ZERBAXA 1g / 0.5g powder for concentrate infusion solution medication leaflet

Zerbaxa 1 g/0.5 g powder for concentrate for solution for infusion

Each vial contains ceftolozane sulfate equivalent to 1 g ceftolozane and tazobactam sodium equivalentto 0.5 g tazobactam.

After reconstitution with 10 mL diluent, the total volume of the solution in the vial is 11.4 mL, whichcontains 88 mg/mL of ceftolozane and 44 mg/mL of tazobactam.

Each vial contains 10 mmol (230 mg) of sodium.

When the powder is reconstituted with 10 mL of sodium chloride 9 mg/mL (0.9%) solution forinjection, the vial contains 11.5 mmol (265 mg) of sodium.

For the full list of excipients, see section 6.1.

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

White to yellowish powder.

Zerbaxa is indicated for the treatment of the following infections in adults (see section 5.1):

- Complicated intra-abdominal infections (see section 4.4);

- Acute pyelonephritis;

- Complicated urinary tract infections (see section 4.4);

- Hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP).

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

The recommended intravenous dose regimen for patients with creatinine clearance > 50 mL/min isshown by infection type in Table 1.

Table 1: Intravenous dose of Zerbaxa by type of infection in patients with creatinine clearance> 50 mL/min

Type of infection Dose Frequency Infusion Duration oftime treatment

Complicated intra-abdominal 1 g ceftolozane/Every 1 hour 4-14 daysinfection* 0.5 g tazobactam 8 hours

Complicated urinary tract 1 g ceftolozane/Every 1 hour 7 daysinfection 0.5 g tazobactam 8 hours

Acute pyelonephritis

Hospital-acquired pneumonia, 2 g ceftolozane/Every 1 hour 8-14 daysincluding ventilator-associated 1 g tazobactam 8 hourspneumonia**

*To be used in combination with metronidazole when anaerobic pathogens are suspected.

**To be used in combination with an antibacterial agent active against Gram-positive pathogens whenthese are known or suspected to be contributing to the infectious process.

Elderly (≥ 65 years of age)

No dose adjustment is necessary for the elderly based on age alone (see section 5.2).

In patients with mild renal impairment (estimated creatinine clearance [CrCL] > 50 mL/min), no doseadjustment is necessary (see section 5.2).

In patients with moderate or severe renal impairment, and in patients with end stage renal disease onhaemodialysis, the dose should be adjusted as listed in Table 2 (see sections 5.1 and 6.6).

Table 2: Recommended intravenous dose regimens for Zerbaxa in patients with creatinineclearance ≤ 50 mL/min

Estimated Complicated intra-abdominal Hospital-acquired pneumonia,

CrCL infections, complicated urinary tract including ventilator-associated(mL/min)* infections, and acute pyelonephritis** pneumonia**500 mg ceftolozane/250 mg tazobactam 1 g ceftolozane/0.5 g tazobactam30 to 50intravenously every 8 hours intravenously every 8 hours250 mg ceftolozane/125 mg tazobactam 500 mg ceftolozane/250 mg tazobactam15 to 29intravenously every 8 hours intravenously every 8 hours

A single loading dose of 500 mg A single loading dose of 1.5 gceftolozane/250 mg tazobactam ceftolozane/0.75 g tazobactam followedfollowed after 8 hours by a 100 mg after 8 hours by a 300 mg ceftolozane /

End stage ceftolozane/50 mg tazobactam 150 mg tazobactam maintenance doserenal disease maintenance dose administered every administered every 8 hours for theon 8 hours for the remainder of the remainder of the treatment period (onhaemodialysis treatment period (on haemodialysis days, haemodialysis days, the dose should bethe dose should be administered at the administered at the earliest possible timeearliest possible time following following completion of haemodialysis)completion of haemodialysis)

*CrCL estimated using Cockcroft-Gault formula.

**All doses of Zerbaxa are administered intravenously over 1 hour and are recommended for allindications. The duration of treatment should follow the recommendations in Table 1.

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

The safety and efficacy of ceftolozane/tazobactam in children and adolescents below 18 years of agehave not yet been established. No data are available.

Zerbaxa is to be administered by intravenous infusion over a 1 hour period for all doses.

Precautions to be taken before handling or administering the product

See section 6.2 for incompatibilities.

See section 6.6 for instructions on reconstitution and dilution of the medicinal product beforeadministration.

- Hypersensitivity to the active substances or to any of the excipients listed in section 6.1;

- Hypersensitivity to any cephalosporin antibacterial agent;

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

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions are possible (see sections 4.3and 4.8). If a severe allergic reaction occurs during treatment with ceftolozane/tazobactam, themedicinal product should be discontinued and appropriate measures taken.

Patients who have a history of hypersensitivity to cephalosporins, penicillins or other beta-lactamantibacterial agents may also be hypersensitive to ceftolozane/tazobactam.

Ceftolozane/tazobactam is contraindicated in patients with a history of hypersensitivity to ceftolozane,tazobactam, or cephalosporins (see section 4.3).

Ceftolozane/tazobactam is also contraindicated in patients with severe hypersensitivity (e.g.,anaphylactic reaction, severe skin reaction) to any other type of beta-lactam antibacterial agent (e.g.,penicillins or carbapenems) (see section 4.3).

Ceftolozane/tazobactam should be used with caution in patients with a history of any other type ofhypersensitivity reaction to penicillins or other beta-lactam antibacterial agents.

Effect on renal function

A decline in renal function has been seen in patients receiving ceftolozane/tazobactam.

The ceftolozane/tazobactam dose should be adjusted based on renal function (see section 4.2, Table 2).

In clinical trials of complicated intra-abdominal infections and complicated urinary tract infections,including pyelonephritis, the efficacy of ceftolozane/tazobactam was lower in patients with moderaterenal impairment compared with those with normal or mildly impaired renal function at baseline.

Patients with renal impairment at baseline should be monitored frequently for any changes in renalfunction during treatment and the dose of ceftolozane/tazobactam should be adjusted as necessary.

Limitations of the clinical data

Patients who were immunocompromised, patients with severe neutropenia, and patients with end stagerenal disease on haemodialysis were excluded from clinical trials.

Complicated intra-abdominal infections

In a trial in patients with complicated intra-abdominal infections, the most common diagnosis wasappendiceal perforation or peri-appendiceal abscess (420/970 [43.3%] patients), of which 137/420(32.6%) had diffuse peritonitis at baseline. Approximately 82% of all patients in the trial had

APACHE II (Acute Physiology and Chronic Health Evaluation II) scores of < 10 and 2.3% hadbacteraemia at baseline. In the clinically evaluable (CE) patients, the clinical cure rates forceftolozane/tazobactam were 95.9% in 293 patients aged less than 65 years and 87.8% in 82 patientsaged 65 years or more.

Clinical efficacy data in patients with complicated lower urinary tract infection are limited. In arandomised active-controlled trial 18.2% (126/693) of microbiologically evaluable (ME) patients hadcomplicated lower urinary tract infection, including 60/126 patients who were treated withceftolozane/tazobactam. One of these 60 patients had bacteraemia at baseline.

Clostridioides difficile-associated diarrhoea

Antibacterial-associated colitis and pseudomembranous colitis have been reported withceftolozane/tazobactam (see section 4.8). These types of infection may range in severity from mild tolife-threatening. Therefore, it is important to consider this diagnosis in patients who present withdiarrhoea during or subsequent to the administration of ceftolozane/tazobactam. In suchcircumstances, the discontinuation of therapy with ceftolozane/tazobactam and the use of supportivemeasures together with the administration of specific treatment for Clostridioides difficile should beconsidered.

Non-susceptible micro-organisms

The use of ceftolozane/tazobactam may promote the overgrowth of non-susceptible micro-organisms.

If super infection occurs during or following treatment, appropriate measures should be taken.

Ceftolozane/tazobactam is not active against bacteria that produce beta-lactamase enzymes which arenot inhibited by tazobactam (see section 5.1).

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 withceftolozane/tazobactam (see section 4.8). In clinical studies, there was no evidence of haemolysis inpatients who developed a positive DAGT on treatment.

Ceftolozane/tazobactam contains 230 mg sodium per vial, equivalent to 11.5% of the WHOrecommended maximum daily intake of 2 g sodium for an adult. The reconstituted vial with 10 mL of0.9% sodium chloride (normal saline) for injection contains 265 mg sodium per vial, equivalent to13.3% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

No significant medicinal product interactions are anticipated between ceftolozane/tazobactam andsubstrates, inhibitors, and inducers of cytochrome P450 enzymes (CYPs) based on in vitro and in vivostudies.

In vitro studies demonstrated that ceftolozane, tazobactam and the M1 metabolite of tazobactam didnot i nhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 and did notinduce CYP1A2, CYP2B6, or CYP3A4 at therapeutic plasma concentrations.

Ceftolozane and tazobactam were not substrates for P-gp or BCRP, and tazobactam was not asubstrate for OCT2, in vitro at therapeutic plasma concentrations. In vitro data indicate thatceftolozane did not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, MRP, BSEP, OAT1,

OAT3, MATE1, or MATE2-K in vitro at therapeutic plasma concentrations. In vitro data indicate thatneither tazobactam nor the tazobactam metabolite M1 inhibit P-gp, BCRP, OATP1B1, OATP1B3,

OCT1, OCT2, or BSEP transporters at therapeutic plasma concentrations.

Tazobactam is a substrate for OAT1 and OAT3. In vitro, tazobactam inhibited human OAT1 and

OAT3 transporters with IC50 values of 118 and 147 mcg/mL, respectively. Co-administration ofceftolozane/tazobactam with OAT1 and OAT3 substrate furosemide in a clinical study did notsignificantly increase furosemide plasma exposures (geometric mean ratios of 0.83 and 0.87 for Cmaxand AUC, respectively). However, active substances that inhibit OAT1 or OAT3 (e.g., probenecid)may increase tazobactam plasma concentrations.

There are no data on the use of ceftolozane/tazobactam in pregnant women. Tazobactam crosses theplacenta. It is not known if ceftolozane crosses the placenta.

Animal studies with tazobactam have shown reproductive toxicity (see section 5.3) without evidenceof teratogenic effects. Studies with ceftolozane in mice and rats have not shown evidence ofreproductive toxicity or teratogenicity. Ceftolozane administered to rats during pregnancy and breast-feeding was associated with a decrease in auditory startle response in postnatal day (PND) 60 malepups (see section 5.3).

Zerbaxa should only be used during pregnancy if the expected benefit outweighs the possible risks tothe pregnant woman and foetus.

It is unknown whether ceftolozane and tazobactam are excreted in human milk. A risk tonewborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feedingor to discontinue/abstain from Zerbaxa therapy taking into account the benefit of breast-feeding for thechild and the benefit of therapy for the woman.

The effects of ceftolozane and tazobactam on fertility in humans have not been studied. Fertilitystudies in rats showed no effect on fertility and mating after intraperitoneal administration oftazobactam or intravenous administration of ceftolozane (see section 5.3).

Zerbaxa may have a minor influence on the ability to drive and use machines. Dizziness may occurfollowing administration of Zerbaxa (see section 4.8).

Zerbaxa was evaluated in Phase 3 comparator-controlled clinical trials of complicated intra-abdominalinfections and complicated urinary tract infections (including pyelonephritis).

The most common adverse reactions (≥ 3% in pooled Phase 3 trials of complicated intra-abdominalinfections and complicated urinary tract infections, including pyelonephritis) occurring in patientsreceiving Zerbaxa were nausea, headache, constipation, diarrhoea, and pyrexia and were generallymild or moderate in severity.

Zerbaxa was evaluated in a Phase 3 comparator-controlled clinical trial of hospital-acquiredpneumonia, including ventilator-associated pneumonia.

The most common adverse reactions (≥ 5% in a Phase 3 trial of hospital-acquired pneumonia,including ventilator-associated pneumonia) occurring in patients receiving Zerbaxa were diarrhoea,alanine aminotransferase increased, and aspartate aminotransferase increased and were generally mildor moderate in severity.

The following adverse reactions have been identified during clinical trials with Zerbaxa. Adversereactions are classified according to MedDRA system organ class and frequency. Frequencycategories are derived according to the following conventions: common (≥ 1/100 to < 1/10),uncommon (≥ 1/1,000 to < 1/100) (see Table 3).

Table 3: Adverse reactions identified during clinical trials with ceftolozane/tazobactam

Common Uncommon

System organ class(≥ 1/100 to < 1/10) (≥ 1/1,000 to < 1/100)

Candidiasis includingoropharyngeal and vulvovaginal1,

Infections and infestations Clostridioides difficile colitis2 Clostridioides difficile colitis1,fungal urinary tract infection1,

Clostridioides difficile infection2

Blood and the lymphatic

Thrombocytosis1 Anaemia1system disorders

Hyperglycaemia1,

Metabolism and nutrition

Hypokalemia1 hypomagnesaemia1,disordershypophosphataemia1

Psychiatric disorders Insomnia1, anxiety1

Nervous system disorders Headache1, dizziness1 Ischemic stroke1

Atrial fibrillation1, tachycardia1,

Cardiac disordersangina pectoris1

Vascular disorders Hypotension1 Phlebitis1, venous thrombosis1

Respiratory, thoracic, and

Dyspnoea1mediastinal disorders1 3 1 Gastritis1, abdominal distension1,

Nausea , diarrhoea , constipation ,

Gastrointestinal disorders 3 1 dyspepsia1, flatulence1, ileusvomiting , abdominal painparalytic1

Skin and subcutaneous

Rash1 Urticaria1tissue disorders

Renal and urinary

Renal impairment1, renal failure1disorders

Common Uncommon

System organ class(≥ 1/100 to < 1/10) (≥ 1/1,000 to < 1/100)

General disorders andadministration site Pyrexia1, infusion site reactions1conditions

Alanine aminotransferase increased3,

Coombs test positive3, increasedaspartate aminotransferase increased3,serum gamma-glutamyltransaminases increased2, liver function

Investigations 1test abnormal2 transpeptidase (GGT) , increased, blood alkalineserum alkaline phosphatase1,phosphatase increased2, gamma-

Clostridioides test positive2glutamyltransferase increased21 Specific for the complicated intra-abdominal infections, acute pyelonephritis, and complicatedurinary tract infections indications treated with Zerbaxa (1 g/0.5 g intravenously every 8 hours) forup to 14 days.2 Specific for the hospital-acquired pneumonia, including ventilator-associated pneumonia indicationtreated with Zerbaxa (2 g/1 g intravenously every 8 hours) for up to 14 days.3 Applies across all indications: complicated intra-abdominal infections, acute pyelonephritis,complicated urinary tract infections, and hospital-acquired pneumonia, including ventilator-associatedpneumonia.

The development of a positive direct Coombs test may occur during treatment with Zerbaxa. Theincidence of seroconversion to a positive direct Coombs test was 0.2% in patients receiving Zerbaxaand 0% in patients receiving the comparator in the complicated intra-abdominal infections andcomplicated urinary tract infections clinical trials. The incidence of seroconversion to a positive direct

Coombs test was 31.2% in patients receiving Zerbaxa and 3.6% in patients receiving meropenem inthe hospital-acquired pneumonia, including ventilator-associated pneumonia clinical trial. In clinicalstudies, there was no evidence of haemolysis in patients who developed a positive direct Coombs testin any treatment group.

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 experience with overdose of Zerbaxa. The highest single dose of Zerbaxa used in clinicaltrials was 3 g/1.5 g of ceftolozane/tazobactam administered to healthy volunteers.

In the event of overdose, Zerbaxa should be discontinued and general supportive treatment given.

Zerbaxa can be removed by haemodialysis. Approximately 66% of ceftolozane, 56% of tazobactam,and 51% of the M1 metabolite of tazobactam were removed by dialysis.

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

ATC code: J01DI54.

Ceftolozane belongs to the cephalosporin class of antimicrobials. Ceftolozane exerts bactericidalactivity through binding to important penicillin-binding proteins (PBPs), resulting in inhibition ofbacterial cell-wall synthesis and subsequent cell death.

Tazobactam is a beta-lactam structurally related to penicillins. It is an inhibitor of many molecular

Class A beta-lactamases, including CTX-M, SHV, and TEM enzymes. See below.

Mechanisms of resistance

Mechanisms of bacterial resistance to ceftolozane/tazobactam include:i. Production of beta-lactamases that can hydrolyse ceftolozane and which are not inhibitedby tazobactam (see below)ii. Modification of PBPs

Tazobactam does not inhibit all Class A enzymes.

In addition tazobactam does not inhibit the following types of beta-lactamase:

i. AmpC enzymes (produced by Enterobacterales)ii. Serine-based carbapenemases (e.g., Klebsiella pneumoniae carbapenemases [KPCs])iii. Metallo-beta-lactamases (e.g., New Delhi metallo-beta-lactamase [NDM])iv. Ambler Class D beta-lactamases (OXA-carbapenemases)

For ceftolozane the time that the plasma concentration exceeds the minimum inhibitory concentrationof ceftolozane for the infecting organism has been shown to be the best predictor of efficacy in animalmodels of infection.

For tazobactam the PD index associated with efficacy was determined to be the percentage of the doseinterval during which the plasma concentration of tazobactam exceeds a threshold value(%T > threshold). The time above a threshold concentration has been determined to be the parameterthat best predicts the efficacy of tazobactam in in vitro and in vivo non-clinical models.

Susceptibility testing breakpoints

Minimum inhibitory concentration breakpoints established by the European Committee on

Antimicrobial Susceptibility Testing (EUCAST) are as follows:

Minimum Inhibitory

Concentrations (mg/L)

Pathogen Type of Infection Susceptible Resistant

Enterobacterales Complicated intra-abdominal infections* ≤ 2 > 2

Complicated urinary tract infections*

Acute pyelonephritis*

Hospital-acquired pneumonia, includingventilator-associated pneumonia**

P. aeruginosa Complicated intra-abdominal infections* ≤ 4 > 4

Complicated urinary tract infections*

Acute pyelonephritis*

Hospital-acquired pneumonia, includingventilator-associated pneumonia**

H. influenzae Hospital-acquired pneumonia, including ≤ 0.5 > 0.5ventilator-associated pneumonia**

*Based on 1 g ceftolozane/0.5 g tazobactam intravenously every 8 hours.

**Based on 2 g ceftolozane/1 g tazobactam intravenously every 8 hours.

Clinical efficacy against specific pathogens

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

Complicated intra-abdominal infections

Gram-negative bacteria

Enterobacter cloacae

Escherichia coli

Klebsiella oxytoca

Klebsiella pneumoniae

Proteus mirabilis

Pseudomonas aeruginosa

Gram-positive bacteria

Streptococcus anginosus

Streptococcus constellatus

Streptococcus salivarius

Complicated urinary tract infections, including pyelonephritis

Gram-negative bacteria

Escherichia coli

Klebsiella pneumoniae

Proteus mirabilis

Hospital-acquired pneumonia, including ventilator-associated pneumonia

Gram-negative bacteria

Enterobacter cloacae

Escherichia coli

Haemophilus influenzae

Klebsiella oxytoca

Klebsiella pneumoniae

Proteus mirabilis

Pseudomonas aeruginosa

Serratia marcescens

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

Citrobacter freundii

Citrobacter koseri

Klebsiella (Enterobacter) aerogenes

Morganella morganii

Proteus vulgaris

Serratia liquefaciens

In vitro data indicate that the following species are not susceptible to ceftolozane/tazobactam:

Staphylococcus aureus

Enterococcus faecalis

Enterococcus faecium

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

Zerbaxa in one or more subsets of the paediatric population in complicated intra-abdominal infection,complicated urinary tract infection, and hospital-acquired pneumonia, including ventilator-associatedpneumonia (see section 4.2 for information on paediatric use).

The Cmax and AUC of ceftolozane/tazobactam increase approximately in proportion to dose withinceftolozane single-dose range of 250 mg to 3 g and tazobactam single-dose range of 500 mg to 1.5 g.

No appreciable accumulation of ceftolozane/tazobactam is observed following multiple 1-hour IVinfusions of 1 g/0.5 g ceftolozane/tazobactam or 2 g/1 g ceftolozane/tazobactam administered every8 hours for up to 10 days in healthy adults with normal renal function. The elimination half-life (t½) ofceftolozane or tazobactam is independent of dose.

The binding of ceftolozane and tazobactam to human plasma proteins is low (approximately 16% to21% and 30%, respectively). The mean (coefficient of variation CV%) steady-state volume ofdistribution of ceftolozane/tazobactam in healthy adult males (n=51) following a single 1 g/0.5 g IVdose was 13.5 L (21%) and 18.2 L (25%) for ceftolozane and tazobactam, respectively, similar toextracellular fluid volume.

Following 1 hour intravenous infusions of 2 g/1 g ceftolozane/tazobactam or adjusted based on renalfunction every 8 hours in ventilated patients with confirmed or suspected pneumonia (N=22),ceftolozane and tazobactam concentrations in pulmonary epithelial lining fluid were greater than8 mcg/mL and 1 mcg/mL, respectively, over 100% of the dosing interval. Mean pulmonaryepithelial-to-free plasma AUC ratios of ceftolozane and tazobactam were approximately 50% and62%, respectively and are similar to those in healthy subjects (approximately 61% and 63%,respectively) receiving 1 g/0.5 g ceftolozane/tazobactam.

Ceftolozane is eliminated in the urine as unchanged parent substance and thus does not appear to bemetabolised to any appreciable extent. The beta-lactam ring of tazobactam is hydrolysed to form thepharmacologically inactive, tazobactam metabolite M1.

Ceftolozane, tazobactam and the tazobactam metabolite M1 are eliminated by the kidneys. Followingadministration of a single 1 g/0.5 g IV dose of ceftolozane/tazobactam to healthy male adults greaterthan 95% of ceftolozane was excreted in the urine as unchanged parent substance. More than 80% oftazobactam was excreted as the parent compound with the remaining amount excreted as thetazobactam M1 metabolite. After a single dose of ceftolozane/tazobactam, renal clearance ofceftolozane (3.41 - 6.69 L/h) was similar to plasma clearance (4.10 - 6.73 L/h) and similar to theglomerular filtration rate for the unbound fraction, suggesting that ceftolozane is eliminated by thekidney via glomerular filtration.

The mean terminal elimination half-life of ceftolozane and tazobactam in healthy adults with normalrenal function is approximately 3 hours and 1 hour, respectively.

The Cmax and AUC of ceftolozane/tazobactam increase in proportion to dose. Plasma levels ofceftolozane/tazobactam do not increase appreciably following multiple IV infusions of up to2.0 g/1.0 g administered every 8 hours for up to 10 days in healthy adults with normal renal function.

The elimination half-life (t½) of ceftolozane is independent of dose.

Ceftolozane/tazobactam and the tazobactam metabolite M1 are eliminated by the kidneys.

The ceftolozane dose normalised geometric mean AUC increased up to 1.26-fold, 2.5-fold, and 5-foldin subjects with mild, moderate, and severe renal impairment, respectively, compared to healthysubjects with normal renal function. The respective tazobactam dose normalized geometric mean AUCincreased approximately up to 1.3-fold, 2-fold, and 4-fold. To maintain similar systemic exposures tothose with normal renal function, dosage adjustment is required (see section 4.2).

In subjects with end stage renal disease on haemodialysis, approximately two-thirds of theadministered ceftolozane/tazobactam dose is removed by haemodialysis. The recommended dose incomplicated intra-abdominal infections, complicated urinary tract infections, and acute pyelonephritissubjects with end stage renal disease on haemodialysis is a single loading dose of 500 mg/250 mgceftolozane/tazobactam followed by a 100 mg/50 mg maintenance dose of ceftolozane/tazobactamadministered every 8 hours for the remainder of the treatment period. The recommended dose inhospital-acquired pneumonia, including ventilator-associated pneumonia subjects with end stage renaldisease on haemodialysis is a single loading dose of 1.5 g/0.75 g ceftolozane/tazobactam followed bya 300 mg/150 mg maintenance dose of ceftolozane/tazobactam administered every 8 hours for theremainder of the treatment period. With haemodialysis, the dose should be administered immediatelyfollowing completion of dialysis (see section 4.2).

Augmented renal clearance

Following a single 1-hour intravenous infusion of 2 g/1 g ceftolozane/tazobactam to critically illpatients with CrCL greater than or equal to 180 mL/min (N=10), mean terminal half-life values ofceftolozane and tazobactam were 2.6 hours and 1.5 hours, respectively. Free plasma ceftolozaneconcentrations were greater than 8 mcg/mL over 70% of an 8-hour period; free tazobactamconcentrations were greater than 1 mcg/mL over 60% of an 8-hour period. No dose adjustment ofceftolozane/tazobactam is recommended for hospital-acquired pneumonia, including ventilator-associated pneumonia patients with augmented renal clearance.

As ceftolozane/tazobactam does not undergo hepatic metabolism, the systemic clearance ofceftolozane/tazobactam is not expected to be affected by hepatic impairment. No dose adjustment isrecommended for ceftolozane/tazobactam in subjects with hepatic impairment (see section 4.2).

In a population pharmacokinetic analysis of ceftolozane/tazobactam, no clinically relevant differencesin exposure were observed with regard to age. No dose adjustment of ceftolozane/tazobactam based onage alone is recommended.

Safety and efficacy in paediatric patients have not been established.

In a population pharmacokinetic analysis of ceftolozane/tazobactam, no clinically relevant differencesin AUC were observed for ceftolozane and tazobactam. No dose adjustment is recommended based ongender.

In a population pharmacokinetic analysis of ceftolozane/tazobactam, no clinically relevant differencesin ceftolozane/tazobactam AUC were observed in Caucasians compared to other ethnicities. No doseadjustment is recommended based on race.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity or genotoxicity. Carcinogenicity studies withceftolozane/tazobactam have not been conducted.

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of themaximum human exposure indicating little relevance to clinical use.

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar toclinical exposure levels and with possible relevance to clinical use were as follows: ceftolozaneadministered to rats during pregnancy and breast-feeding was associated with a decrease in auditorystartle response in postnatal day (PND) 60 male pups at maternal doses of 300 and 1,000 mg/kg/day.

A dose of 300 mg/kg/day to rats was associated with a ceftolozane plasma exposure (AUC) valuelower than the ceftolozane plasma AUC value at the highest recommended human dose of 2 gramsevery 8 hours.

Peri/postnatal development was impaired (reduced pup weights, increase in stillbirths, increase in pupmortality) concurrent with maternal toxicity after intraperitoneal administration of tazobactam in therat.

Environmental risk assessment studies have shown that one of the active ingredients, ceftolozane, maypose a risk to surface water organisms (see section 6.6).

Sodium chloride

Arginine

Citric acid, anhydrous

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

3 years.

After reconstitution and dilution, chemical and physical in-use stability has been demonstrated for24 hours at room temperature or 4 days at 2 to 8 ºC. The medicinal product is photosensitive andshould be protected from light when not stored in the original carton.

From a microbiological point of view, the medicinal product should be used immediately uponreconstitution. If not used immediately, in-use storage times and conditions prior to use are theresponsibility of the user and would normally not be longer than 24 hours at 2 to 8 ºC, unlessreconstitution/dilution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2 ºC - 8 ºC).

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

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

20 mL vial (Type I clear glass) with stopper (bromobutyl rubber) and flip-off seal.

Pack size of 10 vials.

Each vial is for single use only.

Aseptic technique must be followed in preparing the infusion solution.

Preparation of doses

The powder for concentrate for solution for infusion for each vial is reconstituted with 10 mL of waterfor injections or sodium chloride 9 mg/mL (0.9%) solution for injection per vial; followingreconstitution the vial should be shaken gently to dissolve the powder. The final volume isapproximately 11.4 mL per vial. The resultant concentration is approximately 132 mg/mL (88 mg/mLof ceftolozane and 44 mg/mL of tazobactam) per vial.

CAUTION: THE RECONSTITUTED SOLUTION IS NOT FOR DIRECT INJECTION.

See section 4.2 for recommended dose regimens for Zerbaxa based on indication and renal function.

The preparation for each dose is shown below.

For preparation of the 2 g ceftolozane/1 g tazobactam dose: Withdraw the entire contents fromtwo reconstituted vials (approximately 11.4 mL per vial) using a syringe and add it to an infusion bagcontaining 100 mL of 0.9% sodium chloride for injection (normal saline) or 5% glucose injection.

For preparation of the 1.5 g ceftolozane/0.75 g tazobactam dose: Withdraw the entire contents fromone reconstituted vial (approximately 11.4 mL per vial) and 5.7 mL from a second reconstituted vialusing a syringe and add it to an infusion bag containing 100 mL of 0.9% sodium chloride for injection(normal saline) or 5% glucose injection.

For preparation of the 1 g ceftolozane/0.5 g tazobactam dose: Withdraw the entire contents(approximately 11.4 mL) of the reconstituted vial using a syringe and add it to an infusion bagcontaining 100 mL of 0.9% sodium chloride for injection (normal saline) or 5% glucose injection.

For preparation of the 500 mg ceftolozane/250 mg tazobactam dose: Withdraw 5.7 mL of thecontents of the reconstituted vial and add it to an infusion bag containing 100 mL of 0.9% sodiumchloride for injection (normal saline) or 5% glucose injection.

For preparation of the 300 mg ceftolozane/150 mg tazobactam dose: Withdraw 3.5 mL of thecontents of the reconstituted vial and add it to an infusion bag containing 100 mL of 0.9% sodiumchloride for injection (normal saline) or 5% glucose injection.

For preparation of the 250 mg ceftolozane/125 mg tazobactam dose: Withdraw 2.9 mL of thecontents of the reconstituted vial and add it to an infusion bag containing 100 mL of 0.9% sodiumchloride for injection (normal saline) or 5% glucose injection.

For p reparation of the 100 mg ceftolozane/50 mg tazobactam dose: Withdraw 1.2 mL of the contentsof the reconstituted vial and add it to an infusion bag containing 100 mL of 0.9% sodium chloride forinjection (normal saline) or 5% glucose injection.

Zerbaxa solution for infusion is clear and colourless to slightly yellow.

Variations in colour within this range do not affect the potency of the product.

One of the active ingredients, ceftolozane, may have harmful effects if it reaches the aquaticenvironment (see section 5.3). Do not throw away any unused medicinal product or waste material viawastewater. Any unused medicinal product or waste material should be disposed of in accordance withlocal requirements. These measures will help protect the environment.

Merck Sharp & Dohme B.V.

Waarderweg 392031 BN Haarlem

The Netherlands

EU/1/15/1032/001

Date of first authorisation: 18 September 2015

Date of latest renewal: 17 April 2020

MM/YYYY

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

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