1.1. Complicated Urinary Tract Infections, including Pyelonephritis

EXBLIFEP® is indicated for the treatment of patients 18 years of age and older with complicated urinary tract infections (cUTI) including pyelonephritis, caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, and Enterobacter cloacae complex.

1.2. Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of EXBLIFEP and other antibacterial drugs, EXBLIFEP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2.1. Recommended Dosage and Administration

The recommended dosage of EXBLIFEP is 2.5 grams (2 grams cefepime and 0.5 grams enmetazobactam) administered every 8 hours by intravenous (IV) infusion over 2 hours in patients 18 years of age and older with an estimated glomerular filtration rate (eGFR) between 60 and 129 mL/min. The duration of treatment is 7 days and up to 14 days for patients with concurrent bacteremia.

2.2. Recommended Dosage in Patients (18 Years of Age and Older) Based on Renal Function

The recommended dosage of EXBLIFEP in patients 18 years of age and older with varying degrees of renal function is described in Table 1 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. For patients with changing renal function, monitor serum creatinine concentrations and eGFR at least daily and adjust the dosage of EXBLIFEP accordingly [see Use in Specific Populations (8.6)].

2.3. Preparation of EXBLIFEP for Intravenous Infusion Administration

2.4. Drug Compatibility

EXBLIFEP is compatible with 0.9% Sodium Chloride Injection, 5% Dextrose injection, and 2.5% Dextrose and 0.45% Sodium Chloride.

Compatibility of EXBLIFEP solution for administration with other drugs has not been established.

5.1. Hypersensitivity Reactions

Hypersensitivity reactions have been reported in patients treated with EXBLIFEP [see Adverse Reactions (6.1)]. Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis, and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs [see Contraindications (4)]. Before therapy with EXBLIFEP is instituted, carefully inquire about previous hypersensitivity reactions to cefepime, cephalosporins, penicillins, or other beta-lactams because cross-hypersensitivity among beta-lactam antibacterial drugs has been reported. If an allergic reaction to EXBLIFEP occurs, discontinue the drug and institute appropriate supportive measures.

5.2. Neurotoxicity

Neurotoxicity has been reported during treatment with cefepime, a component of EXBLIFEP, including life-threatening or fatal occurrences of the following: encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), aphasia, myoclonus, seizures, and nonconvulsive status epilepticus [see Adverse Reactions (6.2)]. Most cases occurred in patients with renal impairment who did not receive appropriate dosage adjustment. However, some cases of neurotoxicity occurred in patients receiving a dosage adjustment appropriate for their degree of renal impairment. In the majority of cases, symptoms of neurotoxicity were reversible and resolved after discontinuation of cefepime and/or after hemodialysis. If neurotoxicity associated with EXBLIFEP therapy occurs, discontinue EXBLIFEP and institute appropriate supportive measures.

5.3. Clostridioides difficile-associated Diarrhea

Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including EXBLIFEP, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.4. Positive Direct Coombs' Tests

Positive direct Coombs' tests with or without hemolysis have been reported during treatment with cefepime, a component of EXBLIFEP. In patients who develop hemolytic anemia, discontinue the drug and institute appropriate therapy. Positive Coombs' test may be observed in newborns whose mothers have received cephalosporin antibacterial drugs before parturition.

5.5. Prolonged Prothrombin Time

Many cephalosporins, including cefepime, a component of EXBLIFEP, have been associated with a decrease in prothrombin activity. Those at risk of developing a prolonged prothrombin time include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy. Prothrombin time should be monitored in patients at risk, and exogenous vitamin K administered as indicated.

5.6. Development of Drug-Resistant Bacteria

Prescribing EXBLIFEP in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

5.7. Interactions with Urine Glucose Testing

The administration of cefepime, a component of EXBLIFEP, may result in a false-positive reaction for glucose in the urine when using some methods (e.g., ClinitestTM tablets) [see Drug Interactions (7.3)].

6.1. Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

EXBLIFEP was evaluated in a phase 3 comparator-controlled clinical trial in cUTI, including pyelonephritis (also referred to as Trial 1), which included 516 patients treated with EXBLIFEP 2.5 grams (2 grams cefepime and 0.5 grams enmetazobactam) every 8 hours infused over 2 hours, and 518 patients treated with the comparator piperacillin/tazobactam 4.5 grams (4 grams piperacillin and 0.5 grams tazobactam) every 8 hours infused over 2 hours. No switch to oral therapy was permitted. Patients were to receive treatment for 7 days; those with baseline bacteremia could receive up to 14 days of treatment. The mean duration of therapy was 8 days in both treatment groups.

The mean age of patients treated with EXBLIFEP was 55 years and 40% of patients were 65 years of age or older. Patients were predominantly female (54%) and White (94%). Most patients were enrolled in Europe (93%).

6.2. Postmarketing Experience

The following adverse reactions and altered laboratory tests have been identified during post-approval use of cefepime or other cephalosporin-class antibacterial drugs. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

Blood and lymphatic system disorders: Agranulocytosis, aplastic anemia, hemolytic anemia, pancytopenia

Nervous system disorders: Encephalopathy (including disturbance of consciousness, hallucinations, stupor, and coma), aphasia, myoclonus, seizures, and nonconvulsive status epilepticus

Immune system disorders: Anaphylaxis including anaphylactic shock, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis

Hepatobiliary disorders: Hepatic dysfunction including cholestasis

Renal and urinary disorders: Renal dysfunction, toxic nephropathy

Vascular disorders: Hemorrhage

7.1. Aminoglycosides

Monitor renal function if aminoglycosides are to be administered with EXBLIFEP because of the increased potential of nephrotoxicity and ototoxicity of aminoglycoside antibacterial drugs.

7.2. Diuretics

Monitor renal function when EXBLIFEP is concomitantly administered with potent diuretics. Nephrotoxicity has been reported following concomitant administration of other cephalosporins with potent diuretics such as furosemide.

7.3. Drug/Laboratory Test Interactions

It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used in patients using EXBLIFEP. The administration of EXBLIFEP may result in a false-positive reaction for glucose in the urine with certain methods [see Warning and Precautions (5.7)].

8.1. Pregnancy

8.2. Lactation

8.4. Pediatric Use

The safety and effectiveness of EXBLIFEP in pediatric patients (younger than 18 years of age) have not been established.

8.5. Geriatric Use

Of the 516 patients treated with EXBLIFEP in the cUTI trial (Trial 1), 204 (40%) patients were 65 years of age and older, while 78 (15%) patients were 75 years of age and older. No overall differences in safety or effectiveness were observed between these patients and younger adult patients, and other reported clinical experience has not identified differences in responses between the elderly and younger adult patients.

Serious neurologic adverse reactions have occurred in geriatric patients with renal insufficiency given unadjusted doses of cefepime, a component of EXBLIFEP including life-threatening or fatal occurrences of the following: encephalopathy, myoclonus, and seizures [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].

No dosage adjustment based on age is required. EXBLIFEP is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored as appropriate. Dosage adjustment for elderly patients should be based on renal function. [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3).

8.6. Renal Impairment

Cefepime and enmetazobactam, the components of EXBLIFEP, are primarily renally excreted. Plasma exposures of both cefepime and enmetazobactam increase with decreasing renal function, therefore dosage adjustments are recommended to compensate for the slower rate of renal clearance in patients with eGFR less than 60 mL/min [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

In patients with eGFR greater than or equal to 130 mL/min, plasma exposures of cefepime and enmetazobactam are decreased. Therefore, dosage adjustments are recommended to compensate for the higher rate of renal clearance in these patients [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

Both cefepime and enmetazobactam are hemodialyzable; thus, EXBLIFEP should be administered after intermittent hemodialysis on hemodialysis days [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

Monitor renal function regularly and adjust the dosage of EXBLIFEP accordingly as renal function may change during the course of therapy.

12.1. Mechanism of Action

EXBLIFEP is an antibacterial drug [see Microbiology (12.4)].

12.2. Pharmacodynamics

Similar to other beta-lactam antibacterial drugs, the percentage of time that unbound plasma concentrations of cefepime exceed the cefepime-enmetazobactam minimum inhibitory concentration (MIC) against the infecting organism has been shown to best correlate with efficacy in animal and in vitro models of infection. The percentage of time that enmetazobactam concentrations exceed a threshold concentration is the index that best predicts efficacy of enmetazobactam in combination with cefepime in animal and in vitro models of infection.

12.3. Pharmacokinetics

12.4. Microbiology

13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1. Complicated Urinary Tract Infections, including Pyelonephritis

A total of 1041 adults with cUTI, including pyelonephritis, were randomized in a 1:1 ratio into in a multinational, double blind, noninferiority trial (Trial 1, NCT03687255), comparing EXBLIFEP (2 grams cefepime and 0.5 grams enmetazobactam) to piperacillin/tazobactam (4 grams piperacillin and 0.5 grams tazobactam) both administered intravenously every 8 hours (infused over 2 hours) for 7 days, or up to 14 days for patients with concurrent bacteremia. No switch from IV to oral antibacterial therapy was permitted.

The microbiological modified intent-to-treat population (mMITT) was the primary efficacy analysis population and included all randomized patients who received any study drug and had at least 1 baseline gram-negative pathogen ≥105 colony-forming-units (CFU)/mL in urine culture or the same pathogen in blood and urine cultures that is not resistant to cefepime/enmetazobactam or piperacillin/tazobactam (defined as MIC ≤ 8/8 mcg/mL or MIC ≤ 64/4 mcg/mL, respectively). A total of 345 and 333 patients were included in the mMITT population in EXBLIFEP and piperacillin/tazobactam treatment groups, respectively.

Patient demographic and baseline characteristics were balanced between treatment groups in the mMITT population. Approximately 95% of patients were Caucasian and 60% were female in both treatment groups. The mean age was 54 years with 38% and 31% of patients greater than 65 years of age in the EXBLIFEP and piperacillin/tazobactam treatment groups, respectively. Mean body mass index was approximately 26.5 kg/m2 in both treatment groups. Concomitant bacteremia was identified in 38 (11%) and 28 (8%) patients at baseline in the EXBLIFEP and piperacillin/tazobactam treatment groups, respectively. The proportion of patients with diabetes mellitus at baseline was 16% and 12% in the EXBLIFEP and piperacillin/tazobactam treatment groups, respectively. The majority of patients (93%) were enrolled from Europe. Overall, in both treatment groups, 51% of patients had pyelonephritis and 49% had cUTI, with 27% and 22% of patients having a non-removable and removable source of infection, respectively. Mean duration of treatment in both treatment groups was 8 days.

EXBLIFEP demonstrated efficacy with regard to composite response, defined as clinical cure and microbiological response, at the Test of Cure (TOC) visit (7 days after the end of treatment) in the mMITT population as shown in Table 7. Clinical cure was defined as the complete resolution (or return to premorbid state) of the baseline signs and symptoms of cUTI or pyelonephritis that were present at Screening (and no new urinary symptoms or worsening of symptoms). Microbiological response was defined as the baseline qualifying Gram-negative pathogen(s) reduced to <103 colony-forming units/mL in urine culture and a negative blood culture for a Gram-negative pathogen that was identified as a uropathogen (if repeated after positive baseline blood culture).

Composite response in patients with bacteremia at baseline was achieved in 27/38 (71%) patients in the EXBLIFEP group and 14/28 (50%) patients in the piperacillin/tazobactam group at the TOC visit in the mMITT population.

Composite response (microbiological and clinical cure) rates by pathogen for the m-MITT population are presented in Table 8.

In a subset of the E. coli and K. pneumoniae isolates, genotypic testing identified certain ESBL groups (e.g., TEM, CTX-M, SHV and OXA) in both treatment groups of the cUTI Trial 1. The proportion of patients with composite response at TOC was 56/76 (74%) and 34/66 (52%) in the EXBLIFEP group, and the piperacillin/tazobactam group, respectively, in patients with ESBL- producing bacteria at baseline.

A sensitivity analysis where patients with organisms resistant to piperacillin/tazobactam, according to the current FDA breakpoints (defined as MIC >16/4 mcg/mL for Enterobacterales and >64/4 mcg/mL for P. aeruginosa) and one patient with Stenotrophomonas maltophilia were excluded from the mMITT population, demonstrated similar efficacy results as in the mMITT population.

Serious Allergic Reactions

Advise patients that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. Advise patients to discontinue EXBLIFEP and seek immediate medical attention if allergic reactions occur [see Warnings and Precautions (5.1)].

Neurotoxicity

Advise patients of neurological adverse reactions that could occur with EXBLIFEP use. Instruct patients or their caregivers to inform their healthcare provider at once of any neurological signs and symptoms, including encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), aphasia (disturbance of speaking and understanding spoken and written language), myoclonus, seizures and nonconvulsive status epilepticus [see Warnings and Precautions (5.2)].

Potentially Serious Diarrhea

Diarrhea is a common problem caused by antibacterial drugs, which usually ends when the antibacterial drug is discontinued. Inform patient that they may develop watery and bloody stools (with or without stomach cramps and fever) during treatment and as late as two or more months after having taken the last dose of the antibacterial drug. Inform patients that they should contact their physician as soon as possible if this occurs [see Warnings and Precautions (5.3)].

Antibacterial Resistance

Counsel patients that antibacterial drugs, including EXBLIFEP, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). Patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed [see Warnings and Precautions (5.6)].

Manufactured for: Allecra Therapeutics SAS, 68300 Saint Louis, France