Cefepime and Enmetazobactam

Interactions

Cefepime and Enmetazobactam interacts in the following cases:

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. The recommended dose in patients with varying degrees of renal function is presented in the table below.

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 cefepime/enmetazobactam 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.

Recommended dose of cefepime/enmetazobactam in patients with renal impairment:

Absolute eGFR (mL/min)	Recommended dose regimen for cefepime/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 0.5 g 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

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.

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. Enmetazobactam should only be used during pregnancy when clearly indicated and only if the benefit for the mother outweighs the risk for the child.

Nursing mothers

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.

Carcinogenesis, mutagenesis and fertility

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.

Effects on ability to drive and use machines

Cefepime/enmetazobactam 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.

Adverse reactions

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.

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 candidiasis^a, vaginal infection
Infections and infestations	Rare	Candida infection^a
Blood and lymphatic system disorders	Very common	Coombs test positive^a
	Common	Prothrombin time prolonged^a, partial thromboplastin time prolonged^a, anaemia^a, eosinophilia^a
	Uncommon	Thrombocytopenia, leukopenia^a, neutropenia^a
	Not known	Aplastic anaemia^b, haemolytic anaemia^b, agranulocytosis^a
Immune system disorders	Rare	Anaphylactic reaction^a, angioedema^a, dermatitis allergic
Immune system disorders	Not known	Anaphylactic shock^a
Metabolism and nutrition disorders	Not known	Urine glucose false positive^a
Psychiatric disorders	Not known	Confusional state^a, hallucination^a
Nervous system disorders	Common	Headache
	Uncommon	Dizziness
	Rare	Convulsion^a, paraesthesia^a, dysgeusia
	Not known	Coma^a, stupor^a, encephalopathy^a, altered state of consciousness^a, myoclonus^a
Vascular disorders	Common	Infusion site phlebitis
	Rare	Vasodilation^a
	Not known	Haemorrhage^b
Respiratory, thoracic and mediastinal disorders	Rare	Dyspnoea^a
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 necrolysis^b, Stevens- Johnson syndrome^b, erythema multiforme^b
Renal and urinary disorders	Uncommon	Blood urea increased, blood creatinine increased
Renal and urinary disorders	Not known	Renal failure^a, toxic nephropathy^b
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	Pyrexia^a, infusion site inflammation
	Rare	Chills^a
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).

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