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 .
1.2Acute 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.
1.3Community-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.
1.4Usage
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.
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 ).
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 ).
5.1Increased 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.
5.2Hypersensitivity 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.
5.3Seizures 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 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.
5.5Development 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.
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 )
ZEVTERA may increase the plasma concentrations of OATP1B1 and OATP1B3 substrates. Concomitant administration is not recommended [see Clinical Pharmacology (12.3) ].
7.2Drug-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.
Pregnancy and breastfeeding
8.1Pregnancy 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.
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.
6.1Clinical 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 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 adverse reactions occurring in ≥ 2% of SAB adult patients receiving ZEVTERA in Trial 1. Table 8: Selected Adverse Reactions Occurring in ≥ 2% of SAB Adult Patients Receiving ZEVTERA in Trial 1 Trial 1 was not designed to evaluate meaningful comparisons of the incidence of adverse reactions in the ZEVTERA and the daptomycin plus or minus aztreonam treatment groups.
Adverse Reaction ZEVTERA ZEVTERA 667 mg IV over 2-hours every 6 hours from Day 1 to Day 8, and every 8 hours from Day 9 onwards, with dosing adjustment based on renal function. 667 mg ceftobiprole medocaril sodium is equivalent to 500 mg of ceftobiprole. N = 191 Daptomycin Daptomycin 6 mg/kg up to 10 mg/kg IV over 0.5 hour every 24 hours, with dosing adjustment based on renal function. ± Aztreonam N = 198 SAB = Staphylococcus aureus bacteremia.
Anemia Anemia includes the following terms: anemia, hemoglobin decreased, hypochromic anemia, and normochromic normocytic anemia. 12% 13% Nausea 10% 4% Hypokalemia Hypokalemia replaces the term blood potassium decreased. 9% 3% Vomiting 8% 2% Hepatic enzyme and bilirubin increased Hepatic enzyme increased includes the following terms: alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, blood bilirubin increased, and hyperbilirubinemia. 8% 10% Diarrhea 7% 3% Blood creatinine increased Blood creatinine increased includes the following terms: acute kidney injury, blood creatinine increased, creatinine renal clearance decreased, oliguria, and renal impairment. 7% 5% Hypertension Hypertension includes the following terms: hypertension, blood pressure increased, and hypertensive crisis. 5% 2% Leukopenia Leukopenia includes the following terms: leukopenia, lymphocyte count decreased, lymphopenia, neutropenia, neutrophil count decreased, and white blood cell count decreased. 4% 3% Pyrexia Pyrexia includes the following terms: hyperthermia and pyrexia. 4% 3% Abdominal pain Abdominal pain includes the following terms: abdominal pain upper and abdominal tenderness. 3% 1% Fungal infection Fungal infection includes the following terms: candida infection, candida sepsis, fungal test positive, oral candidiasis, vulvovaginal candidiasis, and tinea pedis. 3% 2% Headache 3% 3% Dyspnea Dyspnea includes the following terms: dyspnea and respiratory distress. 2% 1% 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) [see Clinical Studies (14.2) ] .
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.
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Composition
Active ingredients
CEFTOBIPROLE MEDOCARIL SODIUM 667MG/VIAL
Official product information
Drugs@FDA lists the approved labels, letters and reviews for application NDA218275.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
