EMBLAVEO Powder for solution for infusion Ref.[110084] Active ingredients: Avibactam Aztreonam Aztreonam and Avibactam

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 betalactam 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.

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 adults (of which 12 patients were treated with Emblaveo) with serious infections due to metallo-β-lactamase (MBL)-producing Gram-negative bacteria (see section 5.1).

Spectrum of activity of aztreonam-avibactam

Aztreonam has little or no activity against the majority of Acinetobacter spp., Gram-positive organisms and anaerobes (see sections 4.2 and 5.1). Additional antibacterial medicinal products should be used when these pathogens are known or suspected to be contributing to the infectious process.

The inhibitory spectrum of avibactam includes many of the enzymes that inactivate aztreonam, including Ambler class A β-lactamases and class C β-lactamases. Avibactam does not inhibit class B enzymes (metallo-β-lactamases) and is not able to inhibit many of the class D enzymes. Aztreonam is generally stable to hydrolysis by class B enzymes (see section 5.1).

Clostridioides difficile-associated diarrhoea

Clostridioides (C.) difficile-associated diarrhoea (CDAD) and pseudomembranous colitis have been reported with aztreonam and may 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 Emblaveo (see section 4.8). Discontinuation of therapy with Emblaveo and administration of specific treatment for C. difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

Non-susceptible organisms

The use of Emblaveo may result in overgrowth of non-susceptible organisms, which may require interruption of treatment or other appropriate measures.

Prolongation of prothrombin time/increased activity of oral anticoagulants

Prolongation of prothrombin time has been reported in patients receiving aztreonam (see section 4.8). Appropriate monitoring should be undertaken when oral anticoagulants are prescribed concomitantly and adjustments in their dose may be necessary to maintain the desired level of anticoagulation.

Interference with serological testing

A positive direct or indirect Coombs test (direct or indirect antiglobulin test) may develop during treatment with aztreonam (see section 4.8).

Sodium

This medicinal product contains approximately 44.6 mg sodium per vial, equivalent to 2.2% of the WHO recommended maximum daily intake (RDI) of 2 g sodium for an adult.

Emblaveo may be diluted with sodium-containing solutions (see section 6.6) and this should be considered in relation to the total sodium from all sources that will be administered to the patient.

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.

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).

Undesirable effects may occur (e.g. dizziness) which may have a minor influence on the ability to drive or use machines (see section 4.8).

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%).

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:

Kounis syndrome

Acute coronary syndrome associated with an allergic reaction (Kounis syndrome) has been reported with other beta-lactam antibiotics.

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 national reporting system listed in Appendix V.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.