Piperacillin+tazobactam

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PIPERACILLIN+TAZOBACTAM (Piperacillin+Tazobactam)

Composition:

Active substances: piperacillin, tazobactam;

One vial contains sodium piperacillin equivalent to piperacillin 4.0 g (g) and sodium tazobactam equivalent to tazobactam 0.5 g (g).

Pharmaceutical form. Powder for solution for infusion.

Main physicochemical properties: white or almost white powder.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Beta-lactam antibiotics, penicillins.

Combinations of penicillins, including with β-lactamase inhibitors. ATC code J01CR05.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of Action.

Piperacillin is a broad-spectrum semisynthetic antibiotic of the penicillin class that inhibits bacterial activity by inhibiting the formation of the cell septum and synthesis of the cell wall.

Tazobactam, a beta-lactam structurally similar to penicillins, is an inhibitor of many beta-lactamases that typically cause resistance to penicillins and cephalosporins; however, it does not inhibit AmpC enzymes or metallo-beta-lactamases. Tazobactam extends the antibacterial spectrum of piperacillin to include many bacteria producing beta-lactamases that are resistant to piperacillin alone.

Pharmacokinetic/Pharmacodynamic Relationship.

The time during which the plasma concentration exceeds the minimum inhibitory concentration (% T > MIC) is considered the primary factor determining the pharmacodynamic efficacy of piperacillin.

Mechanism of Resistance.

There are two main mechanisms of bacterial resistance to piperacillin/tazobactam:

• Inactivation of piperacillin by beta-lactamases not inhibited by tazobactam: beta-lactamases of molecular classes B, C, and D.
• Modification of penicillin-binding proteins (PBPs), leading to reduced affinity of piperacillin for its molecular target in bacteria.

Additionally, changes in bacterial membrane permeability, as well as expression of efflux pumps capable of extruding the drug, may cause or contribute to the development of bacterial resistance to piperacillin/tazobactam, particularly in Gram-negative bacteria.

Clinical Breakpoints for Susceptibility Testing.

EUCAST (European Committee on Antimicrobial Susceptibility Testing) has established clinical breakpoints for the MIC (minimum inhibitory concentration) of piperacillin/tazobactam (2022-01-01, version 12.0). For antimicrobial susceptibility testing, a fixed concentration of tazobactam at 4 mg/L is used.

Pathogenic microorganism	Strain-related threshold values, depending on strain (S ≤ / R >), mg/L of piperacillin
Enterobacterales (formerly Enterobacteriaceae)	8/8
Pseudomonas aeruginosa	< 0.001/161
Staphylococcus species	-2
Enterococcus species	-3
Group A, B, C and G streptococci	-4
Streptococcus pneumoniae	-5
Viridans group streptococci	-6
Haemophilus influenzae	0.250/0.25
Moraxella catarrhalis	-7
Bacteroides species (except B. thetaiotaomicron)	8/8
Prevotella species	0.5/0.5
Fusobacterium necrophorum	0.5/0.5
Clostridium perfringens	0.5/0.5
Cutibacterium acnes	0.25/0.25
Achromobacter xylosoxidans	4/4
Vibrio species	1/1
Species-unrelated susceptibility breakpoints (PK/PD)	8/16
1 For several agents, EUCAST has established breakpoints classifying 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 mechanism renders them resistant 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, isoxazolylpenicillins (oxacillin, cloxacillin, dicloxacillin, and flucloxacillin), and nafcillin. Caution should be exercised with orally administered agents to achieve sufficient effect at the site of infection. Staphylococci tested as 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) is determined based on ampicillin susceptibility. Resistance to ampicillin is uncommon in E. faecalis (should be confirmed by MIC testing) but common in E. faecium. 4 Susceptibility of group A, B, C, and G Streptococcus to penicillins is determined based on benzylpenicillin susceptibility, except for phenoxymethylpenicillin and isoxazolylpenicillins for group B Streptococcus. Group A, B, C, and G Streptococcus do not produce beta-lactamase. Adding a beta-lactamase inhibitor provides no clinical benefit. 5 To exclude beta-lactam resistance mechanisms, an oxacillin 1 µg disk test or MIC test for benzylpenicillin should be used. When the screening result is negative (oxacillin inhibition zone ≥20 mm or benzylpenicillin MIC ≤0.06 mg/L), all beta-lactam agents for which clinical breakpoints are available are considered susceptible without further testing, except cefaclor, which should be considered "Susceptible, increased exposure (I)". Streptococcus pneumoniae does not produce beta-lactamase. Adding a beta-lactamase inhibitor provides no clinical benefit. Susceptibility is determined by ampicillin (MIC or zone diameter). 6 For isolates susceptible to benzylpenicillin, susceptibility can be determined by benzylpenicillin or ampicillin. For isolates resistant to benzylpenicillin, susceptibility is determined based on ampicillin. 7 Susceptibility can be determined by amoxicillin/clavulanic acid.

Susceptibility. The prevalence of acquired resistance in isolated species may vary depending on the geographical location and time; therefore, local information on bacterial resistance is necessary, especially when treating severe infections. When necessary, specialists should be consulted if the local prevalence of resistance has reached a level at which the drug's usefulness, at least for certain types of infections, is questionable.

Groups of strains according to susceptibility to piperacillin/tazobactam.

Mainly susceptible strains Aerobic gram-positive microorganisms

Enterococcus faecalis (only isolates susceptible to ampicillin or penicillin)

Listaeria monocytogenes

Staphylococcus aureus (only methicillin-susceptible isolates)

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

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

Aerobic gram-negative microorganisms

Citrobacter koseri

Haemophilus influenzae

Moraxella catarrhalis

Proteus mirabilis

Anaerobic gram-positive microorganisms

Clostridium species

Eubacterium species

Anaerobic gram-positive microorganisms cocci ††

Anaerobic gram-negative microorganisms

Bacteroides fragilis group

Fusobacterium species

Porphyromonas species

Prevotella species

Strains that may develop resistance

Aerobic gram-positive microorganisms

Enterococcus faecium

Streptococcus pneumoniae †

Streptococcus viridans group †

Aerobic gram-negative microorganisms

Acinetobacter baumannii

Citrobacter freundii

Enterobacter species

Escherichia coli

Klebsiella pneumoniae

Morganella morganii

Proteus vulgaris

Providencia ssp.

Pseudomonas aeruginosa

Serratia species

Resistant organisms

Aerobic gram-positive microorganisms

Corynebacterium jeikeium

Aerobic gram-negative 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 only to piperacillin. Resistance of S. pyogenes to penicillin has not been reported. †† Including Anaerococcus, Finegoldia, Parvimonas, Peptoniphilus, and Peptostreptococcus spp.

Pharmacokinetics.

Absorption. Peak concentrations following intravenous administration (over more than 30 minutes) of piperacillin and tazobactam at a dose of 4 g / 0.5 g were 298 mcg/mL and 34 mcg/mL, respectively.

Distribution. Both piperacillin and tazobactam are approximately 30% bound to plasma proteins. Protein binding of piperacillin and tazobactam is not affected by the presence of other compounds. Protein binding of tazobactam metabolites is negligible.

Piperacillin and tazobactam readily distribute into body tissues and fluids, including intestinal mucosa, gallbladder, lungs, bile, and bone. Tissue concentrations generally range from 50% to 100% compared to plasma concentrations. Drug distribution into cerebrospinal fluid is low, as with other penicillins, unless patients have inflamed meninges.

Biotransformation. Piperacillin is metabolized to a minor desethyl metabolite, which exhibits minimal microbiological activity. Tazobactam is metabolized to a single microbiologically inactive metabolite.

Elimination. Piperacillin and tazobactam are eliminated by the kidneys via glomerular filtration and tubular secretion.

Piperacillin is rapidly excreted unchanged; 68% of the administered dose is excreted in urine. Tazobactam and its metabolite are primarily eliminated by the kidneys. 80% of the administered dose is excreted unchanged, the remainder as a single metabolite. Piperacillin, tazobactam, and the desethyl metabolite of piperacillin are also secreted in bile.

After single or multiple doses of piperacillin/tazobactam administered to healthy volunteers, the plasma elimination half-life ranged from 0.7 to 1.2 hours, with dose and infusion duration having no effect on this parameter. The elimination half-life of both piperacillin and tazobactam increases with decreased renal clearance.

Administration of tazobactam does not have a significant effect on the pharmacokinetics of piperacillin. Piperacillin decreases the elimination rate of tazobactam.

Special patient populations. The elimination half-life of piperacillin and tazobactam increased by approximately 25% and 18%, respectively, in patients with hepatic cirrhosis compared to healthy volunteers.

The elimination half-life of both piperacillin and tazobactam increases with decreased creatinine clearance. The half-life was doubled for piperacillin and quadrupled for tazobactam at creatinine clearance less than 20 mL/min compared to patients with normal renal function.

Hemodialysis removed 30–50% of piperacillin/tazobactam, and an additional 5% of the tazobactam dose was eliminated as metabolite. Peritoneal dialysis removed 6% to 21% of the doses of piperacillin and tazobactam, respectively, and an additional 18% of the tazobactam dose as metabolite.

Children. In a population pharmacokinetic analysis, the estimated clearance in children aged 9 months to 12 years was similar to that in adults, with a mean value of 5.64 (standard error 0.34) mL/min/kg in this population. Estimated piperacillin clearance in children aged 2–9 months is 80% of this value. The mean volume of distribution of piperacillin in this population is 0.243 L/kg (standard error 0.011) and is independent of age.

Elderly patients. Mean elimination half-life values of piperacillin and tazobactam were 32% and 55% higher, respectively, in elderly patients compared to younger patients. This difference may be explained by age-related changes in creatinine clearance.

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

Preclinical safety data.

Preclinical data based on conventional repeated-dose toxicity and genotoxicity studies show no special risk for humans. Carcinogenicity studies with piperacillin/tazobactam have not been conducted.

Fertility and general reproductive studies in rats using intraperitoneal administration of tazobactam or the combination piperacillin/tazobactam showed reduced litter size and increased fetuses with delayed ossification and rib changes, concurrent with maternal toxicity. Fertility in the F1 generation and embryonic development in the F2 generation were not impaired.

Teratogenicity studies using intravenous administration of tazobactam or the combination piperacillin/tazobactam in mice and rats resulted in a slight reduction in fetal weight in rats at maternally toxic doses, but no teratogenic effects were observed.

Peri-/postnatal developmental disturbances (reduced pup weight, increased stillbirths, increased pup mortality) along with maternal toxicity were observed after intraperitoneal administration of tazobactam or the combination piperacillin/tazobactam in rats.

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 in diabetic foot syndrome).

For the treatment of patients with bacteremia associated with or secondary to any of the above-mentioned infections.

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

Note: use for the treatment of bacteremia caused by extended-spectrum beta-lactamase (ESBL)-producing E. coli and K. pneumoniae (resistant to ceftriaxone) is not recommended in adult patients (see section "Pharmacodynamics").

Children aged 2 to 12 years:

• Complicated intra-abdominal infections.

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

It is recommended to follow official guidelines for the use of antibacterial agents.

Contraindications.

Hypersensitivity to the active substances or to any other penicillin antibiotics. History of severe immediate allergic reactions to any other beta-lactam agents (e.g., cephalosporins, monobactams, or carbapenems).

Interaction with other medicinal products and other forms of interaction.

Non-depolarizing muscle relaxants. Concomitant administration of piperacillin with vecuronium results in prolonged neuromuscular blockade. Due to similar mechanisms of action, neuromuscular blockade induced by any non-depolarizing muscle relaxant may be prolonged when piperacillin is administered.

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

Methotrexate. Piperacillin may reduce methotrexate excretion. In patients receiving methotrexate, serum levels should be monitored to avoid methotrexate toxicity.

Probenecid. Concomitant administration of probenecid with piperacillin/tazobactam results in prolonged elimination half-life and reduced renal clearance of both piperacillin and tazobactam. However, this does not affect the maximum plasma concentration of either drug.

Aminoglycosides. Piperacillin alone or in combination with tazobactam does not cause clinically significant changes in the pharmacokinetics of tobramycin in patients with normal renal function or mild to moderate renal impairment. Tobramycin administration did not notably affect the pharmacokinetics of piperacillin/tazobactam or its metabolite M1.

Inactivation of tobramycin and gentamicin by piperacillin has been demonstrated in patients with severe renal impairment.

For information on the use of piperacillin/tazobactam with aminoglycosides, see sections "Method of administration and dosage" and "Incompatibilities."

Vancomycin. Studies have shown an increased incidence of acute kidney injury in patients receiving piperacillin/tazobactam and vancomycin concomitantly compared to vancomycin alone (see section "Special precautions for use"). In some studies, this interaction was dose-dependent with regard to vancomycin.

No pharmacokinetic interactions between piperacillin/tazobactam and vancomycin have been observed.

Effect on laboratory test results. Non-enzymatic methods for glucose testing in urine may yield false-positive results, as with other penicillin-group drugs. Therefore, during therapy with this medicinal product, enzymatic methods are recommended for glucose testing in urine.

Some chemical methods for measuring urinary protein may yield false-positive results. No interference is expected with 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 this medicinal product. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses have been reported with the Bio-Rad Laboratories Platelia Aspergillus EIA test.

Positive results from the above-mentioned laboratory tests in patients receiving this medicinal product should be confirmed using alternative diagnostic methods.

Special precautions for use.

The decision to prescribe piperacillin/tazobactam for treatment of each individual patient should be based on the appropriateness of using a broad-spectrum semi-synthetic penicillin, determined according to factors such as the severity of the infection and resistance to other acceptable antibacterial agents.

Before initiating therapy with piperacillin/tazobactam, a detailed patient history regarding hypersensitivity reactions to penicillins, other β-lactam agents (such as cephalosporins, monobactams, or carbapenems), and other allergens should be obtained. Severe, and occasionally fatal, hypersensitivity reactions (anaphylactic/anaphylactoid reactions, including shock) have been reported in patients receiving penicillin therapy, including piperacillin/tazobactam. These reactions are more likely to occur in patients with a history of hypersensitivity to multiple allergens. Severe hypersensitivity reactions require immediate discontinuation of the antibiotic and may necessitate administration of epinephrine and other emergency measures.

The drug may cause severe skin adverse reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) (see section "Adverse reactions"). If a patient develops skin rash, their condition should be closely monitored, and piperacillin/tazobactam should be discontinued if skin lesions progress.

Haemophagocytic lymphohistiocytosis (HLH): Cases of HLH have been reported in patients receiving piperacillin/tazobactam, often after treatment exceeding 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 haemophagocytosis). Patients who develop early signs of pathological immune activation should be evaluated immediately. If HLH is diagnosed, treatment with piperacillin/tazobactam should be discontinued.

Antibiotic-associated pseudomembranous colitis may present as severe and persistent diarrhea, sometimes life-threatening. Symptoms of pseudomembranous colitis may occur during or after antibacterial therapy. In such cases, the drug should be discontinued.

Therapy with this medicinal product may lead to the emergence of resistant microorganisms, potentially causing superinfection.

In some patients receiving beta-lactam antibiotics, bleeding symptoms have been observed. These reactions were sometimes associated with coagulation disorders, including prolonged clotting time, platelet aggregation abnormalities, and prolonged prothrombin time. Such disorders were most frequently observed in patients with renal impairment. If bleeding occurs, antibiotic administration should be discontinued and appropriate treatment initiated.

Since prolonged therapy may lead to leukopenia and neutropenia, periodic monitoring of blood parameters is recommended.

Neurological complications, including seizures, may occur when high doses of the drug are administered (particularly in patients with impaired renal function), as with other penicillin-class agents (see section "Adverse reactions").

Each dose of this medicinal product contains 9.44 mmol (or 217 mg) of sodium. Caution is advised when administering to patients on a sodium-restricted diet.

Hypokalemia may occur in patients with low potassium reserves or in those concurrently receiving medications that may reduce potassium levels. Periodic monitoring of electrolyte levels may be recommended for such patients.

Renal function impairment.

Due to the potential nephrotoxicity of piperacillin/tazobactam, caution is advised when administering the drug to patients with impaired renal function and those on hemodialysis (see section "Adverse reactions"). Intravenous doses and dosing intervals must be adjusted according to the degree of renal impairment (see section "Dosage and administration"). Additional analysis using data from a large-scale, multicenter, randomized, controlled trial evaluating glomerular filtration rate (GFR) after administration of commonly used antibiotics in critically ill patients showed that piperacillin/tazobactam use was associated with a lower rate of reversible improvement in GFR compared to other antibiotics. This additional analysis concluded that piperacillin/tazobactam may delay the recovery of renal function in these patients.

Concomitant use of piperacillin/tazobactam and vancomycin may be associated with an increased incidence of acute kidney injury (see section "Interaction with other medicinal products and other forms of interaction").

Use during pregnancy or breastfeeding.

Pregnancy. There are no or limited data on the use of this medicinal product in pregnant women. Animal studies have shown fetal toxicity, but teratogenic effects were not observed at doses toxic to the maternal organism. Piperacillin and tazobactam cross the placenta. The drug should be used during pregnancy only if the potential benefit outweighs the potential risk to the woman and the fetus.

Breastfeeding. Piperacillin passes into breast milk in small concentrations. The concentration of tazobactam in breast milk has not been studied. The use of this medicinal product in breastfeeding women is recommended only if the expected benefit outweighs the potential risk to the mother and child.

Fertility. In rat studies, intraperitoneal administration of tazobactam or the combination piperacillin/tazobactam showed no effect on reproductive function or fertility.

Ability to influence the ability to drive and use machines.

No studies on the effect on the ability to drive vehicles or operate machinery have been conducted.

Dosage and Administration.

Dosage. The dose and frequency of administration of the medicinal product depend on the severity and location of the infection, as well as on the likely causative pathogens.

Adults and children aged 12 years and older.

Infections. The usual dose of the medicinal product is 4.5 g (4 g piperacillin / 0.5 g tazobactam) administered every 8 hours.

For hospital-acquired pneumonia and bacterial infections in patients with neutropenia, the recommended dose is 4 g piperacillin / 0.5 g tazobactam every 6 hours. This dosing regimen may also be used for treatment of patients with severe forms of other documented infections.

The table below provides the recommended dosing frequency for adult patients and children aged 12 years and older, specifying the indications or conditions:

Dosing frequency	Indications for use of the medicinal product at a dosage of 4.5 g
Every 6 hours	Severe pneumonia
	Fever in neutropenic adults likely to be due to bacterial infection
Every 8 hours	Complicated urinary tract infections (including pyelonephritis)
	Complicated intra-abdominal infections
	Skin and soft tissue infections (including infectious complications in diabetic foot syndrome)

Patients with renal impairment.

The intravenous dose should be adjusted according to the degree of renal impairment as indicated below (each patient should be monitored for signs of active substance toxicity; the dose and dosing interval should be appropriately adjusted):

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

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

Patients with hepatic impairment.

Dose adjustment is not required.

Elderly patients.

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

Children aged 2 to 12 years.

Infections. The table below provides the recommended dosage and dosing frequency according to body weight for children aged 2 to 12 years, with indications or conditions specified:

Dose according to body weight and frequency of administration	Indications or conditions
80 mg piperacillin / 10 mg tazobactam per kilogram of body weight every 6 hours	Fever in children with neutropenia likely caused by bacterial infection*
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 4.5 g administered over 30 minutes.

Patients with impaired renal function.

The intravenous dose should be adjusted according to the degree of renal function impairment as indicated below (each patient must be monitored for signs of active substance toxicity; the dose and dosing interval should be appropriately adjusted):

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

For children undergoing hemodialysis, an additional dose of 40 mg piperacillin / 5 mg tazobactam per kg of body weight is required after each dialysis session.

Children under 2 years of age.

The efficacy and safety of the medicinal product for the treatment of children under 2 years of age have not been established.
Controlled clinical trial data are lacking.

Duration of treatment. The usual duration of treatment for most indications is 5–14 days. However, the duration of therapy should be determined based on the patient's condition, severity of infection, and results of clinical and bacteriological examinations.

Method of administration. The medicinal product should be administered by intravenous infusion over 30 minutes.

Instructions for preparation of solution for intravenous use.

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

The contents of the vial should be reconstituted with the solvent in the volume specified in the table below. Shake the vial until the powder is completely dissolved. With continuous shaking, reconstitution is completed within 5–10 minutes.

Contents of the vial	Volume of diluent* to be added to the vial
Piperacillin/tazobactam 2 g / 0.25 g	10 ml
Piperacillin/tazobactam 4 g / 0.5 g	20 ml

* Compatible reconstituting solvents:

• 0.9% sodium chloride solution;
• sterile water for injection (maximum recommended volume of sterile water for injection per dose is 50 mL);
• 5% glucose solution.

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

The reconstituted solution 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) with one of the following compatible diluents:

• 0.9% (9 mg/mL) sodium chloride solution;
• 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 malate/acetate solution.

Concomitant administration with aminoglycosides.

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

Aminoglycoside	Piperacillin/tazobactam dose	Volume of piperacillin + tazobactam diluent (mL)	Aminoglycoside concentration range* (mg/mL)	Compatible solutions
Amikacin	2 g / 0.25 g 4 g / 0.5 g	50, 100, 150	1.75–7.5	0.9% sodium chloride solution or 5% glucose solution
Gentamicin	2 g / 0.25 g 4 g / 0.5 g	50, 100, 150	0.7–3.32	0.9% sodium chloride solution or 5% glucose solution

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

Compatibility of piperacillin/tazobactam with other aminoglycosides has not been established. Only the concentrations and diluents for amikacin and gentamicin combined with piperacillin/tazobactam dose, as listed in the table, have been demonstrated suitable for concomitant administration via a Y-type catheter. Simultaneous co-administration via a Y-type catheter by any method other than that specified above may result in inactivation of the aminoglycoside by piperacillin/tazobactam (see section "Incompatibility").

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

The solution is intended for single use only. Unused solution must be discarded.

Children. Do not use in children under 2 years of age.

Overdose.

Symptoms. There have been reports of piperacillin/tazobactam overdose. Most manifestations of overdose, including nausea, vomiting, and diarrhea, were observed following administration of usual recommended doses. Neuromuscular excitation or seizures may occur in patients receiving doses exceeding the recommended intravenous doses (particularly in patients with renal impairment).

Treatment. In case of overdose, further administration of piperacillin/tazobactam should be discontinued. There is no known specific antidote.

Treatment is supportive and symptomatic, depending on the patient's condition.

Excess serum concentrations of piperacillin or tazobactam can be reduced by hemodialysis (see section "Special precautions for use").

Adverse Reactions

The most commonly reported adverse drug reaction is diarrhea (observed in 1 out of 10 patients). The most severe adverse reactions are pseudomembranous colitis and toxic epidermal necrolysis, which occurred in 1–10 patients per 10,000.

The frequency of occurrence 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 adverse event frequencies is applied: very common (≥ 1/10); common (≥ 1/100 – < 1/10); uncommon (≥ 1/1000 – < 1/100); rare (≥ 1/10000 – < 1/1000); and frequency not known (cannot be estimated from the available data).

Organ systems	Adverse reactions and their frequency
Infections and infestations	Common: candidiasis superinfection* Uncommon: pseudomembranous colitis
Blood and lymphatic system disorders	Common: thrombocytopenia, anemia* Uncommon: leukopenia Rare: agranulocytosis Frequency unknown: pancytopenia*, neutropenia, hemolytic anemia*, thrombocytosis*, eosinophilia*
Immune system disorders	Frequency unknown: anaphylactoid shock*, anaphylactic shock*, anaphylactoid reaction*, anaphylactic reaction*, hypersensitivity reactions*
Metabolism and nutrition disorders	Uncommon: hypokalemia
Psychiatric disorders	Common: insomnia Frequency unknown: delirium*
Nervous system disorders	Common: headache Uncommon: seizure*
Vascular disorders	Uncommon: arterial hypotension, phlebitis, thrombophlebitis, hot flushes
Respiratory, thoracic and mediastinal disorders	Rare: epistaxis Frequency unknown: eosinophilic pneumonia
Gastrointestinal disorders	Very common: diarrhea Common: abdominal pain, vomiting, constipation, nausea, dyspepsia Rare: stomatitis
Hepatobiliary disorders	Frequency unknown: hepatitis*, jaundice
Skin and subcutaneous tissue disorders	Common: rash, pruritus Uncommon: erythema multiforme*, urticaria, maculopapular rash* Rare: toxic epidermal necrolysis* Frequency unknown: Stevens-Johnson syndrome*, exfoliative dermatitis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)*, acute generalized exanthematous pustulosis*, bullous dermatitis, purpura
Musculoskeletal, connective tissue and bone disorders	Uncommon: arthralgia, myalgia
Renal and urinary disorders	Frequency unknown: renal failure, tubulointerstitial nephritis*
General disorders and administration site conditions	Common: pyrexia, injection site reactions Uncommon: chills
Investigations	Common: increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), decreased total blood protein and albumin, positive direct Coombs test, increased creatinine, alkaline phosphatase, blood urea, prolonged activated partial thromboplastin time Uncommon: decreased blood glucose, increased blood bilirubin, prolonged prothrombin time Frequency unknown: prolonged bleeding time, increased blood gamma-glutamyl transferase

* Adverse reactions identified during the post-marketing period.

Piperacillin therapy has been associated with an increased incidence of fever and rash in patients with cystic fibrosis.

Effects of beta-lactam antibiotics.

Beta-lactam antibiotics, including piperacillin/tazobactam, may cause symptoms of encephalopathy and seizures (see section "Special precautions for use").

Reporting of suspected adverse reactions.

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

Shelf life. 3 years.

Storage conditions.

Store in the original packaging, protected from light, at a temperature not exceeding 25 °C. Keep out of the reach of children.

The shelf life of the reconstituted solution is 24 hours when stored at a temperature not exceeding 25 °C and 48 hours when stored in a refrigerator (at a temperature of 2 to 8 °C).

From a microbiological standpoint, the reconstituted solution should be used immediately. If the reconstituted medicinal product is not used immediately, the storage period should not exceed 24 hours when stored in a refrigerator at a temperature of 2 to 8 °C, provided reconstitution was not performed under controlled and validated aseptic conditions.

Incompatibilities.

The medicinal product Piperacillin+Tazobactam must not be mixed with other medicinal products except those specified in the section "Dosage and method of administration".

If the medicinal product must be administered simultaneously with another antibiotic (e.g., with aminoglycosides), the agents should be administered separately. Mixing beta-lactam antibiotics with aminoglycosides in vitro may lead to significant inactivation of the aminoglycoside.

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

Due to chemical instability, the medicinal product must not be used in solutions containing only sodium bicarbonate.

Piperacillin+Tazobactam must not be added to blood products or albumin hydrolysates.

Packaging.

Powder for solution for infusion, 4.5 g in vials. 1 vial per cardboard box.

Prescription category. Prescription only.

Manufacturer. Reyoung Pharmaceutical Co., Ltd.

Manufacturer's address and place of business.

No. 1, Ruiyang Road, Yucheng County, Shandong Province, People's Republic of China.