ZEVTERA (ceftobiprole medocaril sodium for injection) for HCPs home page

Efficacy and Safety

Overall success and demonstrated safety profile

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ERADICATE Trial

ERADICATE—one of the largest double-blind, randomized controlled clinical trials in SAB1,2

ZEVTERA demonstrated efficacy in a Phase 3 noninferiority trial2

Double-blind, randomized, multicenter, multinational, clinical trial in hospitalized adults with complicated SAB, including right-sided infective endocarditis (modified ITT population N=387)2,3

Screeninga,b

Confirmed SAB based on ≥1 positive blood culture within 72h prior to randomization

Clinical evidence of complicated SAB or definitive right-sided infective endocarditis

RANDOMIZED 1:1

ACTIVE TREATMENT (UP TO 42 DAYS)

ZEVTERA (n=189)

667 mg IV q6h on Days 1‑8;
667 mg IV q8h from Day 9 onwards

Daptomycin ±
Aztreonam (n=198)

Daptomycin: 6‑10 mg/kg
IV q24h

DAY 42
POST-TREATMENT EVALUATION (DAY 70)

Primary Endpoint:
Overall successc

Key Secondary Endpoints:
Microbiologic eradicationd; time to SAB bloodstream clearance

Baseline characteristics of ERADICATE trial participants

ZEVTERA was studied in patients with complicated SAB, including those with MRSA and right‑sided infective endocarditis2,3

Median age: 58 years, range 19 to 91 years; 31% aged ≥ 65 years3

69% of patients were male3

Frequent concomitant factors among trial participants with complicated SAB included3:

  • 61% with acute bacterial skin and skin structure infections
  • 24% with bacteremia caused by MRSA
  • 14% with intra-abdominal abscesses
  • 13% with osteoarticular infections
  • 13% on chronic dialysis
  • 6.5% with definite right-sided infective endocarditis

aComplicated SAB was defined as persistent S. aureus bacteremia (positive blood cultures despite receipt of appropriate antibiotics for ≥3 days before randomization); S. aureus bacteremia associated with long-term hemodialysis; or S. aureus bacteremia arising from soft-tissue infection, abdominal abscess, osteoarticular infection, septic thrombophlebitis, septic pulmonary embolus, epidural or cerebral abscess, or native-valve infective endocarditis on the right side of the heart (according to modified Duke criteria).2

bKey exclusion criteria included treatment with a potentially effective systemic antibiotic for more than 48 hours within the 7 days prior to randomization; concomitant infections with Gram-negative bacteria that are not susceptible to either ZEVTERA or aztreonam; severe neutropenia; or community- or hospital-acquired pneumonia.2‑4

cOverall success was defined as survival, symptom improvement, SAB clearance, absence of new SAB-related complications, and no use of other potentially effective antibiotics.2

dMicrobiologic eradication was defined as no growth of S. aureus based on a negative blood culture and confirmation by ≥1 repeat negative blood culture.4

ITT, intention-to-treat; MRSA, methicillin-resistant Staphylococcus aureus; SAB, Staphylococcus aureus bacteremia.

Clinical Response

Key clinical outcomes in the ERADICATE trial2,3

ZEVTERA achieved noninferiority for overall success* compared to daptomycin ± aztreonam in the ERADICATE trial (mITT population) at PTE (post-treatment evaluation) visit at 70 days post-randomization.2,3,a

Slide table to view more.
Bar chart comparing clinical success rates: ZEVTERA 82.0% (n=189) vs. Daptomycin ± Aztreonam 77.3% (n=198); between group difference 5.1% (95% CI: –2.9 to 13.0).

*Overall success was defined as survival, symptom improvement, SAB clearance, absence of new SAB-related complications, and no use of other potentially effective antibiotics.

aThe lower boundary of the 95% CI of the between group difference was -7.1%, which was greater than the prespecified noninferiority margin of -15%, indicating the noninferiority of ZEVTERA to daptomycin in the ERADICATE trial.2

bBetween-group difference of ceftobiprole minus daptomycin ± aztreonam using Cochran-Mantel-Haenszel weights method adjusted for actual stratum (dialysis status and prior antibacterial treatment use).3

CI, confidence interval; mITT, modified intention-to-treat; MSSA, methicillin-sensitive Staphylococcus aureus.

ZEVTERA demonstrated bloodstream clearance across both MSSA and MRSA infections2,3

Time to SAB Bloodstream Clearance in Patients with MSSA2,3

In patients with MSSA, SAB bloodstream clearance was achieved after a median of 3 days in 94% of patients in the ZEVTERA group and after a median of 4 days in 95% of patients in the daptomycin ± aztreonam group

Slide table to view more.
Bar chart showing average time to clinical response: ZEVTERA (3 days) vs. Daptomycin ± Aztreonam (4 days).

Safety

ZEVTERA—consistent safety and tolerability3*

The safety of ZEVTERA has been evaluated in 835 adult patients across three Phase 3 clinical trials.3

In the 42-day treatment period in the ERADICATE trial†, the most common adverse reactions occurring in > 2% of patients receiving ZEVTERA included3:

Slide table to view more.
Adverse reactionZevtera
N=191		Daptomycin ± Aztreonam
N=198
Anemiaa12%13%
Nausea10%4%
Hypokalemiab9%3%
Vomiting8%2%
Hepatic enzyme and bilirubin increasedc8%10%
Diarrhea7%3%
Blood creatinine increasedd7%5%
Hypertensione5%2%
Leukopeniaf4%3%
Pyrexiag4%3%
Abdominal painh3%1%
Fungal infectioni3%2%
Headache3%3%
Dyspneaj2%1%

aAnemia includes: Anemia, Hemoglobin decreased, Hypochromic anemia, Normochromic normocytic anemia.3

bHypokalemia replaces: Blood potassium decreased.3

cHepatic enzyme increased: Alanine aminotransferase increased, Aspartate aminotransferase increased, Blood alkaline phosphatase increased, Gamma-glutamyltransferase increased, Blood bilirubin increased, Hyperbilirubinemia.3

dBlood creatinine increased includes: Acute kidney injury, Blood creatinine increased, Creatinine renal clearance decreased, Oliguria, Renal impairment.

eHypertension includes: Hypertension, Blood pressure increased, Hypertensive crisis.

fLeukopenia includes: Leukopenia, Lymphocyte count decreased, Lymphopenia, Neutropenia, Neutrophil count decreased, White blood cell count decreased.3

gPyrexia includes: Hyperthermia, Pyrexia.3

hAbdominal pain includes: Abdominal pain upper, Abdominal tenderness.3

iFungal infection includes: Candida infection, Candida sepsis, Fungal test positive, Oral candidiasis, Vulvovaginal candidiasis, Tinea pedis.3

jDyspnea includes: Dyspnea, Respiratory distress.3

IV, intravenous

Resistance

In surveillance and clinical studies, resistance to ZEVTERA was uncommon5,6

In the ERADICATE trial, there was no resistance development on therapy with ZEVTERA2

In the daptomycin ± aztreonam group, three patients (1.5%), two with MSSA and one with MRSA, experienced MICs increasing by at least four-fold and became non-susceptible to daptomycin

MIC, minimum inhibitory concentration.

No cross-resistance with other classes of antimicrobials has been identified3

May retain activity against certain cephalosporin-resistant pathogens

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It's Clear...

...Achieve rapid bloodstream clearance rates* with ZEVTERA.2,3

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*Based on data from the ERADICATE trial, a Phase 3, randomized, double-blind, noninferiority study comparing ZEVTERA with daptomycin ± aztreonam in patients with complicated SAB. The median time to bloodstream clearance was 4 days in both groups.2,3

INDICATIONS & USAGE

Indications

ZEVTERA® (ceftobiprole medocaril sodium for injection), for intravenous use, is indicated for the treatment of:

  • Adult patients with Staphylococcus aureus bloodstream infections (bacteremia) (SAB), including those with right-sided infective endocarditis, caused by methicillin-susceptible and methicillin-resistant isolates.
  • 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.
  • Adult and pediatric patients (3 months to less than 18 years) 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.

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.

Important Safety Information

Contraindications:

ZEVTERA is contraindicated in patients with a known history of severe hypersensitivity to ZEVTERA, or to other members of the cephalosporin class.

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.
  • 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.
  • Seizures and other adverse central nervous system (CNS) reactions have been reported during treatment with ZEVTERA and other cephalosporins. If CNS adverse reactions, including seizures, occur, evaluate patients to determine whether ZEVTERA should be discontinued.
  • Clostridioides difficile-associated diarrhea (CDAD) has been reported with nearly all systemic antibacterial agents, including ZEVTERA, and may range in severity from mild diarrhea to fatal colitis. If CDAD is suspected or confirmed, the risk/benefit of continuing treatment with ZEVTERA should be assessed.

Adverse Reactions:

  • SAB (adult patients): The most common adverse reactions occurring in ≥ 2% of adult patients were anemia, nausea, hypokalemia, vomiting, hepatic enzyme and bilirubin increased, diarrhea, blood creatinine increased, hypertension, leukopenia, pyrexia, abdominal pain, fungal infection, headache, and dyspnea.
  • ABSSSI (adult patients): The most common adverse reactions occurring in ≥ 2% of adult patients were nausea, diarrhea, headache, injection site reaction, hepatic enzyme increase, rash, vomiting, and dysgeusia.

  • 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.
    • 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.

You are encouraged to report negative side effects of prescription drugs to the FDA. To report SUSPECTED ADVERSE REACTIONS, please contact:

Innoviva Specialty Therapeutics, Inc.™ 1‑800‑651‑3861 medinfo@istx.com

U.S. Food and Drug Administration 1‑800‑FDA‑1088 www.fda.gov/medwatch

Before administering, please see the Full Prescribing Information for ZEVTERA.