Zerbaxa^® (Powder) Instructions for Use

Marketing Authorization Holder

MSD Pharmaceuticals, LLC (Russia)

Manufactured By

Steri-Pharma LLC (USA)

Packaging and Quality Control Release

STERI-PHARMA LLC (USA)

Or

FAREVA Mirabel (France)

ATC Code

J01DI54 (Ceftolozane and beta-lactamase inhibitor)

Active Substances

Ceftolozane (Rec.INN registered by WHO)

Tazobactam (Rec.INN registered by WHO)

Dosage Form

Zerbaxa®

Powder for concentrate for solution for infusion preparation 1000 mg+500 mg: fl. 10 pcs.

Dosage Form, Packaging, and Composition

Powder for the preparation of concentrate for the preparation of solution for infusion from white to yellow.

Excipients : anhydrous citric acid – 21 mg, sodium chloride – 487 mg, arginine – 600 mg (q.s. to pH 6.5±0.5).

Colorless glass vials with a capacity of 20 ml (10) – cardboard boxes^×.

^× package opening control may be present.

Clinical-Pharmacological Group

Broad-spectrum penicillin antibiotic with a beta-lactamase inhibitor

Pharmacotherapeutic Group

Antibiotic, cephalosporin + beta-lactamase inhibitor

Pharmacological Action

A combined antibacterial agent containing the beta-lactamase inhibitor tazobactam and the cephalosporin antibiotic ceftolozane, intended for intravenous administration. The bactericidal activity of ceftolozane is due to the inhibition of bacterial cell wall synthesis and is mediated by its binding to penicillin-binding proteins (PBPs).

Ceftolozane is an inhibitor of Pseudomonas aeruginosa PBPs, in particular, PBP1b, PBP1c, and PBP3) and Escherichia coli (in particular, PBP3). Tazobactam is a beta-lactam antibiotic structurally related to penicillin. Tazobactam has low clinically significant in vitro activity against bacteria due to reduced affinity for PBPs. It is an inhibitor of many molecular class A beta-lactamases, including CTX-M, SHV, and TEM enzymes.

In vitro activity of this combination has been demonstrated against Enterobacteriaceae in the presence of some extended-spectrum beta-lactamases (ESBLs) and other beta-lactamases of the following groups: TEM, SHV, CTX-M, and OXA. In vitro activity of this combination was also observed against studied isolates of P. aeruginosa, which have chromosomal AmpC, loss of outer membrane porin (OprD), or stimulation of efflux pumps (MexXY, MexAB).

Mechanisms of bacterial resistance to ceftolozane and tazobactam include: production of beta-lactamases that destroy ceftolozane, which are not inhibited by tazobactam; modification of PBPs.

Tazobactam does not inhibit all class A enzymes. Furthermore, tazobactam does not inhibit the following types of beta-lactamases: serine-based carbapenemases (e.g., Klebsiella pneumoniae carbapenemase (KPC)); metallo-beta-lactamases (e.g., New Delhi metallo-beta-lactamase (NDM)); Ambler class D beta-lactamases (OXA-carbapenemases); some AmpC produced by Enterobacteriaceae.

When choosing or modifying antibacterial therapy, information on the susceptibility of bacteria causing the infection, as well as local epidemiology, should be taken into account.

Isolates resistant to other cephalosporins may be susceptible to ceftolozane+tazobactam, although cross-resistance may be observed.

This combination is active against the following microorganisms both in vitro and in infections caused by these pathogens.

Complicated intra-abdominal infections: gram-negative microorganisms – Enterobacter cloacae, Escherichia coli Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa; gram-positive microorganisms –
Streptococcus anginosus Streptococcus constellatus Streptococcus salivarius.

Complicated urinary tract infections, including pyelonephritis gram-negative microorganisms – Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis.

Clinical efficacy against the following microorganisms has not been established , although in vitro studies suggest their susceptibility to this combination in the absence of acquired resistance mechanisms: gram-negative microorganisms – Citrobacter freundii, Citrobacter koseri, Enterobacter aerogenes, Morganella morganii, Proteus vulgaris, Serratia liquefacians, Serratia marcescens.

According to in vitro data, the following microorganism species are not susceptible to this combination: Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium.

Pharmacokinetics

C_max and AUC of ceftolozane and tazobactam increase proportionally with doses. Plasma concentrations of ceftolozane and tazobactam do not significantly increase with multiple intravenous administrations of the drug containing this combination in doses up to 3 g (ceftolozane 2 g + tazobactam 1 g), administered every 8 hours for up to 10 days to healthy adults with normal renal function.

The binding of ceftolozane and tazobactam to plasma proteins is approximately from 16% to 21% and 30%, respectively. The mean V_d of ceftolozane and tazobactam in healthy adult males, after a single intravenous administration of a dose of ceftolozane 1 g + tazobactam 0.5 g), was 13.5 L (21%) and 18.2 L (25%) respectively, which is similar to the volume of extracellular fluid.

Ceftolozane is mainly excreted by the kidneys unchanged and does not appear to be significantly metabolized. The beta-lactam ring of tazobactam is hydrolyzed to form the pharmacologically inactive metabolite M1.

Ceftolozane, tazobactam, and the tazobactam metabolite are excreted by the kidneys. After administration of a single intravenous dose of 1 g/0.5 g ceftolozane+tazobactam to healthy adult males, more than 95% of ceftolozane was excreted by the kidneys unchanged. More than 80% of tazobactam was excreted as the parent compound, with the remaining amount excreted as the tazobactam metabolite M1. After administration of a single dose of this combination, the renal clearance of ceftolozane (3.41-6.69 L/h) was comparable to the plasma clearance (4.10-6.73 L/h) and to the GFR for the unbound fraction, indicating that ceftolozane is excreted by the kidneys via glomerular filtration.

The mean T_1/2 of ceftolozane and tazobactam in healthy adults with normal renal function is approximately 3 h and 1 h, respectively.

Ceftolozane, tazobactam, and the tazobactam metabolite M1 are excreted by the kidneys. The dose-normalized mean geometric AUC of ceftolozane was increased 1.26-fold, 2.5-fold, and 5-fold in volunteers with mild, moderate, and severe renal impairment, respectively, compared to healthy volunteers with normal renal function. The corresponding dose-normalized mean geometric AUC of tazobactam increased approximately 1.3-fold, 2-fold, and 4-fold.

Indications

Treatment of infections caused by microorganisms susceptible to the combination of ceftolozane + tazobactam in patients aged 18 years and older: in combination with metronidazole for the treatment of complicated intra-abdominal infections caused by the following gram-negative and gram-positive microorganisms – Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus and Streptococcus salivarius;
Treatment of complicated urinary tract infections, including pyelonephritis, caused by the following gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and Pseudomonas aeruginosa.

To prevent the development of bacterial resistance and preserve the effectiveness of the drug and other antibacterial drugs, this combination should be used only when it is proven or highly suspected that the infection is caused by a microorganism susceptible to the drug. If information on the pathogen and its susceptibility is available, this data should be considered when choosing or modifying antibacterial therapy. In the absence of such data, local epidemiology and bacterial susceptibility monitoring data may aid in the selection of empirical therapy.

ICD codes

Dosage Regimen

Administer intravenously as an infusion over 1 hour every 8 hours. The duration of treatment depends on the severity and location of the infectious process, as well as clinical and microbiological efficacy.

For patients with CrCl>50 ml/min, a single dose of the combination is 1.5 g.

For patients with CrCl≤50 ml/min, dose adjustment is necessary.

Since elderly patients are more likely to have reduced renal function, caution should be exercised when selecting the dose, and monitoring of renal function is also recommended.

Adverse Reactions

Infections and parasitic diseases uncommon – candidiasis, incl. oropharyngeal and vulvovaginal, Clostridium difficile colitis, fungal urinary tract infection.

Blood and lymphatic system disorders common – thrombocytosis; uncommon – anemia.

Metabolism and nutrition disorders common – hypokalemia; uncommon – hyperglycemia, hypomagnesemia, hypophosphatemia.

Psychiatric disorders common – insomnia, anxiety.

Nervous system disorders common – headache, dizziness; uncommon – ischemic stroke.

Cardiac disorders common – decreased blood pressure; uncommon – atrial fibrillation, tachycardia, angina pectoris, phlebitis, venous thrombosis.

Respiratory, thoracic and mediastinal disorders uncommon – dyspnea.

Gastrointestinal disorders common – nausea, diarrhea, constipation, vomiting, abdominal pain; uncommon – gastritis, abdominal distension, dyspepsia, flatulence, paralytic ileus.

Skin and subcutaneous tissue disorders common – rash; uncommon – urticaria.

Renal and urinary disorders uncommon – renal impairment, renal failure.

General disorders and administration site conditions common – fever, administration site reactions.

Investigations common – increased ALT, AST; uncommon – positive Coombs test, increased GGT, increased ALP.

Contraindications

Hypersensitivity to the components of the combination, hypersensitivity to cephalosporins, severe hypersensitivity reactions (e.g., anaphylactic reactions, severe skin reactions) to any other beta-lactam antibiotic (e.g., penicillins or carbapenems).

With caution

Renal impairment; non-severe hypersensitivity reactions to any other beta-lactam antibiotic (e.g., penicillins or carbapenems); Clostridium difficile-associated diarrhea (in history); elderly age.

Use in Pregnancy and Lactation

There are no data on the use of ceftolozane+tazobactam in pregnant women. It is unknown whether ceftolozane crosses the placental barrier. Tazobactam crosses the placental barrier. Animal studies of tazobactam demonstrated reproductive toxicity without teratogenic effects. The drug containing this combination should be used during pregnancy only if the expected treatment benefit for the mother outweighs the potential risk to the fetus.

It is unknown whether ceftolozane and tazobactam are excreted in human breast milk. Risk to newborns/infants cannot be ruled out. The decision to discontinue breastfeeding or discontinue/interrupt drug therapy should be made taking into account the benefit of breastfeeding for the child and the benefit of the drug for the mother.

Use in Hepatic Impairment

The drug is approved for use in hepatic impairment

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age

Special Precautions

If severe allergic reactions occur during the use of ceftolozane+tazobactam, the drug should be discontinued and appropriate measures taken. Patients with a history of hypersensitivity to cephalosporins, penicillins, or other beta-lactam antibiotics may also be hypersensitive to ceftolozane+tazobactam.

Caution should be exercised when using ceftolozane+tazobactam in patients with a history of any other types of hypersensitivity reactions to penicillins or other beta-lactam antibiotics.

In clinical studies, the efficacy of ceftolozane+tazobactam was lower in patients with moderate renal impairment compared to patients with baseline normal renal function or mild renal impairment. In patients with baseline renal impairment, any changes in renal function should be regularly monitored during treatment and the dose of ceftolozane+tazobactam should be adjusted if necessary.

Cases of antibiotic-associated colitis and pseudomembranous colitis have been reported with the use of ceftolozane+tazobactam. These types of infections can range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients with diarrhea that occurs during or after the use of ceftolozane+tazobactam. In these cases, the possibility of discontinuing ceftolozane+tazobactam therapy and implementing supportive measures along with specific treatment for Clostridium difficile should be assessed. The use of drugs that inhibit intestinal peristalsis is contraindicated.

The use of ceftolozane+tazobactam may promote the overgrowth of non-susceptible microorganisms. If superinfection occurs during or after treatment, appropriate measures should be taken.

A positive direct antiglobulin test (DAT) result is possible with the use of ceftolozane+tazobactam. The frequency of seroconversion based on DAT results in patients taking ceftolozane+tazobactam was 0.2% in clinical studies. In clinical studies, there were no signs of hemolysis in patients who had a positive DAT result during treatment.

Effect on ability to drive and operate machinery

May have a minor influence on the ability to drive and operate machinery. Dizziness may occur after using this combination.

Drug Interactions

Tazobactam is a substrate of OAT1 and OAT3. In vitro, tazobactam inhibited human OAT1 and OAT3 transporters with IC₅₀ values of 118 µg/ml and 147 µg/ml, respectively.

In clinical studies, concomitant use of ceftolozane+tazobactam with the OAT1 and OAT3 substrate furosemide did not significantly increase the plasma exposure of furosemide (mean geometric C_max and AUC ratios were 0.83 and 0.87, respectively). However, active substances that inhibit OAT1 or OAT3 (e.g., probenecid) may increase the plasma concentration of tazobactam. Concomitant use of tazobactam with the OAT1/OAT3 inhibitor probenecid demonstrated a 71% increase in the T_1/2 of tazobactam.

In vitro studies have demonstrated no antagonism between ceftolozane+tazobactam and other antibacterial drugs (including meropenem, amikacin, aztreonam, levofloxacin, tigecycline, rifampicin, linezolid, daptomycin, vancomycin, and metronidazole).

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.