ZEVTERA

1 INDICATIONS AND USAGE ZEVTERA is a cephalosporin antibacterial indicated for the treatment of: Adult patients with Staphylococcus aureus bloodstream infections (bacteremia) (SAB), including those with right-sided infective endocarditis ( 1.1 ), Adult patients with acute bacterial skin and skin structure infections (ABSSSI) ( 1.2 ), and Adult and pediatric patients (3 months to less than 18 years old) with community-acquired bacterial pneumonia (CABP) ( 1.3 ). To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZEVTERA and other antibacterial drugs, ZEVTERA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria ( 1.4 ). 1.1 Staphylococcus aureus Bloodstream Infection (Bacteremia) ZEVTERA is indicated for the treatment of adult patients with Staphylococcus aureus bloodstream infection (bacteremia) (SAB), including those with right-sided infective endocarditis, caused by methicillin-susceptible and methicillin-resistant isolates . 1.2 Acute Bacterial Skin and Skin Structure Infections ZEVTERA is indicated for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following gram-positive and gram-negative microorganisms: Staphylococcus aureus (methicillin-susceptible and methicillin-resistant isolates), Streptococcus pyogenes, and Klebsiella pneumoniae. 1.3 Community-Acquired Bacterial Pneumonia ZEVTERA is indicated for the treatment of adult and pediatric patients (3 months to less than 18 years old) with community-acquired bacterial pneumonia (CABP) caused by susceptible isolates of the following gram-positive and gram-negative microorganisms: Staphylococcus aureus (methicillin-susceptible isolates), Streptococcus pneumoniae, Haemophilus influenzae , Haemophilus parainfluenzae , Escherichia coli , and Klebsiella pneumoniae. 1.4 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZEVTERA and other antibacterial drugs, ZEVTERA should be used only to treat or prevent infections that are proven, or strongly suspected, to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2 DOSAGE AND ADMINISTRATION The recommended dosage of ZEVTERA for adult patients with SAB, ABSSSI and CABP is described in the table below ( 2.1 ): Indication in Adults Dose Frequency SAB 667 mg Every 6 hours on Days 1 to 8 Every 8 hours from Day 9 ABSSSI 667 mg Every 8 hours CABP 667 mg Every 8 hours Duration of treatment in adult patients is up to 42 days for SAB and 5 days to 14 days for ABSSSI and CABP ( 2.1 ). Administer each prepared intravenous infusion solution of ZEVTERA over 2 hours at a concentration of 2.67 mg/mL ( 2.1 , 2.6 ). The recommended dosage of ZEVTERA for pediatric patients (3 months to less than 18 years old) with CABP is described below ( 2.2 ). Pediatric Age Group for CABP Dose Frequency 12 years to less than 18 years old 13.3 mg/kg (up to 667 mg/dose) Every 8 Hours Greater than or equal to 3 months and less than 12 years old 20 mg/kg (up to 667 mg/dose) Every 8 Hours Duration of treatment in pediatric patients is 7 days to 14 days for CABP ( 2.1 ). Administer each prepared intravenous infusion solution of ZEVTERA over 2 hours at a concentration of 2.67 mg/mL for pediatric patients aged 12 years to less than 18 years old and at a concentration of 5.33 mg/mL for pediatric patients aged 3 months to less than 12 years old ( 2.2 , 2.6 ). Reduce the dosage in adult patients with CL CR less than 50 mL/min, including patients with CL CR less than 15 mL/min on hemodialysis ( 2.3 and 8.6 ). Increase the dosage in adult patients with CL CR greater than 150 mL/min ( 2.3 ). Reduce the dosage in pediatric patients aged 2 years old to less than 18 years old with eGFR less than 50 mL/min/1.73 m 2 and greater than or equal to 15 mL/min/1.73 m 2 ( 2.4 and 8.6 ). See Full Prescribing Information for instructions for preparation of ZEVTERA solution infusion solution ( 2.5 ). 2.1 Recommended Dosage and Administration for SAB, ABSSSI and CABP in Adult Patients The recommended dosage of ZEVTERA for the treatment of adult patients with SAB, ABSSSI and CABP is described in Table 1. The duration of treatment in adult patients is up to 42 days for SAB and 5 days to 14 days for ABSSSI and CABP. Administer each prepared intravenous infusion solution of ZEVTERA over 2 hours at a concentration of 2.67 mg/mL to adult patients [see Dosage and Administration (2.5) ]. Table 1: Recommended Dosage Regimen for SAB, ABSSSI and CABP in Adult Patients Indication Duration of treatment in adult patients is up to 42 days for SAB and 5 days to 14 days for ABSSSI and CABP. Dose Frequency Administer each prepared intravenous infusion solution of ZEVTERA over 2 hours at a concentration of 2.67 mg/mL [see Dosage and Administration (2.5) ] SAB 667 mg 667 mg of ceftobiprole medocaril sodium is equivalent to 500 mg of ceftobiprole. Every 6 hours on Days 1 to 8 Every 8 hours from Day 9 ABSSSI 667 mg Every 8 hours CABP 667 mg Every 8 hours 2.2 Recommended Dosage and Administration for CABP in Pediatric Patients (3 months to less than 18 years old) For treatment of pediatric patients with CABP, the recommended dosage of ZEVTERA is described in Table 2, based on patient age and weight [see Clinical Pharmacology (12.3) ] . The duration of treatment for CABP in pediatric patients (3 months to less than 18 years old) is 7 days to 14 days. Administer each prepared intravenous infusion solution of ZEVTERA over 2 hours at a concentration of 2.67 mg/mL for patients 12 years to less than 18 years old and at a concentration of 5.33 mg/mL for patients greater than or equal to 3 months to less than 12 years old [see Dosage and Administration (2.5) ]. Table 2: Recommended Dosage Regimen in Pediatric Patients with CABP Pediatric Age Group Dose Duration of treatment for CABP in pediatric patients is 7 days to 14 days. Frequency 12 years to less than 18 years old 13.3 mg/kg (up to 667 mg/dose 13.3 mg/kg of ceftobiprole medocaril sodium is equivalent to 10 mg/kg of ceftobiprole; 20 mg/kg ceftobiprole medocaril sodium is equivalent to 15 mg/kg of ceftobiprole. 667 mg cefto…

5 WARNINGS AND PRECAUTIONS Increased Mortality with Unapproved use in Ventilator-Associated Bacterial Pneumonia (VABP) Patients: The safety and effectiveness of ZEVTERA for the treatment of VABP has not been established and the use of ZEVTERA for VABP is not approved ( 5.1 ). Hypersensitivity Reactions: Discontinue ZEVTERA if a hypersensitivity reaction occurs, and institute appropriate treatment ( 5.2 ). Seizures and other adverse central nervous system (CNS) reactions have been associated with the use of ZEVTERA. If seizures or other CNS adverse reactions occur, evaluate patients to determine whether ZEVTERA should be discontinued ( 5.3 ). Clostridioides difficile -associated diarrhea (CDAD) has been reported with nearly all systemic antibacterial agents, including ZEVTERA. Evaluate if diarrhea occurs ( 5.4 ). 5.1 Increased Mortality with Unapproved Use in Ventilator-Associated Bacterial Pneumonia Patients In Trial 4, an increase in mortality was seen in the subgroup of patients with ventilator-associated bacterial pneumonia (VABP) who were treated with ZEVTERA (35/103 [34%] versus 24/102 [24%] in comparator-treated patients) [see Adverse Reactions (6.1) ] . The cause of this increased mortality has not been established. Generally, deaths were associated with complications of infection or underlying co-morbidities. The safety and effectiveness of ZEVTERA for the treatment of VABP has not been established and the use of ZEVTERA for VABP is not approved. 5.2 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, were observed in ZEVTERA-treated patients in clinical trials [see Adverse Reactions (6.1) ] . Serious and occasionally fatal hypersensitivity reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Before therapy with ZEVTERA is instituted, careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or other beta-lactam antibacterial drugs should be made. Maintain clinical supervision if this product is to be given to a penicillin- or other beta-lactam-allergic patient, because cross sensitivity among beta-lactam antibacterial agents has been established. Discontinue ZEVTERA if a hypersensitivity reaction occurs, and institute appropriate treatment. 5.3 Seizures and Other Central Nervous System Reactions Seizures and other adverse central nervous system (CNS) reactions have been reported during treatment with ZEVTERA and other cephalosporins [see Adverse Reactions (6.1) ] . Nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with cephalosporins particularly in patients with a history of epilepsy or when recommended dosages of cephalosporins were exceeded due to renal impairment. Adjust ZEVTERA dosing based on creatinine clearance [see Dosage and Administration (2.3 , 2.4) ] . Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions, including seizures, occur, patients should undergo a neurological evaluation to determine whether ZEVTERA should be discontinued. 5.4 Clostridioides difficile -Associated Diarrhea Clostridioides difficile -associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including ZEVTERA, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after …

4 CONTRAINDICATIONS ZEVTERA is contraindicated in patients with a known history of severe hypersensitivity to ZEVTERA, or to other members of the cephalosporin class [see Warnings and Precautions (5.2) ]. ZEVTERA is contraindicated in patients with a known history of severe hypersensitivity to ZEVTERA, or to other members of the cephalosporin class ( 4 ).

7 DRUG INTERACTIONS Organic Anion Transporting Polypeptide 1B1/1B3 (OATP1B1/OATP1B3) Substrates: ZEVTERA may increase the plasma concentrations of OATP1B1 and OATP1B3 substrates. Concomitant administration is not recommended ( 7.1 ) 7.1 Organic Anion Transporting Polypeptide 1B1/1B3 (OATP1B1/OATP1B3) Substrates ZEVTERA may increase the plasma concentrations of OATP1B1 and OATP1B3 substrates. Concomitant administration is not recommended [see Clinical Pharmacology (12.3) ]. 7.2 Drug-Laboratory Test Interactions 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.

8.1 Pregnancy 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 definitively 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 post-natal survival up to day 4 after birth). No adverse effects were observed in surviving pups during the post-natal postweaning development period (days 5-22) at doses up to 360 mg/kg.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in the Warnings and Precautions section: Increased Mortality in Ventilator-Associated Bacterial Pneumonia Patients [see Warnings and Precautions (5.1) ] Hypersensitivity Reactions [see Contraindications (4) and Warning and Precautions (5.2) ] Seizures and Other Central Nervous System Reactions [see Warnings and Precautions (5.3) ] Clostridioides difficile -Associated Diarrhea [see Warnings and Precautions (5.4) ] SAB (adult patients): The most common adverse reactions occurring in ≥ 4% of adult patients were anemia, nausea, hypokalemia, vomiting, hepatic enzyme and bilirubin increased, diarrhea, blood creatinine increased, hypertension, leukopenia, and pyrexia ( 6.1 ). ABSSSI (adult patients): The most common adverse reactions occurring in ≥ 2% of adult patients were nausea, diarrhea, headache, injection site reaction, hepatic enzyme increased, rash, vomiting, and dysgeusia ( 6.1 ). CABP (adult and pediatric patients 3 months to less than 18 years of age): Adult Patients: The most common adverse reactions occurring in ≥ 2% of adult patients were nausea, hepatic enzyme increased, vomiting, diarrhea, headache, rash, insomnia, abdominal pain, phlebitis, hypertension, and dizziness ( 6.1 ). Pediatric Patients: The most common adverse reactions occurring in ≥ 2% of pediatric patients were vomiting, headache, hepatic enzyme increased, diarrhea, infusion site reaction, phlebitis and pyrexia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact ISTx, LLC at 1-800-651-3861 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of ZEVTERA was evaluated in adults in four controlled comparative phase 3 clinical trials (Trials 1 through 4) which included 1221 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%). The safety of ZEVTERA was also evaluated in pediatric patients aged 3 months to less than 18 years in a controlled phase 3 clinical trial (Trial 5) which included 138 patients 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 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 [see Clinical Studies (14.1) ] . 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…