Brand name: Zevtera
Drug class: Fifth Generation Cephalosporins

Introduction

Ceftobiprole medocaril sodium is a cephalosporin antibacterial.

Uses for Ceftobiprole Medocaril Sodium

Ceftobiprole Medocaril Sodium has the following uses:

Ceftobiprole medocaril sodium is indicated for the treatment of:

• Adult patients with Staphylococcus aureus bloodstream infections (bacteremia) (SAB), including those with right-sided infective endocarditis

• Adult patients with acute bacterial skin and skin structure infections (ABSSSI)

• Adult and pediatric patients (3 months to less than 18 years of age) with community-acquired bacterial pneumonia (CABP)

To reduce the development of drug-resistant bacteria and maintain the effectiveness of ceftobiprole medocaril and other antibacterial drugs, ceftobiprole medocaril should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Ceftobiprole Medocaril Sodium Dosage and Administration

General

Ceftobiprole medocaril sodium is available in the following dosage form(s) and strength(s):

For injection: 667 mg of ceftobiprole medocaril sodium (equivalent to 500 mg of ceftobiprole) as a lyophilized powder for reconstitution in a single-dose vial.

Administration

Ceftobiprole medocaril sodium must first be reconstituted in the vial and then further diluted prior to administration by IV infusion over a period of 2 hours. Aseptic technique must be followed in preparing the infusion solution. See full prescribing information for instructions on preparation of the infusion solution.

Dosage

Pediatric Patients

Dosage

The recommended dosage of ceftobiprole medocaril sodium for pediatric patients (3 months to less than 18 years of age) with CABP is described in the table below:

Duration of treatment in pediatric patients is 7 days to 14 days for CABP.

Administer each prepared IV infusion solution of ceftobiprole medocaril sodium over 2 hours at a concentration of 2.67 mg/mL for pediatric patients 12 years to less than 18 years of age and at a concentration of 5.33 mg/mL for pediatric patients 3 months to less than 12 years of age.

Reduce the dosage in pediatric patients 2 years to less than 18 years of age with eGFR less than 50 mL/min/1.73 m² and greater than or equal to 15 mL/min/1.73 m².

Adults

Dosage

The recommended dosage of ceftobiprole medocaril sodium for adults with SAB, ABSSSI, or CABP is described in the table below:

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 IV infusion solution of ceftobiprole medocaril sodium over 2 hours at a concentration of 2.67 mg/mL.

Reduce the dosage in adult patients with Cl_cr less than 50 mL/minute, including patients with Cl_crless than 15 mL/minute on hemodialysis.

Increase the dosage in adult patients with Cl_cr greater than 150 mL/minute.

Cautions for Ceftobiprole Medocaril Sodium

Contraindications

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

Warnings/Precautions

Warnings

Increased Mortality with Unapproved Use in Ventilator-Associated Bacterial Pneumonia

In an active-controlled, randomized, double-blind, multicenter, phase 3 trial in patients with hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (VABP), an increase in mortality was seen in the subgroup of patients with VABP who were treated with ceftobiprole medocaril sodium (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 ceftobiprole medocaril sodium for the treatment of VABP has not been established and the use of ceftobiprole medocaril sodium for VABP is not approved.

Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis, were observed in ceftobiprole medocaril-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 ceftobiprole medocaril 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 the drug if a hypersensitivity reaction occurs, and institute appropriate treatment.

Seizures and Other Central Nervous System Reactions

Seizures and other adverse central nervous system (CNS) reactions have been reported during treatment with ceftobiprole medocaril 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 ceftobiprole medocaril sodium 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 ceftobiprole medocaril should be discontinued.

Clostridioides difficile-Associated Diarrhea

Clostridioides difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including ceftobiprole medocaril sodium for injection, 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.

Development of Drug-Resistant Bacteria

Prescribing ceftobiprole medocaril sodium 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.

Specific Populations

Pregnancy

There are no available data with use of ceftobiprole medocaril sodium 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. IV 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. IV administration of ceftobiprole medocaril sodium 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.

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.

Lactation

There are no data on the presence of ceftobiprole medocaril in human milk, the effects of ceftobiprole on the breastfed infant, or the effects of the drug on milk production. Animal studies have shown that ceftobiprole medocaril was excreted in milk of lactating rats at low concentrations. 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 ceftobiprole medocaril sodium and any potential adverse effects on the breastfed child from the drug or from the underlying maternal conditions.

Pediatric Use

The safety and effectiveness of ceftobiprole medocaril sodium have been established for the treatment of CABP in pediatric patients 3 months to less than 18 years of age. Use of the drug in this age group is supported by evidence from an adequate and well-controlled trial of ceftobiprole medocaril sodium in adults, with additional pharmacokinetic, safety and efficacy data from pediatric trials.

The safety and effectiveness of ceftobiprole medocaril sodium have not been established for the treatment of CABP in pediatric patients less than 3 months of age.

The safety and effectiveness of ceftobiprole medocaril sodium have not been established for the treatment of ABSSSI and SAB in pediatric patients.

Geriatric Use

Of the 835 adult CABP, ABSSSI, and SAB patients treated with ceftobiprole medocaril sodium in the principal efficacy trials, 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 ceftobiprole medocaril sodium were observed between patients 65 years of age and older and younger adult patients.

No clinically significant changes in the pharmacokinetics of ceftobiprole medocaril sodium 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.

Renal Impairment

Adult Patients:The ceftobiprole medocaril sodium dosage is reduced in adult patients with Cl_cr < 50 mL/minute, including patients with Cl_cr < 15 mL/minute either receiving or not receiving hemodialysis. Renal impairment (Cl_cr < 50 mL/minute) increases ceftobiprole AUC in adult patients, which may increase the risk of adverse reactions. ceftobiprole medocaril sodium is removed by hemodialysis; thus, the drug should be administered after intermittent hemodialysis on hemodialysis days.

Pediatric Patients: The ceftobiprole medocaril sodium dosage is reduced in pediatric patients 2 years to less than 18 years of age with renal impairment (eGFR 15 to < 50 mL/min/1.73 m²). Use in pediatric patients 2 years to less than 18 years of age with renal impairment (eGFR 15 to < 50 mL/min/1.73 m²) is predicted to increase ceftobiprole AUC, which may increase the risk of 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 of age with eGFR < 15 mL/min/1.73 m² either receiving or not receiving hemodialysis on ceftobiprole pharmacokinetics is unknown.

Adults with Augmented Renal Clearance: Increase the ceftobiprole medocaril sodium dosing frequency in adult patients with augmented renal clearance (Cl_cr > 150 mL/minute). Use in adult patients with augmented renal clearance (Cl_cr > 150 mL/minute) is predicted to decrease ceftobiprole exposure, which may reduce efficacy of the drug. The effect of augmented renal clearance function (Cl_cr > 150 mL/minute) on ceftobiprole pharmacokinetics in pediatric patients is unknown.

Common Adverse Effects

The most common adverse reactions occurring in ≥ 4% of adult patients with SAB were anemia, nausea, hypokalemia, vomiting, hepatic enzyme and bilirubin increased, diarrhea, blood creatinine increased, hypertension, leukopenia, and pyrexia.

The most common adverse reactions occurring in ≥ 2% of adult patients with ABSSSI were nausea, diarrhea, headache, injection site reaction, hepatic enzyme increased, rash, vomiting, and dysgeusia.

The most common adverse reactions occurring in ≥ 2% of adult patients with CABP were nausea, hepatic enzyme increased, vomiting, diarrhea, headache, rash, insomnia, abdominal pain, phlebitis, hypertension, and dizziness.

The most common adverse reactions occurring in ≥ 2% of pediatric patients with CABP were vomiting, headache, hepatic enzyme increased, diarrhea, infusion site reaction, phlebitis, and pyrexia.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Organic Anion Transporting Polypeptide 1B1/1B3 (OATP1B1/OATP1B3) Substrates

Ceftobiprole medocaril sodium may increase the plasma concentrations of OATP1B1 and OATP1B3 substrates. Concomitant administration is not recommended.

Drug-Laboratory Test Interactions

Dipstick Tests: ceftobiprole medocaril sodium 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 ceftobiprole medocaril sodium 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.

Actions

Mechanism of Action

Ceftobiprole is a cephalosporin with bactericidal activity by inhibition of bacterial cell wall synthesis. Ceftobiprole has in vitro activity against gram-positive and gram-negative bacteria, including methicillin-resistant and susceptible Staphylococcus aureus. Bactericidal activity is mediated through binding to essential penicillin-binding proteins (PBPs) and inhibiting their transpeptidase activity, which is essential for the synthesis of the peptidoglycan layer of the bacterial cell wall. Ceftobiprole has a high affinity for S. aureus PBPs 1–4, including PBP2a in methicillin-resistant Staphylococcus aureus, and PBP2x and PBP2b in penicillin-resistant Streptococcus pneumoniae.

Ceftobiprole medocaril sodium has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections: Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant isolates), Streptococcus pyogenes, Klebsiella pneumoniae, Streptococcus pneumoniae, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, and Klebsiella pneumoniae.

At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ceftobiprole medocaril sodium against isolates of similar genus or organism group. However, the efficacy of ceftobiprole medocaril sodium in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials: Staphylococcus epidermidis, Staphylococcus hominis, Staphylococcus lugdunensis, Streptococcus agalactiae, Streptococcus mitis group, Streptococcus dysgalactiae, Streptococcus anginosus group, Citrobacter koseri, Enterobacter cloacae, Klebsiella aerogenes, Moraxella catarrhalis, Morganella morganii, and Proteus mirabilis.

Ceftobiprole is not active against gram-negative bacteria producing extended-spectrum β-lactamases (ESBLs) from the TEM, SHV or CTX-M families, serine carbapenemases (such as KPC), class B metallo-β-lactamases, class C (AmpC cephalosporinases) if expressed at high levels, and Ambler class D β-lactamases including carbapenemases.

No cross-resistance with other classes of antimicrobials has been identified. Although cross-resistance may occur, some isolates resistant to other cephalosporins may be susceptible to ceftobiprole.

Advice to Patients

• Advise patients (or caregiver) that hypersensitivity reactions were reported with the use of ceftobiprole medocaril sodium and that serious and occasionally fatal serious allergic reactions could occur and require immediate treatment. Advise patients to discontinue ceftobiprole medocaril sodium if a hypersensitivity reaction occurs and inform their healthcare provider about any previous hypersensitivity reactions to the drug, other beta-lactams (including cephalosporins), or other allergens.

• Advise patients (or caregiver) that seizures and other adverse CNS reactions have been reported during treatment with ceftobiprole medocaril sodium. If CNS adverse reactions, including seizures, occur, advise patients to inform their healthcare provider to determine whether the drug should be discontinued.

• Advise patients (or caregiver) that diarrhea is a common problem caused by antibacterial drugs, including ceftobiprole medocaril sodium. 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.

• Patients should be counseled that antibacterial drugs, including ceftobiprole medocaril sodium, should be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). Patients should be advised that the medication should be administered exactly as directed.

Additional Information

AHFSfirstRelease™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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