Zerbaxa · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-097036 · has-adverse-reaction-information · PDF-Seite 7

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. 7 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 Common Uncommon System organ class (≥ 1/100 to < 1/10) (≥ 1/1 000 to < 1/100) Candidiasis including oropharyngeal and vulvovaginal1, 2 Infections and infestations Clostridioides difficile colitis Clostridioides difficile colitis1, fungal urinary tract infection1, Clostridioides difficile infection2 Blood and the lymphatic Thrombocytosis1 Anaemia1 system disorders

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HOS-097032 · has-contraindication-information · PDF-Seite 4

- 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

HOS-097031 · has-indication-information · PDF-Seite 2

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.

HOS-097034 · has-interaction-information · PDF-Seite 6

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. 6

HOS-097035 · has-pregnancy-information · PDF-Seite 7

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).

HOS-097033 · has-warning-information · PDF-Seite 5

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

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