4.1. Therapeutic indications

EXBLIFEP is indicated for the treatment of the following infections in adults (see sections 4.4 and 5.1):

- Complicated urinary tract infections (cUTI), including pyelonephritis

- 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.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2. Posology and method of administration

Posology

For complicated urinary tract infections (cUTI), including pyelonephritis, the recommended dose for patients with normal renal function is 2 g/0.5 g cefepime/enmetazobactam every 8 hours administered as an intravenous infusion over 2 hours.

In patients with augmented renal clearance (eGFR > 150 mL/min) prolongation of the infusion to 4 hours is recommended (see section 5.2).

For hospital-acquired pneumonia (HAP), including ventilator associated pneumonia (VAP), the recommended dose for patients with normal renal function is 2 g/0.5 g cefepime/enmetazobactam every 8 hours administered as an intravenous infusion over 4 hours.

The usual duration of treatment is 7 to 10 days. In general, administration should not be less than 7 days and not longer than 14 days. In patients with bacteraemia treatment up to 14 days may be required.

Special populations

Elderly

No dose adjustment is necessary for the elderly based on age alone (see section 5.2).

Renal impairment

Dose adjustment is recommended in patients with renal impairment who have an absolute estimated glomerular filtration rate (eGFR) less than 60 mL/min (see section 5.2). The recommended dose in patients with varying degrees of renal function is presented in Table 1.

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).

For patients with changing renal function, serum creatinine concentrations and eGFR should be monitored at least daily and the dose of EXBLIFEP adjusted accordingly.

For patients with Hospital-acquired pneumonia (HAP), including ventilator associated pneumonia (VAP), infusion time should be 4 hours regardless of the renal impairment status.

Table 1: Recommended dose of EXBLIFEP in patients with renal impairment

Absolute eGFR (mL/min)

Recommended dose regimen for EXBLIFEP

(cefepime and enmetazobactam)

Dosing interval

Mild (60 - <90)

cefepime 2 g and enmetazobactam 0.5 g

Every 8 hours

Moderate (30- <60)

cefepime 1 g and enmetazobactam 0.25 g

Every 8 hours

Severe (15- <30)

cefepime 1 g and enmetazobactam 0.25 g

Every 12 hours

End stage renal disease (<15)

cefepime 1 g and enmetazobactam 0.25 g

Every 24 hours

Patients requiring hemodialysis

cefepime 1 g and enmetazobactam 0.25 g loading dose on the first day of therapy and cefepime 0.5g and enmetazobactam 0.125 g thereafter (every 24 hours but after the haemodialysis session on haemodialysis days).

Every 24 hours

Patients undergoing continuous ambulatory peritoneal dialysis (CAPD)

cefepime 2 g and enmetazobactam 0.5 g

Every 48 hours

Hepatic impairment

No dose adjustment is necessary in patients with hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy in children below 18 years of age has not yet been established. No data are available.

Method of administration

EXBLIFEP is administered via intravenous infusion.

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 cephalosporin antibacterial agent.

- Severe hypersensitivity (e.g., anaphylactic reaction, severe skin reaction) to any other type of beta-lactam antibacterial agent (e.g., penicillins, carbapenems or monobactams).

4.4. Special warnings and precautions for use

Hypersensitivity reactions

Serious and occasionally fatal hypersensitivity reactions have been reported with cefepime and cefepime-enmetazobactam (see section 4.3 and 4.8).

Patients who have a history of hypersensitivity to other beta-lactam antibiotics may also be hypersensitive to cefepime-enmetazobactam. Before treatment initiation, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to beta-lactam antibiotics (see section 4.3).

Cefepime-enmetazobactan should be administered with caution to patients with a history of asthma or allergic diathesis.

The patient must be carefully monitored during the first administration. If an allergic reaction occurs, treatment must be discontinued immediately and adequate emergency measures must be initiated.

Renal impairment

Dose adjustments should be made in patients with renal impairment who have an absolute eGFR less than 60 mL/min (see section 4.2).

Reversible encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures (including nonconvulsive status epilepticus), and/or renal failure have been reported with cefepime/enmetazobactam when the dose has not been reduced in patients with renal impairment. In some cases, neurotoxicity was reported in patients with renal impairment despite dose adjustments.

Renal function should be monitored carefully if medicinal products with nephrotoxic potential, such as aminoglycosides and potent diuretics, are administered concomitantly with cefepime-enmetazobactam.

Clostridioides difficile associated diarrhoea (CDAD)

CDAD has been reported with cefepime-enmetazobactam, and may range in severity from mild diarrhoea to fatal colitis. CDAD must be considered in patients who present with diarrhoea during or subsequent to the administration of cefepime-enmetazobactam. Discontinuation of therapy with cefepime-enmetazobactam and the use of supportive measures together with the 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 cefepime-enmetazobactam may result in overgrowth of non-susceptible organisms, which may require interruption of treatment or other appropriate measures.

Elderly

No dose adjustment based on age is required. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored.

Limitations of the clinical data

Hospital-acquired pneumonia, including ventilator-associated pneumonia

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

Limitations of the spectrum of antibacterial activity

Cefepime has little or no activity against the majority of Gram-positive organisms and anaerobes (see sections 4.2 and 5.1). Additional antibacterial agents should be used when these pathogens are known or suspected to be contributing to the infectious process.

The inhibitory spectrum of enmetazobactam includes class A extended spectrum β-lactamases (ESBLs). Enmetazobactam does not reliably inhibit the class A carbapenemase Klebsiella pneumoniae carbapenemase (KPC) and does not inhibit class B, class C or class D beta-lactamases. Cefepime is generally stable to hydrolysis by class C AmpC and class D OXA-48 enzymes (see section 5.1).

Interference with serological testing

A positive direct or indirect Coombs test without evidence of haemolysis may develop during treatment with cefepime-enmetazobactam as seen with cefepime.

Cephalosporin antibiotics may produce a false-positive reaction for glucose in the urine with copper reduction tests (Benedict's or Fehling's solution or with Clinitest tablets), but not with enzyme-based tests (glucose oxidase) for glycosuria. Therefore, it is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.

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

No clinical interaction studies have been performed with enmetazobactam. However, based on in vitro studies and considering routes of elimination, the pharmacokinetic interaction potential for enmetazobactam is low.

Concomitant treatment with bacteriostatic antibiotics may interfere with the action of beta-lactam antibiotics. Cephalosporin antibiotics can potentiate the action of coumarin anticoagulants as seen with cefepime.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of cefepime-enmetazobactam in pregnant women.

Animal studies indicate reproductive toxicity at relevant clinical exposure of enmetazobactam but no signs of teratogenicity (see section 5.3). Enmetazobactam should only be used during pregnancy when clearly indicated and only if the benefit for the mother outweighs the risk for the child.

Breast-feeding

Physico-chemical data suggest excretion of cefepime-enmetazobactam in human milk and cefepime-enmetazobactam has been shown to be excreted in milk from rat. A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from cefepime-enmetazobactam therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

The effects of cefepime and enmetazobactam on fertility in humans have not been studied. No impairment of fertility has been seen in male and female rats treated with cefepime or enmetazobactam (see section 5.3).

4.7. Effects on ability to drive and use machines

EXBLIFEP has moderate influence on the ability to drive and use machines.

Possible adverse reactions such as altered state of consciousness, dizziness, confusion or hallucinations may alter the ability to drive and use machines (see sections 4.4, 4.8 and 4.9).

4.8. Undesirable effects

Summary of the safety profile

The most common adverse reactions that occurred in the Phase 3 study were alanine aminotransferase (ALT) increased (4.8%), aspartate aminotransferase (AST) increased (3.5%), diarrhoea (2.9%), and infusion site phlebitis (1.9%). A serious adverse reaction of Clostridioides difficile colititis occurred in 0.2% (1/516).

Tabulated list of adverse reactions

The following adverse reactions have been reported with cefepime alone during clinical studies or post marketing surveillance and/or identified during Phase 2 or/and Phase 3 studies with cefepime-enmetazobactam.

Adverse reactions are classified according to System Organ Class, frequency, preferred term using MedDRA terminology. 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) and not known (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2. Frequency of adverse reactions by system organ class

System organ class

Frequency

MedDRA preferred term (PT)

Infections and infestations

Uncommon

Clostridioides difficile associated diarrhoea (CDAD), oral candidiasisa, vaginal infection

Rare

Candida infectiona

Blood and lymphatic system disorders

Very common

Coombs test positivea

Common

Prothrombin time prolongeda, partial thromboplastin time prolongeda, anaemiaa, eosinophiliaa

Uncommon

Thrombocytopenia, leukopeniaa, neutropeniaa

Not known

Aplastic anaemiab, haemolytic anaemiab, agranulocytosisa

Immune system disorders

Rare

Anaphylactic reactiona, angioedemaa,

dermatitis allergic

Not known

Anaphylactic shocka

Metabolism and nutrition disorders

Not known

Urine glucose false positivea

Psychiatric disorders

Not known

Confusional statea, hallucinationa

Nervous system disorders

Common

Headache

Uncommon

Dizziness

Rare

Convulsiona, paraesthesiaa, dysgeusia

Not known

Comaa, stupora, encephalopathya, altered state of consciousnessa, myoclonusa

Vascular disorders

Common

Infusion site phlebitis

Rare

Vasodilationa

Not known

Haemorrhageb,

Respiratory, thoracic and mediastinal disorders

Rare

Dyspnoeaa

Gastrointestinal disorders

Common

Diarrhoea

Uncommon

Pseudomembranous colitis, colitis, vomiting, nausea,

Rare

Abdominal pain, constipation

Hepatobiliary disorders

Common

Alanine aminotransferase increased, Aspartate aminotransferase increased, Blood bilirubin increased,

Alkaline phosphatase increased

Skin and subcutaneous tissue disorders

Common

Rash

Uncommon

Erythema, urticaria, pruritus

Not known

Toxic epidermal necrolysisb, Stevens- Johnson syndromeb, erythema multiformeb

Renal and urinary disorders

Uncommon

Blood urea increased, blood creatinine increased

Not known

Renal failurea, toxic nephropathyb

Reproductive system and breast disorders

Rare

Vulvovaginal pruritus

General disorders and administration site condition

Common

Infusion site reaction, injection site pain, injection site inflammation

Uncommon

Pyrexiaa, infusion site inflammation

Rare

Chillsa

Investigations

Common

Amylase increased, lipase increased, lactate dehydrogenase increased

a: Adverse reactions reported only with cefepime alone.

b: Adverse reactions that are generally accepted as being attributable to other compounds in the class (class effects).

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

Symptoms

Symptoms of overdose include encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, and seizures (see section 4.8).

Management

Accidental overdosing has occurred when large doses were given to patients with impaired renal function (see sections 4.2 and 4.4).

In case of severe overdose, especially in patients with compromised renal function, haemodialysis will aid in the removal of cefepime and enmetazobactam from the body; peritoneal dialysis is of no value (see section 5.2).