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  • Zerbaxa 1 g/0.5 g
    / MSD


    Active Ingredient *

    Status in Israel
    RX

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    Vial

    10 X 20 ml

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    Dosage

    Recommended intravenous dose regimen for patients with creatinine clearance > 50 mL/min:
    Complicated intra-abdominal infection*: 1 g ceftolozane / 0.5 g tazobactam, Every 8 hours.
    Infusion time: 1 hour. 
    Duration of treatment: 4-14 days.
    Complicated urinary tract infection Acute pyelonephritis: 1 g ceftolozane / 0.5 g tazobactam, Every 8 hours.
    Infusion time: 1 hour. 
    Duration of treatment: 7 days.
    *To be used in combination with metronidazole when anaerobic pathogens are suspected.
    Special populations
    Elderly (≥ 65 years of age): No dose adjustment is necessary for the elderly based on age alone.
    Renal impairment: In patients with mild renal impairment (estimated creatinine clearance [CrCL] > 50 mL/min), no dose adjustment is necessary.
    In patients with moderate or severe renal impairment, and in patients with end stage renal disease on haemodialysis, the dose should be adjusted as listed in Table 2 at the attached doctor’s leaflet.
    Hepatic impairment: No dose adjustment is necessary in patients with hepatic impairment.
    Paediatric population: The safety and efficacy of ceftolozane/tazobactam in children and adolescents below 18 years of age have not yet been established. No data are available.
    Method of administration: Zerbaxa is for intravenous infusion. The infusion time is 1 hour for 1 g / 0.5 g of Zerbaxa.
    See prescribing information for full details.


    Indications

    Zerbaxa is indicated for the treatment of the following infections in adults:
    – Complicated intra-abdominal infections;
    – Acute pyelonephritis caused by pathogens resistant to other treatments as confirmed by urine culture;
    – Complicated urinary tract infections.
    Consideration should be given to official guidance on the appropriate use of antibacterial agents.


    Contra-Indications

    Hypersensitivity to the active substances or to any of the excipients;
    Hypersensitivity to any cephalosporin antibacterial agent;
    Severe hypersensitivity (e.g., anaphylactic reaction, severe skin reaction) to any other type of beta-lactam antibacterial agent (e.g., penicillins or carbapenems).


    Special Precautions

    Hypersensitivity reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions are possible.
    If a severe allergic reaction occurs during treatment with ceftolozane/tazobactam, the medicinal product should be discontinued and appropriate measures taken.
    Patients who have a history of hypersensitivity to cephalosporins, penicillins or other beta-lactam antibacterial agents may also be hypersensitive to ceftolozane/tazobactam.
    Ceftolozane/tazobactam is contraindicated in patients with a history of hypersensitivity to ceftolozane, tazobactam, or cephalosporins.
    Ceftolozane/tazobactam is also contraindicated in patients with severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of beta-lactam antibacterial agent (e.g. penicillins or carbapenems).
    Ceftolozane/tazobactam should be used with caution in patients with a history of any other type of hypersensitivity reaction to penicillins or other beta-lactam antibacterial agents.
    Effect on renal function: A decline in renal function has been seen in patients receiving ceftolozane/tazobactam.
    Impaired renal function: The ceftolozane/tazobactam dose should be adjusted based on renal function.
    In clinical trials the efficacy of ceftolozane/tazobactam was lower in patients with moderate renal impairment compared with those with normal or mildly impaired renal function at baseline. Patients with renal impairment at baseline should be monitored frequently for any changes in renal function during treatment and the dose of ceftolozane/tazobactam should be adjusted as necessary.
    Limitations of the clinical data: Patients who were immunocompromised and patients with severe neutropenia were excluded from clinical trials.
    In a trial in patients with complicated intra-abdominal infections, the most common diagnosis was appendiceal perforation or peri-appendiceal abscess (420/970 [43.3%] patients), of which 137/420 (32.6%) had diffuse peritonitis at baseline. Approximately 82% of all patients in the trial had APACHE II (Acute Physiology and Chronic Health Evaluation II) scores of < 10 and 2.3% had bacteraemia at baseline. In the clinically evaluable (CE) patients, the clinical cure rates for ceftolozane/tazobactam were 95.9% in 293 patients aged less than 65 years and 87.8% in 82 patients aged 65 years or more.
    Clinical efficacy data in patients with complicated lower urinary tract infection are limited. In a randomised active-controlled trial 18.2% (126/693) of microbiologically evaluable (ME) patients had complicated lower urinary tract infection (cLUTI), including 60/126 patients who were treated with ceftolozane/tazobactam. One of these 60 patients had bacteraemia at baseline.
    Clostridium difficile-associated diarrhoea: Antibacterial-associated colitis and pseudomembranous colitis have been reported with ceftolozane/tazobactam. These types of infection may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of ceftolozane/tazobactam. In such circumstances, the discontinuation of therapy with ceftolozane/tazobactam and the use of supportive measures together with the administration of specific treatment for Clostridium difficile should be considered.
    Non-susceptible micro-organisms: The use of ceftolozane/tazobactam may promote the overgrowth of non-susceptible micro-organisms. If super infection occurs during or following treatment, appropriate measures should be taken.
    Ceftolozane/tazobactam is not active against bacteria that produce beta-lactamase enzymes which are not inhibited by tazobactam.
    Direct antiglobulin test (Coombs test) seroconversion and potential risk of haemolytic anaemia: The development of a positive direct antiglobulin test (DAGT) may occur during treatment with ceftolozane/tazobactam. The incidence of DAGT seroconversion in patients receiving ceftolozane/tazobactam
    was 0.2% in the clinical trials. In clinical studies, there was no evidence of haemolysis in patients who developed a positive DAGT on treatment.
    Sodium content: Ceftolozane/tazobactam contains 10.0 mmol (230 mg) of sodium per vial. The reconstituted vial with 10 mL of 0.9% sodium chloride (normal saline) for injection contains 11.5 mmol (265 mg) of sodium. This should be taken into consideration while treating patients on controlled-sodium diet.


    Side Effects

    The most common adverse reactions (≥ 3% in pooled Phase 3 trials) occurring in patients receiving Zerbaxa were nausea, headache, constipation, diarrhoea, and pyrexia and were generally mild or moderate in severity.
    See prescribing information for full details.


    Drug interactions

    No significant medicinal product interactions are anticipated between ceftolozane/tazobactam and substrates, inhibitors, and inducers of cytochrome P450 enzymes (CYPs) based on in vitro and in vivo studies.
    In vitro studies demonstrated that ceftolozane, tazobactam and the M1 metabolite of tazobactam did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 and did not induce CYP1A2, CYP2B6, or CYP3A4 at therapeutic plasma concentrations.
    Ceftolozane and tazobactam were not substrates for P-gp or BCRP, and tazobactam was not a substrate for OCT2, in vitro at therapeutic plasma concentrations. In vitro data indicate that ceftolozane did not inhibit
    P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, MRP, BSEP, OAT1, OAT3, MATE1, or MATE2-K in vitro at therapeutic plasma concentrations. In vitro data indicate that neither tazobactam nor the tazobactam metabolite M1 inhibit P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, or BSEP transporters at therapeutic
    plasma concentrations.
    Tazobactam is a substrate for OAT1 and OAT3. In vitro, tazobactam inhibited human OAT1 and OAT3 transporters with IC50 values of 118 and 147 mcg/mL, respectively. Co-administration of ceftolozane/tazobactam with OAT1 and OAT3 substrate furosemide in a clinical study did not significantly increase furosemide plasma exposures (geometric mean ratios of 0.83 and 0.87 for Cmax and AUC,
    respectively). However, active substances that inhibit OAT1 or OAT3 (e.g., probenecid) may increase tazobactam plasma concentrations.


    Pregnancy and Lactation

    Pregnancy: There are no data on the use of ceftolozane/tazobactam in pregnant women. Tazobactam crosses the placenta. It is not known if ceftolozane crosses the placenta. Zerbaxa should only be used during pregnancy if the expected benefit outweighs the possible risks to the pregnant woman and foetus.
    Lactation: It is unknown whether ceftolozane and tazobactam are excreted in human milk. A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Zerbaxa therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
    See prescribing information for full details.


    Overdose

    There is no experience with overdose of Zerbaxa. The highest single dose of Zerbaxa used in clinical trials was 3 g / 1.5 g of ceftolozane/tazobactam administered to healthy volunteers.
    In the event of overdose, Zerbaxa should be discontinued and general supportive treatment given. Zerbaxa can be removed by haemodialysis. Approximately 66% of ceftolozane, 56% of tazobactam, and 51% of the M1
    metabolite of tazobactam were removed by dialysis.


    Important notes

    Storage: Store in a refrigerator (2°C – 8°C).


    Manufacturer
    Merck Sharp & Dohme Corp., USA
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