Vabomere 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.

Vabomere 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.

Vabomere 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 (see sections 4.4 and 5.1).

Posology
Table 1 shows the recommended intravenous dose for patients with a creatinine clearance (CrCl) ≥40 ml/min (see sections 4.4 and 5.1).

Table 1: Recommended intravenous dose for patients with a creatinine clearance (CrCl) ≥40 ml/min¹

¹ As calculated using the Cockcroft-Gault formula

² Treatment may continue up to 14 days

Special populations
Elderly population
No dose adjustment based on age is required (see section 5.2). 

Renal impairment
Table 2 shows the recommended dose adjustments for patients with a CrCl ≤39 ml/min.

Meropenem and vaborbactam are removed by haemodialysis (see section 5.2). Doses adjusted for renal impairment should be administered after a dialysis session. 

Table 2: Recommended intravenous doses for patients with a CrCl ≤39 ml/min¹

¹ As calculated using the Cockcroft-Gault formula

² Refer to Table 1 for the recommended duration of treatment

Hepatic impairment
No dose adjustment is required in patients with hepatic impairment (see sections 4.4 and 5.2).

Paediatric population
The safety and efficacy of meropenem/vaborbactam in children and adolescents younger than 18 years of age have not yet been established. No data are available.

Method of administration
Intravenous use.

Vabomere is administered by intravenous infusion over 3 hours.

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

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 Vabomere, careful inquiry should be made concerning previous hypersensitivity reactions to beta-lactam antibiotics.

If a severe allergic reaction occurs, treatment with Vabomere 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.

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).

Hepatic function monitoring
Hepatic function should be closely monitored during treatment with meropenem/vaborbactam due to the risk of hepatic toxicity (hepatic dysfunction with cholestasis and cytolysis) (see section 4.8).

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 test (Coombs test) seroconversion
A positive direct or indirect Coombs test may develop during treatment with meropenem/vaborbactam as seen with meropenem (see section 4.8).

Clostridium difficile-associated diarrhoea
Clostridium difficile-associated diarrhoea has been reported with meropenem/vaborbactam. The condition can range in severity from mild diarrhoea to fatal colitis and should be considered in patients who present with diarrhoea during or subsequent to the administration of meropenem/vaborbactam (see section 4.8). Discontinuation of therapy with Vabomere and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

Concomitant use with valproic acid/sodium valproate/valpromide
Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium may reduce plasma levels of valproic acid to concentrations below the therapeutic range as a result of this interaction, thus increasing the risk of breakthrough seizures. If administration of Vabomere is necessary, supplemental anticonvulsant therapy should be considered (see section 4.5).

Limitations of the clinical data
Complicated intra-abdominal infections
The use of meropenem/vaborbactam to treat patients with complicated intra-abdominal infections is based on experience with meropenem alone and pharmacokinetic-pharmacodynamic analyses of meropenem/vaborbactam.

Hospital-acquired pneumonia, including ventilator-associated pneumonia
The use of meropenem/vaborbactam to treat patients with hospital-acquired pneumonia, including ventilator-associated pneumonia, is based on experience with meropenem alone and pharmacokinetic-pharmacodynamic analyses for meropenem/vaborbactam.

Patients with limited treatment options
The use of meropenem/vaborbactam to treat patients with infections due to bacterial organisms who have limited treatment options is based on pharmacokinetic/pharmacodynamic analyses for meropenem/vaborbactam and on limited data from a randomised clinical trial in which 32 patients were treated with meropenem/vaborbactam and 15 patients were treated with best available therapy for infections caused by carbapenem-resistant organisms (see section 5.1).

Spectrum of activity of meropenem/vaborbactam
Meropenem does not have activity against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) or vancomycin-resistant Enterococci (VRE). Alternative or additional antibacterial agents should be used when these pathogens are known or suspected to be contributing to the infectious process.

The inhibitory spectrum of vaborbactam includes class A carbapenemases (such as KPC) and Class C carbapenemases. Vaborbactam does not inhibit class D carbapenemases such as OXA-48 or class B metallo-β-lactamases such as NDM and VIM (see section 5.1).

Non-susceptible organisms
The use of meropenem/vaborbactam may result in the overgrowth of non-susceptible organisms, which may require interruption of treatment or other appropriate measures.

Vabomere contains sodium
Vabomere contains sodium. This medicinal product contains 250 mg sodium per vial, equivalent to 12.5% of the WHO recommended maximum daily intake of 2 g of sodium for an adult.

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 Vabomere 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 transporters 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 drug. 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 Vabomere 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) 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-administration of Vabomere with an oral anticoagulant.

Contraceptives
Vabomere may decrease the efficacy of hormonal contraceptive drugs containing oestrogen and/or progesterone. Women of childbearing potential should be advised to use alternative effective contraceptive methods during treatment with Vabomere and for a period of 28 days after discontinuation of treatment.

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 Vabomere 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).

Meropenem/vaborbactam 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 (see section 4.4). Meropenem/vaborbactam may cause headache, paraesthesia, lethargy and dizziness (see section 4.8). 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 trials 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 trials 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 trials 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.

Table 3: Frequency of adverse reactions by system organ class

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:

• Saudi Arabia

The National Pharmacovigilance Centre (NPC)
SFDA Call Center: 19999
E-mail: npc.drug@sfda.gov.sa
Website: https://ade.sfda.gov.sa

• Other GCC States

Please contact the relevant competent authority.

There is no experience with overdose of meropenem/vaborbactam.

Limited post-marketing experience with meropenem alone indicates that if adverse reactions occur following overdose, they are consistent with the adverse reaction profile described in section 4.8, are generally mild in severity and resolve on withdrawal or dose reduction.

In the event of overdose, discontinue Vabomere and institute general supportive treatment. In individuals with normal renal function, rapid renal elimination will occur.

Meropenem and vaborbactam can be removed by haemodialysis. In subjects with end stage renal disease (ESRD) administered 1 g meropenem and 1 g vaborbactam, the mean total recovery in dialysate following a haemodialysis session was 38% and 53% for meropenem and vaborbactam, respectively.

Pharmacotherapeutic group: antibacterials for systemic use, carbapenems, ATC code: J01DH52

Mechanism of action
Meropenem exerts bactericidal activity by inhibiting peptidoglycan cell wall synthesis as a result of binding to and inhibition of activity of essential penicillin-binding proteins (PBPs).

Vaborbactam is a non-beta-lactam inhibitor of class A and class C serine beta-lactamases, including Klebsiella pneumoniae carbapenemase, KPC. It acts by forming a covalent adduct with beta-lactamases and is stable to beta-lactamase-mediated hydrolysis. Vaborbactam does not inhibit class B enzymes (metallo-β-lactamases) or class D carbapenemases. Vaborbactam has no antibacterial activity.

Resistance
Mechanisms of resistance in Gram-negative bacteria that are known to affect meropenem/vaborbactam include organisms that produce metallo-β-lactamases or oxacillinases with carbapenemase activity.

Mechanisms of bacterial resistance that could decrease the antibacterial activity of meropenem/vaborbactam include porin mutations affecting outer membrane permeability and overexpression of efflux pumps.

Antibacterial activity in combination with other antibacterial agents
In vitro studies demonstrated no antagonism between meropenem/vaborbactam and levofloxacin, tigecycline, polymyxin, amikacin, vancomycin, azithromycin, daptomycin or linezolid.

Susceptibility testing break points
Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:

¹For susceptibility testing purposes, the concentration of vaborbactam is fixed at 8 mg/L.

Pharmacokinetic/pharmacodynamic relationship
The antimicrobial activity of meropenem has been shown to best correlate with the percent of the dosing interval during which the free meropenem concentrations in plasma exceed the meropenem minimum inhibitory concentration. For vaborbactam, the PK-PD index associated with antimicrobial activity is the ratio of free vaborbactam plasma AUC: meropenem/vaborbactam MIC.

Clinical efficacy against specific pathogens
Efficacy has been demonstrated in clinical studies against the following pathogens that were susceptible to meropenem/vaborbactam in vitro.

Complicated urinary-tract infections, including pyelonephritis
Gram-negative micro-organisms:

• Escherichia coli
• Klebsiella pneumoniae
• Enterobacter cloacae species complex

Clinical efficacy has not been established against the following pathogens that are relevant to the approved indications although in vitro studies suggest that they would be susceptible to meropenem and/or meropenem/vaborbactam in the absence of acquired mechanisms of resistance.

Gram-negative micro-organisms:

• Citrobacter freundii
• Citrobacter koseri
• Enterobacter aerogenes
• Klebsiella oxytoca
• Morganella morganii
• Proteus mirabilis
• Providencia spp.
• Pseudomonas aeruginosa
• Serratia marcescens

Gram-positive micro-organisms:

• Staphylococcus saprophyticus
• Staphylococcus aureus (methicillin susceptible isolates only)
• Staphylococcus epidermidis (methicillin susceptible isolates only)
• Streptococcus agalactiae

Anaerobic micro-organisms:

• Bacteroides fragilis
• Bacteroides thetaiotaomicron
• Clostridium perfringens
• Peptoniphilus asaccharolyticus
• Peptostreptococcus species (including P. micros, P anaerobius, P. magnus)
• Bacteroides caccae
• Prevotella bivia
• Prevotella disiens

Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with meropenem/vaborbactam in one or more subsets of the paediatric population in the treatment of infections due to Gram-negative bacteria (see section 4.2 for information on paediatric use).

Distribution
The plasma protein binding of meropenem is approximately 2%. The plasma protein binding of vaborbactam is approximately 33%.

The steady-state volumes of distribution of meropenem and vaborbactam in patients were 20.2 L and 18.6 L, respectively, following doses of 2 g meropenem/2 g vaborbactam infused over 3 hours every 8 hours, indicating that both compounds distribute into a volume of distribution consistent with the extracellular fluid compartment.

Both meropenem and vaborbactam penetrate into human bronchial epithelial lining fluid (ELF) with concentrations around 65% and 79% of unbound plasma concentrations of meropenem and vaborbactam, respectively. The concentration time profiles are similar for ELF and plasma.

Biotransformation
Meropenem is mostly eliminated unchanged. About 25% of the administered dose is eliminated as the inactive open ring form.

Vaborbactam does not undergo metabolism.

Elimination
The terminal half-life (t½) is 2.30 hours and 2.25 hours for meropenem and vaborbactam, respectively.

Both meropenem and vaborbactam are primarily excreted via the kidneys. Approximately 40-60% of a meropenem dose is excreted unchanged within 24 - 48 hours with a further 25% recovered as the microbiologically inactive hydrolysis product. The elimination of meropenem by the kidneys resulted in high therapeutic concentrations in urine. The mean renal clearance for meropenem was 7.7 L/h. The mean non-renal clearance for meropenem was 4.8 L/h, which comprises both fecal elimination (~2% of the dose) and degradation due to hydrolysis.

Approximately 75 to 95% of vaborbactam is excreted unchanged in the urine over a 24 - 48 hour period. The elimination of vaborbactam by the kidneys resulted in high concentrations in the urine. The mean renal clearance for vaborbactam was 10.5 L/h.

Linearity/non-linearity
The C_max and AUC of meropenem and vaborbactam are linear across the dose range studied (1 g to 2 g for meropenem and 0.25 g to 2 g for vaborbactam) when administered as a single 3-hour intravenous infusion. There is no accumulation of meropenem or vaborbactam following multiple intravenous infusions administered every 8 hours for 7 days in subjects with normal renal function.

Effect of vaborbactam/meropenem on enzymes and transporters
Neither meropenem nor vaborbactam inhibit CYP450 enzymes in vitro at pharmacologically relevant concentrations.

Both meropenem and vaborbactam do not inhibit renal or hepatic transporters at pharmacologically relevant concentrations.

Special populations
Renal impairment
Pharmacokinetic studies with meropenem and vaborbactam in patients with renal impairment have shown that the plasma clearance of both meropenem and vaborbactam correlates with creatinine clearance.

Hepatic impairment
As meropenem/vaborbactam does not undergo hepatic metabolism, the systemic clearance of meropenem/vaborbactam is not expected to be affected by hepatic impairment.

Elderly
Pharmacokinetic data from a population pharmacokinetic analysis showed a reduction in plasma clearance of meropenem/vaborbactam that correlates with age-associated reduction in creatinine clearance.

Gender and race
In a population pharmacokinetic analysis there was no effect of gender or race on the pharmacokinetics of meropenem and vaborbactam.

Meropenem
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, reproduction toxicity or genotoxicity. Carcinogenicity studies have not been conducted with meropenem.

Vaborbactam
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, reproduction toxicity or genotoxicity. Carcinogenicity studies have not been conducted with vaborbactam.

In repeat dose toxicity studies in dogs, minimal hepatic inflammation was observed after 14 days and 28 days of exposure to vaborbactam alone or combined meropenem/vaborbactam.

-     Sodium carbonate

Vabomere is not chemically compatible with glucose-containing solutions. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Store below 30°C.

Store in the original package.

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

50 ml type I clear glass vials with bromobutyl rubber stoppers and sealed with aluminum flip-off overseals.

Pack size: 6 Vials.

Standard aseptic techniques must be used for solution preparation and administration.

The powder for concentrate for solution for infusion must be reconstituted and further diluted prior to use.

Reconstitution
20 ml of 9 mg/ml (0.9%) sodium chloride solution for injection (normal saline) should be withdrawn from a 250 ml infusion bag of 9 mg/ml (0.9%) sodium chloride solution for injection for each vial and reconstituted with the appropriate number of vials of meropenem/vaborbactam for the corresponding Vabomere dosage:

• Reconstitute 2 vials for Vabomere 2 g/2 g dose
• Reconstitute 1 vial for Vabomere 1 g/1 g and Vabomere 0.5 g/0.5 g doses

After mixing gently to dissolve, the reconstituted meropenem/vaborbactam solution will have an approximate meropenem concentration of 0.05 g/ml and an approximate vaborbactam concentration of 0.05 g/ml. The final volume is approximately 21.3 ml. The reconstituted solution is not for direct injection. The reconstituted solution must be diluted before intravenous infusion.

Dilution
To prepare Vabomere 2 g/2 g dose for intravenous infusion: Immediately after reconstitution of two vials, the entire reconstituted vial contents should be withdrawn from each of the two vials and added back into the 250 ml infusion bag of sodium chloride 9 mg/ml (0.9%) solution for injection (normal saline). The final infusion concentration of meropenem and vaborbactam will be about 8 mg/ml each.

To prepare Vabomere 1 g/1 g dose for intravenous infusion: Immediately after reconstitution of one vial, the entire reconstituted vial contents should be withdrawn from the vial and added back into the 250 ml infusion bag of sodium chloride 9 mg/ml (0.9%) solution for injection (normal saline). The final infusion concentration of meropenem and vaborbactam will be about 4 mg/ml each.

To prepare Vabomere 0.5 g/0.5 g dose for intravenous infusion: Immediately after reconstitution of one vial, 10.5 ml of the reconstituted vial contents should be withdrawn from the vial and added back into the 250 ml infusion bag of 9 mg/ml (0.9%) sodium chloride solution for injection (normal saline). The final infusion concentration of meropenem and vaborbactam will be 2 mg/ml each.

The diluted solution should be inspected visually for particulate matter. The colour of the diluted solution is clear to light yellow.

Following dilution, the infusion should be completed within 4 hours when stored at 20-25°C, or within 22 hours when refrigerated at 2-8°C.

Any unused product or waste material should be disposed of in accordance with local requirements.