Dilution of Reconstituted ZEVTERA Solution and Administration of the Diluted Product

After reconstitution with the appropriate diluent, further dilute the reconstituted ZEVETRA solution, using aseptic technique with the appropriate diluent, to the appropriate volume of ZEVTERA infusion solution as described in Table 5 below.

Storage of Reconstituted ZEVTERA Solution in Vials

Upon reconstitution with the appropriate diluent, the reconstituted ZEVTERA solution in the vial should be transferred and diluted into the appropriate container. If it is not possible to dilute the reconstituted ZEVTERA solution immediately, the reconstituted solution may be stored refrigerated for up to 24 hours, and at room temperature for up to 1 hour. Discard any unused reconstituted solution.

Storage of Diluted ZEVTERA Solution in Infusion Bags

ZEVTERA solutions for infusions can be stored at room temperature or refrigerated at 2 °C to 8 °C. If the infusion solution is stored in the refrigerator, it should be equilibrated to room temperature prior to administration. ZEVTERA solutions should not be exposed to direct sunlight. The infusion solution does not need to be protected from light during administration. Do not freeze ZEVTERA solutions for infusions.

Storage for diluted ZEVTERA infusion solutions at a concentration of 2.67 mg/mL and 5.33 mg/mL for varying storage conditions are described in Tables 6 and 7 below.

Overview of the Safety Evaluation of ZEVTERA

ZEVTERA was evaluated in four controlled comparative phase 3 clinical trials (TRIALS 1 through 4) which included 1221 adult patients treated with ZEVTERA 667 mg (equivalent to 500 mg of ceftobiprole) administered by IV infusion over 2 hours every 6 to 8 hours and 1248 patients treated with comparator for a treatment period up to 42 days. The median age of patients treated with ZEVTERA was 56 years, ranging between 18 and 95 years old. Patients treated with ZEVTERA were predominantly male (64%) and White (82%).

ZEVTERA was also evaluated in a controlled phase 3 clinical trial (TRIAL 5) which included 138 pediatric patients aged from 3 months to less than 18 years with CABP and hospital-acquired bacterial pneumonia (HABP) requiring hospitalization. Although HABP was included in the safety data, the safety and effectiveness of ZEVTERA for the treatment of HABP has not been established and ZEVTERA is not approved for the treatment of HABP.

Adult Patients

Clinical Trials Experience in Adult Patients with Staphylococcus aureus Bloodstream Infection (Bacteremia)

ZEVTERA was evaluated in an active-controlled randomized, double-blind, multicenter phase 3 trial (TRIAL 1) in patients with Staphylococcus aureus bloodstream infection (bacteremia) (SAB) including right-sided infective endocarditis. In TRIAL 1, 191 patients received ZEVTERA 667 mg (equivalent to 500 mg of ceftobiprole) administered as a 2-hour IV infusion every 6 hours from Day 1 to Day 8, and ZEVTERA 667 mg every 8 hours from Day 9 onwards, and 198 patients were treated with a comparator (daptomycin administered as an IV 0.5 hour infusion, 6 mg/kg up to 10 mg/kg every 24 hours, with optional aztreonam). The dose of study drugs were adjusted based on renal function.

The median age of patients treated with ZEVTERA was 57 years, ranging between 20-89 years old with approximately 30% aged greater than or equal to 65 years. Patients treated with ZEVTERA were predominantly male (68%), White (95%), and from Europe (93%). The median duration of treatment was 21 days in both treatment arms.

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation

In TRIAL 1, a total of 36/191 (18.8%) patients with SAB treated with ZEVTERA and 45/198 (22.7%) of patients with SAB treated with daptomycin ± aztreonam experienced serious adverse reactions. Discontinuation of treatment due to any adverse reaction occurred in 18/191 (9.4%) of patients treated with ZEVTERA, and 18/198 (9.1%) of patients treated with daptomycin ± aztreonam. In patients treated with ZEVTERA, the most common adverse reactions leading to discontinuation were nausea, vomiting, rash, and urticaria, each occurring in 2/191 (1%). Deaths occurred in 17/191 (8.9%) patients treated with ZEVTERA and 18/198 (9.1%) patients treated with daptomycin ± aztreonam.

Common Adverse Reactions

Table 8 lists the most common selected adverse reactions occurring in ≥ 2% of SAB patients receiving ZEVTERA in TRIAL 1.

Clinical Trials Experience in Adult Patients with Acute Bacterial Skin And Skin Structure Infections

ZEVTERA was evaluated in an active-controlled, randomized, double-blind, multicenter phase 3 trial (TRIAL 2) in patients with acute bacterial skin and skin structure infections (ABSSSI).

In TRIAL 2, 334 patients received ZEVTERA 667 mg (equivalent to 500 mg of ceftobiprole) administered as a 2-hour IV infusion every 8 hours, and 342 patients were treated with vancomycin plus aztreonam. The daily dose of vancomycin was 2 grams, as a 1 gram fixed dose or 15 mg/kg, administered as a 2-hour IV infusion every 12 hours. Aztreonam was administered as a 1 gram fixed dose as a 0.5-hour IV infusion every 12 hours and the requirement for aztreonam therapy was reassessed at the 72-hour study visit. The dose of study drugs was adjusted based on renal function.

The median age of patients treated with ZEVTERA was 51 years ranging from 18–89 years old with approximately 12% aged greater than or equal to 65 years. Patients treated with ZEVTERA were mostly male (59%), White (95%), and from the United States (60%). Patients across treatment arms received treatment for a median duration of 6 days.

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation

In TRIAL 2, a total of 6/334 (1.8%) ABSSSI patients treated with ZEVTERA and 12/342 (3.5%) of ABSSSI patients treated with vancomycin plus aztreonam experienced serious adverse reactions. Discontinuation of treatment due to any adverse reaction occurred in 6/334 (1.8%) of patients treated with ZEVTERA, and 10/342 (2.9%) of patients treated with vancomycin plus aztreonam. In patients treated with ZEVTERA, the most common adverse reactions leading to discontinuation were

dysgeusia and both pruritus and rash, occurring in 1/334 (0.3%). Deaths occurred in 1/334 (0.3%) patients treated with ZEVTERA and 2/342 (0.6%) patients treated with vancomycin plus aztreonam.

Common Adverse Reactions

Table 9 lists the most common selected adverse reactions occurring in ≥ 2% of ABSSSI patients receiving ZEVTERA in TRIAL 2.

Clinical Trials Experience in Adult Patients with Community-Acquired Bacterial Pneumonia

ZEVTERA was evaluated in an active-controlled, randomized, double-blind, multicenter phase 3 study in adult patients with community-acquired bacterial pneumonia (CABP).

In TRIAL 3, 310 patients received ZEVTERA 667 mg (equivalent to 500 mg of ceftobiprole) every 8 hours as a 2-hour IV infusion, and 322 patients were treated with ceftriaxone 2 grams as a 0.5 hour IV infusion with or without linezolid 600 mg every 12 hours as a 60-minute IV infusion. The dose of ZEVTERA was adjusted based on renal function.

The median age of patients treated with ZEVTERA was 56 years, ranging from 18–90 with approximately 36% aged greater or equal to 65 years. Approximately 62% of patients were White, 45% were from outside Europe or the United States, and 57% were male. Patients across treatment arms received treatment for a median duration of 9 days.

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation in Adult Patients

In TRIAL 3, a total of 35/310 (11.3%) patients with CABP treated with ZEVTERA and 37/322 (11.5%) patients with CABP treated with ceftriaxone ± linezolid experienced serious adverse reactions. Discontinuation of treatment due to any adverse reaction occurred in 18/310 (5.8%) of patients treated with ZEVTERA, and 12/322 (3.7%) of patients treated with ceftriaxone ± linezolid. The most common adverse reaction leading to discontinuation in patients treated with ZEVTERA was vomiting, occurring in 4/310 (1.3%). Deaths occurred in 9/310 (2.9%) patients treated with ZEVTERA and 9/322 (2.8%) in patients treated with ceftriaxone ± linezolid.

Common Adverse Reactions in Adult Patients

Table 10 lists the most common selected adverse reactions occurring in ≥ 2% of CABP patients receiving ZEVTERA in TRIAL 3.

Clinical Trials Experience in Adult Patients with Unapproved Use of Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia

ZEVTERA was evaluated in an active-controlled, randomized, double-blind, multicenter, phase 3 trial in patients with hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP) [TRIAL 4]. Although HABP/VABP are included in the safety data, the safety and effectiveness of ZEVTERA for the treatment of HABP/VABP have not been established and ZEVTERA is not approved for HABP or VABP.

In TRIAL 4, 386 patients received ZEVTERA 667 mg (equivalent to 500 mg of ceftobiprole) every 8 hours as a 2-hour IV infusion, and 386 patients were treated with ceftazidime 2 grams every 8 hours as a 2-hour IV infusion with or without linezolid 600 mg every 12 hours as a 1-hr infusion. The dose of ZEVTERA and ceftazidime were adjusted based on renal function.

The median age of patients treated with ZEVTERA was 62.5 years (range 18 - 95) with approximately 47% aged 65 years or older. Approximately 81% of the patients were White, most were outside of the United States (88%) and 72% were male. Patients across treatment arms received treatment for a median duration of 8 days.

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation in Adult Patients

In TRIAL 4, a total of 140/386 (36.3%) HABP/VABP patients treated with ZEVTERA and 123/386 (31.9%) HABP/VABP patients treated with ceftazidime ± linezolid experienced serious adverse reactions. Discontinuation of treatment due to any adverse reaction occurred in 54/386 (14%) of patients treated with ZEVTERA, and 40/386 (10.4%) of patients treated with ceftazidime ± linezolid. Deaths occurred in 88/386 patients (22.8%) treated with ZEVTERA and 84/386 patients (21.8%) treated with ceftazidime ± linezolid. In the subgroup of patients with VABP, 35/103 patients treated with ZEVTERA died (34.0%) versus 24/102 (23.5%) of the patients treated with ceftazidime ± linezolid. In the subgroup of patients with HABP, 53/283 patients treated with ZEVTERA died (18.7%) versus 60/284 patients treated with ceftazidime ± linezolid (21.1%).

Common Adverse Reactions in Adult Patients

Common adverse reactions occurring in >2% of HABP/VABP patients who received ceftobiprole in TRIAL 4 include diarrhea, hypokalemia, hyponatremia, hepatic enzyme increased, vomiting, anemia, rash, phlebitis, nausea, abdominal pain, and seizures.

Selected Adverse Reactions of ZEVTERA in Adult Patients

The following selected adverse reactions were reported in ZEVTERA-treated adult patients at a rate of less than 2% in Trials 1, 2, 3 and 4.

Pediatric Patients

Clinical Trials Experience in Pediatric Patients with Community-Acquired Bacterial Pneumonia

ZEVTERA was evaluated in an active-controlled, randomized, investigator-blind, multicenter phase 3 study in pediatric patients aged from 3 months to less than 18 years with HABP or CABP requiring hospitalization. Although patients with HABP are included in the safety data, the safety and effectiveness of ZEVTERA for the treatment of HABP has not been established and ZEVTERA is not approved for HABP.

In TRIAL 5, 94 patients received ZEVTERA 13.3 mg/kg (equivalent to 10 mg/kg of ceftobiprole) to 26.7 mg/kg (equivalent to 20 mg/kg of ceftobiprole – higher than the recommended approved dose) [see Dosage and Administration (2.2, 2.4)]. ZEVTERA was administered by intravenous infusion every 8 hours, age-adjusted for dose and infusion duration (2-hour or 4-hour infusion). In the comparator arm, 44 patients received either ceftriaxone 50-80 mg/kg IV as a single daily dose (maximum 2 grams/day) for CABP or ceftazidime 50 mg/kg IV every 8 hours (maximum 6 grams/day) for HABP, with or without vancomycin 10-15 mg/kg IV every 6 hours (maximum 2 grams/day). The median age of study patients was 5 years, ranging from 0.6 to 17 years. All patients were from Europe, 100% were classified as White and 56% of patients were male.

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation in Pediatric Patients

In TRIAL 5, a total of 7/94 (7.4%) pediatric patients treated with ZEVTERA and 2/44 (4.5%) patients in the comparator group experienced serious adverse reactions. Discontinuation of treatment due to any adverse reaction occurred in 4/94 (4.3%) of patients treated with ZEVTERA and 0/44 patients treated in the comparator group. Specific adverse reactions leading to treatment discontinuation in patients who received ZEVTERA included aggravated pneumonia, pleuritis, urticaria, and hypersensitivity, each occurring in 1/94 (1.1%). There were no deaths in either arm of the pediatric study.

The most common selected adverse reactions, occurring in ≥ 2% of pediatric patients treated with ceftobiprole, were vomiting (7.4%) headache (3.2%), hepatic enzyme increased (including alanine aminotransferase increased and aspartate aminotransferase increased) (3.2%), diarrhea, infusion site reaction, phlebitis, and pyrexia (all 2.1%).

Dipstick Tests

ZEVTERA may result in false-positive results in dipstick tests (urine protein, ketones, or occult blood). Use alternate clinical laboratory methods of testing to confirm positive tests.

Serological Testing

Treatment with ZEVTERA has the potential to interfere with serological testing, such as the Coombs test. In clinical studies there was no evidence of hemolytic anemia in adults or children. However, the possibility that hemolytic anemia may occur cannot be ruled out. Patients experiencing anemia during or after treatment should be investigated for this possibility.

Risk Summary

There are no available data with use of ZEVTERA in pregnant women 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 in pregnant women have not established drug-associated risks of 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, and cannot definitely establish the absence of risk.

Intravenous administration of ceftobiprole medocaril to pregnant rats and monkeys during organogenesis showed no evidence of adverse fetal developmental outcomes at doses approximately 1.4 times and 0.9 times, respectively, the maximum recommended human dose (MRHD). Some evidence of maternal toxicity (slight reduction in body weight and food consumption) was noted in pregnant monkeys at 0.9 times the MRHD. Intravenous administration of ceftobiprole medocaril to rats 2-weeks prior to mating, during organogenesis, and through lactation resulted in no adverse fertility or fetal development effects in offspring at doses approximately 1.4 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 risks of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Pregnant rats administered ceftobiprole medocaril intravenously at doses up to 360 mg/kg/day (approximately 1.4 times the MRHD based on total body surface area (BSA)-normalized comparisons) during organogenesis on gestation days (GD) 6 to 17 showed no adverse fetal development effects. Maternal body weight gain and food consumption were slightly decreased at 360 mg/kg/day.

Pregnant cynomolgus monkeys were administered ceftobiprole medocaril intravenously at doses up to 120 mg/kg/day (approximately 0.9 times the MRHD based on BSA comparison) during organogenesis (GD 20 to 50). Maternal body weight gain and food consumption were slightly reduced at 120 mg/kg/day. This dose was associated with a slight increase in abortion rate (approximately 10% above historical controls). No other fetal development adverse effects (i.e., no fetal malformations) were observed at the high dose.

In a pre- and post-natal development toxicity study, ceftobiprole medocaril was administered intravenously to pregnant rats during organogenesis starting at GD 6 and continuing to lactation day 21 (L21) at doses up to 360 mg/kg (approximately 1.4 times the MRHD based on BSA comparisons). Maternal toxicity (mortality, reduced food consumption and body weight gain in surviving females during gestation) was observed at the high dose. Effects in the offspring were also observed at the high dose during the post-natal pre-weaning period (decrease in the number of pups born per litter and decreased postnatal survival up to day 4 after birth). No adverse effects were observed in surviving pups during the postnatal postweaning development period (days 5-22) at doses up to 360 mg/kg.

Risk Summary

There are no data on the presence of ceftobiprole in human milk, the effects of ceftobiprole on the breastfed infant, or the effects of ceftobiprole on milk production. Animal studies have shown that ceftobiprole was excreted in milk of lactating rats at low concentrations (see Data). When a drug is present in animal milk, it is likely the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ZEVTERA and any potential adverse effects on the breastfed child from ZEVTERA or from the underlying maternal conditions.

Data

During pregnancy, rats were administered ceftobiprole at doses of 175, 250, and 360 mg/kg/day from 14-days pre-mating through lactation/postpartum day 21. Ceftobiprole was detected in the milk of lactating rats 2 hours post-dose on lactation day 20 at levels approximately 20% of the corresponding maternal plasma ceftobiprole levels. The concentration of ceftobiprole in animal milk does not necessarily predict the concentration of drug in human milk.

Adult Patients

The ZEVTERA dosage is reduced in adult patients with CLCR < 50 mL/min, including patients with a CLCR < 15 mL/min either receiving or not receiving hemodialysis [see Dosage and Administration (2.3)].

Renal impairment (CLCR < 50 mL/min) increases ceftobiprole AUC in adult patients [see Clinical Pharmacology (12.3)], which may increase the risk of ZEVTERA adverse reactions.

ZEVTERA is removed by hemodialysis; thus, ZEVTERA should be administered after intermittent hemodialysis on hemodialysis days [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

Pediatric Patients

The ZEVTERA dosage is reduced in pediatric patients 2 years to less than 18 years old with renal impairment (eGFR 15 to < 50 mL/min/1.73 m2) [see Dosage and Administration (2.4)].

Use in pediatric patients 2 years to less than 18 years old with renal impairment (eGFR 15 to < 50 mL/min/1.73 m2) is predicted to increases ceftobiprole AUC [see Clinical Pharmacology (12.3)], which may increase the risk of ZEVTERA adverse reactions. The effect of any degree of renal impairment in pediatric patients younger than 2 years of age or in pediatric patients 2 years to less than 18 years old with an eGFR < 15 mL/min/1.73 m2 either receiving or not receiving hemodialysis on ceftobiprole pharmacokinetics is unknown.

Augmented Renal Clearance

Increase the ZEVTERA dosing frequency in adult patients with augmented renal clearance (CLCR > 150 mL/min).

Use in adult patients with augmented renal clearance (CLCR > 150 mL/min) is predicted to decrease ceftobiprole exposure [see Clinical Pharmacology (12.3)], which may reduce ZEVTERA efficacy. The effect of augmented renal clearance function (CLCR > 150 mL/min) on ceftobiprole pharmacokinetics in pediatric patients is unknown.

Time Above the Minimum Inhibitory Concentration (MIC)

The time that the unbound plasma concentration of ceftobiprole exceeds the MIC of Staphylococcus aureus , Streptococcus pneumoniae, and species of Enterobacterales correlates with efficacy in a neutropenic murine thigh infection model [see Clinical Pharmacology (12.4)].

Cardiac Electrophysiology

At a dose 1 to 2 times the maximum recommended dose, ZEVTERA does not prolong the QT interval to any clinically relevant extent.

Specific Populations

No clinically significant differences in the pharmacokinetics of ceftobiprole were observed in adults based on age (18 to 91 years), gender (36% female), or race/ethnicity (88% white, 3% Black, 5% Asian). The effect of hepatic impairment on ceftobiprole pharmacokinetics is unknown.

Patients with Renal Impairment

No clinically significant differences in the pharmacokinetics of ceftobiprole were observed in adult subjects and subjects with mild renal impairment (CLCR 50 to 80 mL/min). Ceftobiprole AUC increased 2.5-fold in adult subjects with moderate renal impairment (CLCR 30 to < 50 mL/min) and 3.3-fold in severe renal impairment (CLCR < 30 mL/min). The effect of any degree of renal impairment in pediatric patients less than 2 years of age or in pediatric patients with CLCR < 15 mL/min/1.73 m2 on ceftobiprole pharmacokinetics is unknown.

End-stage Renal Disease Requiring Dialysis

No clinically significant difference in the pharmacokinetics of ceftobiprole were observed in adult patients with ESRD (CLCR < 15 mL/min) compared to healthy adult subjects based on limited PK data and pharmacokinetic modeling and simulation. Ceftobiprole was demonstrated to be removed by hemodialysis in patients receiving ZEVTERA.

Patients with Augmented Renal Clearance

A clinically significant reduction in ceftobiprole exposure is predicted in adult patients with augmented renal clearance (CLCR > 150 mL/min) based upon a mechanistic understanding of this drug. The effect of augmented renal clearance (CLCR > 150 mL/min) on ceftobiprole pharmacokinetics in pediatric patients is unknown.

Pediatric Use

No clinically significant differences in the pharmacokinetics of ceftobiprole were observed between pediatric patients from birth to < 18 years with normal renal function following administration of an intravenous dose of ZEVTERA. ZEVTERA is not approved for use in pediatric patients less than 3 months of age [see Use in Specific Populations (8.4)].

Drug Interaction Studies

In Vitro Studies

Ceftobiprole does inhibit or induce CYP450 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5.

Transporter Systems: Ceftobiprole is an inhibitor of OATP1B1, OATP1B3, MRP2 and BSEP but is not an inhibitor of P-glycoprotein, BCRP, OAT1, OAT3, OCT1, OCT2, or MATE1.

Mechanism of Action

Ceftobiprole is a cephalosporin with bactericidal activity by inhibition of bacterial cell wall synthesis. Ceftobiprole has in vitro activity against gram-positive and gram-negative bacteria, including methicillin-resistant and susceptible Staphylococcus aureus. Bactericidal activity is mediated through binding to essential penicillin-binding proteins (PBPs) and inhibiting their transpeptidase activity, which is essential for the synthesis of the peptidoglycan layer of the bacterial cell wall. Ceftobiprole has a high affinity for S. aureus PBPs 1 – 4, including PBP2a in methicillin-resistant Staphylococcus aureus, and PBP2x and PBP2b in penicillin-resistant Streptococcus pneumoniae.

Resistance

Ceftobiprole is not active against gram-negative bacteria producing extended-spectrum β-lactamases (ESBLs) from the TEM, SHV or CTX-M families, serine carbapenemases (such as KPC), class B metallo-β-lactamases, class C (AmpC cephalosporinases) if expressed at high levels), and Ambler class D β-lactamases including carbapenemases.

No cross-resistance with other classes of antimicrobials has been identified. Although cross-resistance may occur, some isolates resistant to other cephalosporins may be susceptible to ceftobiprole.

Interaction with Other Antimicrobials

In vitro studies have not demonstrated any antagonism between ceftobiprole and other commonly-used antibacterial agents (e.g., gentamicin, vancomycin, daptomycin, rifampicin) against strains of Staphylococcus aureus. Against Escherchia coli, no antagonism was observed between ceftobiprole and doripenem or levofloxacin.

Activity against Bacteria in Animal Infection Models

Ceftobiprole demonstrated activity in a neutropenic murine thigh infection model reducing tissue counts of MRSA. Ceftobiprole was effective in treating experimental murine septicemia for strains of MSSA, MRSA, S. pneumoniae (including strains of penicillin-resistant S. pneumoniae [PRSP]), E. coli expressing TEM-1 and Act-1 AmpC cephalosporinase, K. pneumoniae, C. freundii, S. marcescens, and P. mirabilis. In an acute mouse model of pneumonia ceftobiprole was effective against S. pneumoniae (ceftobiprole MICs < 0.5 μg/mL)including a strain of PRSP ). In a rabbit model of meningitis ceftobiprole was effective at clearing strains of E. coli, K. pneumoniae and β-lactamase positive and negative H. influenzae. In both a rat and rabbit model of endocarditis, ceftobiprole did not sterilize but was effective in reducing cardiac vegetations of MRSA including a vancomycin intermediate strain (ceftobiprole MIC ≤ 2 μg/mL). Similarly in both a rat and rabbit model of osteomyelitis, ceftobiprole was effective in clearing MRSA infection (ceftobiprole MIC ≤ 1μg/mL). The clinical significance of the above findings in animal infection models is not known.

Antimicrobial Activity

ZEVTERA has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see Indications and Usage (1.3)].

SAB

Gram-positive bacteria

• Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant isolates)

ABSSSI

Gram-positive bacteria

• Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant isolates)
• Streptococcus pyogenes

Gram-negative bacteria

• Klebsiella pneumoniae

CABP

Gram-positive bacteria

• Staphylococcus aureus (including methicillin-susceptible isolates)
• Streptococcus pneumoniae

Gram-negative bacteria

• Escherichia coli
• Klebsiella pneumoniae
• Haemophilus influenzae
• Haemophilus parainfluenzae

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 ZEVTERA against isolates of similar genus or organism group. However, the efficacy of ZEVTERA in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-positive bacteria

• Staphylococcus epidermidis
• Staphylococcus hominis
• Staphylococcus lugdunensis
• Streptococcus agalactiae
• Streptococcus mitis group
• Streptococcus dysgalactiae
• Streptococcus anginosus group

Gram-negative bacteria

• Citrobacter koseri
• Enterobacter cloacae
• Klebsiella aerogenes
• Moraxella catarrhalis
• Morganella morganii
• Proteus mirabilis

Susceptibility Test Methods

For specific information regarding susceptibility testing methods, interpretive criteria, and associated test methods and quality control standards recognized by FDA for ZEVTERA, see: https://www.fda.gov/STIC.

Carcinogenesis

No animal studies have been performed to evaluate the carcinogenic potential of ZEVTERA as none were warranted.

Mutagenesis

Ceftobiprole medocaril was negative in a standard bacterial reverse mutation test, however, the test was limited by bactericidal activity. Further genetic toxicology studies performed in vitro in mammalian cells showed that both ceftobiprole medocaril (pro-drug) and ceftobiprole (active metabolite) induced mutations at the TK locus in mouse lymphoma L5178Y TK+/- cells, however the pro-drug did not induce mutations in an in vitro HPRT forward mutation assay in CHO cells.

Ceftobiprole medocaril was positive for structural chromosome aberrations in human peripheral blood lymphocytes. When administered intravenously, ceftobiprole medocaril was negative for clastogenic effects in the in vivo mouse bone marrow micronucleus assay.

Impairment of Fertility

Administration of repeated doses of intravenous ceftobiprole medocaril at doses up to 360 mg/kg (approximately 1.4 times the MRHD based on BSA comparisons) to male and female rats starting approximately 2 weeks prior to mating, during mating and continuing through implantation (up to GD 7) were without effect on fertility or early fetal development.

Adult Patients

Trial design

The efficacy of ZEVTERA in the treatment of adult patients with SAB, including right-sided infective endocarditis, was demonstrated in a randomized, controlled, double-blind, multinational, multicenter trial (Trial 1) (NCT03138733). In this trial, adult patients were randomized to either ZEVTERA 667 mg (equivalent to 500 mg of ceftobiprole) IV every 6 hours from study Day 1 to Day 8, and 667 mg IV every 8 hours from study Day 9 onwards) or daptomycin (6 mg/kg up to 10 mg/kg IV every 24 hours) plus optional aztreonam for coverage of gram-negative co-infections (the comparator). Randomization was stratified by study site, dialysis status, and use of prior antibacterial drugs.The study was performed in two cohorts based on findings in animal studies [see Nonclinical Toxicology (13.2)]. The initial cohort was enrolled to receive a maximum treatment duration of 28 days. Based on a safety evaluation of cohort 1, patients could be enrolled in cohort 2 to receive a treatment duration of up to 42 days. The duration of study treatment was based on the investigator's clinical evaluation.

Study patients were required to have at least one positive blood culture for S. aureus obtained within 72 hours prior to randomization, signs and symptoms of bacteremia (fever, elevated white blood cell count or immature neutrophils, tachycardia, or hypotension), and at least one of the following conditions of complicated S. aureus bacteremia: chronic dialysis, persistent SAB, acute bacterial skin and skin structure infection, metastatic infections of native tissue, osteomyelitis, epidural or cerebral abscess, or definite native-valve right-sided infective endocarditis by Modified Duke's Criteria. Patients with uncomplicated S. aureus bacteremia, left-sided infective endocarditis, prosthetic heart valves, foreign body material that could not be removed, severe neutropenia, or pneumonia, were excluded from the study.

Upon entry, patients were classified for likelihood of endocarditis using the modified Duke's criteria (definite, possible, or rejected). Echocardiography, including a transesophageal echocardiogram, was to be performed during screening or within 7 days following study enrollment. Final diagnoses were to be made by the study investigators within 7 days of randomization. The final diagnosis for persistent S. aureus bacteremia was made by an independent treatment-blinded Data Review Committee (DRC).

Baseline Demographic and Disease Characteristics

A total of 390 patients (192 ZEVTERA, 198 daptomycin) with SAB were randomized from 60 centers in the USA, Europe, Latin America, and South Africa. The modified ITT (mITT) population was used for the primary efficacy analysis, comprising 387 patients (189 ZEVTERA, 198 daptomycin ± aztreonam) who received study drugs and had a baseline blood culture positive for S. aureus.

Patient demographic and baseline characteristics were balanced between the treatment groups. The median age among the 387 patients in the mITT population was 58 years, ranging from 19 to91 years), with 31% aged ≥ 65 years, 69% of patients were male, and 96% were White.

Frequent conditions of complicated SAB included acute bacterial skin and skin structure infections (61%), intra-abdominal abscesses (14%), osteoarticular infections (13%), and patients on chronic dialysis (13%).  A total of 6.5% of patients had definite right-sided infective endocarditis. A total of 24% had bacteremia caused by methicillin-resistant S. aureus (MRSA).

Efficacy Results

The primary efficacy outcome in the study was overall success at the post-treatment evaluation (PTE) visit at 70 days post-randomization in the mITT population, as assessed by the independent DRC.

Overall success required survival, symptom improvement, S. aureus bacteremia bloodstream clearance, no new S. aureus bacteremia complications, and no use of other potentially effective antibacterial drugs.

Overall success rates at the PTE visit in the mITT population were 69.8% (132/189) in patients treated with ZEVTERA and 68.7% (136/198) in patients treated withthe comparator. The overall primary study outcome and in pre-defined subgroups in the mITT population is shown in Table 12.

For patients enrolled in Ukraine, overall success rates at the PTE visit in the mITT population were 77/84 (84.1%) in patients treated with ZEVTERA and 82/92 (89.1%) in patients treated with the comparator. For patients enrolled outside Ukraine, overall success rates at the PTE visit in the mITT population were 58/101 (57.4%) in patients treated with ZEVTERA and 54/106 (50.9%) in patients treated with the comparator.

All-cause mortality between randomization and the PTE visit was observed in 17/189 (9.0%) patients treated with ZEVTERA, and 18/198 (9.1%) patients treated with the comparator. Other key secondary efficacy outcomes included microbiological eradication at the PTE visit in the mITT population, which was achieved in 82% of patients treated with ZEVTERA and 77% of patients treated with the comparator, and the development of new S. aureus bacteremia complications, which occurred in 6% of patients treated with ZEVTERA and 6% of patients treated with the comparator. S. aureus bloodstream clearance, defined as 2 consecutive study days with negative blood cultures for S. aureus with no subsequent S. aureus relapse or reinfection, was achieved after a median of 4 days in each treatment group.

S. aureus bloodstream clearance in patients with MSSA was achieved after a median of 3 days in patients treated with ZEVTERA and after a median of 4 days in patients treated with the comparator.

S. aureus bloodstream clearance in patients with MRSA was achieved after a median of 5 days in each treatment group.

Failure of treatment due to relapse of S. aureus bacteremia was assessed by the DRC in two patients (1%) treated with ZEVTERA, and in four patients (2%) treated in the comparator arm. No increase in ceftobiprole MIC was observed for the two isolates from the ZEVTERA treated patients.

Adult Patients

Trial Design

The efficacy of ZEVTERA in the treatment of adult patients with ABSSSI was demonstrated in a randomized, controlled, double-blind, multinational, multicenter trial (Trial 2) (NCT03137173). Patients were randomized to either ZEVTERA 667 mg (equivalent to 500 mg of ceftobiprole) IV every 8 hours or vancomycin plus aztreonam (vancomycin 1 gram or 15 mg/kg IV every 12 hours, aztreonam 1 gram IV every 12 hours). Randomization was stratified by study site and type of ABSSSI. Treatment duration was 5 to 14 days. Patients could receive concomitant metronidazole for suspected anaerobic infection. A switch to oral therapy was not allowed.

The study enrolled adult patients with ABSSSI (cellulitis/erysipelas, major cutaneous abscess, wound infection) with a lesion area of at least 75 cm2, systemic or regional signs of infection, and a requirement for IV antibiotic treatment. Patients with other forms of ABSSSI, uncomplicated skin and skin structure infections, or infections related to prosthetic devices, were excluded.

The ITT primary analysis population comprised all patients randomized.

The primary endpoint, assessed in the ITT population, was early clinical response 48–72 hours after start of treatment. Early clinical response required a reduction of the primary skin lesion by at least 20%, survival for at least 72 hours, and the absence of concomitant antibacterial treatment or additional unplanned surgery.

The main secondary endpoint was investigator-assessed clinical success at the test-of-cure (TOC) visit 15 to 22 days after randomization and at least 5 days after the end-of-treatment.

A total of 679 patients (335 ZEVTERA, 344 vancomycin plus aztreonam) were randomized from 32 centers in the USA and Europe. The microbiological ITT (mITT) population included 506 patients with at least one valid baseline pathogen.

Baseline Demographic and Disease Characteristics

Patient demographic and baseline characteristics in the ITT population were balanced between the treatment groups. Approximately 95% of patients were classified as White, 59% were male, the median age was 50 years (range: 18 to 89), and the mean body mass index was 28 kg/m2, 62% of patients were enrolled in the USA, and 38% in Europe. A history of diabetes was present in 11% of patients and current injection drug use was reported in 33% of patients. The types of ABSSSI included cellulitis/erysipelas (33%), wound infection (39%), and major cutaneous abscesses (28%). The median area of the primary skin infection was 259 cm2.

Efficacy Results

The primary and main secondary outcomes are shown in Table 13.

Clinical response rates at TOC by the most common baseline pathogens in the microbiological ITT (mITT) population, defined as all randomized patients with a baseline pathogen, are presented in Table 14.

Adult Patients

Trial Design

The efficacy of ZEVTERA in the treatment of adult patients with community-acquired bacterial pneumonia (CABP) was demonstrated in a randomized, controlled, double-blind, multinational, multicenter study (Trial 3) (NCT00326287). 638 adults hospitalized with CABP and requiring IV antibacterial treatment for at least 3 days were included in the intent-to-treat (ITT) population, comparing ZEVTERA 667 mg (equivalent to 500 mg of ceftobiprole) IV every 8 hours to ceftriaxone (2 grams IV every 24 hours) with optional linezolid (600 mg IV every 12 hours) for the coverage of resistant gram-positive pathogens, including methicillin-resistant S. aureus (MRSA). Randomization was stratified by Pneumonia Outcomes Research Team (PORT) classification I to III versus IV to V, and by the need for adjunctive treatment with linezolid or matching placebo. The treatment duration was 5–14 days. No adjunctive macrolide therapy was allowed. A switch to oral cefuroxime (500 mg every 12 hours) was allowed after at least 72 hours of IV study treatment for patients who met stringent protocol-specified criteria for improvement and were candidates for hospital discharge.

The study enrolled adult patients hospitalized with CABP based on clinical signs and symptoms, fever and/or leukocytosis/leukopenia, and new radiographic evidence of pulmonary infiltrates. Patients with known bronchial obstruction, pulmonary malignancies, cystic fibrosis, lung abscess, pleural effusion as the primary source of infection, active tuberculosis, or pneumonia known or suspected to be caused by atypical bacteria, were excluded from study participation, as were patients with known or suspected extrapulmonary complications such as concomitant meningitis, endocarditis, septic arthritis, or osteomyelitis.

The ITT primary analysis population comprised all patients randomized. The clinically evaluable (CE) population comprised patients in the ITT population who received at least 48 hours of study medication and met protocol-defined criteria regarding clinical evaluability.

The protocol-specified primary efficacy analyses included clinical cure rates at TOC visit, 7 to 14 days after the end-of-treatment (EOT) in the co-primary ITT and CE populations.

The ITT population comprised 638 patients (314 ZEVTERA, 324 ceftriaxone ± linezolid), in 103 centers in the USA, Asia, Europe, and Latin America. The CE population comprised 469 patients, and the microbiological ITT (mITT) population comprised 184 patients with at least one valid baseline pathogen.

Baseline Demographic and Disease Characteristics

Patient demographic and baseline characteristics in the ITT population were balanced between the treatment groups. Approximately 62% of patients were classified as White, and 57% were male. The median age was 56 years (range 18–94). 48% of patients were categorized at baseline as PORT classification III to V, and 22% of patients as PORT classification IV or V. 40% of patients did not receive any prior antibacterial drugs within 30 days of randomization. 12% of patients in the ceftriaxone arm received adjunctive linezolid, and 52% of patients in the ITT population switched to oral antibacterial therapy after at least 72 hours of IV study treatment.

Efficacy Results

The results for clinical cure at the test-of-cure visit at Day 7 to 14 after end of treatment are shown in Table 15.

The 30-day all-cause mortality rates in the ITT population were 5/314 (1.6%) for patients treated with ZEVTERA, and 8/324 (2.5%) for patients treated with ceftriaxone ± linezolid group.

As this study was designed prior to the current regulatory guidelines, post-hoc re-analyses were conducted to determine the consistency of study results with these guidelines. These post-hoc analyses considered an earlier timepoint of clinical success at Day 3 in patients in the ITT population, based on survival and the improvement in at least two, and no worsening in any, of the following symptoms: pleuritic chest pain, cough, purulent sputum production or respiratory secretion, tachypnea.

Clinical success at Day 3 was also evaluated in the following analysis populations which were also defined post-hoc:

The Day 3-ITT population included 97% (618 of 638) of ITT patients who had at least two of the following symptoms at baseline: difficulty breathing, cough, production of purulent sputum, or chest pain.

The Day 3-modified ITT population included Day 3-ITT patients with baseline PORT classification of PORT Risk Class ≥ III, at least two of fever, hypothermia, hypotension, tachycardia, and tachypnea, as well as, at least one of new-onset hypoxemia, rales or pulmonary consolidation, and leukocytosis or leukopenia and new radiographic infiltrates (not related to another disease process) consistent with the diagnosis of bacterial pneumonia.

The Day 3-micro ITT population was the subset of the Day 3-ITT patients who had a valid pathogen at baseline.

Results of early clinical success at Day 3 in the Day 3-ITT and Day 3- modified ITT populations are shown in Table 16 below:

Clinical response rates at TOC by most common baseline pathogen in the mITT population, defined as all randomized patients with a baseline pathogen, are presented in Table 17.

Pediatric Patients (3 months to < 18 Years of Age) with CABP

The pediatric pneumonia phase 3 study was a randomized, investigator-blind, active-controlled study in pediatric patients 3 months to < 18 years of age with CABP or hospital-acquired bacterial pneumonia (HABP) requiring IV antibacterial drug treatment (Trial 5) (NCT03439124). Although patients with HABP were included in the study, the safety and effectiveness of ZEVTERA for the treatment of HABP have not been established and ZEVTERA is not approved for the treatment of HABP.

138 pediatric patients were randomized in a 2:1 ratio to ZEVTERA 13.3 mg/kg (equivalent to 10 mg/kg of ceftobiprole) to 26.7 mg/kg (equivalent to 20 mg/kg of ceftobiprole - higher than the recommended approved dose) [see Dosage and Administration (2.2, 2.4)]. ZEVTERA was administered by intravenous infusion every 8 hours based on age with a maximum dose of ZEVTERA 667 mg (equivalent to 500 mg of ceftobiprole) (n = 94) or a standard-of-care cephalosporin antibacterial drug (n = 44) for a treatment duration of 7 to 14 days. A switch to an age-appropriate oral antibacterial drug after study Day 3 was allowed.

The primary objective of this study was to evaluate the safety of ZEVTERA. The study was not powered for comparative inferential efficacy analysis, and no efficacy endpoint was identified as primary.

The numbers of patients in the age groups evaluated in the ZEVTERA arm were as follows: 18  pediatric patients aged 12 to < 18 years, 27 pediatric patients aged 6 to < 12 years, 37 pediatric patients aged 2 to < 6 years, and 12 pediatric patients (infants) aged 3 months to < 2 years.

Of the 138 pediatric patients enrolled in the ITT/Safety population, 94% had CABP requiring hospitalization, and 6% had HABP. Patients with ventilator-associated HABP were excluded from the study.

The median treatment duration with ZEVTERA was 6.0 days; 88% of patients treated with ZEVTERA switched to oral antibacterial drugs to complete treatment.

The clinical response was determined at study Day 4, the EOT visit, and at the TOC visit 7 to 14 days after the EOT visit. The ITT population included all patients randomized.

In the ITT population, the clinical response rates in the ZEVTERA and comparator arms were, respectively, 95.7% and 93.2% on Day 4 (between-group difference 2.6% [95% confidence interval (CI): -5.5, 14.7]), 96.8% and 100% at the EOT visit (between-group difference -3.2% [95% CI: -9.1, 5.5]), and 90.4% and 97.7% at the TOC visit (between-group difference -7.3% [95% CI: -15.7, 3.6]).