Vaborem · 4.4 Special warnings and precautions for use · 1

HOS-287251 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile 7 The most common adverse reactions that occurred among 322 patients from the pooled Phase 3 studies were headache (8.1%), diarrhoea (4.7%), infusion site phlebitis (2.2%) and nausea (2.2%). Severe adverse reactions were observed in two patients (0.6 %), one infusion related reaction and one blood alkaline phosphatase increased respectively. In one additional patient, a serious adverse reaction of infusion related reaction was reported (0.3%). Tabulated list of adverse reactions The following adverse reactions have been reported with meropenem alone and/or identified during the Phase 3 studies with Vaborem. Adverse reactions are classified according to frequency and System Organ Class. Adverse reactions listed in the table with a frequency of “unknown” were not observed in patients participating in studies with Vaborem or meropenem but have been reported in the post-marketing setting for meropenem alone. Frequencies are defined as: 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); unknown (cannot be estimated from the available data). Within each System Organ Class, undesirable effects are presented in order of decreasing seriousness. Table 3: Frequency of adverse reactions by system organ class System organ class Common Uncommon Rare Unknown (≥1/100 to <1/10) (≥1/1,000 to (≥1/10,000 to (cannot be <1/100) <1/1,000) estimated from the available data) Infections and Clostridioides infestations difficile colitis Vulvovaginal candidiasis Oral candidiasis Blood and Thrombocythaemia Leucopenia Agranulocytosis lymphatic system disorders Neutropenia Haemolytic anaemia Eosinophilia T

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HOS-287247 · has-contraindication-information · PDF-Seite 4

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

HOS-287246 · has-indication-information · PDF-Seite 2

Vaborem is indicated for the treatment of the following infections in adults (see sections 4.4 and 5.1): • Complicated urinary tract infection (cUTI), including pyelonephritis • Complicated intra-abdominal infection (cIAI) • Hospital-acquired pneumonia (HAP), including ventilator associated pneumonia (VAP). Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above. Vaborem is also indicated for the treatment of infections due to aerobic Gram-negative organisms in adults 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-287249 · has-interaction-information · PDF-Seite 6

In vitro data suggests a potential for induction of CYP1A2 (meropenem), CYP3A4 (meropenem and vaborbactam) and potentially other PXR regulated enzymes and transporters (meropenem and vaborbactam). When administering Vaborem concomitantly with medicinal products that are predominantly metabolised by CYP1A2 (e.g theophylline), CYP3A4 (e.g alprazolam, midazolam, tacrolimus, sirolimus, cyclosporine, simvastatin, omeprazole, nifedipine, quinidine and ethinylestradiol) and/or CYP2C (e.g. warfarin, phenytoin) and/or transported by P-gp (e.g. dabigatran, digoxin) there could be a potential risk of interaction which may result in decreased plasma concentrations and activity of the co-administered medicinal product. Therefore, patients taking such medicinal products should be monitored for possible clinical signs of altered therapeutic efficacy. Both meropenem and vaborbactam are substrates of OAT3 and as such, probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem and the same mechanism could apply for vaborbactam. Co-administration of probenecid with Vaborem is not recommended, as it may result in increased plasma concentrations of meropenem and vaborbactam. Concomitant administration of meropenem and valproic acid has been associated with reductions in valproic acid concentrations with subsequent loss in seizure control. Data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid’s glucuronide metabolite (VPA g) 6 back to valproic acid, thus decreasing the serum concentrations of valproic acid. Therefore, supplemental anticonvulsant therapy should be administered when concomitant administration of valproic acid and meropenem/vaborbactam cannot be avoided (see section 4.4). Oral anticoagulants Simultaneous administration of antibacterial agents with warfarin may augment its anticoagulant effects. There have been many reports of increases in the anticoagulant effects of orally administered anticoagulants, including warfarin in patients, who are concomitantly receiving antibacterial agents. The risk may vary with the underlying infection, age and general status of the patient so that the contribution of the antibacterial agent to the increase in international normalised ratio (INR) is difficult to assess. It is recommended that the INR should be monitored frequently during and shortly after co-administrati

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HOS-287250 · has-pregnancy-information · PDF-Seite 7

Pregnancy There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of meropenem/vaborbactam in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Vaborem during pregnancy. Breast-feeding Meropenem has been reported to be excreted in human milk. It is unknown whether vaborbactam is excreted in human milk or animal milk. Because a risk to the newborns/infants cannot be excluded, breastfeeding must be discontinued prior to initiating therapy. Fertility The effects of meropenem/vaborbactam on fertility in humans have not been studied. Animal studies conducted with meropenem and vaborbactam do not indicate harmful effects with respect to fertility (see section 5.3).

HOS-287248 · has-warning-information · PDF-Seite 4

Hypersensitivity reactions Serious and occasionally fatal hypersensitivity reactions have been reported with meropenem and/or meropenem/vaborbactam (see sections 4.3 and 4.8). Patients who have a history of hypersensitivity to carbapenems, penicillins or other beta-lactam antibacterial agents may also be hypersensitive to meropenem/vaborbactam. Before initiating therapy with Vaborem, careful inquiry should be made concerning previous hypersensitivity reactions to beta-lactam antibiotics. If a severe allergic reaction occurs, treatment with Vaborem must be discontinued immediately and adequate emergency measures must be initiated. Severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme (EM) and acute generalised exanthematous pustulosis (AGEP) have been reported in patients receiving meropenem (see section 4.8). If signs and symptoms suggestive of these reactions appear, meropenem should be withdrawn immediately and an alternative treatment should be considered. 4 Rhabdomyolysis Rhabdomyolysis has been reported with the use of meropenem, a component of meropenem/vaborbactam. If signs or symptoms of rhabdomyolysis are observed, meropenem/vaborbactam should be discontinued and appropriate therapy initiated. Seizures Seizures have been reported during treatment with meropenem (see section 4.8). Patients with known seizure disorders should continue anticonvulsant therapy. Patients who develop focal tremors, myoclonus, or seizures should be evaluated neurologically and placed on anticonvulsant therapy if not already instituted. If necessary, the dose of meropenem/vaborbactam should be adjusted based on renal function (see section 4.2). Alternatively, meropenem/vaborbactam should be discontinued (see section 4.5). Drug-induced liver injury (DILI) Hepatic function should be closely monitored during treatment with meropenem/vaborbactam due to the risk of DILI (see section 4.8). If severe DILI occurs, treatment discontinuation should be considered as clinically appropriate. Meropenem/vaborbactam should be reintroduced only if assessed as essential for treatment. Patients with pre-existing liver disorders should have liver function monitored during treatment with meropenem/vaborbactam. There is no dose adjustment necessary (see section 4.2). Antiglobulin t

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