EMBLAVEO 1.5g / 0.5g powder for concentrate infusion solution medication leaflet

Emblaveo 1.5 g/0.5 g powder for concentrate for solution for infusion

Each vial contains 1.5 g aztreonam and avibactam sodium equivalent to 0.5 g avibactam.

After reconstitution, 1 mL of solution contains 131.2 mg of aztreonam and 43.7 mg of avibactam (seesection 6.6).

Emblaveo contains approximately 44.6 mg sodium per vial.

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion (powder for concentrate).

White to slightly yellow lyophilised cake.

Emblaveo is indicated for the treatment of the following infections in adult patients (see sections 4.4and 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 inadult patients with limited treatment options (see sections 4.2, pct. 4.4, and 5.1).

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

It is recommended that Emblaveo should be used to treat infections due to aerobic Gram-negativeorganisms in adult patients with limited treatment options only after consultation with a physician withappropriate experience in the management of infectious diseases.

Dose in adults with estimated creatinine clearance (CrCL) > 50 mL/min

Table 1 shows the recommended intravenous dose for patients with a creatinine clearance(CrCL) > 50 mL/min. A single loading dose is followed by maintenance doses beginning at the nextdosing interval.

Table 1. Recommended intravenous dose by type of infection in adult patients with

CrCLa > 50 mL/min

Type of infection Dose of Infusion Dosing Duration ofaztreonam-avibactam time interval treatment

Loading MaintenancecIAIb 2 g/0.67 g 1.5 g/0.5 g 3 hours Every 5-10 days6 hours

HAP, including VAP 2 g/0.67 g 1.5 g/0.5 g 3 hours Every 7-14 days6 hourscUTI, including 2 g/0.67 g 1.5 g/0.5 g 3 hours Every 5-10 dayspyelonephritis 6 hours

Infections due to aerobic 2 g/0.67 g 1.5 g/0.5 g 3 hours Every Duration in

Gram-negative 6 hours accordanceorganisms in patients with the site ofwith limited treatment infection andoptions may continuefor up to14 daysa Calculated using the Cockcroft-Gault formula.b To be used in combination with metronidazole when anaerobic pathogens are known orsuspected to be contributing to the infectious process.

No dosage adjustment is required in elderly patients based on age (see section 5.2).

No dosage adjustment is required in patients with mild renal impairment (estimated CrCL > 50 to≤ 80 mL/min).

Table 2 shows the recommended dose adjustments for patients with estimated creatinine clearance≤ 50 mL/min. A single loading dose is followed by maintenance doses beginning at the next dosinginterval.

Table 2. Recommended doses for patients with estimated CrCL ≤ 50 mL/min

Estimated CrCL Dose of aztreonam-avibactamb Infusion time Dosing interval(mL/min)a Loading Maintenance> 30 to ≤ 50 2 g/0.67 g 0.75 g/0.25 g 3 hours Every 6 hours> 15 to ≤ 30 1.35 g/0.45 g 0.675 g/0.225 g 3 hours Every 8 hours≤ 15 mL/min, on 1 g/0.33 g 0.675 g/0.225 g 3 hours Every 12 hoursintermittenthaemodialysisc,da Calculated using the Cockcroft-Gault formula.b Dose recommendations are based on PK modelling and simulation.c Both aztreonam and avibactam are removed by haemodialysis; on haemodialysis days

Emblaveo should be administered after the haemodialysis session.d Aztreonam-avibactam should not be used in patients with CrCl ≤ 15 mL/min unlesshaemodialysis or another form of renal replacement therapy is initiated.

In patients with renal impairment, close monitoring of estimated creatinine clearance is advised (seesections 4.4 and 5.2).

There are insufficient data to make dosing adjustment recommendations for patients undergoing renalreplacement therapy other than haemodialysis (e.g. continuous veno-venous hemofiltration orperitoneal dialysis). Patients receiving continuous renal replacement therapy (CRRT) need a higherdose than patients on haemodialysis. For patients receiving continuous renal replacement therapy, thedose should be adjusted guided by the CRRT clearance (CLCRRT in mL/min).

No dosage adjustment is required in patients with hepatic impairment (see section 5.2).

The safety and efficacy of Emblaveo in paediatric patients < 18 years of age have not yet beenestablished. No data are available.

Emblaveo is administered by intravenous infusion over 3 hours.

For instructions on reconstitution and dilution of the medicinal product before administration, seesection 6.6.

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 ofbeta-lactam antibacterial agent (e.g. penicillins, cephalosporins or carbapenems).

Prior to treatment, it should be established if the patient has a history of hypersensitivity reactions toaztreonam or other beta-lactam medicinal products. Emblaveo is contraindicated in patients who havea 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 anyother type of hypersensitivity reaction to other beta-lactam medicinal products. In case of severehypersensitivity reactions, Emblaveo must be discontinued immediately and adequate emergencymeasures must be initiated.

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 bereduced according to the degree of renal impairment (see section 4.2). There have been some reportsof neurological sequelae with aztreonam (e.g. encephalopathy, confusion, epilepsy, impairedconsciousness, 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 renalfunction. CrCL should be monitored in patients with changing renal function and the dose of

Emblaveo adjusted accordingly (see section 4.2).

Elevated liver enzymes have been observed with Emblaveo (see section 4.8). In patients with hepaticimpairment, 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 includingpyelonephritis, is based on experience with aztreonam alone, pharmacokinetic-pharmacodynamicanalyses of aztreonam-avibactam, and on limited data from the randomised clinical study of 422 adultswith cIAI or HAP/VAP.

The use of aztreonam-avibactam to treat infections due to aerobic Gram-negative organism in patientswith limited treatment options is based on pharmacokinetic/pharmacodynamic analysis foraztreonam-avibactam and on limited data from the randomised clinical study of 422 adults with cIAIor HAP/VAP (of which 17 patients with carbapenem-resistant [meropenem-resistant] organisms weretreated with Emblaveo), and the randomised clinical study of 15 adults (of which 12 patients weretreated 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-positiveorganisms and anaerobes (see sections 4.2 and 5.1). Additional antibacterial medicinal products shouldbe 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 Benzymes (metallo-β-lactamases) and is not able to inhibit many of the class D enzymes. Aztreonam isgenerally 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 beenreported with aztreonam and may range in severity from mild to life-threatening. This diagnosisshould be considered in patients who present with diarrhoea during or subsequent to the administrationof Emblaveo (see section 4.8). Discontinuation of therapy with Emblaveo and administration ofspecific treatment for C. difficile should be considered. Medicinal products that inhibit peristalsisshould not be given.

Non-susceptible organisms

The use of Emblaveo may result in overgrowth of non-susceptible organisms, which may requireinterruption 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 concomitantlyand 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 duringtreatment with aztreonam (see section 4.8).

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 beconsidered 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 whichmight 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 clinicalinteraction study of aztreonam-avibactam and probenecid has not been conducted, co-dosing withprobenecid is not recommended.

Aztreonam is not metabolized by cytochrome P450 enzymes. In vitro, avibactam showed nosignificant inhibition of cytochrome P450 enzymes and no cytochrome P450 induction in the clinicallyrelevant exposure range. Avibactam does not inhibit the major renal or hepatic transporters in vitro inthe clinically relevant exposure range; therefore, the drug-drug interaction potential via thesemechanisms is considered low.

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 toreproductive toxicity (see section 5.3). Animal studies with avibactam have shown reproductivetoxicity without evidence of teratogenic effects (see section 5.3).

Aztreonam/avibactam should only be used during pregnancy when clearly indicated and only if thebenefit for the mother outweighs the risk for the child.

Aztreonam is excreted in human milk in concentrations that are less than 1% of those insimultaneously 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 fromaztreonam/avibactam therapy taking into account the benefit of breast-feeding for the child and thebenefit of therapy for the woman.

No human data on the effect of aztreonam/avibactam on fertility are available. Animal studies withaztreonam 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 todrive or use machines (see section 4.8).

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%).

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 frequencycategories, 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), orfrequency 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 beestimatedfrom theavailabledata)

Infections and Vulvovaginal Superinfectioninfestations candidiasis

Vaginal infection

Blood and Anaemia Eosinophil Pancytopenialymphatic system count increaseddisorders Thrombocytosis Neutropenia

Leukocytosis

Thrombocytopenia Prothrombin timeprolonged

Activated partialthromboplastintime prolonged

Coombs testpositive

Coombs direct testpositive

Coombs indirecttest positive

Immune system Anaphylacticdisorders reaction

Drughypersensitivity

Psychiatric Confusional state Insomniadisorders

Nervous system Dizziness Encephalopathy Seizuredisorders

Headache Paraesthesia

Hypoaesthesiaoral

Dysgeusia

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 beestimatedfrom theavailabledata)

Eye disorders Diplopia

Ear and labyrinth Vertigodisorders

Tinnitus

Cardiac disorders Extrasystoles

Vascular Haemorrhagedisorders

Flushing

Respiratory, Bronchospasm Dyspnoeathoracic andmediastinal Wheezingdisorders

Sneezing

Nasal congestion

Gastrointestinal Diarrhoea Clostridium Pseudomembranoudisorders difficile colitis s colitis

Nausea

Gastrointestinal Breath odour

Vomiting haemorrhage

Abdominal pain Mouthulceration

Hepatobiliary Aspartate Gamma- Hepatitisdisorders aminotransferase glutamyltransferincreased ase increased Jaundice

Alanine Blood alkalineaminotransferase phosphataseincreased increased

Transaminasesincreased

Skin and Rash Angioedemasubcutaneoustissue disorders Toxic epidermalnecrolysis

Dermatitisexfoliative

Erythemamultiforme

Purpura

Urticaria

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 beestimatedfrom theavailabledata)

Petechiae

Pruritus

Hyperhidrosis

Musculoskeletal Myalgiaand connectivetissue disorders

Renal and urinary Blood creatininedisorders increased

Reproductive Breast tendernesssystem and breastdisorders

General disorders Phlebitis Chest Malaiseand discomfortadministration Thrombophlebitissite conditions Asthenia

Infusion siteextravasation

Injection site pain

Kounis syndrome

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Overdose can cause encephalopathy, confusion, epilepsy, impaired consciousness, and movementdisorders particularly in patients with renal impairment (see section 4.4).

If necessary, aztreonam and avibactam may be partially removed by haemodialysis.

During a 4-hour haemodialysis session, 38% of the aztreonam dose and 55% of the avibactam dose isremoved.

Pharmacotherapeutic group: Antibacterials for systemic use, other beta-lactam antibacterials,monobactams, ATC code: J01DF51

Aztreonam inhibits bacterial peptidoglycan cell wall synthesis following binding to penicillin-bindingproteins (PBPs), which leads to bacterial cell lysis and death. Aztreonam is generally stable tohydrolysis by class B enzymes (metallo-β-lactamases).

Avibactam is a non β-lactam, β-lactamase inhibitor that acts by forming a covalent adduct with theenzyme that is stable to hydrolysis. Avibactam inhibits both Ambler class A and class C β-lactamasesand some class D enzymes, including extended-spectrum β-lactamases (ESBLs), Klebsiellapneumoniae carbapenemase (KPC) and OXA-48 carbapenemases, and AmpC enzymes. Avibactamdoes not inhibit class B enzymes and is not able to inhibit many class D enzymes.

Bacterial resistance mechanisms that could potentially affect aztreonam-avibactam includeβ-lactamase enzymes refractory to inhibition by avibactam and able to hydrolyse aztreonam, mutant oracquired PBPs, decreased outer membrane permeability to either compound, and active efflux ofeither compound.

Antibacterial activity in combination with other antibacterial agents

No synergy or antagonism was demonstrated in in vitro drug combination studies withaztreonam-avibactam and amikacin, ciprofloxacin, colistin, daptomycin, gentamicin, levofloxacin,linezolid, metronidazole, tigecycline, tobramycin, and vancomycin.

Susceptibility testing breakpoints

MIC (minimum inhibitory concentration) interpretative criteria for susceptibility testing have beenestablished by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) foraztreonam/avibactam and are listed here: https://www.ema.europa.eu/documents/other/minimum-inhibitory-concentration-mic-breakpoints_en.xlsx

The antimicrobial activity of aztreonam against specific pathogens has been shown to best correlatewith the percent time of free drug concentration above the aztreonam-avibactam minimum inhibitoryconcentration over the dose interval (%fT > MIC of aztreonam-avibactam). For avibactam, thepharmacokinetic/pharmacodynamic (PK-PD) index is the percent time of the free drug concentrationabove a threshold concentration over the dose interval (%fT > CT).

Antibacterial activity against specific pathogens

In vitro studies suggest that the following pathogens would be susceptible to aztreonam-avibactam inthe absence of acquired mechanisms of resistance:

Aerobic Gram-negative organisms

- Citrobacter freundii complex

- Citrobacter koseri

- Escherichia coli

- Enterobacter cloacae complex

- Klebsiella aerogenes

- Klebsiella pneumoniae

- Klebsiella oxytoca

- Morganella morganii

- Proteus mirabilis

- Proteus vulgaris

- Providencia rettgeri

- Providencia stuartii

- Raoultella ornithinolytica

- Serratia spp.

- Pseudomonas aeruginosa

- Serratia marcescens

- Stenotrophomonas maltophilia

In vitro studies indicate that the following species are not susceptible to aztreonam-avibactam:

- Acinetobacter spp.

- Aerobic Gram-positive organisms

- Anaerobic organisms

The European Medicines Agency has deferred the obligation to submit the results of studies with

Emblaveo in one or more subsets of the paediatric population for the treatment of infections caused byaerobic Gram-negative bacteria in patients with limited treatment options (see section 4.2 forinformation on paediatric use).

General introduction

The aztreonam and avibactam geometric mean (CV%) steady-state maximum plasma concentration(Cmax,ss) and area under the concentration-time curve over 24 hours (AUC24,ss) in Phase 3 patients withnormal renal function (n = 127) after multiple 3-hour infusions of 1.5 g aztreonam/0.5 g avibactamadministered every 6 hours were 54.2 mg/L (40.8) and 11.0 mg/L (44.9), respectively, and 833mg*h/L (45.8) and 161 mg*h/L (47.5), respectively. Pharmacokinetic parameters of aztreonam andavibactam following single- and multiple-dose administration of aztreonam-avibactam in combinationwere similar to those determined when aztreonam or avibactam were administered alone.

The human protein binding of avibactam and aztreonam is concentration independent and low,approximately 8% and 38%, respectively. The steady-state volumes of distribution of aztreonam andavibactam were comparable, about 20 L and 24 L, respectively, in patients with complicatedintra-abdominal infections following multiple doses of 1.5 g/0.5 g aztreonam-avibactam every 6 hoursinfused over 3 hours.

Aztreonam crosses the placenta and is excreted in the breast milk.

Penetration of aztreonam into pulmonary epithelial lining fluid (ELF) has not been studied clinically; amean ratio of concentration in bronchial secretions to concentration in serum of 21% to 60% has beenreported in intubated patients at 2 to 8 hours after a single aztreonam 2 g intravenous dose.

Avibactam penetrates into human bronchial ELF with concentrations around 30% that of plasma, anda similar concentration time profile between ELF and plasma. Avibactam penetrates into thesubcutaneous tissue at the site of skin infections, with tissue concentrations approximately equal tofree drug concentrations in plasma.

Penetration of aztreonam into the intact blood-brain barrier is limited, resulting in low levels ofaztreonam in the cerebrospinal fluid (CSF) in the absence of inflammation; however, concentrations in

CSF are increased when the meninges are inflamed.

Aztreonam is not extensively metabolised. The principal metabolite is inactive and is formed byopening of the beta-lactam ring due to hydrolysis. Recovery data indicate that about 10% of the dose isexcreted as this metabolite. No metabolism of avibactam was observed in human liver preparations(microsomes and hepatocytes). Unchanged avibactam was the major drug-related component inhuman plasma and urine following dosing with [14C]-avibactam.

The terminal half-lives (t½) of both aztreonam and avibactam are approximately 2 to 3 hours afterintravenous administration.

Aztreonam is excreted in the urine by active tubular secretion and glomerular filtration.

Approximately 75% to 80% of an intravenous or intramuscular dose was recovered in the urine. Thecomponents of urinary radioactivity were unchanged aztreonam (approximately 65% recovered within8 hours), the inactive β-lactam ring hydrolysis product of aztreonam (approximately 7%) and unknownmetabolites (approximately 3%). Approximately 12% of aztreonam is excreted into faeces.

Avibactam is excreted unchanged into the urine with a renal clearance of approximately 158 mL/min,suggesting active tubular secretion in addition to glomerular filtration. The percentage unchanged drugexcreted in urine was independent of administered dose and accounted for 83.8% to 100% of theavibactam dose at steady-state. Less than 0.25% of avibactam is excreted into faeces.

The pharmacokinetics of both aztreonam and avibactam are approximately linear across the doserange studied (1500 mg to 2000 mg aztreonam; 375 mg to 600 mg avibactam). No appreciableaccumulation of aztreonam or avibactam was observed following multiple intravenous infusions of1500 mg/500 mg of aztreonam-avibactam administered every 6 hours for up to 11 days in healthyadults with normal renal function.

Elimination of aztreonam and avibactam is decreased in patients with renal impairment. The averageincreases in avibactam AUC are 2.6-fold, 3.8-fold, 7-fold and 19.5-fold in subjects with mild (heredefined as CrCL 50 to 79 mL/min), moderate (here defined as CrCL 30 to 49 mL/min), severe renalimpairment (CrCL < 30 mL/min, not requiring dialysis) and end-stage renal disease, respectively,compared to subjects with normal renal function (here defined as CrCL > 80 mL/min). Doseadjustment is needed in patients with estimated CrCL ≤ 50 mL/min, see section 4.2.

The pharmacokinetics of avibactam in patients with any degree of hepatic impairment has not beenstudied. As aztreonam and avibactam do not appear to undergo significant hepatic metabolism, thesystemic clearance of either active substance is not expected to be significantly altered by hepaticimpairment.

Elderly patients (≥ 65 years)

Mean elimination half-life of both aztreonam and avibactam is increased, and plasma clearancedecreased in the elderly, consistent with age-related reduction in renal clearance of aztreonam andavibactam.

The pharmacokinetics of aztreonam-avibactam have not been evaluated in paediatric patients.

Gender, race and body weight

The pharmacokinetics of aztreonam-avibactam is not significantly affected by gender or race. In apopulation pharmacokinetic analysis of aztreonam-avibactam, no clinically relevant differences inexposures were observed in adult patients with body mass index (BMI) ≥ 30 kg/m2 compared to adultpatients with BMI < 30 kg/m2.

Aztreonam

Aztreonam non-clinical data reveal no special hazard for humans based on conventional studies ofsafety pharmacology, repeated dose toxicity, genotoxicity, or toxicity to reproduction. Carcinogenicitystudies have not been conducted with aztreonam by the intravenous route.

Avibactam

Avibactam non-clinical data reveal no special hazard for humans based on conventional studies ofsafety pharmacology, repeated dose toxicity or genotoxicity. Carcinogenicity studies have not beenconducted with avibactam.

Aztreonam and avibactam combination toxicity

A 28-day combination toxicology study in rats indicated that avibactam did not alter the safety profileof aztreonam when given in combination.

Reproduction toxicity

Animal studies with aztreonam do not indicate direct or indirect harmful effects with respect tofertility, pregnancy, embryonal/foetal development, parturition or postnatal development.

In pregnant rabbits administered avibactam at 300 and 1 000 mg/kg/day, there was a dose-relatedlower mean foetal weight and delayed ossification, potentially related to maternal toxicity. Plasmaexposure levels at maternal and foetal NOAEL (100 mg/kg/day) indicate moderate to low margins ofsafety.

In the rat, no adverse effects were observed on embryofoetal development or fertility. Followingadministration of avibactam throughout pregnancy and lactation in the rat, there was no effect on pupsurvival, growth or development, however there was an increase in incidence of dilation of the renalpelvis and ureters in less than 10% of the rat pups at maternal exposures greater than or equal toapproximately 2.8 times human therapeutic exposures.

Arginine

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

Dry powder30 months.

The reconstituted vial should be used within 30 minutes for preparation of the infusion bag or stocksolution that delivers the appropriate dose of ATM-AVI for intravenous infusion.

Infusion bags

If the intravenous solution is prepared with sodium chloride (0.9%) solution for injection or Lactated

Ringer’s solution, the chemical and physical in-use stability has been demonstrated for 24 hours at2 °C - 8 °C followed by up to 12 hours at up to 30 °C.

If the intravenous solution is prepared with glucose (5%) solution for injection, the chemical andphysical in-use stability has been demonstrated for 24 hours at 2 °C - 8 °C followed by up to 6 hoursup to 30 °C.

From a microbiological point of view, the medicinal product should be used immediately, unlessreconstitution and dilution have taken place in controlled and validated aseptic conditions. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andmust not exceed those stated above.

Store in a refrigerator (2 °C - 8 °C).

Store in the original package in order to protect from light.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

30 mL glass vial (Type I) closed with a rubber (chlorobutyl) stopper and aluminium seal with flip-offcap.

The medicinal product is supplied in packs of 10 vials.

The powder must be reconstituted with sterile water for injections and the resulting concentrate mustthen be immediately diluted prior to use. The reconstituted solution is a clear, colourless to yellowsolution and is free of visible particles.

Standard aseptic techniques should be used for solution preparation and administration. Doses must beprepared in an appropriately sized infusion bag.

Parenteral medicinal products should be inspected visually for particulate matter prior toadministration.

Each vial is for single use only.

The total time interval between starting reconstitution and completing preparation of the intravenousinfusion should not exceed 30 minutes.

Emblaveo (aztreonam/avibactam) is a combination product; each vial contains 1.5 g of aztreonam and0.5 g of avibactam in a fixed 3:1 ratio.

Instructions for preparing adult doses in an INFUSION BAG:

NOTE: The following procedure describes the steps to prepare an infusion solution with a finalconcentration of 1.5-40 mg/mL of aztreonam and 0.50-13.3 mg/mL of avibactam. All calculationsshould be completed prior to initiating these steps.

1. Prepare the reconstituted solution (131.2 mg/mL of aztreonam and 43.7 mg/mL of avibactam):

a) Insert the needle through the vial closure and inject 10 mL of sterile water for injections.b) Withdraw the needle and shake the vial gently to give a clear, colourless to yellow solutionfree of visible particles.2. Prepare the final solution for infusion (final concentration must be 1.5-40 mg/mL of aztreonamand 0.50-13.3 mg/mL of avibactam):

Infusion bag: Further dilute the reconstituted solution by transferring an appropriatelycalculated volume of the reconstituted solution to an infusion bag containing any of thefollowing: sodium chloride (0.9%) solution for injection, glucose (5%) solution for injection,or Lactated Ringer’s solution.

Refer to Table 4 below.

Table 4. Preparation of Emblaveo for adult doses in an INFUSION BAG

Total dose Volume to withdraw from Final volume after(aztreonam/avibactam) reconstituted vial(s) dilution in infusion baga,b2000 mg/667 mg 15.2 mL 50 mL to 250 mL1500 mg/500 mg 11.4 mL 50 mL to 250 mL1350 mg/450 mg 10.3 mL 50 mL to 250 mL750 mg/250 mg 5.7 mL 50 mL to 250 mL675 mg/225 mg 5.1 mL 50 mL to 250 mL

All other doses Volume (mL) calculated Volume (mL) will varybased on dose required: based on infusion bag sizeavailability and preferred

Dose (mg aztreonam) ÷ final concentration131.2 mg/mL aztreonam (Must be 1.5-40 mg/mL ofaztreonam and

Or 0.50-13.3 mg/mL ofavibactam)

Dose (mg avibactam) ÷43.7 mg/mL avibactama Dilute to final aztreonam concentration of 1.5-40 mg/mL (final avibactam concentration of0.50-13.3 mg/mL) for in-use stability up to 24 hours at 2 °C - 8 °C, followed by up to12 hours up to 30 °C for infusion bags containing sodium chloride (0.9%) solution forinjection or Lactated Ringer’s solution.

b Dilute to final aztreonam concentration of 1.5-40 mg/mL (final avibactam concentration of0.50-13.3 mg/mL) for in-use stability up to 24 hours at 2 °C - 8 °C, followed by up to6 hours up to 30 °C for infusion bags containing glucose (5%) solution for injection.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Brussels

Belgium

EU/1/24/1808/001

Date of first authorisation: 22 April 2024

Detailed information on this medicinal product is available on the website of the European

Medicines Agency https://www.ema.europa.eu.