Consumer medicine information

Zerbaxa Powder for Injection

Ceftolozane; Tazobactam

BRAND INFORMATION

Brand name

Zerbaxa

Active ingredient

Ceftolozane; Tazobactam

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zerbaxa Powder for Injection.

What is in this leaflet

This leaflet answers some common questions about ZERBAXA. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you having ZERBAXA against the benefits this medicine is expected to have for you.

If you have any concerns about being given this medicine, ask your doctor or pharmacist.

Keep this leaflet. You may need to read it again.

What ZERBAXA is used for

ZERBAXA contains two active ingredients:

  • Ceftolozane, an antibiotic that belongs to the group of "cephalosporins". Ceftolozane can kill many kinds of bacteria that can cause infection.
  • Tazobactam belongs to the group of medicines known as “beta-lactamase inhibitors”. Tazobactam can help ceftolozane work against some resistant types of bacteria.

When ceftolozane and tazobactam are given together, more types of bacteria are killed.

ZERBAXA is used in adults age 18 years or older to treat:

  • Complicated abdominal and urinary system infections, including a condition called pyelonephritis.
  • Nosocomial pneumonia (an infection of the lungs that can occur while in the hospital or in recently hospitalized patients), including a condition called “ventilator-associated pneumonia” (an infection of the lungs that can occur while on a respirator).

Your doctor may have prescribed ZERBAXA for another reason. Ask your doctor if you have any questions about why ZERBAXA has been prescribed for you.

ZERBAXA is only available with a doctor's prescription.

ZERBAXA is not addictive.

Before you are given ZERBAXA

When you must not be given it

Do not have ZERBAXA:

  • if you are allergic to ceftolozane, tazobactam or any of the other ingredients of this medicine
  • if you are highly allergic to beta-lactam class antibiotics (such as penicillin), or medicines known as "cephalosporins" (e.g., cephalexin)

Some symptoms of an allergic reaction may include skin rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing.

Before you are given it

Tell your doctor:

  • if you know you are, or have previously been hypersensitive to cephalosporins, penicillins or other antibacterial medicines.
  • if you have recently had diarrhoea, or have had diarrhoea before taking this medicine.
  • if you know you have difficulty fighting off infections, are receiving medicines to help fight infections, or have neutropenia (low white blood cell count).
  • if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you are pregnant or plan to become pregnant. Your doctor will advise if you should receive ZERBAXA during pregnancy.

Tell your doctor if you are breast-feeding or plan to breast-feed. Your doctor will discuss the possible risks and benefits of using ZERBAXA while you are breast-feeding.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including medicines you buy without a prescription from a pharmacy or health food shop.

Some medicines and ZERBAXA may interfere with each other, including:

  • probenecid (a medicine for gout)
  • diclofenac (a medicine to treat pain and inflammation associated with arthritis)
  • cimetidine (a medicine used to treat heartburn and stomach ulcers)

These medicines may increase the time it takes for tazobactam to leave your body.

Some medicines may be affected by ZERBAXA or may affect how well it works. You may need different amounts of these medicines, or you may need to be given different medicines. Your doctor will advise you.

If you have not told your doctor or pharmacist about any of the above, tell them before you receive ZERBAXA.

Use in children

This medicine should not be given to children under 18 years old because there is not enough information on use in this age group.

How ZERBAXA is given

How much is given

Adults
The recommended dose depends on the type of infection that you have, where the infection is in your body and how serious the infection is. Your doctor will decide on the dose that you need. The recommended dose is one or two vials of ZERBAXA (containing 1000 mg of ceftolozane and 500 mg of tazobactam) every 8 hours, which is given into one of your veins (directly into the bloodstream).

Patients with kidney problems
Your doctor may need to reduce the dose of ZERBAXA or how often you are given it. Your doctor may also want to test your blood to make sure that your treatment is at the right dose, especially if you have to take this medicine for a long time.

How is it given

Your doctor or other healthcare professional will give you this medicine through an infusion (a drip for 1 hour) into one of your veins.

How long is it given for

Treatment with ZERBAXA normally lasts between 4 and 14 days, depending on the severity and location of the infection and how your body responds to treatment.

Your doctor will determine when your treatment should be stopped.

If you are given too much (overdose)

As this product is administered by a doctor or healthcare professional, it is very unlikely that you will be given too much ZERBAXA. However, if you have any concerns, talk to your doctor or other health care professional.

Whilst you are receiving ZERBAXA

Things you must do

If you develop diarrhoea whilst being given ZERBAXA, tell your doctor immediately. Do this even if it occurs several weeks after stopping ZERBAXA. This may be a sign of a serious side effect that affects the bowel. You may need urgent medical care.

If you think you have not been given a dose of ZERBAXA, tell your doctor or other healthcare professional immediately.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are being given ZERBAXA.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

For patients treated for complicated bacterial infections within the abdomen and urinary tract system, the more common side effects (may affect up to 1 in 10 people) include:

  • Headache
  • Abdominal pain (stomach ache)
  • Constipation
  • Diarrhoea
  • Nausea
  • Vomiting
  • Increase in liver enzymes (from blood tests)
  • Rash
  • Fever (high temperature)
  • Decrease in blood pressure
  • Decrease in potassium (from blood tests)
  • Increase in number of certain types of blood cells known as platelets
  • Dizziness
  • Anxiety
  • Insomnia
  • Local problems (e.g., abnormal redness of the skin, inflammation, pain, itching, or rash) when putting a substance into a vein (infusion site reactions)

Uncommon side effects (may affect up to 1 in 100 people) include:

  • Inflammation of the large intestine due to C. difficile bacteria
  • Inflammation of the stomach
  • Abdominal bloating
  • Indigestion
  • Excessive gas in stomach or bowel
  • Obstruction of the intestine
  • Yeast infection in the mouth (thrush)
  • Yeast infection of female genitalia
  • Fungal urinary tract infection
  • Increase in sugar (glucose) levels (from blood tests)
  • Decrease in magnesium levels (from blood tests)
  • Decrease in phosphate levels (from blood tests)
  • Ischemic stroke (stoke caused by reduced blood flow in brain)
  • Blood clot in a vein (venous thrombosis)
  • Low red blood cell counts
  • Atrial fibrillation (a condition involving rapid or irregular heartbeat
  • Fast heart beat
  • Chest pain or feeling of tightness, pressure or heaviness in chest (angina pectoris)
  • Coombs test positive (a blood test that looks for antibodies that may fight against your red blood cells)
  • Itchy rash or swelling on the skin (hives)
  • Kidney problems
  • Kidney disease
  • Shortness of breath

For patients treated for nosocomial pneumonia, the more common side effects (may affect up to 1 in 10 people) include:

  • Inflammation of the large intestine due to C. difficile bacteria
  • Diarrhea
  • Vomiting
  • Increase in liver enzymes (from blood tests)

Uncommon side effects (may affect up to 1 in 100 people) include:

  • Infection due to C. difficile bacteria
  • C. difficile test positive (from stool test)
  • Coombs test positive (a blood test that looks for antibodies that may fight against your red blood cells)

Like all medicines, this medicine can cause side effects, although not everybody gets them.

This is not a complete list of all possible side effects. Your doctor or pharmacist has a more complete list. Others may occur in some people and there may be some side effects not yet known.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

After being given ZERBAXA

Storage

ZERBAXA will be stored in the pharmacy or on the ward.

ZERBAXA is stored in its original packaging in a refrigerator between 2 and 8 degrees Celsius.

Heat and light can destroy some medicines

Disposal

Hospital staff will dispose of this medicine safely.

Product description

What does ZERBAXA Powder for Injection look like?

ZERBAXA is a white to slightly yellow powder supplied in glass containers (vials).

The powder is mixed with sterile liquid to give a clear, colourless to yellow solution for infusion by your doctor.

Ingredients

Active ingredients

  • Ceftolozane sulfate
  • Tazobactam

Inactive ingredients

  • Citric acid
  • Sodium Chloride
  • Arginine

Sponsor

Australian Sponsor

Merck Sharp and Dohme (Australia) Pty Ltd
Level 1, Building A,
26 Talavera Road
Macquarie Park NSW 2113
Australia

Australian Registration Number: 229608

This leaflet was prepared in
April 2020.

CCPPI-MK7625A-IV-112018

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Zerbaxa

Active ingredient

Ceftolozane; Tazobactam

Schedule

S4

 

1 Name of Medicine

Ceftolozane sulfate/tazobactam sodium.

6.7 Physicochemical Properties

Ceftolozane sulfate.

Ceftolozane sulfate is a semisynthetic antibiotic and is described chemically as 1H-pyrazolium, 5-amino-4[[[(2-aminoethyl)amino]carbonyl] amino]-2-[[(6R,7R)-7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1carboxy-1-methylethoxy)imino] acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2-en-3yl] methyl]-1-methyl-,sulfate (1:1).
The empirical formula of ceftolozane sulfate is C23H31N12O8S2+.HSO4- with a molecular weight of 764.77.

Tazobactam sodium.

Tazobactam sodium is described chemically as Sodium(2S,3S,5R)-3-methyl-7-oxy-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo-[3.2.0] heptane-2- carboxylate-4,4-dioxide.
The empirical formula of tazobactam sodium is C10H11N4NaO5S with a molecular weight of 322.28.

Chemical structure.


CAS number.

Ceftolozane sulfate: 936111-69-2.
Tazobactam sodium: 89785-84-2.

2 Qualitative and Quantitative Composition

Each vial contains 1000 mg of ceftolozane (as ceftolozane sulfate) and 500 mg tazobactam (as tazobactam sodium).
Ceftolozane sulfate is a white to off white hygroscopic powder that is freely soluble in water and 0.0 5M sodium perchlorate, insoluble in isopropyl alcohol, acetonitrile, dichloromethane and methyl-tert-butyl ether and slightly soluble in N-methylpyrrolidone. The pH of a 20 mg/mL (2%) aqueous solution is 1.92. The pKa is 9.3, 3.2, and 1.9. Ceftolozane sulfate is a single stereoisomer with the 6R, 7R configuration.
Tazobactam sodium is a white to off-white, hygroscopic powder, that is freely soluble in water and slightly soluble in ethanol and acetone. The pH of an aqueous solution of the drug substance is 5.0-7.0. The specific optical rotation is between +138.0° and 152.0°.
After reconstitution with 10 mL diluent, the concentrations are 100 mg/mL ceftolozane equivalent and 50 mg/mL tazobactam equivalent.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Zerbaxa (ceftolozane sulfate/tazobactam sodium) is a white to yellow powder for solution.
Zerbaxa (ceftolozane/tazobactam) solutions range from clear, colourless solutions to solutions that are clear and slightly yellow.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antibacterials for systemic use, combination of cephalosporins and beta-lactamase inhibitors. ATC code: J01DI54.

Mechanism of action.

Zerbaxa (ceftolozane/ tazobactam) is an antibacterial drug product composed of a cephalosporin and a beta-lactamase inhibitor.
Ceftolozane belongs to the cephalosporin class of antimicrobials. Ceftolozane exerts bactericidal activity through binding to important penicillin binding proteins (PBPs), resulting in inhibition of cell wall synthesis and subsequent cell death. Ceftolozane has a high affinity to Pseudomonas aeruginosa PBPs [PBP1b (IC50 0.07 mg/L), PBP1c (IC50 0.64 mg/L), PBP2 (IC50 1.36 mg/L), PBP3 (IC50 0.02 mg/L) and PBP4 (IC50 0.29 mg/L)] and Escherichia coli PBP3 (IC50 0.03 mg/L).
Tazobactam, a beta-lactam structurally related to penicillins, is a potent, irreversible inhibitor of Class A broad spectrum and extended spectrum beta-lactamases and class C cephalosporinases, which commonly cause resistance to penicillins and cephalosporins. Tazobactam extends the antimicrobial spectrum of ceftolozane to include beta-lactamase producing bacteria.
Zerbaxa (ceftolozane/ tazobactam) is stable to common mechanisms of resistance found in Gram-negative bacteria, including production of broad spectrum beta-lactamases (TEM-1, TEM-2, SHV-1), extended spectrum beta-lactamases (TEM-3, SHV-2, CTX-M-14, CTX-M-15), chromosomal pseudomonal AmpC, oxacillinases (OXA-2, OXA-5, OXA-23), loss of outer membrane porin (OprD) and upregulation of efflux pumps (MexXY, MexAB). These mechanisms of resistance can reduce the activity of penicillins, cephalosporins, and carbapenems in Pseudomonas aeruginosa and Enterobacteriaceae, including Escherichia coli and Klebsiella pneumoniae.
In vitro Zerbaxa (ceftolozane/ tazobactam) showed little potential to antagonise or be antagonised by other antibacterial agents.
In the 2017 surveillance study (PACTS, program to assess ceftolozane/tazobactam susceptibility) the overall ceftolozane/tazobactam susceptibility of 3948 Enterobacteriaceae isolates collected from all sources from European hospitals was 88% and against extended spectrum beta-lactamase (ESBL), non-carbapenem resistant Enterobacteriaceae isolates the percent ceftolozane/tazobactam susceptibility was 74.3%. The overall ceftolozane/tazobactam susceptibility of 878 P. aeruginosa isolates collected from European hospitals was 88.2%. When ceftolozane/tazobactam was tested against isolates non-susceptible to ceftazidime, meropenem or piperacillin/tazobactam, the percent susceptibility to ceftolozane/tazobactam was 52.4%, 61.4% and 58.4%, respectively.

Mechanisms of resistance.

Zerbaxa (ceftolozane/ tazobactam) has a low potential for development of resistance in Pseudomonas aeruginosa and Enterobacteriaceae including ESBL producing strains.
Bacterial resistance mechanisms that affect Zerbaxa (ceftolozane/ tazobactam) include drug inactivation by serine carbapenamases, such as KPC, and metallobeta lactamases.
Isolates resistant to other cephalosporins may be susceptible to Zerbaxa (ceftolozane/ tazobactam) although cross-resistance may occur.

Susceptibility testing breakpoints.

Ceftolozane and tazobactam susceptibility testing is performed with a fixed 4 microgram/mL concentration of tazobactam. Minimum inhibitory concentrations (MIC) values should be interpreted according to the criteria shown in Table 6. Disk diffusion testing should be determined using 30 microgram ceftolozane/10 microgram tazobactam disks and results interpreted according to criteria provided in Table 6.

Susceptibility.

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert microbiology advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Susceptibility of specific pathogens to Zerbaxa (ceftolozane/ tazobactam).

The following pathogens were recovered from clinical trials and reported susceptible to Zerbaxa (ceftolozane/ tazobactam) in in vitro testing. For clinical efficacy against these pathogens, please see Section 5.1 Pharmacodynamic Properties, Clinical trials.

Complicated intra-abdominal infections.

Gram-negative bacteria.

Enterobacter cloacae, Escherichia coli, Escherichia coli (CTX-M-14 ESBL-producing strains including those also expressing TEM-1), Escherichia coli (CTX-M-15 ESBL producing strains including those also expressing one or both of the following: OXA-1/30, TEM 1), Klebsiella oxytoca, Klebsiella pneumoniae, Klebsiella pneumoniae (CTX-M-15 ESBL producing strains including those also expressing one or more of the following: OXA-1/30, TEM-1, SHV-1, SHV-11, SHV-32), Proteus mirabilis, Pseudomonas aeruginosa.

Gram-positive bacteria.

Streptococcus anginosus, Streptococcus constellatus, Streptococcus salivarius.

Gram-negative anaerobes.

Bacteroides fragilis, Bacteroides ovatus*, Bacteroides thetaiotaomicron*, Bacteroides vulgatus*.
* In combination with metronidazole.

Complicated urinary tract infections, including pyelonephritis.

Gram-negative bacteria.

Escherichia coli, Escherichia coli (fluoroquinolone resistant strains), Escherichia coli (CTX-M-14 ESBL producing strains including those also expressing TEM-1), Escherichia coli (CTX-M-15 ESBL producing strains including those also expressing one or more of the following: CTX-M-27, OXA-1/30, TEM-1, TEM-176), Klebsiella pneumoniae, Klebsiella pneumoniae (fluoroquinolone resistant strains), Klebsiella pneumoniae (CTX-M-15 ESBL-producing strains including those also expressing one or more of the following: OXA-1/30, OXA-10, SHV-1, SHV-11, TEM-1), Proteus mirabilis, Pseudomonas aeruginosa.

Nosocomial pneumonia, including ventilator-associated pneumonia.

Gram-negative bacteria.

Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella (Enterobacter) aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens.

Antibacterial activity against other relevant pathogens.

Clinical efficacy has not been established against the following pathogens although in vitro studies suggest that they would be susceptible to Zerbaxa (ceftolozane/ tazobactam) in the absence of acquired mechanisms of resistance.

Gram-negative bacteria.

Burkholderia cepacia, Citrobacter freundii, Citrobacter koseri, Moraxella catarrhalis, Morganella morganii, Pantoea agglomerans, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Serratia liquefaciens.

Gram-positive aerobic bacteria.

Streptococcus agalactiae, Streptococcus intermedius, Streptococcus pyogenes, Streptococcus pneumoniae.

Anaerobic microorganisms.

Fusobacterium spp., Prevotella spp.

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

Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium.

Pharmacokinetic/ pharmacodynamic relationship(s).

Similar to other beta-lactam antimicrobial agents, the time that the plasma concentration of ceftolozane exceeds the minimum inhibitory concentration (MIC) of the infecting organism has been shown to be the best predictor of efficacy in animal models of infection. The PK-PD analyses in efficacy and safety clinical trials for cIAI and cUTI, and nosocomial pneumonia support the recommended dose regimens of Zerbaxa (cetolozane/ tazobactam).

Clinical trials.

Zerbaxa (ceftolozane/ tazobactam) demonstrated clinical and microbiological efficacy against ESBL producing E. coli (CTX-M-14/15 producing isolates) and K. pneumoniae (CTX-M-15 producing isolates) in two well controlled randomized phase 3 studies in complicated intra-abdominal infections and complicated urinary tract infections, including pyelonephritis. Zerbaxa (ceftolozane/ tazobactam) demonstrated clinical and microbiological efficacy against E. coli and K. pneumoniae strains with resistance to fluoroquinolones, including strains with amino acid substitutions in GyrA and ParC.

Data from clinical studies.

Complicated intra-abdominal infections.

Ceftolozane/ tazobactam plus metronidazole showed non-inferiority to meropenem with regard to clinical cure rates at the test-of-cure (TOC) visit in both the clinically evaluable (CE) and intent to treat (ITT) populations. Clinical cure rates at the TOC visit are displayed by patient population in Table 7. Clinical cure rates at the TOC visit by pathogen in the microbiologically evaluable (ME) population are presented in Table 8.

Complicated urinary tract infections, including pyelonephritis.

Ceftolozane/ tazobactam was superior to levofloxacin with regard to the microbiological eradication rates at the test of cure (TOC) visit in both the microbiologically modified intent-to-treat (mMITT) and microbiologically evaluable (ME) populations (Table 9). Microbiological eradication rates at the TOC visit by pathogen in the ME population are presented in Table 10.
In patients with levofloxacin resistant pathogens at baseline, ceftolozane/tazobactam was superior to levofloxacin with regards to microbiological eradication rate in the ME population, 58/89 (65.2%) in the ceftolozane/ tazobactam treatment arm and 42/99 (42.4%) in the levofloxacin treatment arm (95% CI: 22.7 [8.47, 35.73]).
In the ME population, the microbiological eradication rate in patients with concurrent bacteremia were 21/24 (87.5%) for ceftolozane/ tazobactam and 20/26 (76.9%) for levofloxacin.

ESBL producing strains of gram negative pathogens in phase 3 studies.

The clinical response rates of ceftolozane/ tazobactam and comparators against E. coli and K. pneumoniae strains producing CTX-M-14/15 ESBLs in the phase 3 clinical trials are shown in Table 11.

Cardiac electrophysiology.

In a randomized, positive and placebo-controlled crossover thorough QTc study, 51 healthy subjects were administered a single therapeutic dose (1000 mg/500 mg) and a supratherapeutic dose (3.0 g/1.5 g) of ceftolozane/ tazobactam. No significant effects of Zerbaxa (ceftolozane/ tazobactam) on heart rate, electrocardiogram morphology, PR, QRS, or QT interval were detected. Therefore, Zerbaxa (ceftolozane/ tazobactam) does not affect cardiac repolarization.

Nosocomial pneumonia, including ventilator-associated pneumonia.

A total of 726 adult patients hospitalized with ventilated nosocomial pneumonia (including hospital-acquired pneumonia and ventilator-associated pneumonia) were enrolled in a multinational, double-blind study comparing Zerbaxa 3 g (ceftolozane 2 g and tazobactam 1 g) intravenously every 8 hours to meropenem (1 g intravenously every 8 hours) for 8 to 14 days of therapy.
The primary efficacy endpoint was clinical response, defined as complete resolution or significant improvement in signs and symptoms of the index infection at the test-of-cure (TOC) visit which occurred 7 to 14 days after the end of treatment. All-cause mortality at day 28 was a pre-specified key secondary endpoint. The analysis population for both the primary and key secondary endpoints was the intent-to-treat (ITT) population, which included all randomized patients.
Of the 726 patients in the ITT population the median age was 62 years and 44% of the population was greater than or equal to 65 years of age, with 22% of the population greater than or equal to 75 years of age. The majority of patients were white (83%), male (71%) and were from Eastern Europe (64%). The median APACHE II score was 17 and 33% of subjects had a baseline APACHE II score of greater than or equal to 20. All subjects were on mechanical ventilation and 519 (71%) had VAP. At randomization, the majority of subjects had been hospitalized for greater than or equal to 5 days (77%), ventilated for greater than or equal to 5 days (49%) and in an ICU (92%). Approximately 36% of patients had renal impairment at baseline and 14% had moderate or severe impairment (CrCL less than 50 mL/min). Approximately 13% of subjects had failed prior antibiotic treatment for nosocomial pneumonia and bacteremia was present at baseline in 15% of patients. Key comorbidities included chronic obstructive pulmonary disease (COPD), diabetes mellitus, and congestive heart failure at rates of 12%, 22% and 16%, respectively.
In the ITT population, Zerbaxa was non-inferior to meropenem with regard to the primary endpoint of clinical cure rates at the TOC visit and key secondary endpoint of all-cause mortality at day 28 with a predefined margin of 12.5% (Table 12).
In the ITT population, the clinical cure rates in patients with renal hyperclearance at baseline (CrCL greater than or equal to 150 mg/mL) were 40/67 (59.7%) for Zerbaxa and 39/64 (60.9%) for meropenem; day 28 all-cause mortality rates were 10/67 (14.9%) and 7/64 (10.9%), respectively. In those patients who failed prior antibiotic therapy for nosocomial pneumonia, the clinical cure rates were 26/53 (49.1%) for Zerbaxa and 15/40 (37.5%) for meropenem; day 28 all-cause mortality rates were 12/53 (22.6%) and 18/40 (45%), respectively. In patients with bacteremia at baseline, clinical cure rates were 30/64 (46.9%) for Zerbaxa and 15/41 (36.6%) for meropenem; day 28 all-cause mortality rates were 23/64 (35.9%) and 13/41 (31.7%), respectively. Per pathogen clinical and microbiologic responses were assessed in the microbiologic intention to treat population (mITT), which consisted of all randomized subjects who had a baseline lower respiratory tract (LRT) pathogen that was susceptible to at least one of the study therapies, and in the microbiologically evaluable (ME) population, which included protocol-adherent mITT patients. In the mITT and ME populations, the most prevalent pathogens isolated from baseline LRT cultures were Klebsiella pneumoniae (34.6% and 38.6%, respectively) and Pseudomonas aeruginosa (25% and 28.8%, respectively).
Among all Enterobacteriaceae, 157 (30.7%) in the mITT and 84 (36.1%) in the ME were ESBL-positive; among all K. pneumoniae isolates, 105 (20.5%) in the mITT and 57 (24.5%) in the ME were ESBL-positive. AmpC-overexpression among P. aeruginosa was detected in 15 (2.9%) and 9 (3.9%) of the P. aeruginosa isolates in the mITT and ME populations, respectively. Clinical cure rates at TOC by pathogen in the mITT and ME populations are presented in Table 13. In the mITT population clinical cure rates in patients with a Gram-negative pathogen at baseline were 157/259 (60.6%) for Zerbaxa and 137/240 (57.1%) for meropenem; results were consistent in the ME population with 85/113 (75.2%) and 78/117 (66.7%) clinical cure rates, respectively.
Microbiologic response rates at TOC by pathogen in the mITT and ME populations are presented in Table 14. In the mITT population microbiologic response rates in patients with a Gram-negative pathogen at baseline were 189/259 (73%) for Zerbaxa and 163/240 (67.9%) for meropenem; results were consistent in the ME population with 79/113 (69.9%) and 73/117 (62.4%) microbiologic response rates, respectively.
In the mITT population, per subject microbiologic cure was achieved in 193/264 (73.1%) of Zerbaxa -treated patients and in 168/247 (68.0%) of meropenem-treated patients. Similar results were achieved in the ME population in 81/115 (70.4%) and 74/118 (62.7%) patients, respectively.
In a subset of Enterobacteriaceae isolates from both arms of the trial that met pre-specified criteria for beta-lactam susceptibility, genotypic testing identified certain ESBL groups (e.g. TEM, SHV, CTX-M, OXA) in 157/511 (30.7%).

5.2 Pharmacokinetic Properties

Absorption.

The Cmax and AUC of ceftolozane/tazobactam increase approximately in proportion to dose within ceftolozane single-dose range of 250 mg to 3 g and tazobactam single-dose range of 500 mg to 1.5 g. Ceftolozane and tazobactam pharmacokinetics are similar following single- and multiple-dose administration. No appreciable accumulation of ceftolozane/tazobactam is observed following multiple 1-hour IV infusions of ceftolozane/tazobactam 1000 mg/500 mg administered every 8 hours for up to 10 days in healthy adults with normal renal function.

Distribution.

The binding of ceftolozane and tazobactam to human plasma proteins is low (approximately 16% to 21% and 30%, respectively). The mean (CV%) steady-state volume of distribution of ceftolozane/tazobactam in healthy adult males (n = 51) following a single 1000 mg/500 mg IV dose was 13.5 L (21%) and 18.2 L (25%) for ceftolozane and tazobactam, respectively, similar to extracellular fluid volume.
Following 1 hour intravenous infusions of Zerbaxa 3 g (ceftolozane 2 g and tazobactam 1 g) or adjusted based on renal function every 8 hours in ventilated patients with confirmed or suspected pneumonia (N = 22), mean minimum ceftolozane and tazobactam epithelial lung lining fluid concentrations at the end of the dosing interval were 8.2 microgram/mL and 1.0 microgram/mL, respectively. Mean pulmonary epithelial-to-free plasma AUC ratios of ceftolozane and tazobactam respectively were approximately 50% and 62% for the ventilated patients, compared to approximately 61% and 63% for healthy individuals administered ceftolozane 1 g and tazobactam 0.5 g.

Metabolism.

Ceftolozane is eliminated in the urine as unchanged parent drug and thus does not appear to be metabolised to any appreciable extent. The beta-lactam ring of tazobactam is hydrolyzed to form the pharmacologically inactive, tazobactam metabolite M1.

Excretion.

Ceftolozane, tazobactam, and the tazobactam metabolite M1 are eliminated by the kidneys. Following administration of a single IV dose of ceftolozane/ tazobactam 1000 mg/500 mg to healthy male adults greater than 95% of ceftolozane was excreted in the urine as unchanged parent drug. More than 80% of tazobactam was excreted as the parent compound with the remainder excreted as the tazobactam M1 metabolite. After a single dose of ceftolozane/ tazobactam 1000 mg/500 mg, renal clearance of ceftolozane (3.41 - 6.69 L/h) was similar to plasma clearance (4.10 to 6.73 L/h) and similar to the glomerular filtration rate for the unbound fraction, suggesting that ceftolozane is eliminated by the kidney via glomerular filtration.
The mean terminal elimination half-life of ceftolozane and tazobactam in healthy adults with normal renal function is approximately 3 hours and 1 hour, respectively. The elimination half-life (t½) of ceftolozane or tazobactam is independent of dose.

Specific populations.

Renal impairment.

Ceftolozane, tazobactam, and the tazobactam metabolite M1 are eliminated by the kidneys.
The ceftolozane dose normalized geometric mean AUC increased up to 1.26-fold, 2.5-fold, and 5-fold in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects with normal renal function. The respective tazobactam dose normalized geometric mean AUC increased approximately up to 1.3-fold, 2-fold, and 4-fold. In subjects with end stage renal disease (ESRD) on haemodialysis, the exposure to ceftolozane, tazobactam and its M1 metabolite are substantially increased when not on dialysis. Approximately two-thirds of the administered ceftolozane/ tazobactam dose is removed by haemodialysis. To maintain similar systemic exposures to those with normal renal function, dosage adjustment in all renal impairment patients with ≤ 50 mL/min CrCL (see Section 4.2 Dose and Method of Administration) and timing of dose relative to haemodialysis treatment in ESRD patients on haemodialysis is required (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).

Augmented renal clearance.

Following a single 1 hour intravenous infusion of Zerbaxa 3 g (ceftolozane 2 g and tazobactam 1 g) to critically ill patients with CrCL greater than or equal to 180 mL/min (N = 10), mean terminal half-life values of ceftolozane and tazobactam were 2.6 hours and 1.5 hours, respectively. Free plasma ceftolozane concentrations were greater than 8 microgram/mL over 70% of an 8-hour period; free tazobactam concentrations were greater than 1 microgram/mL over 60% of an 8-hour period. No dose adjustment of Zerbaxa is recommended for nosocomial pneumonia patients with augmented renal clearance (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Hepatic impairment.

As ceftolozane/tazobactam does not undergo hepatic metabolism, the systemic clearance of ceftolozane/ tazobactam is not expected to be affected by hepatic impairment. No dose adjustment is recommended for ceftolozane/ tazobactam in subjects with hepatic impairment (see Section 4.2 Dose and Method of Administration).

Elderly.

In a population pharmacokinetic analysis of ceftolozane/tazobactam, no clinically relevant differences in exposure were observed with regard to age. No dose adjustment of ceftolozane/tazobactam based on age alone is recommended. Dosage adjustment for Zerbaxa in elderly patients should be based on renal function (see Section 4.2 Dose and Method of Administration).

Paediatric patients.

Safety and effectiveness in pediatric patients (< 18 years of age) have not been established.

Gender.

In a population pharmacokinetic analysis of ceftolozane/tazobactam, no clinically relevant differences in AUC were observed for ceftolozane and tazobactam. No dose adjustment is recommended based on gender (see Section 4.2 Dose and Method of Administration).

Ethnicity.

In a population pharmacokinetic analysis of ceftolozane/ tazobactam, no clinically relevant differences in ceftolozane/ tazobactam AUC were observed in Caucasians compared to other ethnic groups combined. No dose adjustment is recommended based on ethnicity.

5.3 Preclinical Safety Data

Genotoxicity.

Zerbaxa (ceftolozane/tazobactam) was not genotoxic in vivo. Zerbaxa (ceftolozane/tazobactam) was negative for genotoxicity in an in vitro mouse lymphoma assay and an in vivo rat bone-marrow micronucleus assay. In an in vitro chromosomal aberration assay in Chinese hamster ovary cells, Zerbaxa (ceftolozane/tazobactam) was positive for structural aberrations, but only at highly toxic concentrations.
Ceftolozane was negative for genotoxicity in an in vitro microbial mutagenicity (Ames) assay, an in vitro chromosomal aberration assay in Chinese hamster lung fibroblast cells, an in vitro mouse lymphoma assay, an in vitro HPRT point mutation assay in Chinese hamster ovary cells, an in vivo mouse micronucleus assay, and an in vivo unscheduled DNA synthesis (UDS) assay.
Tazobactam was negative for genotoxicity in an in vitro microbial mutagenicity (Ames) assay, an in vitro chromosomal aberration assay in Chinese hamster lung cells, a HPRT point mutation assay in Chinese hamster ovary cells, an in vivo rat chromosomal aberration assay, an in vivo mouse bone-marrow micronucleus assay, and a UDS assay. Tazobactam was positive for genotoxicity in an in vitro mouse lymphoma assay at ≥ 3000 microgram/mL.

Carcinogenicity.

Carcinogenicity studies with ceftolozane, tazobactam, or Zerbaxa (ceftolozane/tazobactam) have not been conducted.

4 Clinical Particulars

4.1 Therapeutic Indications

Zerbaxa (ceftolozane/ tazobactam) is indicated for the treatment of the following infections in adults suspected or proven to be caused by designated susceptible microorganisms.
Complicated intra-abdominal infections in combination with metronidazole.
Complicated urinary tract infections, including pyelonephritis.
Nosocomial pneumonia, including ventilator-associated pneumonia (VAP).
Consideration should be given to published therapeutic guidelines on the appropriate use of antibacterial agents.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients (see Section 6.1 List of Excipients).
Known serious hypersensitivity to ceftolozane/ tazobactam, or members of the cephalosporin class, or other members of the beta-lactam class.

4.4 Special Warnings and Precautions for Use

Hypersensitivity reactions.

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions are possible.
Patients who have a history of hypersensitivity to cephalosporins, penicillins or other beta-lactam antibacterials may also be hypersensitive to ceftolozane/tazobactam. Zerbaxa (ceftolozane/tazobactam) is contraindicated in patients with a history of hypersensitivity to piperacillin/ tazobactam or members of the cephalosporin class (see Section 4.3 Contraindications). Zerbaxa (ceftolozane/tazobactam) should be used with caution in patients with a history of any other type of hypersensitivity reaction to penicillins or any other type of beta-lactam antibacterial agent. If a severe allergic reaction occurs during treatment with Zerbaxa (ceftolozane/tazobactam), the medicinal product should be discontinued and appropriate measures taken. Serious acute hypersensitivity (anaphylactic reactions) requires immediate emergency treatments.

Effect on renal function.

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

Use in renal impairment.

Ceftolozane, tazobactam, and the tazobactam metabolite M1 are eliminated by the kidneys.
In clinical trials of cIAI and cUTI, the efficacy of ceftolozane/tazobactam was lower in patients with moderate renal impairment compared with those with normal or mildly impaired renal function at baseline. The ceftolozane/tazobactam dose should be adjusted based on renal function (see Section 4.2 Dose and Method of Administration, Table 2). Patients with renal impairment at baseline should be monitored frequently for any changes in renal function during treatment and the dose of ceftolozane/tazobactam should be adjusted as necessary.
To maintain similar systemic exposures to those with normal renal function, dosage adjustment is required (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration).
In subjects with end stage renal disease on hemodialysis, approximately two-thirds of the administered ceftolozane/tazobactam dose is removed by haemodialysis. The recommended dose in subjects with end stage renal disease on haemodialysis is a single loading dose of 500 mg/250 mg ceftolozane/tazobactam followed by a 100 mg/50 mg maintenance dose of ceftolozane/tazobactam administered every 8 hours for the remainder of the treatment period. With haemodialysis, the dose should be administered immediately following completion of dialysis (see Section 4.2 Dose and Method of Administration).

Limitations of the clinical data.

Patients who were immunocompromised, patients with severe neutropenia, and patients with end stage renal disease on haemodialysis (ESRD) were excluded from clinical trials.

Clostridium difficile-associated diarrhoea.

Antibacterial-associated colitis and pseudomembranous colitis have been reported with Zerbaxa (ceftolozane/tazobactam) (see Section 4.8 Adverse Effects (Undesirable Effects)). These types of infection may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of Zerbaxa (ceftolozane/tazobactam). In such circumstances, the discontinuation of therapy with Zerbaxa (ceftolozane/tazobactam) and the use of supportive measures together with the administration of specific treatment for Clostridium difficile should be considered.

Immunosuppression.

The experience in patients who are severely immunocompromised, receiving immunosuppressive therapy, and patients with severe neutropenia is limited since these populations were excluded from phase 3 trials.

Severe cutaneous adverse reactions.

Severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalised exanthematous pustulosis (AGEP) have been reported in patients taking beta-lactam antibiotics. When SCAR is suspected, Zerbaxa should be discontinued immediately and an alternative treatment should be considered.

Gender.

No dose adjustment is recommended based on gender (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration).

Ethnicity.

No dose adjustment is recommended based on ethnicity (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration).

Use in hepatic impairment.

No dose adjustment is recommended for ceftolozane/tazobactam in subjects with hepatic impairment (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

No dose adjustment of ceftolozane/tazobactam based on age alone is recommended. Ceftolozane/tazobactam is substantially excreted by the kidney and the risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function and adjust dosage based on renal function (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration).

Paediatric use.

The safety and effectiveness of ceftolozane/tazobactam in children and adolescents below 18 years of age has not yet been established.

Effects on laboratory tests.

The development of a positive direct Coombs test may occur during treatment with Zerbaxa. The incidence of seroconversion to a positive direct Coombs test was 0.2% in patients receiving Zerbaxa and 0% in patients receiving the comparator in the cUTI and cIAI 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 in the nosocomial pneumonia clinical trial. In clinical studies, there was no evidence of haemolysis in patients who developed a positive direct Coombs test in any treatment group.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No significant drug-drug interactions are anticipated between ceftolozane/ tazobactam and substrates, inhibitors, and inducers of cytochrome P450 enzymes (CYPs) based on in vitro and in vivo studies.
Coadministration of ceftolozane/ tazobactam with OAT1 and OAT3 substrate furosemide does not increase furosemide plasma concentration. However, drugs that inhibit OAT1 or OAT3 (e.g. probenecid, diclofenac, cimetidine) may increase tazobactam plasma concentrations. No other significant drug-drug interactions involving membrane transporters are anticipated.
Zerbaxa (ceftolozane/ tazobactam) must not be mixed with other medicinal products for infusion, except those mentioned (see Section 4.2 Dose and Method of Administration, Preparation of doses).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of ceftolozane and tazobactam on fertility in humans have not been studied. Ceftolozane had no adverse effect on fertility in male or female rats at intravenous doses up to 1000 mg/kg/day. The mean plasma exposure (AUC) value at this dose is approximately 1.4 times the mean daily human ceftolozane exposure value at the highest recommended human dose of 2 grams every 8 hours.
In a rat fertility study with intraperitoneal tazobactam twice-daily, male and female fertility parameters were not affected at doses less than or equal to 640 mg/kg/day (approximately 2 times the highest recommended human dose of 1 gram every 8 hours based on body surface comparison).
(Category B1)
There are no adequate and well-controlled trials in pregnant women with either ceftolozane or tazobactam. Because animal reproduction studies are not always predictive of human response, Zerbaxa (ceftolozane/tazobactam) should be used during pregnancy only if the potential benefit outweighs the possible risks to the pregnant woman and the fetus.
Embryo-fetal development studies performed with intravenous ceftolozane in mice and rats with doses up to 2000 and 1000 mg/kg/day, respectively, revealed no evidence of harm to the fetus. The mean plasma exposure (AUC) values associated with these doses are approximately 3.5 (mice) and 2 (rats) times the mean daily human ceftolozane exposure at the highest recommended human dose of 2 grams every 8 hours. It is not known if ceftolozane crosses the placenta in animals.
In a pre-postnatal study in rats, intravenous ceftolozane administered during pregnancy and lactation (Gestation Day 6 through Lactation Day 20) was associated with a decrease in auditory startle response in postnatal day 60 pups at maternal doses of greater than or equal to 300 mg/kg/day. A dose of 300 mg/kg/day to rats was associated with a ceftolozane plasma exposure (AUC) value lower than the ceftolozane plasma AUC value at the highest recommended human dose of 2 grams every 8 hours. The plasma exposure (AUC) associated with a NOAEL dose of 100 mg/kg/day in rats is approximately 0.2 fold the highest recommended human dose of 2 grams every 8 hours.
In an embryo-fetal study in rats, tazobactam administered intravenously at doses up to 3000 mg/kg/day (approximately 10 times the highest recommended human dose of 1 gram every 8 hours based on body surface area comparison) produced maternal toxicity (decreased food consumption and body weight gain) but was not associated with fetal toxicity. In rats, tazobactam was shown to cross the placenta. Concentrations in the fetus were less than or equal to 10% of those found in maternal plasma.
In a pre-postnatal study in rats, tazobactam administered intraperitoneally twice daily at the end of gestation and during lactation (Gestation Day 17 through Lactation Day 21) produced decreased maternal food consumption and bodyweight gain at the end of the gestation and significantly more stillbirths with a tazobactam dose of 1280 mg/kg/day (approximately 4 times the highest recommended human dose of 1 gram every 8 hours based on body surface area comparison). No effects on the development, function, learning or fertility of F1 pups were noted, but postnatal bodyweights for F1 pups delivered to dams receiving 320 and 1280 mg/kg/day tazobactam were significantly reduced 21 days after delivery. F2 generation fetuses were normal for all doses of tazobactam. The NOAEL for reduced F1 bodyweights was considered to be 40 mg/kg/day, a dose lower than the highest recommended human dose of 1 gram every 8 hours based on body surface area comparison.
It is unknown whether ceftolozane and tazobactam are excreted in human breast milk. Women who are breast-feeding should be treated only if the expected benefit outweighs the possible risks to the woman and child.

4.8 Adverse Effects (Undesirable Effects)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and also may not reflect rates observed in practice.

Complicated intra-abdominal infections and complicated urinary tract infections, including pyelonephritis.

Zerbaxa (ceftolozane/tazobactam) was evaluated in phase 3 comparator-controlled clinical trials of cIAI and cUTI, which included a total of 1015 patients treated with Zerbaxa (ceftolozane/tazobactam, 1500 mg every 8 hours, adjusted based on renal function where appropriate) and 1032 patients treated with comparator (levofloxacin 750 mg daily in cUTI or meropenem 1 g every 8 hours in cIAI) for up to 14 days. The mean age of treated patients was 48 to 50 years (range 18 to 92 years), across treatment arms and indications. In both indications, about 25% of the subjects were 65 years of age or older. Most patients (75%) enrolled in the cUTI trial were female, and most patients (58%) enrolled in the cIAI trial were male. Most patients (> 70%) in both trials were enrolled in Eastern Europe and were white. Table 4 lists adverse reactions occurring in 1% or greater of patients receiving Zerbaxa (ceftolozane/tazobactam) in phase 3 cIAI and cUTI clinical trials.
The most common adverse reactions (5% or greater in either indication) occurring in patients receiving Zerbaxa (ceftolozane/tazobactam) were nausea, diarrhoea, headache, and pyrexia.
Treatment discontinuation due to adverse events occurred in 2.0% (20/1015) of patients receiving Zerbaxa (ceftolozane/tazobactam) and 1.9% (20/1032) of patients receiving comparator drugs. Renal impairment (including the terms renal impairment, renal failure, and renal failure acute) led to discontinuation of treatment in 5/1015 (0.5%) subjects receiving Zerbaxa (ceftolozane/tazobactam) and none in the comparator arms.

Increased mortality.

In the cIAI trials (phase 2 and 3), death occurred in 2.5% (14/564) of patients receiving Zerbaxa (ceftolozane/tazobactam) and in 1.5% (8/536) of patients receiving meropenem. The causes of death varied and included worsening and/or complications of infection, surgery and underlying conditions.

Less common adverse reactions in phase 3 cIAI and cUTI clinical trials.

The following selected adverse reactions were reported in Zerbaxa (ceftolozane/tazobactam) treated subjects at a rate of less than 1%:

Cardiac disorders.

Tachycardia, angina pectoris.

Gastrointestinal disorders.

Gastritis, abdominal distension, dyspepsia, flatulence, ileus paralytic.

Infections and infestations.

Candidiasis, including oropharyngeal and vulvovaginal, fungal urinary tract infection, Clostridium difficile colitis.

Investigations.

Increased serum gamma-glutamyl transpeptidase (GGT), increased serum alkaline phosphatase, positive Coombs test.

Metabolism and nutrition disorders.

Hyperglycemia, hypomagnesemia, hypophosphatemia.

Nervous system disorders.

Ischemic stroke.

Renal and urinary system.

Renal impairment, renal failure.

Respiratory, thoracic and mediastinal disorders.

Dyspnoea.

Skin and subcutaneous tissue disorders.

Urticaria, severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalised exanthematous pustulosis (AGEP) have been reported with beta-lactam antibiotics.

Vascular disorders.

Venous thrombosis.

Nosocomial pneumonia, including ventilator-associated pneumonia.

Zerbaxa was evaluated in a phase 3 comparator-controlled clinical trial for nosocomial pneumonia, which included a total of 361 patients treated with Zerbaxa (3 g every 8 hours, adjusted based on renal function where appropriate) and 359 patients treated with comparator (meropenem 1 g every 8 hours) for up to 14 days. The mean age of treated patients was 60 years (range 18 to 98 years), across treatment arms. About 44% of the subjects were 65 years of age or older. Most patients (71%) enrolled in the trial were male. All subjects were mechanically ventilated and 92% were in an intensive care unit (ICU) at randomization. The median APACHE II score was 17. Table 5 lists adverse reactions occurring in 2% or greater of patients receiving Zerbaxa in a phase 3 nosocomial pneumonia clinical trial.
Treatment discontinuation due to treatment-related adverse events occurred in 1.1% (4/361) of patients receiving Zerbaxa and 1.4% (5/359) of patients receiving meropenem.

Less common adverse reactions in a phase 3 nosocomial pneumonia clinical trial.

The following selected adverse reactions were reported in Zerbaxa-treated subjects at a rate of less than 2%:

Infections and infestations.

Clostridium difficile infection.

Investigations.

Liver function test abnormal, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, Clostridium test positive, Coombs direct test positive.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Each vial is for single use in one patient only. Discard any residue.
Zerbaxa (ceftolozane/ tazobactam) does not contain a bacteriostatic preservative. Aseptic technique must be followed in preparing the infusion solution.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to use whenever solution and container permit. Zerbaxa (ceftolozane/ tazobactam) infusions range from clear, colourless solutions to solutions that are clear and slightly yellow.
Variations in colour within this range do not affect the potency of the product.

Method of administration.

Zerbaxa (ceftolozane/ tazobactam) is intended for intravenous infusion. The sterile powder in the vial can be reconstituted with either sterile water for injection or 0.9% sodium chloride for injection (normal saline).

Caution.

The reconstituted solution is not for direct injection.
Zerbaxa (ceftolozane/ tazobactam) must not be mixed with other medicinal products except those mentioned in Preparation of doses, below.
Zerbaxa (ceftolozane/ tazobactam) should not be infused simultaneously with other medications via the same intravenous line.
The reconstituted solution should range from clear and colourless to clear and slightly yellow. Variations in colour within this range do not reflect the potency of the medicinal product.
The recommended infusion time is 1 hour for Zerbaxa (1000 mg ceftolozane/500 mg tazobactam).

Preparation of doses.

Constitute each vial of Zerbaxa with 10 mL of sterile water for injection or 0.9% sodium chloride for injection (normal saline) and gently shake to dissolve. The final volume is approximately 11.4 mL per vial. The resultant concentration is approximately 132 mg/mL.
To prepare the required dose, withdraw the appropriate volume determined from Table 1 from the reconstituted vial(s). Add the withdrawn volume to an infusion bag containing 100 mL of 0.9% sodium chloride for injection (normal saline) or 5% glucose injection.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to use whenever solution and container permit. Variations in colour within this range do not affect the potency of the product.

Dosage regimen.

The recommended dose regimen of Zerbaxa (ceftolozane/ tazobactam) for injection in patients 18 years or older and creatinine clearance (CrCL) greater than 50 mL/min is shown in Table 2 by infection type.
The duration of therapy should be guided by the severity and site of infection and the patient's clinical and bacteriological progress as shown in Table 2.

Duration of treatment.

The usual duration of treatment for indications is in the range of 4 to 14 days. However, the duration of treatment should be guided by the severity of the infection, the infection site, the infecting pathogen(s) and the patient's clinical and bacteriological response.

Special population.

Patients with renal impairment.

Ceftolozane/ tazobactam is eliminated primarily by the kidneys.
In patients with moderate or severe renal impairment, and in patients with end stage renal disease on haemodialysis, the dose should be adjusted as listed in Table 3.
In patients with mild renal impairment (estimated CrCL greater than 50 mL/min), no dose adjustment is necessary (see Section 5.2 Pharmacokinetic Properties).

Patients with hepatic impairment.

No dose adjustment is necessary in patients with hepatic impairment (see Section 5.2 Pharmacokinetic Properties).

Elderly (≥ 65 years of age).

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

Gender.

No dose adjustment is necessary based on gender (see Section 5.2 Pharmacokinetic Properties).

Ethnicity.

No dose adjustment is necessary based on race (see Section 5.2 Pharmacokinetic Properties).

Paediatric population.

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

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Zerbaxa (ceftolozane/tazobactam) on the ability to drive and use machines have been performed.

4.9 Overdose

In the event of overdose, Zerbaxa (ceftolozane/tazobactam) should be discontinued and general supportive treatment should be given. Zerbaxa (ceftolozane/tazobactam) can be removed by haemodialysis. Approximately 66% of ceftolozane, 56% of tazobactam, and 51% of the M1 metabolite of tazobactam were removed by approximately 3-4 hour period of haemodialysis. However, no information is available on the use of haemodialysis to treat overdosage.
The highest single dose of Zerbaxa (ceftolozane/tazobactam) received in clinical trials was 3.0 g/1.5 g of ceftolozane/tazobactam. At this dosage, no adverse pharmacological effects have been observed.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia) or 0800 764 766 (New Zealand).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each vial contains the following inactive ingredients: sodium chloride, arginine and anhydrous citric acid.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned (see Section 4.2 Dose and Method of Administration).

6.3 Shelf Life

The expiry date can be found on the packaging. In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG).

6.4 Special Precautions for Storage

Store in a refrigerator (2°C - 8°C).
Store in the original packaging to protect from light.
To reduce microbiological hazard, use as soon as practicable after reconstitution/preparation. If storage is necessary, hold at 2°C - 8°C for not more than 24 hours.

6.5 Nature and Contents of Container

Single-use 20 mL vial (Type I clear glass) with stopper (bromobutyl rubber) and flip-off seal.
Pack sizes of 10 vials.
The vials contain a white to yellow powder.

6.6 Special Precautions for Disposal

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

Summary Table of Changes