EXBLIFEP Powder for concentrate for solution for infusion Ref.[109327] Active ingredients: Cefepime Cefepime and Enmetazobactam

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 cefepimeenmetazobactam.

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 pharmacokineticpharmacodynamic 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.

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.

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).

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).

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 cefepimeenmetazobactam.

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:

^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 national reporting system listed in Appendix V.

This medicinal product must not be mixed with other medicinal products or solutions except those mentioned in section 6.6.

There is a physical-chemical incompatibility with the following antibiotics: metronidazole, vancomycin, gentamicin, tobramycin sulphate and netilmicin sulphate. Should concomitant therapy be indicated, such agents must be administered separately.