Meropenem and Vaborbactam

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 meropenem/vaborbactam 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.

Meropenem and vaborbactam are removed by haemodialysis. Doses adjusted for renal impairment should be administered after a dialysis session.

Recommended intravenous doses for patients with a CrCl ≤39 ml/min¹:

¹ As calculated using the Cockcroft-Gault formula

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 meropenem/vaborbactam is not recommended, as it may result in increased plasma concentrations of meropenem and vaborbactam.

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.

As a precautionary measure, it is preferable to avoid the use of meropenem/vaborbactam during pregnancy.

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.

Meropenem/vaborbactam combination has moderate influence on the ability to drive and use machines. Seizures have been reported during treatment with meropenem alone, especially in patients treated with anticonvulsants. Meropenem/vaborbactam may cause headache, paraesthesia, lethargy and dizziness. Therefore, caution should be exercised when driving or using machines.

Summary of the safety profile

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 meropenem/vaborbactam. 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 meropenem/vaborbactam 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.

Frequency of adverse reactions by system organ class: