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. To reduce the development of drug-resistant bacteria and maintain the effectiveness of EXBLI...
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. The recommended dosage of EXBLIFEP in pa...
EXBLIFEP 2.5 grams (cefepime and enmetazobactam) for injection is supplied as a white to off-white sterile powder for reconstitution in single-dose, clear glass vials sealed with a rubber stopper (not made with natural rubber latex) and an aluminum overseal. Each vial is supplied in cartons of 10 vials (NDC 83289-101-02). Each vial contains 2 grams of cefepime and 0.5 grams of enmetazobactam. Store EXBLIFEP vials ...
www.fda.gov/medwatchwww.fda.gov/STICEXBLIFEP® 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.
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.
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.
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)].
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| eGFRa (mL/min) | Recommended Dosage Regimen for EXBLIFEP (cefepime and enmetazobactam)b | Dosing Interval | Infusion Time |
| Greater than or equal to 130 | EXBLIFEP 2.5 grams (2 grams cefepime and 0.5 grams enmetazobactam) | Every 8 hours | 4 hours |
| 90 to 129 | EXBLIFEP 2.5 grams (2 grams cefepime and 0.5 grams enmetazobactam) | Every 8 hours | 2 hours |
| 60 to 89 | EXBLIFEP 2.5 grams (2 grams cefepime and 0.5 grams enmetazobactam) | Every 8 hours | 2 hours |
| 30 to 59 | EXBLIFEP 1.25 grams (1 gram cefepime and 0.25 grams enmetazobactam) | Every 8 hours | 2 hours |
| 15 to 29 | EXBLIFEP 1.25 grams (1gram cefepime and 0.25 grams enmetazobactam) | Every 12 hours | 2 hours |
| less than 15 or receiving intermittent hemodialysisc | Loading dose of EXBLIFEP 1.25 grams (1 gram cefepime and 0.25 grams enmetazobactam) on the first day of treatment, followed by EXBLIFEP 0.625 grams (0.5 grams cefepime and 0.125 grams enmetazobactam) | Every 24 hours | 2 hours |
Preparation
EXBLIFEP is supplied as a dry powder in a single-dose vial that must be reconstituted and further diluted prior to intravenous infusion as outlined below. EXBLIFEP does not contain preservatives. Aseptic technique must be used for reconstitution and dilution. Prepare the required dose for intravenous infusion using the steps described below:
| EXBLIFEP (cefepime and enmetazobactam) Dose | Number of Vials to Reconstitute for Further Dilution | Volume to Withdraw from Each Reconstituted Vial for Further Dilution | Volume of Infusion Bag |
|---|---|---|---|
| 2.5 grams (2 grams cefepime and 0.5 grams enmetazobactam) | 1 vial | Entire contents (approximately 13 mL) | 250 mL |
| 1.25 grams (1 gram cefepime and 0.25 grams enmetazobactam) | 1 vial | Partial contents (6.5 mL) | 250 mL |
| 0.625 grams (0.5 grams cefepime and 0.125 grams enmetazobactam) | 1 vial | Partial contents (3.3 mL) | 250 mL |
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.
EXBLIFEP 2.5 grams (cefepime and enmetazobactam) for injection, is supplied as a white to off-white sterile powder for reconstitution in single-dose vials, containing 2 grams cefepime and 0.5 grams enmetazobactam.
EXBLIFEP is contraindicated in patients with a history of serious hypersensitivity reactions to the components of EXBLIFEP (cefepime and enmetazobactam) or other beta-lactam antibacterial drugs [see Warnings and Precautions (5.1)].
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.
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.
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.
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.
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.
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.
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)].
The following adverse reactions are discussed in greater detail in the Warnings and Precautions section:
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%).
Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation
Treatment was discontinued due to adverse reactions in 3% (13/516) of patients receiving EXBLIFEP and in 2% (10/518) of patients receiving piperacillin/tazobactam. The most common adverse reactions leading to discontinuation of EXBLIFEP were hypersensitivity, nausea, and increased transaminases, each 0.4% (2/516). The other adverse reactions resulting in discontinuation of EXBLIFEP were abdominal pain, bacterial infection, chest pain, eructation, fungal infection, gastroenteritis, headache, insomnia, pneumonia, restlessness, and urinary retention, each 0.2% (1/516). Death was reported in 3 (0.6%) patients who received EXBLIFEP and in 3 (0.6%) patients who received piperacillin/tazobactam.
Common Adverse Reactions
The most frequently reported adverse reactions (5% or greater) in patients receiving EXBLIFEP were transaminases increased, bilirubin increased, headache, and phlebitis/infusion site reactions. Table 3 lists selected adverse reactions occurring in 1% or greater of patients receiving EXBLIFEP in Trial 1.
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Adverse Reactions | EXBLIFEP (N=516) N (%) | Piperacillin/Tazobactam (N=518) N (%) |
| Transaminases increaseda | 101 (20) | 103 (20) |
| Bilirubin increasedb | 36 (7) | 21 (4) |
| Headachec | 26 (5) | 12 (2) |
| Phlebitis/Infusion site reactionsd | 24 (5) | 2 (<1) |
| Diarrhea | 21 (4) | 26 (5) |
| Anemiae | 16 (3) | 16 (3) |
| Hypersensitivityf | 10 (2) | 3 (<1) |
| Vomiting | 9 (2) | 6 (1) |
| Nausea | 6 (1) | 3 (<1) |
Other Adverse Reactions Associated With EXBLIFEP
The following selected adverse reactions were reported in EXBLIFEP-treated patients at a rate of less than 1% in Trial 1:
Blood and lymphatic system disorders: eosinophilia, partial thromboplastin time prolonged, thrombocytopenia
Gastrointestinal Disorders: eructation
Infections and Infestations: Clostridioides difficile colitis
Laboratory Investigations: alkaline phosphatase increased
Vascular Disorders: epistaxis
Metabolism and nutrition disorders: hypocalcemia, hyperkalemia
Nervous System Disorders: dizziness
Psychiatric Disorders: restlessness
Renal and urinary disorders: blood urea nitrogen increased, blood creatinine increased
Other Adverse Reactions Associated with Cefepime in Other Clinical Trials
Additionally, adverse reactions reported with cefepime alone in other clinical trials that were not reported in the EXBLIFEP-treated patients in Trial 1 are listed below:
Infections and infestations: oral candidiasis, vaginitis
Blood and lymphatic system disorders: Coombs' test positive (without hemolysis), prothrombin time prolonged, leukopenia, neutropenia
General disorders and administration site conditions: pyrexia,
Laboratory Investigations: increased calcium, increased phosphorus, decreased phosphorus
Laboratory Changes Associated with EXBLIFEP
The incidence of patients with increases in ALT, AST, or total bilirubin laboratory values greater than specified levels is presented in Table 4.
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Laboratory Parameter | EXBLIFEP (N=516) n/Nw (%) | Piperacillin/Tazobactam (N=518) n/Nw (%) |
| Alanine aminotransferase (U/L) | ||
| >3x ULN | 14/514 (3) | 6/515 (1) |
| Aspartate aminotransferase (U/L) | ||
| >3x ULN | 11/514 (2) | 6/515 (1) |
| Bilirubin, total (mg/dL) | ||
| >2x ULN | 2/514 (<1) | 7/515 (1) |
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
Monitor renal function if aminoglycosides are to be administered with EXBLIFEP because of the increased potential of nephrotoxicity and ototoxicity of aminoglycoside antibacterial drugs.
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.
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)].
Risk Summary
There are no available data with the use of EXBLIFEP, or enmetazobactam during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Available data from published observational studies and case reports over several decades with cephalosporin use, including cefepime, in pregnant women have not established drug-associated risks of major birth defects, miscarriage or adverse maternal or fetal outcomes (see Data ).
Cefepime
Cefepime was not associated with adverse developmental outcomes in rats, mice, or rabbits when administered parenterally during organogenesis. The doses used in these studies were 1.6 (rats), approximately equal to (mice), and 0.3 times (rabbits) the maximum recommended human dose (MRHD) (see Data ).
Enmetazobactam
Intravenous administration of enmetazobactam to pregnant rats and rabbits during organogenesis was associated with maternal toxicity and reduced fetal weights, but not fetal malformations at approximately 7 times and 11 times, respectively, the MRHD (1.5 g/day).
Intravenous administration of enmetazobactam to pregnant rats during organogenesis through lactation resulted in reduction of maternal body weights and reduced fetal body weights and delayed pinna detachment in first-generation offspring in the absence of any other adverse effects on the survival, growth, and development of first- and second-generation offspring at exposures 7-times the MRHD (see Data ).
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Human Data
Cefepime
While available studies cannot definitively establish the absence of risk, published data from case-control studies and case reports over several decades have not identified an association with cephalosporin use, including cefepime, during pregnancy and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups.
Animal Data
Cefepime
Cefepime was not embryocidal and did not cause fetal malformations when administered parenterally during the period of organogenesis to rats at doses up to 1000 mg/kg/day, to mice at doses up to 1200 mg/kg/day, or to rabbits at doses up to 100 mg/kg/day. These doses are 1.6 times (rats), approximately equal to (mice), and 0.3 times (rabbits) the maximum recommended clinical dose based on body surface area.
Enmetazobactam
Enmetazobactam was administered to pregnant rats in intravenous doses of 125, 250, and 500 mg/kg/day during the period of organogenesis from Gestation Day (GD) 6 through GD 17. Maternal weight gain was reduced at 500 mg/kg/day (approximately 7 times the MRHD based on plasma AUC comparison). No fetal malformations were observed with any dose of enmetazobactam, but fetal weights were reduced in the high-dose group. The dose at which no maternal or fetal toxicity occurred was 250 mg/kg/day (approximately 3 times the MRHD based on plasma AUC comparison).
Enmetazobactam was administered intravenously to pregnant rabbits in doses of 50, 150, and 300 mg/kg/day during the period of organogenesis from GD 7 through GD 19. Maternal body weight gains were reduced in the mid- and high-dose groups (approximately 11 and 25 times the MRHD respectively based on plasma AUC comparison). No fetal malformations were observed, but the mean values for total litter weights and fetal weights were decreased in the mid- and high-dose groups, and mean placental weights were decreased in the high-dose group. The dose at which no maternal or fetal toxicity occurred was 50 mg/kg/day (approximately 3-times the MRHD based on plasma AUC comparison).
In a pre-postnatal study, enmetazobactam was administered intravenously to pregnant rats from GD 6 through the lactation period until Lactation Day 20 in maternal doses of 125, 250, and 500 mg/kg/day. Maternal body weights and the body weights of first-generation offspring were reduced, and pinna detachment in first-generation off-spring was delayed with the maternal dose of 500 mg/kg/day (approximately 7-times the MRHD based on plasma AUC comparison). No other adverse effects on the survival, development, behavior, or reproduction of first-generation offspring occurred with any of the maternal enmetazobactam doses up to 500 mg/kg/day. The survival, growth and development of second-generation offspring were not adversely affected by maternal enmetazobactam doses up to 500 mg/kg/day (approximately 7-times the MRHD based on plasma AUC comparison). The dose at which no maternal toxicity or toxicity in first-generation offspring occurred was 250 mg/kg/day (approximately 3-times the MRHD based on plasma AUC comparison). No adverse effects occurred in second-generation offspring at 500 mg/kg/day (approximately 7-times the MRHD based on plasma AUC comparison).
Risk Summary
Cefepime
Cefepime is present in human breast milk at low concentrations (approximately 0.5 mcg/mL) following a single intravenous dose of 1000 mg. A nursing infant consuming approximately 1000 mL of human milk per day would receive approximately 0.5 mg of cefepime per day (see Data).
Enmetazobactam
Enmetazobactam was present in the milk of lactating rats (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. There is no information regarding the effects of cefepime, enmetazobactam or their combination on the breastfed infant or on milk production.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for EXBLIFEP and any potential adverse effects on the breastfed child from EXBLIFEP or from the underlying maternal condition.
Data
Human Data
Cefepime
A pharmacokinetic study was conducted in 9 healthy lactating women to evaluate the concentrations of cefepime in plasma and breast milk following a single intravenous dose of 1000 mg. The mean breast milk concentrations of cefepime during the first 8 hours post-dose were approximately 0.5 mcg/mL and then declined and became undetectable between 12- and 24-hours post-dose. The mean cumulative breast milk excretion of cefepime over 24 hours was 0.01% of the administered dose. The pharmacokinetics of cefepime are similar between lactating and non-lactating women.
Animal Data
Enmetazobactam
In a pharmacokinetic study in rats intended to assess the potential for enmetazobactam secretion into milk, 5 pregnant rats were administered 500 mg/kg/day enmetazobactam by intravenous bolus from Gestation Day (GD) 6 through the day of birth and the subsequent lactation period until Lactation Day (LD) 20. On LD 14, lactation milk was collected 30 minutes after dosing from the 5 maternal rats, and enmetazobactam was measured. Concentrations of enmetazobactam in rat milk ranged from 34 to 317 mcg/ml which is approximately equivalent to 2.6% to 24% of the highest plasma concentrations. The concentration of enmetazobactam in animal milk does not necessarily predict the concentration of drug in human milk.
The safety and effectiveness of EXBLIFEP in pediatric patients (younger than 18 years of age) have not been established.
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).
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.
Patients who receive an overdose should be carefully observed and given supportive treatment.
Cefepime and enmetazobactam can be removed by hemodialysis [see Clinical Pharmacology (12.3)]. No clinical information is available on the use of hemodialysis to treat EXBLIFEP overdosage.
Symptoms of overdose include encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures, neuromuscular excitability and nonconvulsive status epilepticus [see Warnings and Precautions (5.2), Adverse Reactions (6.2), and Dosage and Administration (2.2)].
EXBLIFEP (cefepime and enmetazobactam) for injection is a combination product that contains cefepime, a cephalosporin antibacterial drug, and enmetazobactam, a beta-lactamase inhibitor, for intravenous administration.
Cefepime, present as cefepime hydrochloride monohydrate, is a white to pale yellow powder. The chemical name for cefepime is (6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-3-((1-methylpyrrolidinium-1-yl)methyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate. The empirical formula of cefepime hydrochloride monohydrate is C19H24N6O5S2·2HCl·H2O, the molecular weight is 571.50, and its chemical structure is:
Figure 1: Structure of Cefepime
Enmetazobactam is a white to off-white powder, with a molecular weight of 314.38. The chemical name for enmetazobactam is (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide. Its empirical formula is C11H14N4O5S and its chemical structure is:
Figure 2: Structure of Enmetazobactam
EXBLIFEP 2.5 grams (cefepime and enmetazobactam) for injection is supplied as a white to off-white sterile powder for reconstitution. Each vial contains 2 grams of cefepime (equivalent to 2.3 g of cefepime hydrochloride), 0.5 grams of enmetazobactam, and 1.414 grams of L-arginine.
EXBLIFEP is an antibacterial drug [see Microbiology (12.4)].
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.
Cardiac Electrophysiology
At approximately 12 times the peak enmetazobactam concentrations of the maximum recommended dosing regimen of EXBLIFEP, clinically significant QTc interval prolongation was not observed.
Pharmacokinetic (PK) Parameters
The pharmacokinetic properties of cefepime and enmetazobactam are summarized in Table 5 as mean (SD) in patients with cUTI and eGFR greater than or equal to 60 mL/min.
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| Pharmacokinetic Parameters | Cefepime | Enmetazobactam |
| Exposure | ||
| Cmax (μg/mL)1 | 99.8 (26.4) | 19.8 (6.3) |
| AUClast (μg•h/mL)1 | 379.5 (123.3) | 75.3 (30.8) |
| Distribution | ||
| % Bound to human plasma protein | 20% | Negligible |
| Vss (L) | 20.02 (6.44) | 25.26 (9.97) |
| Proportionality | Exposure approximately proportional to dose following IV administration | |
| Accumulation | Similar pharmacokinetics following single and multiple dosing | |
| Elimination | ||
| CL (L/h) | 5.8 (1.9) | 7.6 (2.9) |
| T1/2 (h) | 2.7 (1.1) | 2.6 (1.1) |
| Metabolism 2 | Minimally metabolized | |
| Excretion | ||
| Major route of elimination | Renal | |
| % Excreted unchanged in urine | 85% | 90% |
Specific Populations
No clinically significant differences in the pharmacokinetics of cefepime or enmetazobactam were observed based on age (18 – 94 years), gender, or weight (45 – 135 kg). There was insufficient information to evaluate the effect of race on the pharmacokinetics of cefepime or enmetazobactam.
Patients with Renal Impairment
In a single-dose trial evaluating the effect of renal impairment on the pharmacokinetics of cefepime and enmetazobactam, dose-normalized systemic exposures of cefepime and enmetazobactam were higher at all levels of renal impairment compared to healthy subjects with CLcr greater than or equal to 90 mL/min (Table 6). In subjects with creatinine clearance (CLcr) < 15 mL/min on hemodialysis, the fraction of the dose removed by hemodialysis was 0.30 and 0.35 for cefepime and enmetazobactam, respectively [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].
| Pharmacokinetic Parameters | Cefepime | Enmetazobactam |
| ≥60 to <90 | 1.9 | 1.8 |
| ≥30 to <60 | 3 | 3 |
| ≥15 to <30 | 5.3 | 5.3 |
| <15 | 12 | 11 |
Patients with eGFR 130 mL/min or Greater
Increased cefepime and enmetazobactam clearance have been observed in patients with eGFR of 130 mL/min or greater. An EXBLIFEP (2 g cefepime and 0.5 g enmetazobactam) dose every 8 h infused over 4 hours provided cefepime and enmetazobactam exposures comparable to those in patients with eGFR 90 to 129 mL/min who received EXBLIFEP (2 g cefepime and 0.5 g enmetazobactam) dose every 8 h over 2 hours [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].
Patients with Hepatic Impairment
Cefepime and enmetazobactam are primarily cleared renally; therefore, hepatic impairment is not likely to have a significant effect on cefepime or enmetazobactam exposures.
Drug Interactions
Clinical Studies
No drug-drug interactions were observed among cefepime, enmetazobactam and piperacillin in a clinical study in healthy subjects.
In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically
Cytochrome P450 (CYP) Enzymes: At therapeutic plasma concentrations, enmetazobactam does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. Enmetazobactam inhibits CYP2E1. Enmetazobactam does not induce CYP1A2, CYP2B6, or CYP3A4.
Membrane Transporter Systems: Enmetazobactam is not a substrate of P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, BSEP, OAT1, OAT3, MATE1, or MATE2-K. In vitro data also indicated that enmetazobactam did not inhibit P-gp, MATE1, MATE2-K, OATP1B1, OATP1B3, OCT1, OAT3, BSEP, MRP3, MRP4 and NTCP.
No in vitro CYP450 enzyme or membrane transporter drug interaction studies were conducted with cefepime.
Mechanism of Action
The cefepime component of EXBLIFEP is a cephalosporin antibacterial drug. The bactericidal action of cefepime results from the inhibition of cell wall synthesis. Cefepime penetrates the cell wall of most gram-positive and gram-negative bacteria to bind penicillin-binding protein (PBP) targets. Cefepime is stable to hydrolysis by some beta-lactamases, including penicillinases and cephalosporinases produced by gram-negative and gram-positive bacteria, with the exception of extended spectrum beta-lactamases (ESBL), some oxacillinases, and carbapenem hydrolyzing beta-lactamases.
The enmetazobactam component of EXBLIFEP is a beta-lactamase inhibitor that protects cefepime from degradation by certain serine beta-lactamases such as ESBL.
Resistance
Mechanisms of resistance to EXBLIFEP may include the production of beta-lactamases that are not inhibited by enmetazobactam, modification of PBPs by target alteration, overexpression of efflux pumps, and outer membrane porin mutations.
Clinical isolates may produce multiple beta-lactamases, express varying levels of beta-lactamases, or have amino acid sequence variations, and other resistance mechanisms that have not been identified.
Culture and susceptibility information and local epidemiology should be considered in selecting or modifying antibacterial therapy.
Cefepime-enmetazobactam demonstrated in vitro activity against Enterobacterales in the presence of some beta-lactamases and extended-spectrum beta-lactamases (ESBL) of the following groups: CTX-M, SHV, TEM, and VEB. EXBLIFEP is not active against bacteria that produce KPC, metallo-beta-lactamases or some oxacillinases (OXA). Cefepime is inherently stable to hydrolysis by some AmpC cephalosporinases and OXA-48.
In the Phase 3 cUTI trial with EXBLIFEP, some isolates of Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae species complex, Citrobacter braakii, Citrobacter freundii, and Proteus mirabilis, that produced beta-lactamases had a minimum inhibitory concentration ≤4 μg/mL for EXBLIFEP. These isolates carried genes for one or more beta-lactamases of the following enzyme groups: CTX-M, TEM, SHV, VEB, CMY, and OXA-48.
In the Phase 3 cUTI trial with EXBLIFEP, some beta-lactamases were also produced by isolates of K. pneumoniae and an isolate of E. cloacae that had a minimum inhibitory concentration ≥16 mcg/mL for EXBLIFEP. The K. pneumoniae isolates contained genes for NDM-1, OXA-48, or KPC-3 along with CTX-M, CMY, TEM, and/or SHV. The E. cloacae isolate encoded CTX-M.
No cross-resistance with other non-beta-lactam classes of antimicrobials has been identified. Some isolates resistant to carbapenems and to cephalosporins may be susceptible to EXBLIFEP.
Interaction with Other Antimicrobials
In vitro synergy studies did not demonstrate antagonism between EXBLIFEP and azithromycin, aztreonam, ceftazidime-avibactam, clindamycin, daptomycin, doxycycline, levofloxacin, linezolid, meropenem, metronidazole, trimethoprim-sulfamethoxazole, or vancomycin.
Activity against Cefepime Non-susceptible Bacteria in Animal Infection Models
Enmetazobactam restored activity of cefepime in animal models of infection (e.g., mouse thigh infection, urinary tract infection, pulmonary infection and sepsis) caused by cefepime-resistant, ESBL-producing (e.g., CTX-M, SHV, TEM) Enterobacterales.
Antimicrobial Activity
EXBLIFEP has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see Indications and Usage (1.1)].
Gram-negative bacteria:
The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for EXBLIFEP against isolates of similar genus or organism group. However, the efficacy of EXBLIFEP in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials. Gram-negative bacteria:
Susceptibility Test Methods
For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: www.fda.gov/STIC.
Carcinogenesis
Long-term carcinogenicity studies have not been performed with cefepime or enmetazobactam.
Mutagenesis
Cefepime
In chromosomal aberration studies, cefepime was positive for clastogenicity in primary human lymphocytes, but negative in Chinese hamster ovary cells. In other in vitro assays (bacterial and mammalian cell mutation, DNA repair in primary rat hepatocytes, and sister chromatid exchange in human lymphocytes), cefepime was negative for genotoxic effects. Moreover, in vivo assessments of cefepime in mice (2 chromosomal aberration and 2 micronucleus studies) were negative for clastogenicity.
Enmetazobactam
Enmetazobactam was negative for genetic toxicity in vitro in a bacterial reverse mutation assay and a chromosomal aberration assay in Chinese Hamster ovary cells, and in vivo in a mouse micronucleus assay in bone marrow cells.
Impairment of Fertility
Cefepime
No untoward effects on fertility were observed in rats when cefepime was administered subcutaneously at doses up to 1000 mg/kg/day (1.6 times the recommended maximum human dose calculated on a mg/m2 basis).
Enmetazobactam
In male and female fertility studies in rats, enmetazobactam was administered intravenously in doses of 125, 250, and 500 mg/kg/day in males for 28 days before mating and for 14 days before the start of the mating period, throughout the mating period, and until Gestation Day (GD) 7 in females. Enmetazobactam had no adverse effect on fertility in either sex and no effect on early embryonic development in female rats at doses up to 500 mg/kg/day, (approximately 7 times in males and 8 times in females the maximum recommended human dose (1.5 g/day) based on plasma AUC comparison).
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).
| Response at the TOC visit | EXBLIFEP n/N (%) | Piperacillin/ Tazobactam n/N (%) | Difference (%) (95% CI)* |
|---|---|---|---|
| |||
| |||
| Composite Response (Clinical Cure and Microbiological Response) | 273/345 (79.1) | 196/333 (58.9) | 21.2 (14.3, 27.9) |
| Clinical Cure | 319/345 (92.5) | 296/333 (88.9) | 3.5 (-1.0, 8.0) |
| Microbiological Response | 286/345 (82.9) | 216/333 (64.9) | 19.0 (12.3, 25.4) |
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.
| Gram-negative Group or Pathogen | EXBLIFEP n/N (%) | Piperacillin/Tazobactam n/N (%) |
|---|---|---|
| Escherichia coli | 220/264 (83) | 151/254 (59) |
| Klebsiella pneumoniae | 23/34 (68) | 18/32 (56) |
| Pseudomonas aeruginosa | 4/13 (31) | 4/11 (36) |
| Proteus mirabilis | 15/19 (79) | 10/19 (53) |
| Enterobacter cloacae complex | 6/7 (86) | 1/3 (33) |
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.
EXBLIFEP 2.5 grams (cefepime and enmetazobactam) for injection is supplied as a white to off-white sterile powder for reconstitution in single-dose, clear glass vials sealed with a rubber stopper (not made with natural rubber latex) and an aluminum overseal. Each vial is supplied in cartons of 10 vials (NDC 83289-101-02).
Each vial contains 2 grams of cefepime and 0.5 grams of enmetazobactam.
Store EXBLIFEP vials refrigerated at 2°C to 8°C (36°F to 46°F); excursions are permitted to 15°C to 25°C (59°F to 77°F) [see USP, Controlled Room Temperature (CRT)]. Keep the vials in the outer carton to protect from light.
Storage conditions for reconstituted and diluted solutions of EXBLIFEP for injection are described in another section of labeling [see Dosage and Administration (2.3)].
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
Principal Display Panel – 2.5 g Carton Label
NDC: 83289-101-02
10 single-dose Vials
EXBLIFEP 2.5 g per vial *
(cefepime and enmetazobactam) for injection
For intravenous infusion after reconstitution and dilution
Single-Dose Vial. Discard Unused Portion
Rx Only
Every source-derived product name is available through these pages.
| Product NDC | Package NDC |
|---|---|
| 83289-101 | 83289-101-02 |
Every source-derived ingredient row is available through these pages.
| Name | UNII | Kind |
|---|---|---|
| cefepime hydrochloride | I8X1O0607P | ACTIM |
| enmetazobactam | 80VUN7L00C | ACTIM |
| arginine | 94ZLA3W45F | IACT |
OpenFDA label data provides additional search and identifier links. DailyMed’s Structured Product Label is the canonical label on FDA.report. Matching records are deduplicated before they are shown below.
| Brand | Generic | Manufacturer | SPL set ID | Effective date | Available safety fields | Join |
|---|---|---|---|---|---|---|
| 26c28132-7b77-4df1-a2ae-96c50892475e | 2da031b1-07ff-48f3-88d2-7e86ba93048a | 2024-02-28 | Warnings, Adverse reactions | 2da031b1-07ff-48f3-88d2-7e86ba93048a |
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