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

HOS-097503 · has-adverse-reaction-information · PDF-Seite 11

Summary of the safety profile In seven Phase 2 and Phase 3 clinical trials, 2024 adults were treated with Zavicefta. The most common adverse reactions occurring in ≥5% of patients treated with Zavicefta were Coombs direct test positive, nausea, and diarrhoea. Nausea and diarrhoea were usually mild or moderate in intensity. Tabulated list of adverse reactions The following adverse reactions have been reported with ceftazidime alone and/or identified during the Phase 2 and Phase 3 trials with Zavicefta. Adverse reactions are classified according to frequency and System Organ Class. Frequency categories are derived from adverse reactions and/or potentially clinically significant laboratory abnormalities, and are defined according to the following conventions: Very common (≥1/10) Common (≥1/100 and <1/10) Uncommon (≥1/1,000 and <1/100) Rare (≥1/10,000 and <1/1000) Very rare (<1/10,000) Not known (cannot be estimated from the available data) 11 Table 7: Frequency of adverse reactions by system organ class System organ Very Common Uncommon Very rare Not known class common Infections and Candidiasis Clostridioides infestations (including difficile colitis Vulvovaginal candidiasis and Pseudomembranous Oral candidiasis) colitis Blood and Coombs Eosinophilia Neutropenia Agranulocytosis lymphatic direct system test Thrombocytosis Leukopenia Haemolytic disorders positive anaemia Thrombocytopenia Lymphocytosis Immune system Anaphylactic disorders reaction Nervous Headache Paraesthesia system disorders Dizziness Cardiac Kounis disorders syndromea,* Gastrointestinal Diarrhoea Dysgeusia disorders Abdominal pain

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HOS-097499 · has-contraindication-information · PDF-Seite 7

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 β-lactam antibacterial agent (e.g. penicillins, monobactams or carbapenems). 7

HOS-097498 · has-indication-information · PDF-Seite 2

Zavicefta is indicated in adults and paediatric patients from birth for the treatment of the following infections (see sections 4.4 and 5.1): • Complicated intra-abdominal infection (cIAI) • Complicated urinary tract infection (cUTI), including pyelonephritis • Hospital-acquired pneumonia (HAP), including ventilator associated pneumonia (VAP) Treatment of adult patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above. Zavicefta is also indicated for the treatment of infections due to aerobic Gram-negative organisms in adults and paediatric patients from birth with limited treatment options (see sections 4.2, 4.4 and 5.1). Consideration should be given to official guidance on the appropriate use of antibacterial agents.

HOS-097501 · has-interaction-information · PDF-Seite 10

In vitro, avibactam is a substrate of OAT1 and OAT3 transporters which might contribute to the active uptake of avibactam from the blood compartment and, therefore, affect its excretion. Probenecid (a potent OAT inhibitor) inhibits this uptake by 56% to 70% in vitro and, therefore, has the potential to alter the elimination of avibactam. Since a clinical interaction study of avibactam and probenecid has not been conducted, co-administration of avibactam with probenecid is not recommended. Avibactam showed no significant inhibition of cytochrome P450 enzymes in vitro. Avibactam and ceftazidime showed no in vitro cytochrome P450 induction at clinically relevant concentrations. Avibactam and ceftazidime do not inhibit the major renal or hepatic transporters in the clinically relevant exposure range, therefore the interaction potential via these mechanisms is considered to be low. Clinical data have demonstrated that there is no interaction between ceftazidime and avibactam, and between ceftazidime/avibactam and metronidazole. Other types of interaction Concurrent treatment with high doses of cephalosporins and nephrotoxic medicinal products such as aminoglycosides or potent diuretics (e.g. furosemide) may adversely affect renal function (see section 4.4). Chloramphenicol is antagonistic in vitro with ceftazidime and other cephalosporins. The clinical relevance of this finding is unknown, but due to the possibility of antagonism in vivo this drug combination should be avoided. 10

HOS-097502 · has-pregnancy-information · PDF-Seite 11

Pregnancy Animal studies with ceftazidime do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Animal studies with avibactam have shown reproductive toxicity without evidence of teratogenic effects (see section 5.3). Ceftazidime/avibactam should only be used during pregnancy if the potential benefit outweighs the possible risk. Breast-feeding Ceftazidime is excreted in human milk in small quantities. It is unknown whether avibactam is 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 ceftazidime/avibactam therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. Fertility The effects of ceftazidime/avibactam on fertility in humans have not been studied. No data are available on animal studies with ceftazidime. Animal studies with avibactam do not indicate harmful effects with respect to fertility (see section 5.3).

HOS-097500 · has-warning-information · PDF-Seite 8

Hypersensitivity reactions Serious and occasionally fatal hypersensitivity reactions are possible (see sections 4.3 and 4.8). In case of hypersensitivity reactions, treatment with Zavicefta must be discontinued immediately and adequate emergency measures must be initiated. There have been reports of hypersensitivity reactions which progressed to Kounis syndrome (acute allergic coronary arteriospasm that can result in myocardial infarction, see section 4.8). Before beginning treatment, it should be established whether the patient has a history of hypersensitivity reactions to ceftazidime, to other cephalosporins or to any other type of β-lactam antibacterial agent. Caution should be used if ceftazidime/avibactam is given to patients with a history of non-severe hypersensitivity to penicillins, monobactams or carbapenems. Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalised exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported with unknown frequency in association with ceftazidime treatment (see section 4.8). Patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, Zavicefta should be withdrawn immediately, and an alternative treatment considered. If the patient has developed a serious reaction such as SJS, TEN, DRESS or AGEP with the use of ceftazidime, treatment with Zavicefta must not be restarted in this patient at any time. Clostridioides difficile - associated diarrhoea Clostridioides difficile - associated diarrhoea has been reported with ceftazidime/avibactam, and can range in severity from mild to life-threatening. This diagnosis should be considered in patients who present with diarrhoea during or subsequent to the administration of Zavicefta (see section 4.8). Discontinuation of therapy with Zavicefta and the administration of specific treatment for Clostridioides difficile should be considered. Medicinal products that inhibit peristalsis should not be given. Renal impairment Ceftazidime and avibactam are eliminated via the kidneys, therefore, the dose should be reduced according to the degree of renal impairment (see section 4.2). Neurological sequelae, including tremor, myoclonus, non-convulsive status epilepticus, convulsion, encephalopathy and coma, h

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