4.1. Therapeutic indications

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.

4.2. Posology and method of administration

Vaborem 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

Type of infection

Dose of Vaborem (meropenem/vaborbactam)2

Frequency

Infusion time

Duration of treatment

Complicated UTI (cUTI), including pyelonephritis

2 g/2 g

Every 8 hours

3 hours

5 to 10 days2

cIAI

2 g/2 g

Every 8 hours

3 hours

5 to 10 days2

Hospital-acquired pneumonia (HAP), including VAP

2 g/2 g

Every 8 hours

3 hours

7 to 14 days

Bacteraemia, in association with, or suspected to be associated with, any of the infections listed above

2 g/2 g

Every 8 hours

3 hours

Duration in accordance with the site of infection

Infections due to aerobic Gram-negative organisms in patients with limited treatment options

2 g/2 g

Every 8 hours

3 hours

Duration in accordance with the site of infection

1 As calculated using the Cockcroft-Gault formula

2 Treatment may continue up to 14 days

Special populations

Elderly

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

CrCl (ml/min)1

Recommended Dosage Regimen2

Dosing Interval

Infusion Time

20 to 39

1 g/1 g

Every 8 hours

3 hours

10 to 19

1 g/1 g

Every 12 hours

3 hours

Less than 10

0.5 g/0.5 g

Every 12 hours

3 hours

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.

Vaborem is administered by intravenous infusion over 3 hours.

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

4.3. Contraindications

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).

4.4. Special warnings and precautions for use

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.

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 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).

Clostridioides difficile-associated diarrhoea

Clostridioides 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 Vaborem (see section 4.8). Discontinuation of therapy with Vaborem and the administration of specific treatment for Clostridioides 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 Vaborem is necessary, supplemental anticonvulsant therapy should be considered (see section 4.5).

Limitations of the clinical data

Complicated intra-abdominal infections

The use of Vaborem 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 Vaborem 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 Vaborem 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 study in which 32 patients were treated with Vaborem 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 β-lactamases. 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.

Controlled sodium diet

Vaborem contains 250 mg of sodium per vial, equivalent to 12,5% of the WHO recommended maximum daily intake of 2 g of sodium for an adult.

4.5. Interaction with other medicinal products and other forms of interaction

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) 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 Vaborem with an oral anticoagulant.

Contraceptives

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

4.6. Fertility, pregnancy and lactation

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).

4.7. Effects on ability to drive and use machines

Vaborem 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.

4.8. Undesirable effects

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 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

(≥1/100 to <1/10)

Uncommon

(≥1/1,000 to <1/100)

Rare

(≥1/10,000 to <1/1,000)

Unknown

(cannot be estimated from the available data)

Infections and infestations

Clostridioides difficile colitis

Vulvovaginal candidiasis

Oral candidiasis

Blood and lymphatic system disorders

Thrombocythaemia

Leucopenia

Neutropenia

Eosinophilia

Thrombocytopenia

Agranulocytosis

Haemolytic anaemia

Immune system disorders

Anaphylactic reaction

Hypersensitivity

Angioedema

Metabolism and nutrition disorders

Hypokalaemia

Hypoglycaemia

Decreased appetite

Hyperkalaemia

Hyperglycaemia

Psychiatric disorders

Insomnia

Hallucination

Delirium

Nervous system disorders

Headache

Tremor

Lethargy

Dizziness

Paraesthesia

Convulsions

Vascular disorders

Hypotension

Phlebitis

Vascular pain

Respiratory, thoracic and mediastinal disorders

Bronchospasm

Gastrointestinal disorders

Diarrhoea

Nausea

Vomiting

Abdominal distension

Abdominal pain

Hepatobiliary disorders

Alanine aminotransferase increased

Aspartate aminotransferase increased

Blood alkaline phosphatase increased

Blood lactate dehydrogenase increased

Blood bilirubin increased

Drug-induced liver injury1

Skin and subcutaneous disorders

Pruritus

Rash

Urticaria

Severe cutaneous adverse reactions (SCAR), such as Toxic epidermal necrolysis (TEN)

Stevens Johnson syndrome (SJS)

Erythema multiforme (EM)

Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)

Acute generalised exanthematous pustulosis (AGEP) (see section 4.4)

Musculoskeletal and connective tissue disorders

Rhabdomyolysis2

Renal and urinary disorders

Renal impairment

Incontinence

Blood creatinine increased

Blood urea increased

General disorders and administration site conditions

Infusion site phlebitis

Pyrexia

Chest discomfort

Infusion site reaction

Infusion site erythema

Injection site phlebitis

Infusion site thrombosis

Pain

Investigations

Blood creatine phosphokinase increased

Direct and indirect Coombs test positive

Injury, poisoning and procedural complications

Infusion related reaction

1 DILI includes hepatitis and liver failure

2 Observed post-marketing with meropenem, a component of Vaborem

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 the Yellow Card Scheme.

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no experience with overdose of Vaborem.

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 Vaborem 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.