Emblaveo · 4.3 Contraindications · 1

HOS-100566 · has-adverse-reaction-information · PDF-Seite 6

Summary of the safety profile The most common adverse drug reactions (ADRs) in patients treated with aztreonam/avibactam (ATM-AVI) were anaemia (6.9%), diarrhoea (6.2%), alanine aminotransferase (ALT) increased (6.2%), and aspartate aminotransferase (AST) increased (5.2%). 6 Tabulated list of adverse reactions The following ADRs have been reported with aztreonam alone and/or identified during Phase 2 and Phase 3 clinical trials with Emblaveo (N = 305). The ADRs listed in the table below are presented by System Organ Class (SOC) and frequency categories, defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), or frequency not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 3. Frequency of adverse drug reactions presented by system organ class System Organ Common Uncommon Rare Frequency Class ≥ 1/100 to < 1/10 ≥ 1/1 000 to ≥ 1/10 000 to not known < 1/100 < 1/1 000 (cannot be estimated from the available data) Infections and Vulvovaginal Superinfection infestations candidiasis Vaginal infection Blood and Anaemia Eosinophil Pancytopenia lymphatic system count increased disorders Thrombocytosis Neutropenia Leukocytosis Thrombocytopenia Prothrombin time prolonged Activated partial

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HOS-100562 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of beta-lactam antibacterial agent (e.g. penicillins, cephalosporins or carbapenems).

HOS-100561 · has-indication-information · PDF-Seite 2

Emblaveo is indicated for the treatment of the following infections in adult patients (see sections 4.4 and 5.1): • Complicated intra-abdominal infection (cIAI) • Hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP) • Complicated urinary tract infection (cUTI), including pyelonephritis Emblaveo is also indicated for the treatment of infections due to aerobic Gram-negative organisms in adult patients 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-100564 · has-interaction-information · PDF-Seite 6

In vitro, aztreonam and avibactam are substrates of organic anion transporters OAT1 and OAT3 which might contribute to the active uptake from the blood compartment and, thereby, renal excretion. Probenecid (a potent OAT inhibitor) inhibits uptake of avibactam by 56% to 70% in vitro and, therefore, has the potential to alter the elimination of avibactam when co-administered. Since a clinical interaction study of aztreonam-avibactam and probenecid has not been conducted, co-dosing with probenecid is not recommended. Aztreonam is not metabolized by cytochrome P450 enzymes. In vitro, avibactam showed no significant inhibition of cytochrome P450 enzymes and no cytochrome P450 induction in the clinically relevant exposure range. Avibactam does not inhibit the major renal or hepatic transporters in vitro in the clinically relevant exposure range; therefore, the drug-drug interaction potential via these mechanisms is considered low.

HOS-100565 · has-pregnancy-information · PDF-Seite 6

Pregnancy There are no or limited amount of data from the use of aztreonam or avibactam in pregnant women. Animal studies with aztreonam do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Animal studies with avibactam have shown reproductive toxicity without evidence of teratogenic effects (see section 5.3). Aztreonam/avibactam should only be used during pregnancy when clearly indicated and only if the benefit for the mother outweighs the risk for the child. Breast-feeding Aztreonam is excreted in human milk in concentrations that are less than 1% of those in simultaneously obtained maternal serum. It is unknown whether avibactam is excreted in human milk. A risk to the breastfed child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from aztreonam/avibactam therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility No human data on the effect of aztreonam/avibactam on fertility are available. Animal studies with aztreonam or avibactam do not indicate harmful effects with respect to fertility (see section 5.3).

HOS-100563 · has-warning-information · PDF-Seite 4

Hypersensitivity reactions Prior to treatment, it should be established if the patient has a history of hypersensitivity reactions to aztreonam or other beta-lactam medicinal products. Emblaveo is contraindicated in patients who have a history of severe hypersensitivity reactions to any beta-lactam agent (see section 4.3). In addition, caution should be exercised when administering aztreonam/avibactam to patients with a history of any other type of hypersensitivity reaction to other beta-lactam medicinal products. In case of severe hypersensitivity reactions, Emblaveo must be discontinued immediately and adequate emergency measures must be initiated. Renal impairment In patients with renal impairment, close monitoring is recommended during treatment with Emblaveo. Aztreonam and avibactam are predominantly eliminated via the kidneys, therefore the dose should be reduced according to the degree of renal impairment (see section 4.2). There have been some reports of neurological sequelae with aztreonam (e.g. encephalopathy, confusion, epilepsy, impaired consciousness, movement disorders) in patients with renal impairment and in association with beta- lactam overdose (see section 4.9). Concomitant treatment with nephrotoxic products (e.g. aminoglycosides) may adversely affect renal function. CrCL should be monitored in patients with changing renal function and the dose of Emblaveo adjusted accordingly (see section 4.2). Hepatic impairment Elevated liver enzymes have been observed with Emblaveo (see section 4.8). In patients with hepatic impairment, close monitoring is recommended during treatment with Emblaveo. 4 Limitations of the clinical data The use of aztreonam-avibactam to treat patients with cIAI, HAP including VAP and cUTI including pyelonephritis, is based on experience with aztreonam alone, pharmacokinetic-pharmacodynamic analyses of aztreonam-avibactam, and on limited data from the randomised clinical study of 422 adults with cIAI or HAP/VAP. The use of aztreonam-avibactam to treat infections due to aerobic Gram-negative organism in patients with limited treatment options is based on pharmacokinetic/pharmacodynamic analysis for aztreonam-avibactam and on limited data from the randomised clinical study of 422 adults with cIAI or HAP/VAP (of which 17 patients with carbapenem-resistant [meropenem-resistant] organisms were treated with Emblaveo), and the randomised clinical study of 15 adult

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