Tazamax

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TAZAMAX (TAZAMAX)

Composition:

Active substances: piperacillin sodium, tazobactam sodium;

One vial contains piperacillin sodium equivalent to piperacillin 4 g and tazobactam sodium equivalent to tazobactam 500 mg.

Pharmaceutical form.

Powder for solution for infusion.

Main physicochemical characteristics: white or almost white powder.

Pharmacotherapeutic group.

Antibacterials for systemic use. Beta-lactam antibiotics, penicillins. Combinations of penicillins, including with 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 and inhibits bacterial activity by blocking the formation of the septal wall and synthesis of the 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 to include bacteria producing beta-lactamases that are normally insensitive 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 (ESBL) from molecular enzyme groups 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, as well as expression of multidrug efflux pumps, may cause or 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)". The 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. Caution should be exercised when administering oral agents to ensure adequate exposure 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 exclude beta-lactam resistance mechanisms, a 1 µg oxacillin disk or MIC testing for benzylpenicillin should be used. When the screening result is negative (oxacillin inhibition zone ≥ 20 mm or benzylpenicillin MIC ≤ 0.06 mg/l), susceptibility to all beta-lactam agents with available clinical breakpoints 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 is 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 geographical region; therefore, it is advisable to obtain local information on resistance, especially when treating severe infections. If necessary, expert advice should be sought when local resistance prevalence is such that the appropriateness of using the medicinal product, at least for certain types of infections, is questionable.

Classification of organisms according to susceptibility to piperacillin/tazobactam

USUALLY SUSCEPTIBLE ORGANISMS

Aerobic Gram-positive bacteria

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

Listeria monocytogenes

Staphylococcus aureus (only methicillin-susceptible isolates)

Staphylococcus spp., coagulase-negative (only methicillin-susceptible isolates)

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

Aerobic Gram-negative microorganisms

Citrobacter koseri

Haemophilus influenzae

Moraxella catarrhalis

Proteus mirabilis

Anaerobic Gram-positive microorganisms

Clostridium spp.

Eubacterium spp.

Anaerobic Gram-positive cocci††

Anaerobic Gram-negative microorganisms

Bacteroides fragilis group

Fusobacterium spp.

Porphyromonas spp.

Prevotella spp.

ORGANISMS THAT MAY DEVELOP RESISTANCE

Aerobic Gram-positive microorganisms

Enterococcus faecium

Streptococcus pneumoniae †

Streptococcus viridans group †

Aerobic Gram-negative microorganisms

Acinetobacter baumannii

Citrobacter freundii

Enterobacter spp.

Escherichia coli

Klebsiella pneumoniae

Morganella morganii

Proteus vulgaris

Providencia spp.

Pseudomonas aeruginosa

Serratia spp.

INTRINSICALLY RESISTANT ORGANISMS

Aerobic Gram-positive microorganisms

Corynebacterium jeikeium

Aerobic Gram-negative microorganisms

Burkholderia cepacia Legionella spp. 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 only to piperacillin. Resistance of S. pyogenes to penicillin has not been reported. †† Including Anaerococcus, Finegoldia, Parvimonas, Peptoniphilus, and Peptostreptococcus spp.

Merino study [bloodstream infections caused by (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 ceftriaxone-resistant bloodstream infections due to 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%. The results were consistent in the per-protocol population analysis: 18 of 170 patients (10.6%) achieved the primary outcome in the piperacillin/tazobactam group 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 to be related to underlying comorbidities rather than the primary infection.

Pharmacokinetics.

Absorption. Peak plasma concentrations of piperacillin and tazobactam after administration of 4 g / 0.5 g as a 30-minute intravenous infusion are 298 µg/mL and 34 µg/mL, respectively.

Distribution. Protein binding of both piperacillin and tazobactam is approximately 30%; the presence of tazobactam does not affect the binding of piperacillin, and vice versa. Piperacillin/tazobactam widely distributes into tissues and body fluids, including intestinal mucosa, gallbladder mucosa, lungs, bile, female reproductive organs (uterus, ovaries, and fallopian tubes), and bone. Tissue concentrations average between 50% and 100% of plasma concentrations. Data on penetration across the blood-brain barrier are lacking.

Metabolism. Piperacillin is metabolized to a desethyl derivative with low antibacterial activity; tazobactam is metabolized to an inactive metabolite. Elimination. Piperacillin and tazobactam are eliminated by the kidneys via glomerular filtration and tubular secretion. Piperacillin is rapidly excreted unchanged, with 68% of the administered dose recovered in urine. Tazobactam and its metabolites are rapidly eliminated by renal excretion, with 80% of the administered dose excreted 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. With reduced creatinine clearance, the elimination half-life of piperacillin and tazobactam is prolonged.

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 tazobactam (as metabolite) are removed. During peritoneal dialysis, approximately 6% of piperacillin and 21% of tazobactam are eliminated, with 18% of tazobactam excreted as its metabolite.

Paediatric population. In a population pharmacokinetic analysis, the estimated 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 Asian (n = 9) and Caucasian (n = 9) volunteers receiving a single 4 g / 0.5 g dose.

Clinical characteristics.

Indications.

The medicinal product is indicated for the treatment of the infections listed below 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 associated with diabetic foot syndrome).

Also indicated for treatment of patients with bacteremia associated or concurrent with any of the above-mentioned infections.

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

Children aged 2 to 12 years:

• complicated intra-abdominal infections.

The medicinal product may be used for the treatment of fever in children with neutropenia likely caused by bacterial infection.

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

Contraindications.

Hypersensitivity to the active substances or to any other penicillin antibiotics. History of severe allergic reaction to another beta-lactam antibiotic (e.g., cephalosporin, monobactam, or carbapenem).

Interaction with other medicinal products and other forms of interaction.

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 induced by any non-depolarizing muscle relaxant may be prolonged by piperacillin administration. 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 agents affecting the blood coagulation system, including platelet function, coagulation parameters should be monitored more frequently.

Methotrexate. Piperacillin may delay methotrexate excretion; therefore, serum methotrexate levels should be monitored in patients to prevent toxic effects.

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

Probenecid should not be used concomitantly with the medicinal product Tazamaks 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 normal 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 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, Tazamaks and aminoglycosides should be administered separately. Piperacillin and aminoglycoside preparations must be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is prescribed. A Y-type catheter may be used only for administration. Tazamaks may be administered via a Y-type catheter only with the aminoglycosides listed in Table 1, provided all the above conditions are met.

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 administration, see the instructions for medical use of the medicinal product.

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

When co-administering intravenously, medical personnel must follow certain requirements, namely:

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

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

Tazamax is incompatible with tobramycin for simultaneous infusion via a Y-type catheter. Vancomycin. Studies have shown an increased incidence of acute kidney injury in patients receiving concomitant piperacillin/tazobactam and vancomycin compared to vancomycin monotherapy (see section "Special instructions"). Some of these studies indicated that the vancomycin interaction was 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, during Tazamax therapy, enzymatic measurement of glucose in urine is recommended.

Several chemical methods for determining protein in urine may 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 Tazamax. 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 Tazamax should be confirmed by other diagnostic methods.

Pharmaceutical compatibility with other medicinal products. Tazamax should not be mixed in the same syringe or infusion container with other medicinal products except for 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 semisynthetic penicillin in view of factors such as the severity of infection and the prevalence of resistance to other relevant antibacterial agents.

Before initiating treatment with Tazamax, a detailed patient history regarding hypersensitivity reactions to penicillins, cephalosporins, and other allergens should be carefully reviewed.

Severe and occasionally fatal hypersensitivity reactions (anaphylaxis, including anaphylactic shock) have been reported in patients receiving penicillin therapy. Severe allergic reactions may require discontinuation of the antibiotic, administration of epinephrine, and other emergency measures. Tazamax 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. Patients who develop a skin rash should be closely monitored, and Tazamax should be discontinued if the condition progresses.

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 drug should be discontinued immediately.

During treatment with Tazamax, microbial resistance may develop, potentially leading to superinfection.

Hemophagocytic lymphohistiocytosis (HLH). Cases of HLH have been reported in patients receiving piperacillin or piperacillin/tazobactam combination therapy, often when treatment lasted longer than 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 bleeding time, platelet aggregation, and prothrombin time; they occur more frequently in patients with renal impairment. If signs of bleeding occur, antibiotic therapy should be discontinued and appropriate treatment initiated.

During Tazamax therapy, a false-positive result in the urine glucose test may occur when using copper reduction-based methods. Therefore, it is recommended to use an enzymatic glucose oxidation test. With prolonged treatment, leukopenia and neutropenia may develop; thus, periodic hematological monitoring is advised.

In severe infections, empirical therapy with Tazamax may be initiated 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 it to patients with impaired renal function and to 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 has been identified as a cause of delayed renal function recovery in these patients. Hypokalemia may develop in patients with low potassium levels or in those concurrently receiving medications capable of reducing potassium levels; in such patients, periodic monitoring of blood electrolyte levels is recommended.

Important information about excipients. This medicinal product contains 9.44 mmol of sodium per vial. Caution is advised when administering to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy. There are no adequate and well-controlled studies of piperacillin/tazobactam combination or of piperacillin or tazobactam alone in pregnant women. Tazamax crosses the placenta. The drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal studies have shown toxicity, but no evidence of teratogenicity was observed at doses that were toxic to the mother.

Breastfeeding. Piperacillin is excreted in breast milk in low concentrations; the concentration of tazobactam in breast milk has not been studied. Therefore, the drug should be used during breastfeeding only if the potential benefit outweighs the potential risk to the mother and infant.

Fertility. In reproductive function studies in rats, no adverse effects on fertility or mating performance were observed after intraperitoneal administration of tazobactam or piperacillin/tazobactam combination.

Ability to affect driving and use of machines.

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

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 of piperacillin / 0.5 g of tazobactam every 8 hours.

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

Table 2 shows the recommended frequency of administration for adult and pediatric patients.

Table 2.

Dosing frequency	Indications
Every 6 hours	Severe pneumonia.
	Febrile neutropenia in adults, 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 as follows (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 piperacillin / 10 mg tazobactam per kilogram of body weight every 6 hours	Febrile neutropenia in children, likely associated with bacterial infections*
100 mg piperacillin / 12.5 mg 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 carefully 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 Tazamaks 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.

Tazamaks 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. The prepared solution should be visually inspected before administration 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 the diluent in the volume specified in the table below. Shake the vial until the powder is completely dissolved. Reconstitution of the solution occurs within 5–10 minutes with continuous shaking.

Table 6

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

* Compatible reconstituting 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 single 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 required volume (from 50 mL to 150 mL) using one of the following compatible diluents:

• 0.9% (9 mg/mL) sodium chloride solution for injection;
• 5% glucose solution;
• 6% dextran in 0.9% (9 mg/mL) sodium chloride;
• Ringer's lactate solution;
• Hartmann's solution;
• Ringer's acetate solution;
• Ringer's acetate/malate solution.

Concomitant administration with aminoglycosides.

Due to in vitro inactivation of aminoglycosides by beta-lactam antibiotics, Tazamaks and aminoglycosides should be administered separately. If concomitant therapy with aminoglycosides is indicated, Tazamaks and aminoglycosides should be reconstituted, diluted, and administered separately. A Y-type catheter should be used for administration. When administering simultaneously via a Y-type catheter, the following requirements must be observed.

Table 7

Aminoglycoside	Tazamaks dose	Solvent volume (ml)	Aminoglycoside concentration range* (mg/ml)	Compatible solvents
Amikacin	4 g / 0.5 g	50, 100, 150	1.75–7.5	0.9% sodium chloride solution or 5% glucose solution
Gentamicin	4 g / 0.5 g	50, 100, 150	0.7–3.32	0.9% sodium chloride solution or 5% glucose solution

* Aminoglycoside dosage depends on body weight, the nature of the infection (serious or life-threatening), and renal function (creatinine clearance).

Compatibility of the medicinal product with other aminoglycosides has not been established. Only the concentrations and diluents for amikacin and gentamicin listed in the table above have been demonstrated suitable for co-administration via a Y-site catheter. Simultaneous co-administration via a Y-site catheter by any other method than specified above may result in inactivation of the aminoglycoside by Tazamaks. See also section "Incompatibilities".

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 adverse symptoms observed in overdose (including nausea, vomiting, and diarrhea) have also been reported during administration of usual doses. Increased neuromuscular excitability or seizures may occur in patients receiving doses exceeding the recommended ones (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 picture. Excessive serum concentrations of piperacillin or tazobactam may be reduced by hemodialysis. After a single 3.375 g dose of piperacillin/tazobactam, hemodialysis removed approximately 31% and 39% of piperacillin and tazobactam, 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 requiring discontinuation of treatment. The frequency of these adverse effects is ≥ 1/100 to < 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 from the available data.

The adverse reactions listed below are classified by organ systems and by frequency of occurrence. The following classification of adverse reaction frequencies is used: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000).

System Organ Classes	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			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 conditions		fever, infusion 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 levels; 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, hypernatraemia, tremor, and encephalopathy (especially in patients with renal impairment) may occur.

In patients with cystic fibrosis, piperacillin therapy has been associated with an increased incidence of fever and skin rashes.

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

Pseudopositive results may be obtained when using certain chemical methods for measuring urinary proteins. However, the use of Tazamax does not affect the results of urinary protein measurement using diagnostic test strips.

The direct Coombs test may yield false-positive results.

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

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

Reporting of suspected adverse reactions

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

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. After reconstitution, the medicinal product is suitable for use within 24 hours when stored in a refrigerator at 2–8 °C.

Keep out of reach of children.

Incompatibilities.

Tazamax should not be mixed in the same syringe or infusion container with other medicinal products except for the diluents specified in the section "Dosage and administration," due to lack of compatibility data.

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.

Tazamax should not be mixed with other substances in a syringe or infusion vial, as compatibility has not been established.

Due to chemical instability, the medicinal product Tazamax should not be used concomitantly with solutions containing sodium bicarbonate.

Tazamax should not be added to blood products or albumin hydrolysate.

Packaging.

4 g / 500 mg per vial. 10 vials per carton.

Prescription status.

Prescription only.

Manufacturer.

Mitim S.r.l. / Mitim S.r.l.

Manufacturer's address and location of business activity.

Via Giovanni Battista Cacciamali 34-38, Brescia, 25125, Italy