Ceftobiprole - Warnings and Precautions

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 .

Hypersensitivity Reactions: Discontinue ZEVTERA if a hypersensitivity reaction occurs, and institute appropriate treatment .

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 .

Clostridioides difficile -associated diarrhea (CDAD) has been reported with nearly all systemic antibacterial agents, including ZEVTERA.

Evaluate if diarrhea occurs .

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 ] .

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 ] .

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 ] .

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.