4.1. Therapeutic indications

Zerbaxa is indicated for the treatment of the following infections in adult and paediatric patients (see sections 4.2 and 5.1):

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

- Acute pyelonephritis;

- Complicated urinary tract infections (see section 4.4);

Zerbaxa is also indicated for the treatment of the following infection in adult patients (18 years or older) (see section 5.1):

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

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

4.2. Posology and method of administration

Posology

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

Table 1: Intravenous dose of Zerbaxa by type of infection in adult patients (18 years or older) with creatinine clearance* > 50 mL/min

Type of infection

Dose

Frequency

Infusion time

Duration of treatment

Complicated intra-abdominal infection**

1 g ceftolozane / 0.5 g tazobactam

Every 8 hours

1 hour

4-14 days

Complicated urinary tract infection

Acute pyelonephritis

1 g ceftolozane / 0.5 g tazobactam

Every 8 hours

1 hour

7 days

Hospital-acquired pneumonia, including ventilator-associated pneumonia***

2 g ceftolozane / 1 g tazobactam

Every 8 hours

1 hour

8-14 days

*Creatinine clearance estimated using Cockcroft-Gault formula.

**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 when these are known or suspected to be contributing to the infectious process.

The recommended intravenous dose regimen for paediatric patients with estimated glomerular filtration rate (eGFR) > 50 mL/min/1.73 m2 is shown by infection type in Table 2.

Table 2: Intravenous dose of Zerbaxa by type of infection in paediatric patients (from birth* to below 18 years of age) with eGFR** > 50 mL/min/1.73 m2

Type of infection

Dose

Frequency

Infusion time

Duration of treatment

Complicated intra-abdominal infection***

20 mg/kg ceftolozane / 10 mg/kg tazobactam up to a maximum dose of 1 g ceftolozane / 0.5 g tazobactam****

Every 8 hours

1 hour

5-14 days*****

Complicated urinary tract infection

Acute pyelonephritis

20 mg/kg ceftolozane / 10 mg/kg tazobactam up to a maximum dose of 1 g ceftolozane / 0.5 g tazobactam****

Every 8 hours

1 hour

7-14 days*****

*Defined as > 32 weeks gestational age and ≥ 7 days postnatal.

**eGFR estimated using Bedside Schwartz equation.

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

****Children weighing > 50 kg should not exceed the maximum dose of 1 g ceftolozane / 0.5 g tazobactam.

*****The total treatment duration shown may include intravenous Zerbaxa followed by appropriate oral therapy.

Special populations

Elderly (≥ 65 years of age)

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

Renal impairment

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

In adult patients with moderate or severe renal impairment, and in adult patients with end stage renal disease on haemodialysis, the dose should be adjusted as listed in Table 3 (see sections 5.1 and 6.6).

Table 3: Recommended intravenous dose regimens for Zerbaxa in adult patients (18 years or older) with creatinine clearance* ≤ 50 mL/min

Estimated

creatinine clearance (mL/min)*

Complicated intra-abdominal infections, complicated urinary tract infections, and acute pyelonephritis**

Hospital-acquired pneumonia, including ventilator-associated pneumonia**

30 to 50

500 mg ceftolozane / 250 mg tazobactam intravenously every 8 hours

1 g ceftolozane / 0.5 g tazobactam intravenously every 8 hours

15 to 29

250 mg ceftolozane / 125 mg tazobactam intravenously every 8 hours

500 mg ceftolozane / 250 mg tazobactam intravenously every 8 hours

End stage renal disease on haemodialysis

A single loading dose of 500 mg ceftolozane / 250 mg tazobactam followed after 8 hours by a 100 mg ceftolozane / 50 mg tazobactam maintenance dose administered every 8 hours for the remainder of the treatment period (on haemodialysis days, the dose should be administered at the earliest possible time following completion of haemodialysis)

A single loading dose of 1.5 g ceftolozane / 0.75 g tazobactam followed after 8 hours by a 300 mg ceftolozane / 150 mg tazobactam maintenance dose administered every 8 hours for the remainder of the treatment period (on haemodialysis days, the dose should be administered at the earliest possible time following completion of haemodialysis)

* Creatinine clearance estimated using Cockcroft-Gault formula.

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

There is insufficient information to recommend a dose regimen for paediatric patients with moderate or severe renal impairment (eGFR ≤ 50 mL/min/1.73 m2) or end stage renal disease (see sections 5.1 and 5.2).

Hepatic impairment

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

Paediatric population

The safety and efficacy of ceftolozane/tazobactam in children and adolescents below 18 years of age have not yet been established for the treatment of hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP).

Method of administration

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 before administration.

4.3. Contraindications

- 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 of beta-lactam antibacterial agent (e.g., penicillins or carbapenems).

4.4. Special warnings and precautions for use

Hypersensitivity reactions

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

Patients who have a history of hypersensitivity to cephalosporins, penicillins or other beta-lactam antibacterial 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 of hypersensitivity reaction to penicillins or other beta-lactam antibacterial agents.

Effect on renal function

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

Impaired renal function

The ceftolozane/tazobactam dose should be adjusted based on renal function (see section 4.2, Table 3).

In clinical trials of complicated intra-abdominal infections and complicated urinary tract infections, including pyelonephritis, the efficacy of ceftolozane/tazobactam was lower in adult patients with moderate renal 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 renal function 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 stage renal disease on haemodialysis were excluded from clinical trials.

Complicated intra-abdominal infections

In a trial in adult patients with complicated intra-abdominal infections, the most common diagnosis was appendiceal 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% had bacteraemia at baseline. In the clinically evaluable (CE) patients, the clinical cure rates for ceftolozane/tazobactam were 95.9% in 293 patients aged less than 65 years and 87.8% in 82 patients aged 65 years or more.

Complicated urinary tract infections

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

Clostridioides difficile-associated diarrhoea

Antibacterial-associated colitis and pseudomembranous colitis have been reported with ceftolozane/tazobactam (see section 4.8). 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 ceftolozane/tazobactam. In such circumstances, the discontinuation of therapy with ceftolozane/tazobactam and the use of supportive measures together with the administration of specific treatment for Clostridioides difficile should be considered.

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 are capable of both degrading ceftolozane and not inhibited by the tazobactam component (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 with ceftolozane/tazobactam (see section 4.8). In clinical studies, there was no evidence of haemolysis in patients who developed a positive DAGT on treatment.

Sodium content

Ceftolozane/tazobactam contains 230 mg sodium per vial, equivalent to 11.5% of the WHO recommended maximum daily intake of 2 g sodium for an adult. The reconstituted vial with 10 mL of 0.9% sodium chloride (normal saline) for injection contains 265 mg sodium per vial, equivalent to 13.3% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5. Interaction with other medicinal products and other forms of interaction

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

In vitro studies demonstrated that ceftolozane, tazobactam and the M1 metabolite of tazobactam did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 and did not induce CYP1A2, CYP2B6, or CYP3A4 at therapeutic plasma concentrations.

Ceftolozane and tazobactam were not substrates for P-gp or BCRP, and tazobactam was not a substrate for OCT2, in vitro at therapeutic plasma concentrations. In vitro data indicate that ceftolozane 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 that neither 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 of ceftolozane/tazobactam with OAT1 and OAT3 substrate furosemide in a clinical study did not significantly increase furosemide plasma exposures (geometric mean ratios of 0.83 and 0.87 for Cmax and AUC, respectively). However, active substances that inhibit OAT1 or OAT3 (e.g., probenecid) may increase tazobactam plasma concentrations.

4.6. Fertility, pregnancy and lactation

Pregnancy

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

Animal studies with tazobactam have shown reproductive toxicity (see section 5.3) without evidence of teratogenic effects. Studies with ceftolozane in mice and rats have not shown evidence of reproductive 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 male pups (see section 5.3).

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

Breast-feeding

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

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

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

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

Zerbaxa was evaluated in a Phase 3 comparator-controlled clinical trial of adult patients with hospital-acquired pneumonia, 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 mild or moderate in severity.

Tabulated list of adverse reactions

The following adverse reactions have been identified during adult clinical trials with Zerbaxa. Adverse reactions are classified according to MedDRA system organ class and frequency. Frequency categories are derived according to the following conventions: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) (see Table 4).

Table 4: Adverse reactions identified during adult clinical trials with ceftolozane/tazobactam

System organ class

Common

(≥ 1/100 to < 1/10)

Uncommon

(≥ 1/1 000 to < 1/100)

Infections and infestations

Clostridioides difficile colitis2

Candidiasis including oropharyngeal and vulvovaginal1, Clostridioides difficile colitis1, fungal urinary tract infection1, Clostridioides difficile infection2

Blood and the lymphatic system disorders

Thrombocytosis1

Anaemia1

Metabolism and nutrition disorders

Hypokalemia1

Hyperglycaemia1, hypomagnesaemia1, hypophosphataemia1

Psychiatric disorders

Insomnia1, anxiety1

Nervous system disorders

Headache1, dizziness1

Ischemic stroke1

Cardiac disorders

Atrial fibrillation1, tachycardia1, angina pectoris1

Vascular disorders

Hypotension1

Phlebitis1, venous thrombosis1

Respiratory, thoracic, and mediastinal disorders

Dyspnoea1

Gastrointestinal disorders

Nausea1, diarrhoea3, constipation1, vomiting3, abdominal pain1

Gastritis1, abdominal distension1, dyspepsia1, flatulence1, ileus paralytic1

Skin and subcutaneous tissue disorders

Rash1

Urticaria1

Renal and urinary disorders

Renal impairment1, renal failure1

General disorders and administration site conditions

Pyrexia1, infusion site reactions1

Investigations

Alanine aminotransferase increased3, aspartate aminotransferase increased3, transaminases increased2, liver function test abnormal2, blood alkaline phosphatase increased2, gamma-glutamyltransferase increased2

Coombs test positive3, increased serum gamma-glutamyl transpeptidase (GGT)1, increased serum alkaline phosphatase1, Clostridioides test positive2

1 Specific for the complicated intra-abdominal infections, acute pyelonephritis, and complicated urinary tract infections indications treated with Zerbaxa (1 g / 0.5 g intravenously every 8 hours) for up to 14 days.

2 Specific for the hospital-acquired pneumonia, including ventilator-associated pneumonia indication treated 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-associated pneumonia.

Paediatric population

The safety assessment in paediatric patients, aged from birth to less than 18 years, is based on the safety data from two trials in which 70 patients with complicated intra-abdominal infections and 100 patients with complicated urinary tract infections (including acute pyelonephritis) received Zerbaxa. The safety profile in these 170 paediatric patients was generally similar to that observed in the adult population with complicated intra-abdominal infections and complicated urinary tract infections (including acute pyelonephritis). There were three additional adverse reactions observed in the paediatric population: neutropenia, increased appetite, and dysgeusia (all frequency common). The most common adverse reactions (≥ 2% in pooled paediatric phase 2 trials) occurring in patients receiving Zerbaxa were diarrhoea, alanine aminotransferase increased, and aspartate aminotransferase increased. Safety data in patients less than 3 months of age with complicated intra‑abdominal infections are limited.

Description of selected adverse reactions

Laboratory values

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 adult complicated intra-abdominal infections and complicated 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 in the adult hospital-acquired pneumonia, including ventilator-associated pneumonia clinical trial. The incidence of seroconversion to a positive direct Coombs test was 45.3% in patients receiving Zerbaxa and 33.3% in patients receiving meropenem in the paediatric complicated intra-abdominal infection clinical trial. The incidence of seroconversion to a positive direct Coombs test was 29.7% in patients receiving Zerbaxa and 8.7% in patients receiving meropenem in the paediatric complicated urinary tract infection clinical trial. In clinical studies, there was no evidence of haemolysis in patients who developed a positive direct Coombs test in any treatment group.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no experience with overdose of Zerbaxa. The highest single dose of Zerbaxa used in clinical trials 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.