Zeftera (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Janssen Pharmaceutica, NV (Belgium)

Manufactured By

Patheon UK, Limited (United Kingdom)

ATC Code

J01DI01 (Ceftobiprole medocaril)

Active Substance

Ceftobiprole (Rec.INN registered by WHO)

Dosage Form

Zeftera

Lyophilizate for the preparation of solution for infusion 500 mg: fl. 1 or 10 pcs.

Dosage Form, Packaging, and Composition

Lyophilizate for the preparation of solution for infusion in the form of a compact, broken or powdery mass of white or from yellowish to slightly brownish color.

Excipients: citric acid monohydrate, sodium hydroxide, nitrogen (inert gas for lyophilization).

Glass vials with a capacity of 20 ml (1) – cardboard packs.
Glass vials with a capacity of 20 ml (10) – cardboard packs.

Clinical-Pharmacological Group

Fifth generation cephalosporin

Pharmacotherapeutic Group

Antibiotic-cephalosporin

Pharmacological Action

Antibiotic of the cephalosporin group. Ceftobiprole medocaril is a water-soluble prodrug of ceftobiprole, a cephalosporin with bactericidal activity against a wide range of gram-positive bacteria, including methicillin-resistant Staphylococcus species, penicillin-resistant Streptococcus pneumoniae, and ampicillin-susceptible Enterococcus faecalis. Ceftobiprole is also active against many gram-negative bacteria, including many strains of the Enterobacter spp. family and Pseudomonas aeruginosa.

Ceftobiprole binds firmly to many important penicillin-binding proteins (PBPs) of both gram-positive and gram-negative bacteria. Ceftobiprole has pronounced bactericidal activity against methicillin-resistant Staphylococcus spp. due to its firm binding to PBP2a of staphylococci, including methicillin-resistant Staphylococcus aureus.

Ceftobiprole is active against most isolates of the following microorganisms both in vitro and in hospital-acquired infections: Gram-positive aerobes – Enterococcus faecalis (vancomycin-susceptible and vancomycin-resistant isolates), Staphylococcus aureus (methicillin-susceptible and methicillin-resistant isolates), Staphylococcus epidermidis, Streptococcus agalactiae, Streptococcus pyogenes, coagulase-negative Staphylococcus spp. strains (methicillin-susceptible and methicillin-resistant isolates, including Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus lugdunensis and Staphylococcus saprophyticus), Streptococcus pneumoniae (penicillin-susceptible, penicillin-intermediate and penicillin-resistant isolates), Streptococcus group viridans; Gram-negative aerobes – Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Citrobacter spp. (including Citrobacter freundii, Citrobacter koseri), Enterobacter aerogenes, Klebsiella oxytoca, Moraxella catarrhalis, Morganella morganii, Neisseria spp., Providencia spp., Serratia marcescens.

Ceftobiprole is resistant to hydrolysis by Staphylococcus aureus penicillinases, as well as to hydrolysis by many class C and class A β-lactamases produced by gram-negative bacteria. Like most cephalosporins, Ceftobiprole is hydrolyzed by extended-spectrum beta-lactamases, carbapenemases and metallo-beta-lactamases. In vitro, selection of high-level resistance was not observed in staphylococci, streptococci and Haemophilus influenzae.

Resistance to ceftobiprole caused by spontaneous mutation in vitro is rare. Cross-resistance between ceftobiprole and some other latest generation cephalosporins has been described. However, some microorganisms resistant to other cephalosporins may be susceptible to ceftobiprole.

Pharmacokinetics

The mean pharmacokinetic parameters of ceftobiprole in adults after a single 500 mg dose administered as a 60-minute infusion and after multiple 500 mg doses administered as 120-minute infusions every 8 hours are shown in Table 1. The pharmacokinetic characteristics are similar after single-dose and multiple-dose administration.

Table 1. Mean (standard deviation) pharmacokinetic parameters of ceftobiprole in adults

C_max and AUC of ceftobiprole increase proportionally to the dose in the range of 125 mg – 1 g. C_ss concentrations are achieved on the first day of treatment; in people with normal renal function, administration of ceftobiprole every 8 hours and every 12 hours does not cause its accumulation.

Distribution

The binding of ceftobiprole to plasma proteins is 16% and is independent of its concentration. V_d at steady state is 18 L and approximates the volume of extracellular fluid in humans.

Metabolism

Biotransformation from ceftobiprole medocaril, which is a prodrug, into the active substance Ceftobiprole occurs rapidly and is catalyzed by plasma esterases. The concentrations of the prodrug are negligible and can be detected in plasma and urine only during the infusion.

Ceftobiprole undergoes minimal metabolism to an open-ring metabolite, which is microbiologically inactive. The concentration of this metabolite is lower than the concentration of ceftobiprole itself and is about 4% of the latter.

Excretion

Ceftobiprole is excreted predominantly unchanged via renal excretion. T_1/2 is about 3 hours. The main mechanism of renal excretion is glomerular filtration, a small part of the dose undergoes tubular reabsorption. In preclinical studies, probenecid did not affect the pharmacokinetics of ceftobiprole, indicating the absence of active tubular secretion of the latter. After a single dose, approximately 89% is found in the urine as active ceftobiprole (83%), the open-ring metabolite (5%), and ceftobiprole medocaril (<1%).

Pharmacokinetics in special clinical cases

The pharmacokinetics of ceftobiprole are similar in healthy volunteers and in patients with mild renal impairment (CrCl 50-80 ml/min). Compared to the AUC in healthy volunteers with normal renal function, the AUC of ceftobiprole was 2.5 and 3.3 times higher in patients with moderate renal impairment (CrCl from 30 ml/min to ≤50 ml/min) and severe renal impairment (CrCl < 30 ml/min), respectively. In patients with moderate and severe renal impairment, a dose reduction of ceftobiprole is recommended. The AUC of ceftobiprole and its microbiologically inactive open-ring metabolite increases in patients requiring hemodialysis compared to the AUC in healthy volunteers.

The pharmacokinetics of ceftobiprole in patients with hepatic impairment have not been studied. Ceftobiprole undergoes minimal hepatic metabolism and is excreted mainly by the kidneys unchanged, so there is no reason to believe that the clearance of ceftobiprole in patients with hepatic impairment will be reduced.

Population pharmacokinetic studies of ceftobiprole did not reveal an independent effect of age on its pharmacokinetic parameters. In elderly patients with normal renal function, no dose reduction of this drug is required.

The values of systemic pharmacokinetic parameters of ceftobiprole were higher in women than in men (C_max by 21% and AUC by 15%); however, the % t>MIC (where t is the time during which the drug concentration exceeds the MIC value) was similar in men and women. Therefore, there is no need to adjust the dose of Zeftera depending on the patient’s sex.

Population pharmacokinetic studies (including Caucasians and a small number of Negroids and other races) did not reveal an effect of race on the pharmacokinetic parameters of ceftobiprole. No dose adjustment of the drug is required depending on the patient’s race.

Indications

• Treatment of complicated skin and skin structure infections, including infected diabetic foot without concomitant osteomyelitis.

ICD codes

Dosage Regimen

For infections that are suspected or proven to be caused by gram-negative bacteria, gram-positive and gram-negative bacteria in infected diabetic foot without concomitant osteomyelitis, the recommended dose of Zeftera is 500 mg every 8 hours as 120-minute IV infusions.

For infections that are suspected or proven to be caused by gram-positive bacteria, the dose of the drug is 500 mg every 12 hours as 60-minute IV infusions. This dosing regimen (with 12-hour intervals) has not been studied in patients with infected diabetic foot.

In elderly patients, no dose adjustment is required.

In patients with mild renal impairment (CrCl 50-80 ml/min), no dose adjustment is required. In moderate renal impairment (CrCl from 30 ml/min to <50 ml/min), the dose of Zeftera is 500 mg every 12 hours as 120-minute IV infusions. In severe renal impairment (CrCl <30 ml/min), the dose of the drug is 250 mg every 12 hours as 120-minute IV infusions. Due to limited clinical data and the expected increase in the concentration of ceftobiprole and its metabolites, Zeftera should be administered with caution to patients with severe renal impairment.

Ceftobiprole is removed by hemodialysis, but there is currently insufficient information to change the dosing regimen in patients on dialysis. Therefore, Zeftera is not recommended for patients on any form of hemodialysis.

There is currently no experience with the use of ceftobiprole in patients with hepatic impairment. However, given that Ceftobiprole undergoes minimal hepatic metabolism and is eliminated primarily by the kidneys, it can be assumed that no dose reduction of ceftobiprole is required in patients with hepatic impairment.

Rules for preparation of the infusion solution

The lyophilized powder should be dissolved in 10 ml of Water for Injections or 5% Glucose solution for injections. The vial contents should be shaken vigorously. Complete dissolution of the powder takes up to 10 minutes. Before dilution in the infusion solution, the resulting foam should be allowed to settle.

For dilution, 10 ml of the prepared solution should be withdrawn from the vial and added to an appropriate container (e.g., polyvinyl chloride or polyethylene bags, glass bottles) containing 250 ml of 0.9% Sodium Chloride solution, 5% Glucose solution or Ringer’s Lactate solution for infusions. The container with the infusion solution should be gently inverted 5-10 times to obtain a homogeneous solution of ceftobiprole. To avoid foam formation, the solution should not be shaken vigorously.

For patients with severe renal impairment, 5 ml of the finished ceftobiprole solution is diluted in 125 ml of 0.9% Sodium Chloride solution, 5% Glucose solution or Ringer’s Lactate solution for infusions.

Before administration, the infusion solution should be visually inspected for the absence of mechanical inclusions, and if any are found, the solution should be discarded.

Adverse Reactions

Adverse effects occurring with a frequency of ≥1% in patients who received 500 mg of ceftobiprole every 8-12 hours as 60-minute or 120-minute infusions are listed in Table 2.

Discontinuation of ceftobiprole was required due to the development of the following adverse effects: skin rash (0.6%), nausea (0.5%), vomiting (0.4%), hypersensitivity reactions (0.3%), hyponatremia (0.3%).

Table 2. Frequency (%) of adverse effects observed in two phase 3 clinical trials with a frequency of ≥1%

In most cases, nausea was mild, resolved spontaneously, and did not require drug discontinuation. Nausea was observed less frequently in patients receiving the drug as 120-minute infusions (10%) than in cases of 60-minute infusions (14%).

The frequency of seizures, anaphylaxis, and Clostridium difficile-associated pseudomembranous colitis with the use of ceftobiprole was less than 1%.

Contraindications

• History of allergic reactions to beta-lactam antibiotics;
• Age under 18 years;
• Hypersensitivity to the components of the drug;
• Hypersensitivity to other cephalosporins.

With caution the drug should be used in patients with renal impairment (CrCl less than 50 ml/min), epilepsy, with a history of seizures, a history of pseudomembranous colitis.

Use in Pregnancy and Lactation

Adequate and strictly controlled clinical studies of the use of Zeftera during pregnancy have not been conducted.

Preclinical studies have shown that Ceftobiprole does not have teratogenic activity and does not affect ossification, fetal body weight and intrauterine development. The results of studies of the effect of drugs on reproductive function in animals cannot always be extrapolated to the corresponding function in humans, so Zeftera can be prescribed to pregnant women only in cases where the expected benefit of therapy for the mother outweighs the potential risk to the fetus.

It is not known whether Ceftobiprole is excreted in human breast milk. Animal studies have shown that Ceftobiprole is excreted in breast milk. Given this, if it is necessary to use the drug during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

There is currently no experience with the use of ceftobiprole in patients with hepatic impairment. However, given that Ceftobiprole undergoes minimal hepatic metabolism and is eliminated primarily by the kidneys, it can be assumed that no dose reduction of ceftobiprole is required in patients with hepatic impairment.

Use in Renal Impairment

In patients with mild renal impairment (CrCl 50-80 ml/min), no dose adjustment is required. In moderate renal impairment (CrCl from 30 ml/min to <50 ml/min), the dose of Zeftera is 500 mg every 12 hours as 120-minute IV infusions. In severe renal impairment (CrCl <30 ml/min), the dose of the drug is 250 mg every 12 hours as 120-minute IV infusions. Due to limited clinical data and the expected increase in the concentration of ceftobiprole and its metabolites, Zeftera should be administered with caution to patients with severe renal impairment.

Pediatric Use

Contraindication: age under 18 years.

Special Precautions

Serious, sometimes fatal, anaphylactic reactions have been described in patients receiving beta-lactam antibiotics. These reactions occur more frequently in patients with allergies to a large number of allergens. Before starting treatment with Zeftera, a thorough history should be taken and the presence of hypersensitivity reactions to other cephalosporins, penicillins or other allergens should be established. If an allergic reaction to Ceftobiprole occurs, it should be discontinued immediately. In case of development of severe acute hypersensitivity reactions (anaphylaxis), emergency therapy is required.

Bacteriological studies should be performed to isolate and identify the causative agents of infections and determine their susceptibility to ceftobiprole. In the absence of such data, empirical therapy should be carried out, guided by local epidemiological data and information on the local susceptibility pattern of microorganisms.

In patients receiving antibacterial agents, including Ceftobiprole, pseudomembranous colitis of varying severity may occur. Therefore, the possibility of pseudomembranous colitis development should be considered in patients who develop diarrhea during treatment with ceftobiprole.

Prolonged use of ceftobiprole, like other antibiotics, may cause overgrowth of non-susceptible microorganisms, including fungi, and therefore the patient’s condition should be periodically assessed. If superinfection occurs during treatment with ceftobiprole, appropriate measures should be taken.

When using ceftobiprole, as with other beta-lactams, the development of seizures is possible. The occurrence of seizures associated with the use of ceftobiprole is most often observed in patients with pre-existing CNS disorders. Therefore, caution is recommended when treating such patients.

Effect on Ability to Drive and Operate Machinery

No studies have been conducted on the effect of Zeftera on the ability to drive vehicles and operate machinery. Taking Zeftera may cause dizziness, which affects the ability to drive vehicles and perform work requiring high concentration and quick psychomotor reactions. Therefore, it is not recommended to use the drug while driving vehicles or engaging in other potentially hazardous activities.

Overdose

There is currently no information on ceftobiprole overdose in humans. The maximum dose administered in phase 1 clinical studies was 3 g/day (1 g every 8 hours).

Treatment of overdose should involve general supportive therapy with monitoring of key physiological parameters. Ceftobiprole plasma concentration can be reduced by hemodialysis.

Drug Interactions

Studies of the interaction of ceftobiprole with other drugs have not been conducted. Ceftobiprole has a minimal potential for interaction with other medicinal products.

Ceftobiprole has been shown to have minimal ability to inhibit the CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 isoenzymes, and lacks the ability to induce these isoenzymes. Due to this, and because the distribution of ceftobiprole is limited to extracellular fluid, it has a low potential to affect the CYP450-mediated metabolic clearance of concomitantly administered drugs. The potential for other drugs to interact with ceftobiprole is also minimal, as only a small portion of its dose is metabolized. Thus, there is no reason to expect clinically significant drug interactions with ceftobiprole.

Ceftobiprole is not secreted by renal tubules, and only a negligible portion of its dose is reabsorbed, so the likelihood of drug interaction at the kidney level is extremely low.

No effect on the pharmacokinetics of ceftobiprole was identified for the following concomitantly used drugs: fentanyl, lidocaine, paracetamol, diclofenac, acetylsalicylic acid, heparin, diphenhydramine, propofol, hydromorphone hydrochloride, methadone, hydrocodone bitartrate, sodium metamizole, and furosemide.

Pharmaceutical Interactions

The compatibility of ceftobiprole with other drugs has not been studied. Ceftobiprole should not be mixed with other drugs or added to solutions containing other medicinal products.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, in the original packaging at a temperature between 2°C (35.6°F) and 8°C (46.4°F).

Shelf Life

The shelf life is 2 years.

Storage of the Prepared Solution and Infusion Solution

The prepared solution can be stored for 1 hour at 25°C (77°F) and for 24 hours at a temperature between 2°C (35.6°F) and 8°C (46.4°F).

Reconstitution, dilution, and infusion must be performed within the timeframes specified in Table 3 below.

Table 3.

The prepared solution and the infusion solution must not be frozen and must not be exposed to direct sunlight.

After removal from the refrigerator, infusion solutions should be allowed to warm to room temperature before infusion. During use, the infusion solution does not need to be protected from light. Preparation of the infusion solution should be carried out in accordance with the instructions for solution preparation and handling.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.