Tazamax powder for solution for infusion 4 g/500 mg vials No. 10

Instructions Tazamax powder for solution for infusion 4 g/500 mg vials No. 10

Composition

active ingredients: piperacillin sodium, tazobactam sodium;

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

Dosage 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.

ATX code J01C R05.

Pharmacological properties

Pharmacodynamics.

Mechanism of action.

Piperacillin is a broad-spectrum semisynthetic penicillin that is active against Gram-positive and Gram-negative aerobic and anaerobic bacteria and inhibits bacterial growth by inhibiting cell membrane formation and cell wall synthesis. Tazobactam, a beta-lactam structurally related to the penicillins, is an inhibitor of many beta-lactamases that commonly cause resistance to penicillins and cephalosporins, but it does not inhibit AmpC enzymes or metallo-beta-lactamases. Tazobactam potentiates and broadens the antimicrobial spectrum of piperacillin, including bacteria that produce beta-lactamases that are normally insensitive to it and other beta-lactam antibiotics.

Pharmacokinetic/pharmacodynamic relationships.

The time above the minimum inhibitory concentration (T > MIC) is considered the main pharmacodynamic factor determining the efficacy of piperacillin.

Mechanism of resistance.

Two main mechanisms of resistance to piperacillin/tazobactam:

• Inactivation of the piperacillin component by those beta-lactamases that are not inhibited by tazobactam: beta-lactamases of molecular class B, C and D. In addition, tazobactam does not provide protection against extended-spectrum beta-lactamases (ESBLs) from the molecular group of enzymes of classes A and D.

• Alteration of penicillin-binding proteins (PBPs), resulting in reduced affinity of piperacillin for its molecular target in bacteria.

In addition, alterations in bacterial membrane permeability, as well as the expression of multidrug efflux pumps, may cause or contribute to bacterial resistance to piperacillin/tazobactam, particularly in Gram-negative bacteria.

The prevalence of acquired resistance of individual species may vary over time and depending on the location, therefore it is advisable to obtain local information on resistance, especially when treating severe infections. If necessary, specialist advice should be sought when the local prevalence of resistance is such that the appropriateness of the drug, at least in some types of infections, is questionable.

Merino study [bloodstream infections caused by ESBL producers].

In a prospective, open-label, randomized, noninferiority, parallel-group clinical trial, piperacillin/tazobactam treatment compared with meropenem did not result in less than 30-day mortality in adult patients with ceftriaxone-nonsusceptible bloodstream infections caused by E. coli or K. pneumoniae.

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

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

This study found an imbalance in mortality rates between the study groups. It was assumed that deaths in the piperacillin/tazobactam group were not due to co-infection but to underlying diseases.

Absorption: Peak concentrations of piperacillin and tazobactam following administration of 4 g/0.5 g over 30 minutes by 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 piperacillin binding, and the presence of piperacillin does affect tazobactam binding. Piperacillin/tazobactam are widely distributed in tissues and body fluids, including intestinal mucosa, gallbladder mucosa, lungs, bile, female reproductive organs (uterus, ovaries, and fallopian tubes), and bone. Mean tissue concentrations are 50 to 100% of plasma concentrations. There is no data on penetration across the blood-brain barrier.

Biotransformation. As a result of metabolism, piperacillin is converted to the desethyl derivative, which has low activity; tazobactam is converted to an inactive metabolite. Excretion. Piperacillin and tazobactam are excreted by the kidneys by glomerular filtration and tubular secretion. Piperacillin is rapidly excreted unchanged, with 68% of the dose recovered in the urine. Tazobactam and its metabolites are rapidly excreted by the kidneys, with 80% of the dose recovered unchanged and the remainder as metabolites. Thereafter, further biliary excretion of piperacillin, tazobactam and desethylpiperacillin is negligible.

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

Special patient populations.

Hepatic impairment: The half-life of piperacillin and tazobactam is increased by approximately 25% and 18%, respectively, in patients with liver cirrhosis compared to healthy volunteers.

Renal impairment: The elimination half-lives of piperacillin and tazobactam increase with decreasing creatinine clearance. At creatinine clearances below 20 mL/min, the elimination half-lives of piperacillin and tazobactam increase 2- and 4-fold, respectively, compared to patients with normal renal function.

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

Pediatric Population: In a population pharmacokinetic analysis, the estimated clearance in patients 9 months to 12 years of age was comparable to that in adults with a mean value of 5.64 (0.34) mL/min/kg. Piperacillin clearance in pediatric patients 2 to 9 months of age 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-lives of piperacillin and tazobactam were 32% and 55% longer, respectively, in elderly patients compared to young patients. This difference may be due 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.

Indication

The medicine is indicated for the treatment of the following infections in adults and children aged 2 years and over.

Adults and children aged 12 years and over:

- 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 of diabetic foot syndrome).

Also used to treat patients with bacteremia associated with or associated with any of the above infections.

The drug can be used to treat fever in patients with neutropenia, presumably caused by a bacterial infection.

Children aged 2 to 12 years:

- complicated intra-abdominal infections.

The drug can be used to treat fever in children with neutropenia, presumably caused by a bacterial infection.

It is recommended to follow official recommendations for the use of antibacterial drugs.

Contraindication

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 types of interactions

Anticoagulants. When used simultaneously with heparin, oral anticoagulants and other agents that affect the blood coagulation system, including platelet function, more frequent studies of the blood coagulation system in dynamics should be performed.

Methotrexate: Piperacillin may delay the elimination of methotrexate, therefore, serum methotrexate levels in patients should be monitored to prevent toxic effects.

Probenecid: As with other penicillin antibiotics, coadministration of probenecid and Tazamax prolongs the half-life and reduces the renal clearance of both piperacillin (by 21%) and tazobactam (by 71%). However, peak plasma concentrations of both drugs are not altered.

Probenecid should not be used with Tazamax unless the benefit outweighs the risk.

Aminoglycosides: Piperacillin, including co-administration with tazobactam, had no significant effect on the pharmacokinetics of tobramycin in patients with normal renal function or in patients with mild to moderate renal impairment. The pharmacokinetics of piperacillin, tazobactam, and metabolites were also not significantly altered by tobramycin.

Inactivation of tobramycin and gentamicin has been observed in patients with acute renal impairment due to piperacillin use.

Given the in vitro inactivation of aminoglycosides by piperacillin in the same solution, it is recommended that Tazamax and aminoglycosides be administered separately. Piperacillin preparations and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is prescribed. Only a Y-type catheter should be used for administration. If all of the above conditions are met, Tazamax can be administered via a Y-type catheter only with the aminoglycosides listed in Table 1.

Table 1

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

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

When administering intravenously, medical personnel must comply with a number of requirements, namely:

– observe aseptic conditions, use the intravenous administration set for 24 hours;

– label the container: patient's name, time and date of administration;

– from time to time check the condition of the solution: transparency, color, presence of foreign particles visible to the naked eye.

The compatibility of Tazamax with other aminoglycosides has not been established. For information on the use of piperacillin/tazobactam with aminoglycosides, see the sections "Incompatibility" and "Special Instructions for Use".

Tazamax is incompatible with tobramycin for simultaneous infusion via a Y-line catheter. Vancomycin: Studies have shown an increased incidence of acute kidney injury in patients receiving concomitant piperacillin/tazobactam and vancomycin compared to vancomycin alone (see section 4.4). Some of these studies have shown that the interaction of vancomycin is dose-dependent.

No pharmacokinetic interaction was found between piperacillin/tazobactam and vancomycin.

Impact on laboratory parameters.

Non-enzymatic methods of measuring urine glucose levels may lead to false-positive results, as with other penicillins. Therefore, enzymatic measurement of urine glucose levels is necessary during therapy with Tazamax.

A number of chemical methods for measuring protein in urine can produce false positive results. This does not affect the measurement of protein levels using dipsticks.

The direct Coombs test may be positive.

Bio-Rad Laboratories Platelia Aspergillus EIA tests may produce false-positive results in patients receiving Tazamax. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses have been reported with the Bio-Rad Laboratories Platelia Aspergillus EIA test.

Positive results of the tests listed above in patients receiving Tazamax should be confirmed by other diagnostic methods.

Pharmaceutical compatibility with other drugs. Tazamax should not be mixed in the same syringe or dropper with other drugs, except for the solvents listed above, since there is no data on compatibility.

Application features

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

Severe and rarely fatal hypersensitivity reactions (anaphylaxis, including shock) have been reported with penicillins in patients treated with penicillins. Severe allergic reactions may require discontinuation of antibiotics, administration of adrenaline, and other emergency measures. Tazamax can cause severe cutaneous adverse reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis. Patients who develop a skin rash should be closely monitored and Tazamax discontinued if the lesion progresses.

Antibiotic-associated pseudomembranous colitis may present with severe, persistent diarrhea that may be life-threatening. Pseudomembranous colitis may occur during or after antibiotic treatment. In these cases, the drug should be discontinued.

During therapy with Tazamax, resistance of microorganisms may develop, which may cause superinfection.

Hemophagocytic lymphohistiocytosis (HLH). Cases of HLH have been reported in patients receiving piperacillin or the combination of piperacillin/tazobactam, often when treatment was continued for more 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, high serum ferritin, cytopenia, and hemophagocytosis). Patients who develop early signs of pathological immune activation should be evaluated promptly. If HLH is diagnosed, treatment with piperacillin or the combination of piperacillin/tazobactam should be discontinued.

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

During therapy with Tazamax, a false-positive result of a urine glucose test using a copper-based reduction method is possible. Therefore, it is recommended to perform a test based on enzymatic glucose oxidation. During long-term treatment, leukopenia and neutropenia may develop, so the patient's hematological status should be periodically determined.

In severe infections, empirical therapy with Tazamax may be initiated before antibiotic susceptibility testing results are available.

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

Renal impairment: Due to the potential for nephrotoxicity, tazobactam should be used with caution in patients with renal impairment and in patients undergoing hemodialysis. Intravenous doses and dosing intervals should be adjusted based on the degree of renal impairment.

In a large multicenter randomized trial evaluating glomerular filtration rate after administration of commonly used antibiotics in critically ill patients, piperacillin/tazobactam was associated with lower glomerular filtration rates compared with other antibiotics. Piperacillin/tazobactam was found to delay the recovery of renal function in these patients. Hypokalemia may occur in patients with low potassium levels or those receiving concomitant medications that may lower potassium levels; electrolytes should be monitored periodically in such patients.

Important information about excipients: This medicinal product contains 9.44 mmol sodium per vial. Caution should be exercised when administering to patients on a controlled sodium diet.

Use during pregnancy or breastfeeding

Pregnancy. There are currently no adequate and well-controlled studies of the combination piperacillin/tazobactam or piperacillin or tazobactam alone in pregnant women. Tazamax crosses the placenta. The drug 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 there was no evidence of teratogenicity at doses toxic to the mother.

Breastfeeding. Piperacillin is excreted in breast milk in small concentrations, the concentration of tazobactam in breast milk has not been studied. Therefore, the drug can be used during breastfeeding only in cases where the expected benefit outweighs the potential risk to the woman and fetus.

Fertility: Reproduction studies in rats following intraperitoneal administration of tazobactam or the piperacillin/tazobactam combination showed no evidence of adverse effects on fertility or mating performance.

Ability to influence reaction speed when driving vehicles or other mechanisms

Studies on the effect on the ability to drive and use other mechanisms have not been conducted. During treatment, the possibility of dizziness and convulsions should be taken into account, which may affect the speed of psychomotor reactions.

Method of administration and doses

The dose and frequency of administration of the drug depend on the course and localization of the infection, as well as the probable pathogens.

Adults and children aged 12 and over.

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 can also be used to treat patients with other listed infections, especially severe ones.

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

Table 2.

Patients with renal failure

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

Table 3

For patients on hemodialysis, one additional dose of 2 g piperacillin/0.25 g tazobactam should be administered after each dialysis session, as hemodialysis removes 30-50% of piperacillin in 4 hours.

Patients with liver failure.

No dose adjustment is 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 shows the frequency of administration and recommended doses per kilogram of body weight for children aged 2 to 12 years by indication or clinical condition.

Table 4

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

Patients with renal insufficiency

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

Table 5

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

Children under 2 years old.

The safety and effectiveness of Tazamax 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 pathogen, and the patient's clinical and bacteriological progress.

Method of administration.

Tazamax 4 g / 0.5 g should be administered by intravenous infusion (over 30 minutes).

Preparation of the solution.

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

Intravenous use.

The contents of the vial should be diluted with the solvent in the amount indicated in the table below. Shake the vial until the powder is completely dissolved. With constant shaking, reconstitution of the solution occurs within 5–10 minutes.

Table 6

* Compatible solvents for recovery:

– 0.9% (9 mg/ml) sodium chloride solution for injection;

– sterile water for injection(1);

– 5% glucose solution.

Reconstituted solutions should be withdrawn from the vial using a syringe. If reconstitution is performed as recommended, withdrawal of the vial contents using a syringe will ensure that the stated amount of piperacillin/tazobactam is available.

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

– 0.9% (9 mg/ml) sodium chloride solution for injection;

– 5% glucose solution;

– dextran 6% 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 use with aminoglycosides.

Due to inactivation of aminoglycosides in vitro by beta-lactam antibiotics, Tazamax and aminoglycosides are recommended for separate administration. If concomitant therapy with aminoglycosides is indicated, Tazamax and aminoglycosides should be reconstituted, diluted, and administered separately. Only a Y-line catheter should be used for administration. When co-administered via a Y-line catheter, the following requirements should be observed.

Table 7

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

The compatibility of the drug with other aminoglycosides has not been established. Only the concentrations and diluents for amikacin and gentamicin with the Tazamax dose listed in the table above have been established as suitable for concomitant use via a Y-line catheter. Simultaneous concomitant administration via a Y-line catheter by any method other than those specified above may result in inactivation of the aminoglycoside by Tazamax. See also section "Incompatibilities".

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

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

Children.

Use for children aged 2 years and over.

Overdose

Symptoms. Most of the adverse reactions seen with overdose (including nausea, vomiting and diarrhoea) have also been observed with normal doses. Patients may experience increased neuromuscular excitability or convulsions at doses exceeding the recommended dose (especially in the presence of renal insufficiency). Treatment. In the event 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 can be reduced by haemodialysis. After a single dose of piperacillin/tazobactam,