Ceftobiprole medocaril sodium
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alara Ece Dagsali, M.D.
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Overview
Ceftobiprole medocaril sodium is a beta-lactam class of antibiotics that is FDA approved for the treatment of 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.. Common adverse reactions include *Increased Mortality in Ventilator-Associated Bacterial Pneumonia Patients
- Hypersensitivity Reactions
- Seizures and Other Central Nervous System Reactions
- Clostridioides difficile-Associated Diarrhea.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
1.1 Staphylococcus aureus Bloodstream Infection (Bacteremia) 1.2 Acute Bacterial Skin and Skin Structure Infections 1.3 Community-Acquired Bacterial Pneumonia 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
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ceftobiprole medocaril sodium in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ceftobiprole medocaril sodium in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
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. The duration of treatment in adult patients with renal impairment 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 with renal impairment
In adult patients with augmented renal clearance (CLCR greater than 150 mL/min), increase the ZEVTERA dosage to 667 mg every 6 hours.
The duration of treatment for CABP in pediatric patients (2 years to less than 18 years old) with renal impairment 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 2 years to less than 12 years old.
There is insufficient information to recommend dosage adjustments in pediatric patients 2 years of age and older with an eGFR less than 15 mL/min/1.73m2.
There is insufficient information to recommend dosage adjustments in pediatric patients less than 2 years of age with any degree of renal impairment.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ceftobiprole medocaril sodium in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ceftobiprole medocaril sodium in pediatric patients.
Contraindications
ZEVTERA is contraindicated in patients with a known history of severe hypersensitivity to ZEVTERA, or to other members of the cephalosporin class
Warnings
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) 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 . 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. Nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with cephalopsorins 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 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 the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile should be discontinued, if possible. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.
5.5 Development of Drug-Resistant Bacteria Prescribing ZEVTERA 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.
Adverse Reactions
Clinical Trials Experience
- Increased Mortality in Ventilator-Associated Bacterial Pneumonia Patients
- Hypersensitivity Reactions
- Seizures and Other Central Nervous System Reactions
- Clostridioides difficile-Associated Diarrhea
Postmarketing Experience
The following adverse reactions and altered laboratory tests have been identified during post-approval use of ZEVTERA and ceftobiprole outside of the United States, or other cephalosporin-class antibacterial drugs. Because these 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.
Altered Laboratory Tests: Positive direct Coombs' test, false-positive test for urinary glucose.
Blood and lymphatic system disorders: Agranulocytosis, aplastic anemia.
Hepatobiliary disorders: Hepatic dysfunction including cholestasis
Immune system disorders: Drug fever, serum sickness-like reaction
Nervous system disorders: Myoclonus
Renal and urinary disorders: Renal dysfunction, toxic nephropathy
Vascular disorders: Hemorrhage, hypertension
Drug Interactions
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 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.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): 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.
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.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ceftobiprole medocaril sodium in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Ceftobiprole medocaril sodium during labor and delivery.
Nursing Mothers
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.
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.
Pediatric Use
The safety and effectiveness of ZEVTERA have been established for the treatment of CABP in pediatric patients 3 months to less than 18 years. Use of ZEVTERA in this age group is supported by evidence from an adequate and well-controlled trial of ZEVTERA in adults, with additional pharmacokinetic, safety and efficacy data from pediatric trials
The safety and effectiveness of ZEVTERA have not been established for the treatment of CABP in pediatric patients less than 3 months of age.
The safety and effectiveness of ZEVTERA have not been established for the treatment of ABSSSI and SAB in pediatric patients.
Geriatic Use
Of the 835 adult CABP, ABSSSI, and SAB patients treated with ZEVTERA in the Trials 1, 2 and 3, 210 patients (25%) were 65 years of age and older, including 85 patients (10%) 75 years of age and older. No overall differences in safety or effectiveness of ZEVTERA were observed between patients 65 years of age and older and younger adult patients.
No clinically significant changes in the pharmacokinetics of ZEVTERA were observed in patients 65 years of age and older compared to younger adult patients
Dosage adjustment for geriatric patients should be based on renal function
Gender
There is no FDA guidance on the use of Ceftobiprole medocaril sodium with respect to specific gender populations.
Race
There is no FDA guidance on the use of Ceftobiprole medocaril sodium with respect to specific racial populations.
Renal Impairment
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
Renal impairment (CLCR < 50 mL/min) increases ceftobiprole AUC in adult patients
ZEVTERA is removed by hemodialysis; thus, ZEVTERA should be administered after intermittent hemodialysis on hemodialysis days
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) 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 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. which may reduce ZEVTERA efficacy. The effect of augmented renal clearance function (CLCR > 150 mL/min) on ceftobiprole pharmacokinetics in pediatric patients is unknown.
Hepatic Impairment
There is no FDA guidance on the use of Ceftobiprole medocaril sodium in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ceftobiprole medocaril sodium in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Ceftobiprole medocaril sodium in patients who are immunocompromised.
Administration and Monitoring
Administration
1.1 Staphylococcus aureus Bloodstream Infection (Bacteremia) 1.2 Acute Bacterial Skin and Skin Structure Infections 1.3 Community-Acquired Bacterial Pneumonia 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
Monitoring
f CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile should be discontinued, if possible. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.
IV Compatibility
There is limited information regarding the compatibility of Ceftobiprole medocaril sodium and IV administrations.
Overdosage
There is no information on clinical signs and symptoms associated with an overdose of ZEVTERA. For patients who receive doses greater than the recommended dosage regimen and have unexpected adverse reactions associated with ZEVTERA, discontinue ZEVTERA, treat symptomatically, and institute general supportive treatment.
ZEVTERA can be removed by hemodialysis. However, no information is available on the use of hemodialysis to treat overdose
Pharmacology
There is limited information regarding Ceftobiprole medocaril sodium Pharmacology in the drug label.
Mechanism of Action
ZEVTERA is an antibacterial drug
Structure
There is limited information regarding Ceftobiprole medocaril sodium Structure in the drug label.
Pharmacodynamics
Ceftobiprole exposure-response relationships and the time course of pharmacodynamic response are 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.
Pharmacokinetics
Ceftobiprole medocaril is the prodrug of the active moiety ceftobiprole. No clinically significant differences in the pharmacokinetics of ceftobiprole were observed with ZEVTERA following single or multiple dose administration. Ceftobiprole exhibits linear and time-independent pharmacokinetics. The Cmax and AUC increase proportionally with the dose over a range of 125 to 1000 mg (0.25 to 2 times the highest approved recommended adult dosage).
The mean pharmacokinetic parameters of ceftobiprole in healthy adults with normal renal function after single and multiple 2-hour IV infusions of ZEVTERA 667 mg (equivalent to 500 mg of ceftobiprole) administered every 8 hours are summarized in Table 11. Pharmacokinetic parameters were similar for single and multiple dose administrations.
Nonclinical Toxicology
There is limited information regarding Ceftobiprole medocaril sodium Nonclinical Toxicology in the drug label.
Clinical Studies
14.1 Staphylococcus aureus Bloodstream Infection (Bacteremia) 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
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
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.
14.2 Acute Bacterial Skin and Skin Structure Infections (ABSSSI)
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.
14.3 Community-Acquired Bacterial Pneumonia
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.
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.
How Supplied
ZEVTERA (ceftobiprole medocaril sodium for injection), a white, yellowish to slightly brownish sterile powder for reconstitution, supplied in a single-dose clear glass vial (NDC# 84312-001-01) sealed with a rubber stopper (not made with natural rubber latex) and an aluminum seal with a flip-off cap. Each vial contains 667 mg ceftobiprole medocaril sodium (equivalent to 500 mg of ceftobiprole) and is supplied in a carton containing 10 single-dose vials (NDC# 84312-001-10).
Storage
Store ZEVTERA vials refrigerated at 2 °C to 8 °C (36 °F to 46 °F) protected from light. Store in carton until time of use.
ZEVTERA must be reconstituted and then further diluted prior to administration by intravenous infusion. Store reconstituted and diluted solution of ZEVTERA as described elsewhere in the labeling
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Patient Counseling Information
Serious Allergic Reactions Advise patients (or caregiver) that hypersensitivity reactions were reported with the use of ZEVTERA and that serious and occasionally fatal serious allergic reactions could occur and require immediate treatment. Advise patients to discontinue ZEVTERA if a hypersensitivity reaction occurs and inform their healthcare provider about any previous hypersensitivity reactions to ZEVTERA, other beta-lactams (including cephalosporins), or other allergens
Seizures and Central Nervous System Adverse Reactions Advise patients (or caregiver) that seizures and other adverse central nervous system (CNS) reactions have been reported during treatment with ZEVTERA. If CNS adverse reactions, including seizures, occur, advise patients to inform their healthcare provider to determine whether ZEVTERA should be discontinued
Potentially Serious Diarrhea Advise patients (or caregiver) that diarrhea is a common problem caused by antibacterial drugs, including ZEVTERA. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection. If severe watery or bloody diarrhea develops, instruct patients to contact their healthcare provider
Antibacterial Resistance Patients should be counseled that antibacterial drugs, including ZEVTERA, should be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). Patients should be told that the medication should be administered exactly as directed
Precautions with Alcohol
Alcohol-Ceftobiprole medocaril sodium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
ZEVTERA
Look-Alike Drug Names
There is limited information regarding Ceftobiprole medocaril sodium Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.