Evrotaz

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT EUROTAZ (EUROTAZ)

Composition:

Active substances: piperacillin, tazobactam;

One vial contains piperacillin sodium equivalent to piperacillin 4 g, tazobactam sodium equivalent to tazobactam 0.5 g.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical characteristics: powder ranging from white to almost white.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Beta-lactam antibiotics, penicillins. Combinations of penicillins, including beta-lactamase inhibitors.

ATC code J01CR05.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Piperacillin is a semisynthetic broad-spectrum penicillin that exhibits activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria. It inhibits bacterial activity by interfering with the formation of the septum and the synthesis of the bacterial cell wall. Tazobactam, a beta-lactam structurally related to penicillins, is an inhibitor of many beta-lactamases that commonly cause resistance to penicillins and cephalosporins; however, it does not inhibit AmpC enzymes or metallo-beta-lactamases. Tazobactam enhances and extends the antimicrobial spectrum of piperacillin by including bacteria that produce beta-lactamases typically resistant to piperacillin and other beta-lactam antibiotics.

Pharmacokinetic/Pharmacodynamic Relationships

Time above the minimum inhibitory concentration (T > MIC) is considered the primary pharmacodynamic parameter determining the efficacy of piperacillin.

Mechanism of Resistance

Two main mechanisms of resistance to piperacillin/tazobactam:

• Inactivation of the piperacillin component by beta-lactamases not inhibited by tazobactam: beta-lactamases of molecular classes B, C, and D. Additionally, tazobactam does not provide protection against extended-spectrum beta-lactamases (ESBLs) from molecular group enzymes of classes A and D.
• Alteration of penicillin-binding proteins (PBPs), leading to reduced affinity of piperacillin for its molecular target in bacteria.

Furthermore, changes in bacterial membrane permeability and overexpression of multidrug efflux pumps may contribute to bacterial resistance to piperacillin/tazobactam, particularly in Gram-negative bacteria.

Breakpoints for minimum inhibitory concentration (MIC) of piperacillin/tazobactam as defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) (EUCAST Clinical Breakpoint Table Version 10.0, effective from 2020.01.01). For susceptibility testing, the concentration of tazobactam is fixed at 4 mg/L.
Pathogenic microorganisms	Species-related breakpoints (susceptible (S) ≤ / resistant (R) >), in mg/L of piperacillin
Enterobacterales (formerly Enterobacteriaceae)	8/16
Pseudomonas aeruginosa	< 0.001/161
Staphylococcus species	-2
Enterococcus species	-3
Streptococcus groups A, B, C and G	-4
Streptococcus pneumoniae	-5
Viridans group streptococci	-6
Haemophilus influenzae	0.25/0.25
Moraxella catarrhalis	-7
Gram-positive anaerobic bacteria (except Clostridioides difficile)	8/16
Gram-negative anaerobic bacteria	8/16
Non-species-related breakpoints (based on pharmacokinetic/pharmacodynamic data)	4/16
1 For several agents, EUCAST has introduced breakpoints that classify wild-type organisms (organisms without phenotypically detected acquired resistance mechanisms to the agent) as "susceptible, increased exposure (I)" instead of "susceptible, standard dosing regimen (S)". Susceptibility breakpoints for these organism-agent combinations are listed as arbitrary, "off-scale" breakpoints with S ≤ 0.001 mg/L. 2 Most staphylococci produce penicillinase, and some are methicillin-resistant. Any of these mechanisms confers resistance to benzylpenicillin, phenoxymethylpenicillin, ampicillin, amoxicillin, piperacillin and ticarcillin. Staphylococci susceptible to benzylpenicillin and cefoxitin may be susceptible to all penicillins. Staphylococci resistant to benzylpenicillin but susceptible to cefoxitin are susceptible to β-lactamase inhibitor combinations, isoxazolyl penicillins (oxacillin, cloxacillin, dicloxacillin and flucloxacillin) and nafcillin. When administering orally, caution should be exercised to ensure adequate effect at the site of infection. Staphylococci found resistant to cefoxitin are resistant to all penicillins. S. saprophyticus susceptible to ampicillin are mecA-negative and susceptible to ampicillin, amoxicillin and piperacillin (with or without a beta-lactamase inhibitor). 3 Susceptibility to ampicillin, amoxicillin and piperacillin (with or without a beta-lactamase inhibitor) can be inferred from ampicillin testing. Resistance to ampicillin is uncommon in E. faecalis (confirmed by MIC), but common in E. faecium. 4 Susceptibility of Streptococcus groups A, B, C and G to penicillins is determined based on benzylpenicillin susceptibility, except for phenoxymethylpenicillin and isoxazolyl penicillins for Streptococcus group B. Streptococcus groups A, B, C and G do not produce beta-lactamase. Adding a beta-lactamase inhibitor provides no clinical benefit. 5 To rule out beta-lactam resistance mechanisms, a 1 µg oxacillin disk should be used or MIC testing with benzylpenicillin performed. When screening results are negative (oxacillin inhibition zone ≥ 20 mm or benzylpenicillin MIC ≤ 0.06 mg/L), susceptibility to all beta-lactam agents for which clinical breakpoints are available can be reported without further testing, except for cefaclor, which should be reported as "susceptible, increased exposure (I)". Streptococcus pneumoniae does not produce beta-lactamase. Adding a beta-lactamase inhibitor provides no clinical benefit. Susceptibility is determined using ampicillin (MIC or zone diameter). 6 For isolates susceptible to benzylpenicillin, susceptibility can be determined using benzylpenicillin or ampicillin. For isolates resistant to benzylpenicillin, susceptibility should be determined based on ampicillin. 7 Susceptibility can be determined using amoxicillin/clavulanic acid.

The prevalence of acquired resistance of individual species may vary over time and by region, so it is advisable to obtain local information on resistance, especially when treating severe infections. If necessary, advice should be sought from a specialist when local resistance prevalence raises doubts about the appropriateness of using the medicinal product, at least for certain types of infections.

Classification of organisms according to susceptibility to piperacillin/tazobactam

USUALLY SUSCEPTIBLE ORGANISMS

Gram-positive aerobic bacteria

Enterococcus faecalis (only ampicillin- or penicillin-susceptible isolates)

Listeria monocytogenes

Staphylococcus aureus (only methicillin-susceptible isolates)

Staphylococcus species, coagulase-negative (only methicillin-susceptible isolates)

Streptococcus agalactiae (Streptococcus group B)† Streptococcus pyogenes (Streptococcus group A)†

Gram-negative aerobic microorganisms

Citrobacter koseri

Haemophilus influenzae

Moraxella catarrhalis

Proteus mirabilis

Gram-positive anaerobic microorganisms

Clostridium species

Eubacterium species

Gram-positive anaerobic cocci††

Gram-negative anaerobic microorganisms

Bacteroides fragilis group

Fusobacterium species

Porphyromonas species

Prevotella species

ORGANISMS WITH POTENTIAL FOR DEVELOPING RESISTANCE

Gram-positive aerobic microorganisms

Enterococcus faecium

Streptococcus pneumoniae †

Streptococcus viridans group †

Gram-negative aerobic microorganisms

Acinetobacter baumannii

Citrobacter freundii

Enterobacter species

Escherichia coli

Klebsiella pneumoniae

Morganella morganii

Proteus vulgaris

Providencia spp.

Pseudomonas aeruginosa

Serratia species

INHERENTLY RESISTANT MICROORGANISMS

Gram-positive aerobic microorganisms

Corynebacterium jeikeium

Gram-negative aerobic microorganisms

Burkholderia cepacia Legionella species Ochrobactrum anthropi

Stenotrophomonas maltophilia

Other microorganisms

Chlamydophila pneumoniae

Mycoplasma pneumoniae

† Streptococci do not produce β-lactamase; resistance in these organisms is due to alterations in penicillin-binding proteins (PBPs), and therefore susceptible isolates are susceptible to piperacillin alone. Resistance of S. pyogenes to penicillin has not been reported. †† Includes Anaerococcus, Finegoldia, Parvimonas, Peptoniphilus, and Peptostreptococcus species.

Merino Study [Bloodstream Infections Caused by Extended-Spectrum Beta-Lactamase (ESBL)-Producing Organisms]

A prospective, open-label, randomized non-inferiority clinical trial comparing piperacillin/tazobactam with meropenem did not demonstrate non-inferiority regarding 30-day mortality in adult patients with bloodstream infections caused by ceftriaxone-non-susceptible E. coli or K. pneumoniae.

Overall, 23 of 187 patients (12.3%) randomized to receive piperacillin/tazobactam reached the primary outcome of 30-day mortality compared to 7 of 191 patients (3.7%) in the meropenem group (risk difference 8.6% [one-sided 97.5% CI from –∞ to 14.5%]; P = 0.90 for non-inferiority). The difference did not meet the pre-specified non-inferiority margin of 5%. Results were consistent in the per-protocol population analysis: 18 of 170 patients (10.6%) in the piperacillin/tazobactam group reached the primary outcome compared to 7 of 186 (3.8%) in the meropenem group (risk difference 6.8% [one-sided 97.5% CI from –∞ to 12.8%]; P = 0.76 for non-inferiority).

Clinical and microbiological responses (secondary outcomes) on day 4 were observed in 121 of 177 patients (68.4%) in the piperacillin/tazobactam group compared to 138 of 185 (74.6%) in the meropenem group (risk difference 6.2% [95% CI from –15.5% to 3.1%]; P = 0.19). For secondary outcomes, two-sided statistical tests were used, with a P value < 0.05 considered significant.

An imbalance in mortality rates between the treatment groups was observed in this study. Deaths in the piperacillin/tazobactam group were considered unrelated to the primary infection and instead attributed to underlying comorbidities.

Pharmacokinetics

Absorption. Maximum plasma concentrations of piperacillin and tazobactam after intravenous infusion of 4 g/0.5 g over 30 minutes are 298 µg/mL and 34 µg/mL, respectively.

Distribution. Protein binding of both piperacillin and tazobactam is approximately 30%, and the presence of tazobactam does not affect piperacillin binding, nor does piperacillin affect tazobactam binding. Piperacillin/tazobactam are widely distributed into body tissues and fluids, including intestinal mucosa, gallbladder mucosa, lungs, bile, female reproductive organs (uterus, ovaries, and fallopian tubes), and bone. Tissue concentrations average 50% to 100% of plasma concentrations. There are no data on penetration across the blood-brain barrier.

Metabolism. Piperacillin is metabolized to a desethyl derivative with low antibacterial activity, while tazobactam is metabolized to an inactive metabolite.

Excretion. Piperacillin and tazobactam are eliminated by the kidneys via glomerular filtration and tubular secretion. Piperacillin is rapidly excreted unchanged in urine, with 68% of the administered dose recovered in urine. Tazobactam and its metabolites are rapidly eliminated by renal excretion, with 80% of the dose recovered unchanged and the remainder as metabolites. Subsequent biliary excretion of piperacillin, tazobactam, and desethylpiperacillin is minimal.

After single and repeated doses of piperacillin and tazobactam in healthy volunteers, the plasma elimination half-life ranged from 0.7 to 1.2 hours and was independent of dose or infusion duration. The half-life of piperacillin and tazobactam increases with decreased creatinine clearance.

Special Patient Populations

Hepatic Impairment. The elimination half-life of piperacillin and tazobactam increases by approximately 25% and 18%, respectively, in patients with liver cirrhosis compared to healthy volunteers.

Renal Impairment. The elimination half-life of piperacillin and tazobactam increases as creatinine clearance decreases. When creatinine clearance is below 20 mL/min, the half-life of piperacillin and tazobactam increases by 2-fold and 4-fold, respectively, compared to patients with normal renal function.

During hemodialysis, 30% to 50% of the administered piperacillin dose and 5% of the tazobactam dose (as metabolite) are removed. During peritoneal dialysis, approximately 6% of piperacillin and 21% of tazobactam are removed, with 18% of tazobactam excreted as its metabolite.

Paediatric Population. In a population pharmacokinetic analysis, the calculated clearance in patients aged 9 months to 12 years was comparable to that in adults, with a mean value of 5.64 (0.34) mL/min/kg. Piperacillin clearance in paediatric patients aged 2 to 9 months was 80% of this value. The mean volume of distribution of piperacillin was 0.243 (0.011) L/kg and was independent of age.

Elderly Patients. The mean elimination half-life of piperacillin and tazobactam was 32% and 55% longer, respectively, in elderly patients compared to younger patients. This difference may be related to age-related changes in creatinine clearance.

Race. No differences in the pharmacokinetics of piperacillin or tazobactam were observed between healthy Mongoloid (n = 9) and Caucasian (n = 9) volunteers receiving a single 4 g/0.5 g dose.

Clinical characteristics.

Indications.

The medicinal product EUROTAZ is indicated for the treatment of the following infections in adults and children aged 2 years and older.

Adults and children aged 12 years and older:

• severe pneumonia (including hospital-acquired and ventilator-associated pneumonia);
• complicated urinary tract infections (including pyelonephritis);
• complicated intra-abdominal infections;
• complicated skin and soft tissue infections (including infectious complications in diabetic foot syndrome).

Treatment of patients with bacteremia associated or related to any of the above-mentioned infections, or suspected to be related.

The medicinal product EUROTAZ may be used for the treatment of patients with neutropenia likely caused by bacterial infection.

Note. The use of the medicinal product is not recommended in adult patients with bacteremia caused by E. coli and K. pneumoniae producing extended-spectrum beta-lactamase (resistant to ceftriaxone).

Children aged 2 to 12 years:

• complicated intra-abdominal infections.

The medicinal product EUROTAZ may be used for the treatment of febrile neutropenic children likely caused by bacterial infection.

It is recommended to follow official guidelines on the use of antibacterial medicinal products.

Contraindications.

Hypersensitivity to the active substances or to any other penicillin antibiotics.

Severe allergic reaction to another beta-lactam antibiotic (e.g., cephalosporin, monobactam, or carbapenem) in medical history.

Interaction with other medicinal products and other types of interactions.

Non-depolarizing muscle relaxants. When piperacillin and vecuronium are administered concomitantly, piperacillin has been shown to prolong vecuronium-induced neuromuscular blockade. Due to the similar mechanism of action, neuromuscular blockade caused by any non-depolarizing muscle relaxant may be prolonged when administered with piperacillin. Monitoring for adverse reactions related to neuromuscular blockade is required when any non-depolarizing muscle relaxant is used concomitantly with piperacillin.

Anticoagulants. When used concomitantly with heparin, oral anticoagulants, and other medicinal products affecting the blood coagulation system, including platelet function, coagulation parameters should be monitored more frequently.

Methotrexate. Piperacillin may delay the excretion of methotrexate; therefore, monitoring of serum methotrexate levels is necessary to prevent toxic effects.

Probenecid. As with other penicillin antibiotics, concomitant administration of probenecid and the medicinal product EUROTAZ prolongs the elimination half-life and reduces renal clearance of both piperacillin (by 21%) and tazobactam (by 71%). However, the maximum plasma concentration of both compounds remains unchanged.

Probenecid should not be used concomitantly with the medicinal product EUROTAZ unless the benefit outweighs the risk.

Aminoglycosides. Piperacillin, including in combination with tazobactam, did not show a significant effect on the pharmacokinetics of tobramycin in patients with preserved renal function as well as in patients with mild to moderate renal impairment. The pharmacokinetics of piperacillin, tazobactam, and their metabolites were also largely unchanged when tobramycin was co-administered.

In patients with acute renal impairment, inactivation of tobramycin and gentamicin has been observed during piperacillin therapy.

Due to in vitro inactivation of aminoglycosides by piperacillin in the same solution, the medicinal product EUROTAZ and aminoglycosides should be administered separately. Piperacillin-containing products and aminoglycosides must be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is prescribed. A Y-type catheter should be used for administration. When all the above conditions are met, the medicinal product EUROTAZ may be administered via a Y-type catheter only with the aminoglycosides listed in Table 1.

Table 1

Aminoglycoside	Dose (mg/L)	Required solution volume	Solution concentration for intravenous administration (mg/mL)	Compatible solution
Amikacin*	250	143–33 mL	1.75–7.5	0.9% sodium chloride solution or 5% glucose solution
Gentamicin*	40	57–12 mL	0.7–3.32	0.9% sodium chloride solution or 5% glucose solution

*Duration of infusion, see the instructions for medical use of the medicinal product.

The dose of aminoglycoside depends on body weight, the nature of infection (serious or life-threatening), and renal function (creatinine clearance).

When administering intravenously in combination, healthcare personnel must follow these requirements:

• maintain aseptic conditions; use an intravenous infusion set within 24 hours;
• label the container with the patient’s name, time, and date of administration;
• periodically check the solution for clarity, color, and presence of visible foreign particles.

Compatibility of the medicinal product EUROTAZ with other aminoglycosides has not been established. Information on the use of piperacillin/tazobactam with aminoglycosides is provided in the sections "Special instructions" and "Incompatibility".

The medicinal product EUROTAZ is incompatible with tobramycin for simultaneous infusion via a Y-site catheter.

Vancomycin. Studies have shown an increased incidence of acute kidney injury in patients receiving piperacillin/tazobactam and vancomycin concomitantly, compared to vancomycin monotherapy (see section "Special instructions"). Some of these studies indicated that the interaction with vancomycin is dose-dependent.

No pharmacokinetic interaction between piperacillin/tazobactam and vancomycin has been observed.

Effect on laboratory parameters

Non-enzymatic methods for measuring glucose levels in urine may lead to false-positive results, as with other penicillins. Therefore, enzymatic methods for measuring glucose in urine are recommended during therapy with this medicinal product.

Several chemical methods for determining protein in urine may also yield false-positive results. This does not affect protein measurement using test strips.

The direct Coombs test may be positive.

Bio-Rad Laboratories Platelia Aspergillus EIA tests may yield false-positive results in patients receiving the medicinal product EUROTAZ. Cross-reactions with non-Aspergillus polysaccharides and polyfurans have been reported with the Bio-Rad Laboratories Platelia Aspergillus EIA test.

Positive test results listed above in patients receiving EUROTAZ should be confirmed by other diagnostic methods.

Pharmaceutical compatibility with other medicinal products. The medicinal product EUROTAZ should not be mixed in the same syringe or infusion container with other medicinal products except the solvents specified above, due to lack of compatibility data.

Special precautions for use.

When selecting piperacillin/tazobactam for treatment of an individual patient, consideration should be given to the appropriateness of using a broad-spectrum synthetic penicillin, taking into account factors such as the severity of infection and the prevalence of resistance to other appropriate antibacterial agents.

Before initiating treatment with the medicinal product EUROTAS, a detailed patient history regarding hypersensitivity reactions to penicillins, cephalosporins, and other allergens should be obtained.

Severe and, rarely, fatal hypersensitivity reactions (including anaphylaxis and anaphylactic shock) have been reported during penicillin therapy. Severe allergic reactions may require discontinuation of the antibiotic, administration of adrenaline, and other emergency measures. The medicinal product EUROTAS may cause severe skin reactions, such as Stevens–Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). Patients who develop a skin rash should be closely monitored, and treatment with EUROTAS should be discontinued if skin lesions progress.

Antibiotic-associated pseudomembranous colitis may present as severe, persistent diarrhea that can be life-threatening. Pseudomembranous colitis may occur during or after antibacterial therapy. In such cases, the medicinal product should be discontinued.

Use of EUROTAS may lead to the development of microbial resistance, potentially resulting in superinfection.

Hemophagocytic lymphohistiocytosis (HLH). Cases of HLH have been reported in patients receiving piperacillin or piperacillin/tazobactam combination therapy, often when treatment duration exceeded 10 days. HLH is a life-threatening syndrome of pathological immune activation characterized by clinical signs and symptoms of excessive systemic inflammation (e.g., fever, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, elevated serum ferritin levels, cytopenia, and hemophagocytosis). Patients who develop early signs of pathological immune activation should be promptly evaluated. If HLH is diagnosed, treatment with piperacillin or piperacillin/tazobactam should be discontinued.

Bleeding has occurred in some patients receiving beta-lactam antibiotics. These reactions have sometimes been associated with changes in laboratory coagulation parameters such as blood clotting time, platelet aggregation, and prothrombin time, particularly in patients with renal impairment. If signs of bleeding occur, antibiotic therapy should be discontinued and appropriate treatment initiated.

When using the medicinal product EUROTAS, a false-positive result in urine glucose testing may occur when using methods based on copper ion reduction. Therefore, it is recommended to use a glucose test based on enzymatic oxidation. Prolonged treatment may lead to the development of leukopenia and neutropenia; therefore, periodic monitoring of the patient's hematological status is recommended.

Empirical therapy with EUROTAS may be initiated for severe infections before antibiotic susceptibility test results are available.

As with other penicillins, neurological complications such as seizures may occur with high doses, particularly in patients with impaired renal function.

Renal impairment. Due to the potential nephrotoxicity of tazobactam, caution is advised when administering to patients with impaired renal function or those undergoing hemodialysis. Intravenous doses and dosing intervals should be adjusted according to the degree of renal impairment.

According to data from a large multicenter randomized study evaluating glomerular filtration rate after administration of commonly used antibiotics for critically ill patients, the use of piperacillin/tazobactam was associated with a lower glomerular filtration rate compared to other antibiotics. The use of piperacillin/tazobactam was identified as a cause of delayed renal function recovery in these patients. Hypokalemia may develop in patients with low potassium levels or those concurrently taking medications that reduce potassium levels; in such patients, periodic monitoring of blood electrolyte levels is recommended.

Important information about excipients. This medicinal product contains 9.4 mmol (216 mg) of sodium per vial. Caution is advised when administering to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy. Adequate and well-controlled studies of piperacillin/tazobactam combination or piperacillin or tazobactam alone in pregnant women are currently lacking. The medicinal product EUROTAS crosses the placenta. It should be used only if the expected benefit to the pregnant woman outweighs the potential risk to the fetus. Animal studies have shown toxicity, but no evidence of teratogenicity was observed at doses toxic to the mother.

Breastfeeding period. Piperacillin is excreted in breast milk in small concentrations; tazobactam concentrations in breast milk have not been studied. Therefore, the medicinal product may be used during breastfeeding only if the expected benefit outweighs the potential risk to the mother and infant.

Fertility. Reproductive function studies in rats following intraperitoneal administration of tazobactam or piperacillin/tazobactam combination showed no adverse effects on fertility or mating performance.

Ability to affect driving and operating machinery.

No studies have been conducted on the effect on the ability to drive or operate machinery. During treatment, the possibility of dizziness and seizures should be considered, as these may affect psychomotor reaction speed.

Administration and Dosage

The dose and frequency of administration of the medicinal product depend on the course and site of infection, as well as on the likely causative pathogens.

Adults and children aged 12 years and older

The usual dose is 4 g piperacillin / 0.5 g tazobactam every 8 hours.

For nosocomial pneumonia and bacterial infections in neutropenic patients, the recommended dose is 4 g piperacillin / 0.5 g tazobactam every 6 hours. This regimen may also be used for treatment of patients with other indicated infections, particularly in severe forms.

Table 2 provides the recommended administration frequency for adult patients and children.

Table 2

Dosing frequency	Indications
Every 6 hours	Severe pneumonia
	Neutropenia in adults (accompanied by fever) likely associated with bacterial infection
Every 8 hours	Complicated urinary tract infections (including pyelonephritis)
	Complicated intra-abdominal infections
	Skin and soft tissue infections (including diabetic foot infections)

Patients with renal impairment

The intravenous dose should be adjusted according to the degree of renal function impairment (each patient should be carefully monitored for signs of drug toxicity; the dose and frequency of administration should be adjusted accordingly).

Table 3

Creatinine clearance (mL/min)	Recommended dose
˃ 40	No dose adjustment required
20–40	Maximum dose: 4 g / 0.5 g every 8 hours
< 20	Maximum dose: 4 g / 0.5 g every 12 hours

For patients undergoing hemodialysis, an additional dose of 2 g piperacillin / 0.25 g tazobactam should be administered after each dialysis session, as hemodialysis removes 30–50% of piperacillin within 4 hours.

Patients with hepatic impairment

Dose adjustment is not required (see section "Pharmacological properties").

Elderly patients

For elderly patients with normal renal function or creatinine clearance above 40 ml/min, dose adjustment is not required.

Children aged 2 to 12 years

Table 4 provides the dosing frequency and recommended doses per kilogram of body weight for children aged 2 to 12 years according to indications or clinical conditions.

Table 4

Dose per kilogram of body weight and frequency of administration	Indication / clinical condition
80 mg of piperacillin / 10 mg of tazobactam per kilogram of body weight every 6 hours	Febrile neutropenia in children, likely associated with bacterial infections*
100 mg of piperacillin / 12.5 mg of tazobactam per kilogram of body weight every 8 hours	Complicated intra-abdominal infections*

* Do not exceed the maximum dose of 4 g / 0.5 g with an infusion duration of 30 minutes.

Patients with renal impairment

The intravenous dose should be adjusted according to the degree of renal function impairment as follows (patients should be closely monitored for signs of drug toxicity; the dose and frequency of administration should be adjusted accordingly):

Table 5

Creatinine clearance (mL/min)	Recommended dose
> 50	No dose adjustment required
≤ 50	70 mg piperacillin / 8.75 mg tazobactam / kg every 8 hours

For children undergoing hemodialysis, an additional dose of 40 mg piperacillin / 5 mg tazobactam / kg should be administered after each dialysis session.

Children under 2 years of age

The safety and efficacy of the medicinal product EUROTAS in children under 2 years of age have not been established.

Duration of treatment

The usual duration of treatment for most indications is 5–14 days. However, the duration of treatment should depend on the severity of the infection, the causative agent, and the clinical and bacteriological response of the patient.

Method of administration

The medicinal product EUROTAS 4 g / 0.5 g should be administered by intravenous infusion (over more than 30 minutes).

Preparation of the solution

The preparation of the solution for intravenous use must be carried out under aseptic conditions. Before administration, the prepared solution should be visually inspected for the absence of particulate matter and discoloration. Only clear solutions free of particulate matter should be used.

Intravenous administration

The contents of the vial should be reconstituted with a solvent in the volume indicated in Table 6. Shake the vial until the powder is completely dissolved. With continuous shaking, reconstitution is achieved within 90 seconds.

Table 6

Contents of the vial	Volume of solvent*, to be added to the vial
4 g / 0.5 g (4 g of piperacillin and 0.5 g of tazobactam)	20 ml

* Reconstitution solvents:

• 0.9% (9 mg/mL) sodium chloride solution for injection;
• sterile water for injection(1);
• 5% glucose solution.

(1) The maximum recommended volume of sterile water for injection per 50 mL dose is 50 mL.

Reconstituted solutions should be withdrawn from the vial using a syringe. If reconstitution is performed according to the recommendations, withdrawal of the vial contents using a syringe will ensure availability of the declared amount of piperacillin/tazobactam.

Reconstituted solutions may be further diluted to the desired volume (from 50 mL to 150 mL) with one of the following compatible diluents:

• 0.9% (9 mg/mL) sodium chloride solution for injection;
• 5% glucose solution;
• sterile water for injection.

Concomitant administration with aminoglycosides

Due to in vitro inactivation of aminoglycosides by beta-lactam antibiotics, EURETAC and aminoglycosides are recommended to be administered separately. If concomitant therapy with aminoglycosides is indicated, EURETAC and aminoglycosides should be reconstituted, diluted, and administered separately.

Any unused medicinal product or waste material must be disposed of in accordance with local requirements.

For single use only. Any unused solution must be discarded.

Children.

Can be used in children aged 2 years and older.

Overdose.

Symptoms. Most of the adverse symptoms observed in overdose (including nausea, vomiting, and diarrhea) have also been reported with administration of usual doses. Increased neuromuscular excitability or seizures may occur in patients receiving doses exceeding the recommended dose (especially in the presence of renal impairment). Treatment. In case of overdose, treatment with piperacillin/tazobactam should be discontinued. There is no known specific antidote. Treatment is supportive and symptomatic, depending on the clinical presentation. Excess serum concentrations of piperacillin or tazobactam can be reduced by hemodialysis. After a single 3.375 g dose of piperacillin/tazobactam, the percentage of piperacillin and tazobactam removed by hemodialysis was approximately 31% and 39%, respectively.

Adverse reactions.

In most cases, adverse effects associated with the use of the medicinal product were not severe (diarrhea, vomiting, nausea, rash) and were tolerated by patients without the need to discontinue treatment.

The frequency of these adverse effects is ≥ 1/100 – < 1/10. The most serious adverse reactions—pseudomembranous colitis and toxic epidermal necrolysis—occur in 1–10 patients per 10,000. The frequency of pancytopenia, anaphylactic shock, and Stevens–Johnson syndrome cannot be estimated based on available data.

The adverse reactions listed below are classified by organ systems and frequency of occurrence. The following classification of frequency is used: very common (≥ 1/10); common (≥ 1/100 – < 1/10); uncommon (≥ 1/1000 – < 1/100); rare (≥ 1/10000 – < 1/1000); very rare (< 1/10000).

Organ systems	Very common	Common	Uncommon	Rare	Very rare
Infections and infestations		fungal infection (candidiasis)*		pseudomembranous colitis, rhinitis
Blood and lymphatic system disorders		thrombocytopenia, anemia*	leukopenia	anemia, bleeding (including purpura, epistaxis, prolonged bleeding time), agranulocytosis	pancytopenia, neutropenia, hemolytic anemia, thrombocytosis, eosinophilia *
Immune system disorders					anaphylactoid or anaphylactic reactions* (including shock*), hypersensitivity reactions*
Metabolism and nutrition disorders			hypokalemia
Psychiatric disorders		insomnia			delirium*
Nervous system disorders		headache	weakness*		hallucinations
Vascular disorders			arterial hypotension, phlebitis, thrombophlebitis, hot flushes, dizziness, flushing	tachycardia, arrhythmia
Respiratory, thoracic and mediastinal disorders				epistaxis, dyspnea	eosinophilic pneumonia
Gastrointestinal disorders	diarrhea	abdominal pain, vomiting, constipation, nausea, dyspepsia		stomatitis, dry mouth
Hepatobiliary disorders					hepatitis*, jaundice
Skin and subcutaneous tissue disorders		rash, pruritus	multiform erythema, urticaria, maculopapular rash	toxic epidermal necrolysis*	Stevens-Johnson syndrome, exfoliative dermatitis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis, bullous dermatitis, purpura
Musculoskeletal and connective tissue disorders			arthralgia, myalgia	muscle weakness
Renal and urinary disorders					renal failure, tubulointerstitial nephritis*
General disorders and administration site reactions		fever, injection site reactions	chills	convulsions
Investigations		increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase; increased blood urea nitrogen; increased serum creatinine; decreased total protein, albumin; positive Coombs test; prolonged activated partial thromboplastin time	decreased blood glucose, increased serum bilirubin, prolonged prothrombin time		prolonged blood clotting time, increased histone acetyltransferase (HAT) activity

*Cases of adverse reactions to piperacillin/tazobactam reported during the post-marketing period.

When used in high doses, hypernatremia, tremor, and encephalopathy (especially in patients with renal impairment) may occur.

In patients with cystic fibrosis, treatment with piperacillin has been associated with an increased incidence of fever and rash.

Effect on laboratory and other diagnostic test results
Administration of the medicinal product EUROTAZ may cause a false-positive reaction for glucose in urine when using copper sulfate-based tests, which is also typical for other penicillins. It is recommended to use methods for glucose determination based on enzymatic oxidation of glucose.

False-positive results may be obtained when measuring urinary proteins using certain chemical methods. However, the use of the medicinal product does not affect the results of protein measurement in urine using diagnostic test strips.

The direct Coombs test may yield false-positive results.

Cross-reactions with polysaccharides and polyfurans not being components of the Aspergillus cell wall have been reported when using the Bio-Rad Laboratories Platelia Aspergillus EIA test kit.

Positive results of the above-mentioned tests in patients treated with EUROTAZ should be confirmed by other diagnostic methods.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after medicinal product registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Incompatibilities.

The medicinal product EUROTAZ must not be mixed in the same syringe or infusion bottle with other medicinal products except for the solvents specified in the section "Instructions for use and dosage."

When administered simultaneously with other antibiotics (e.g., aminoglycosides), these substances must be given separately. Mixing beta-lactam antibiotics with aminoglycosides in vitro may lead to significant inactivation of the aminoglycoside.

EUROTAZ must not be mixed with other substances in a syringe or infusion bottle, as compatibility has not been established.

This medicinal product should be administered via an infusion system separately from any other agents unless compatibility has been proven.

Due to chemical instability, EUROTAZ must not be used concomitantly with solutions containing sodium bicarbonate.

Lactated Ringer's solution (Hartmann's solution) is incompatible with EUROTAZ.

EUROTAZ must not be added to blood products or albumin hydrolysate.

Packaging.

1 vial per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Astral SteriTech Private Limited.

Manufacturer's address and site of manufacturing activity.

911, K.P.R.G., Makarpura, Vadodara, Gujarat - 390010, India.

Marketing Authorization Holder.

ZEVITA.

Address of the Marketing Authorization Holder and/or its representative.

904, Habtown Viva, Western Express Highway, Jogeshwari West, Mumbai Suburban, Maharashtra, 400060, India.