documents/other/minimum-inhibitory-concentration-mic-breakpoints_en.xlsx

As with other beta-lactam antimicrobial agents, the percent time above the minimum inhibitoryconcentration (MIC) of the infecting organism over the dosing interval (%T > MIC) has been shown tobe the parameter that best correlates with the efficacy of ceftaroline.

Clinical efficacy against specific pathogens

Efficacy has been demonstrated in clinical studies against the pathogens listed under each indicationthat were susceptible to ceftaroline in vitro.

Complicated skin and soft tissue infections

Gram-positive micro-organisms

- Staphylococcus aureus (including methicillin-resistant strains)

- Streptococcus pyogenes

- Streptococcus agalactiae

- Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus)

- Streptococcus dysgalactiae

Gram-negative micro-organisms

- Escherichia coli

- Klebsiella pneumoniae

- Klebsiella oxytoca

- Morganella morganii

Community-acquired pneumonia

No cases of CAP due to MRSA were enrolled into the studies. The available clinical data cannotsubstantiate efficacy against penicillin non-susceptible strains of S. pneumoniae.

Gram-positive micro-organisms

- Streptococcus pneumoniae

- Staphylococcus aureus (methicillin-susceptible strains only)

Gram-negative micro-organisms

- Escherichia coli

- Haemophilus influenzae

- Haemophilus parainfluenzae

- Klebsiella pneumoniae

Antibacterial activity against other relevant pathogens

Clinical efficacy has not been established against the following pathogens although in vitro studiessuggest that they would be susceptible to ceftaroline in the absence of acquired mechanisms ofresistance:

Anaerobic micro-organisms

Gram-positive micro-organisms

- Peptostreptococcus spp.

Gram-negative micro-organisms

- Fusobacterium spp.

In vitro data indicate that the following species are not susceptible to ceftaroline:

- Chlamydophila spp.

- Legionella spp.

- Mycoplasma spp.

- Proteus spp.

- Pseudomonas aeruginosa

The Cmax and AUC of ceftaroline increase approximately in proportion to dose within the single doserange of 50 to 1000 mg. No appreciable accumulation of ceftaroline is observed following multipleintravenous infusions of 600 mg every 8 or 12 hours in healthy adults with CrCL > 50 mL/min.

The plasma protein binding of ceftaroline is low (approximately 20%) and ceftaroline is notdistributed into erythrocytes. The median steady-state volume of distribution of ceftaroline in healthyadult males following a single 600 mg intravenous dose of radiolabelled ceftaroline fosamil was20.3 l, similar to the volume of extracellular fluid.

Ceftaroline fosamil (prodrug) is converted into the active ceftaroline in plasma by phosphataseenzymes and concentrations of the prodrug are measurable in plasma primarily during intravenousinfusion. Hydrolysis of the beta-lactam ring of ceftaroline occurs to form the microbiologicallyinactive, open-ring metabolite, ceftaroline M-1. The mean plasma ceftaroline M-1 to ceftaroline AUCratio following a single 600 mg intravenous infusion of ceftaroline fosamil in healthy subjects isapproximately 20-30%.

In pooled human liver microsomes, metabolic turnover was low for ceftaroline, indicating thatceftaroline is not metabolised by hepatic CYP450 enzymes.

Ceftaroline is primarily eliminated by the kidneys. Renal clearance of ceftaroline is approximatelyequal, or slightly lower than the glomerular filtration rate in the kidney, and in vitro transporter studiesindicate that active secretion does not contribute to the renal elimination of ceftaroline.

The mean terminal elimination half-life of ceftaroline in healthy adults is approximately 2.5 hours.

Following the administration of a single 600 mg intravenous dose of radiolabelled ceftaroline fosamilto healthy male adults, approximately 88% of radioactivity was recovered in urine and 6% in faeces.

Dosage adjustments are required in adults, adolescents and children with CrCL ≤ 50 mL/min (seesection 4.2).

There is insufficient information to recommend dosage adjustments in adolescents with ESRD agedfrom 12 to < 18 years and with bodyweight < 33 kg and in children with ESRD aged from 2 to< 12 years. There is insufficient information to recommend dosage adjustments in paediatric patientsaged < 2 years with moderate or severe renal impairment or ESRD.

The pharmacokinetics of ceftaroline in patients with hepatic impairment has not been established. Asceftaroline does not appear to undergo significant hepatic metabolism, the systemic clearance ofceftaroline is not expected to be significantly affected by hepatic impairment. Therefore, no dosageadjustment is recommended for patients with hepatic impairment.

Following administration of a single 600 mg intravenous dose of ceftaroline fosamil, thepharmacokinetics of ceftaroline were similar between healthy elderly subjects (≥ 65 years of age), andhealthy young adult subjects (18-45 years of age). There was a 33% increase in AUC0-∞ in the elderlythat was mainly attributable to age-related changes in renal function. Zinforo dose adjustment is notrequired in elderly patients with creatinine clearance above 50 mL/min.

Dose adjustments are required for neonates, infants, children and adolescents with bodyweight < 33 kg(see section 4.2).

Patients with cystic fibrosis

Cystic fibrosis patients were excluded from CAP clinical trials.

Some case reports and published studies suggest the need for a higher dose of ceftaroline fosamil incystic fibrosis patients due to possibility of altered ceftaroline pharmacokinetics leading tosub-therapeutic levels. Results from a population pharmacokinetic study, based on data pooled fromvarious studies, overall showed no significant, clinically relevant differences in ceftarolinepharmacokinetic parameters in cystic fibrosis patients (age 6 years and above). Ceftaroline clearancewas similar between cystic fibrosis patients and patients with CAP or cSSTI while ceftaroline centralvolume was similar to healthy subjects.

The kidney was the primary target organ of toxicity in both the monkey and rat. Histopathologicfindings included pigment deposition and inflammation of the tubular epithelium. Renal changes werenot reversible but were reduced in severity following a 4 week recovery period.

Convulsions have been observed at relatively high exposures during single and multi-dose studies inboth the rat and monkey (≥ 7 times to the estimated ceftaroline Cmax level of a 600 mg twice a day).

Other important toxicologic findings noted in the rat and monkey included histopathologic changes inthe bladder and spleen.

Genetic toxicology

Ceftaroline fosamil and ceftaroline were clastogenic in an in vitro chromosomal aberration assay,however there was no evidence of mutagenic activity in an Ames test, mouse lymphoma andunscheduled DNA synthesis assay. Furthermore, in vivo micronucleus assays in rat and mouse werenegative. Carcinogenicity studies have not been conducted.

Overall, no adverse effects on fertility or post-natal development were observed in the rat at up to5 times the observed clinical exposure. When ceftaroline was administered during organogenesis,minor changes in foetal weight and delayed ossification of the interparietal bone were observed in therat at exposures below that observed clinically. However, when ceftaroline was administeredthroughout pregnancy and lactation, there was no effect on pup weight or growth. Ceftarolineadministration to pregnant rabbits resulted in an increased foetal incidence of angulated hyoid alae, acommon skeletal variation in rabbit fetuses, at exposures similar to those observed clinically.

Juvenile toxicity

Intravenous bolus dosing of ceftaroline fosamil to suckling rats from post-natal day 7 to 20 was welltolerated at plasma exposures approximately 2-fold higher than those for paediatric patients. Renalcortical cysts were observed in all groups, including controls, on PND50. The cysts involved a smallportion of the kidney and occurred in the absence of significant changes in either renal function orurinary parameters. Therefore, these findings were not considered to be adverse.

Arginine

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

Dry powder: 3 years

The reconstituted vial should be diluted immediately.

The chemical and physical in-use stability has been demonstrated for up to 12 hours at 2-8 °C and6 hours at 25 °C.

From a microbiological point of view, unless the method of opening/reconstitution/dilution precludesthe risk of microbial contamination the medicinal product should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user.

Store below 30 °C.

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

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

20 mL glass vial (Type 1) closed with a rubber (halobutyl) stopper and aluminium seal with flip-offcap.

The medicinal product is supplied in packs of 10 vials.

The powder must be reconstituted with water for injections and the resulting concentrate must then beimmediately diluted prior to use. The reconstituted solution is a pale yellow solution that is free of anyparticles.

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

Zinforo powder should be reconstituted with 20 mL of sterile water for injections. The resultingsolution should be shaken prior to being transferred to an infusion bag or bottle containing eithersodium chloride 9 mg/mL (0.9%) solution for injection, dextrose 50 mg/mL (5%) solution forinjection, sodium chloride 4.5 mg/mL and dextrose 25 mg/mL solution for injection (0.45% sodiumchloride and 2.5% dextrose) or Lactated Ringer’s solution. A 250 mL, 100 mL or 50 mL infusion bagcan be used to prepare the infusion, based on the patient’s volume requirements. The total timeinterval between starting reconstitution and completing preparation of the intravenous infusion shouldnot exceed 30 minutes.

Infusion volumes for paediatric patients will vary according to the weight of the child. The infusionsolution concentration during preparation and administration should not exceed 12 mg/mL ceftarolinefosamil.

Each vial is for single use only.

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

Pfizer Ireland Pharmaceuticals Unlimited Company

Operations Support Group

Ringaskiddy, County Cork

Ireland

EU/1/12/785/001

Date of first authorisation: 23 August 2012

Date of the latest renewal: 24 April 2017

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

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