EMBLAVEO

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

Posology 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 next dosing interval.

Table 1. 5 g 3 hours Every 6 hours Duration in accordance with the site of infection and may continue for up to 14 days a Calculated using the Cockcroft-Gault formula. b To be used in combination with metronidazole when anaerobic pathogens are known or suspected to be contributing to the infectious process.

2). Renal impairment 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 dosing interval. Table 2. 225 g 3 hours Every 12 hours a 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 unless haemodialysis or another form of renal replacement therapy is initiated.

2). g. continuous veno-venous hemofiltration or peritoneal dialysis). Patients receiving continuous renal replacement therapy (CRRT) need a higher dose than patients on haemodialysis. For patients receiving continuous renal replacement therapy, the dose should be adjusted guided by the CRRT clearance (CLCRRT in mL/min).

2). Paediatric population The safety and efficacy of Emblaveo in paediatric patients < 18 years of age have not yet been established. No data are available. Method of administration Intravenous use. Emblaveo is administered by intravenous infusion over 3 hours.

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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 System Organ Class Common ≥ 1/100 to < 1/10 Uncommon ≥ 1/1,000 to < 1/100 Rare ≥ 1/10,000 to < 1/1,000 Frequency not known (cannot be estimated from the available data) Infections and infestations Vulvovaginal candidiasis Vaginal infection Superinfection Blood and lymphatic system disorders Anaemia Thrombocytosis Thrombocytopenia Eosinophil count increased Leukocytosis Pancytopenia Neutropenia Prothrombin time prolonged Activated partial thromboplastin time prolonged Coombs test positive Coombs direct test positive Coombs indirect test positive Immune system disorders Anaphylactic reaction Drug hypersensitivity Psychiatric disorders Confusional state Insomnia Table 3.

Frequency of adverse drug reactions presented by system organ class System Organ Class Common ≥ 1/100 to < 1/10 Uncommon ≥ 1/1,000 to < 1/100 Rare ≥ 1/10,000 to < 1/1,000 Frequency not known (cannot be estimated from the available data) Nervous system disorders Dizziness Encephalopathy Headache Hypoaesthesia oral Dysgeusia Seizure Paraesthesia Eye disorders Diplopia Ear and labyrinth disorders Vertigo Tinnitus Cardiac disorders Extrasystoles Vascular disorders Haemorrhage Hypotension Flushing Respiratory, thoracic and mediastinal disorders Bronchospasm Dyspnoea Wheezing Sneezing Nasal congestion Gastrointestina l disorders Diarrhoea Nausea Vomiting Abdominal pain Clostridium difficile colitis Gastrointestinal haemorrhage Mouth ulceration Pseudomembrano us colitis Breath odour Hepatobiliary disorders Aspartate aminotransferase increased Alanine aminotransferase increased Transaminases increased Gamma- glutamyltransferas e increased Blood alkaline phosphatase increased Hepatitis Jaundice Skin and subcutaneous tissue disorders Rash Angioedema Toxic epidermal necrolysis Dermatitis exfoliative Erythema multiforme Purpura Urticaria Petechiae Pruritus Hyperhidrosis Musculoskeleta l and connective tissue disorders Myalgia Renal and urinary disorders Blood creatinine increased Reproductive system and breast Breast tenderness Table 3.

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. 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.

2). g. 9). g. aminoglycosides) may adversely affect renal function. 2). 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.

1). 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. 1). ) difficile-associated diarrhoea (CDAD) and pseudomembranous colitis have been reported with aztreonam and may range in severity from mild to life-threatening.

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.

1. g. g. penicillins, cephalosporins or carbapenems).