EXBLIFEP Solution for injection Ref.[108537] Active ingredients: Cefepime Cefepime and Enmetazobactam

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 lifethreatening 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)].

The following adverse reactions are discussed in greater detail in the Warnings and Precautions section:

• Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
• Neurotoxicity [see Warnings and Precautions (5.2)]
• Clostridioides difficile-associated Diarrhea [see Warnings and Precautions (5.3)]

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.

Table 3. Selected Adverse Reactions Occurring in 1% or Greater of cUTI Patients Receiving EXBLIFEP in Trial 1:

^a Transaminases increased includes alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, hepatic enzyme increased, liver function test increased, transaminases increased, and hypertransaminasemia.
^b Bilirubin increased includes blood bilirubin increased, bilirubin conjugated increased, and hyperbilirubinemia.
^c Headache includes headache and tension headache.
^d Phlebitis/Infusion site reactions includes phlebitis, thrombophlebitis, thrombophlebitis superficial, injection site inflammation, infusion site extravasation, injection site thrombosis, vessel puncture site pain, vessel puncture site hematoma, and rash erythematous
^e Anemia includes anemia, hypochromic anemia, iron deficiency anemia, and normocytic anemia.
^f Hypersensitivity includes allergic cough, dermatitis allergic, hypersensitivity, periorbital edema, pruritus, rash, and urticaria.
The Trial was not designed to evaluate meaningful comparisons of the incidence of adverse reactions in the EXBLIFEP and Piperacillin/Tazobactam treatment groups.

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.

Table 4. Selected Laboratory Abnormalities Exceeding Specified Levels in Trial 1:

N, total number of patients in treatment arm; Nw, number of patients with baseline lab data available in each baseline toxicity subgroup; n, number of patients meeting criteria; ULN, Upper Limit of Normal

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)].

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 firstgeneration 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 firstgeneration 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.