Tazpen: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TAZPEN (Tazpen)

Composition:

Active substances: piperacillin sodium, tazobactam sodium;

One vial contains piperacillin sodium equivalent to piperacillin 2 g or 4 g and tazobactam sodium equivalent to tazobactam 250 mg (0.25 g) or 500 mg (0.5 g).

Pharmaceutical form.

Powder for solution for injection and infusion.

Main physicochemical properties: lyophilized powder, white to almost white.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Beta-lactam antibiotics, penicillins. Piperacillin and enzyme inhibitor.

ATC code J01CR05.

Pharmacological properties.

Pharmacodynamics.

Piperacillin is a semisynthetic broad-spectrum penicillin that exhibits activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria. It inhibits bacterial activity by interfering with cell septum formation and cell wall synthesis. Tazobactam, a sulfone derivative of triazolylmethylpenicillanic acid, is an inhibitor of many beta-lactamases, including plasmid- and chromosomally-mediated enzymes that often confer resistance to penicillins and cephalosporins, including third-generation cephalosporins. Tazobactam has only minimal antibacterial activity. The presence of tazobactam in the combination drug Tazpen enhances and extends the antimicrobial spectrum of piperacillin to include bacteria that produce beta-lactamases and are normally resistant to piperacillin and other beta-lactam antibiotics. Thus, Tazpen combines the properties of a broad-spectrum antibiotic and a beta-lactamase inhibitor. Tazpen is active against the following microorganisms:

Susceptible (aerobic Gram-positive bacteria) – Brevibacterium spp., Corynebacterium xerosis, Corynebacterium spp., Enterococcus durans, Enterococcus faecalis, Enterococcus spp., Gemella haemolysans, Gemella morbillorum, Lactococcus lactis cremoris, Listeria monocytogenes, Propionibacterium granulosum, Propionibacterium spp., Staphylococcus aureus (methicillin-susceptible), Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus, Staphylococcus sciuri, Staphylococcus xylosus, Staphylococcus spp. (coagulase-negative), Streptococcus agalactiae, Streptococcus anginosus, Streptococcus β-haemolytic group A, Streptococcus β-haemolytic group D, Streptococcus constellatus, Streptococcus gordonii, Streptococcus intermedius, Streptococcus milleri, Streptococcus milleri-group, Streptococcus mitis, Streptococcus morbillorum, Streptococcus oralis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus sanguis, Streptococcus viridans, Streptococcus viridans group, Streptococcus spp.;

Susceptible (aerobic Gram-negative bacteria) – Acinetobacter anitratus, Acinetobacter lwoffii, Aeromonas sobria, Alcaligenes spp., Branhamella catarrhalis, Burkholderia cepacia, Citrobacter diversus, Citrobacter farmeri, Citrobacter freundii, Citrobacter koseri, Citrobacter spp., Eikenella corrodens, Enterobacter agglomerans, Enterobacter cloacae, Enterobacter spp., Escherichia coli, Escherichia hermannii, Escherichia vulneris, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus spp., Klebsiella ornithinolytica, Klebsiella oxytoca, Klebsiella pneumoniae, Klebsiella spp., Morganella morganii, Pasteurella multocida, Proteus indole-positive, Proteus mirabilis, Proteus vulgaris, Proteus spp., Providencia stuartii, Providencia species, Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas putida, Pseudomonas spp., Salmonella arizonae, Salmonella species, Serratia liquefaciens, Serratia marcescens, Serratia odorifera, Serratia spp., Shigella boydii, Shigella dysenteriae, Shigella flexneri, Shigella sonnei;

Susceptible (anaerobic Gram-positive bacteria) – Bifidobacterium spp., Clostridium bifermentans, Clostridium butyricum, Clostridium cadaveris, Clostridium clostridiforme, Clostridium difficile, Clostridium hastiforme, Clostridium limosum, Clostridium perfringens, Clostridium ramosum, Clostridium tertium, Clostridium spp., Eubacterium aerofaciens, Eubacterium lentum, Eubacterium spp., Peptococcus asaccharolyticus, Peptococcus spp., Peptostreptococcus anaerobius, Peptostreptococcus magnus, Peptostreptococcus micros, Peptostreptococcus prevotii, Peptostreptococcus species;

Susceptible (anaerobic Gram-negative bacteria) – Bacteroides caccae, Bacteroides capillosus, Bacteroides distasonis, Bacteroides fragilis, Bacteroides fragilis group, Bacteroides ovatus, Bacteroides putredinis, Bacteroides stercoris, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides ureolyticus, Bacteroides vulgatus, Bacteroides spp., Fusobacterium necrophorum, Fusobacterium nucleatum, Fusobacterium varium, Fusobacterium spp., Porphyromonas asaccharolytica, Porphyromonas gingivalis, Porphyromonas species, Prevotella bivia, Prevotella disiens, Prevotella intermedia, Prevotella melaninogenica, Prevotella oralis, Prevotella spp.;

Intermediate susceptibility (aerobic Gram-positive bacteria) – Enterococcus avium, Enterococcus faecium, Propionibacterium acnes;

Intermediate susceptibility (aerobic Gram-negative bacteria) – Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter spp., Enterobacter aerogenes, Pseudomonas stutzeri, Stenotrophomonas maltophilia, Pseudomonas stutzeri;

Resistant (aerobic Gram-positive bacteria) – Corynebacterium jeikeium, Staphylococcus (coagulase-negative, methicillin-resistant);

Resistant (aerobic Gram-negative bacteria) – Legionella spp., Stenotrophomonas maltophilia.

Table 1

Minimum Inhibitory Concentrations (MIC)

Microorganisms	Susceptible	Intermediate susceptibility	Resistant
Enterobacteriaceae	< 16 mg/l	32–64 mg/l	> 128 mg/l
Pseudomonas spp.	< 64 mg/l	-	> 128 mg/l
Staphylococcus spp.	< 8 mg/l	-	> 16 mg/l
* Streptococcus spp.	< 1 mg/l	-	> 2 mg/l
Anaerobes	< 32 mg/l	64 mg/l	> 128 mg/l

* The prevalence of acquired resistance may vary geographically and over time for individual species.

Pharmacokinetics.

Absorption. Mean plasma concentrations of piperacillin and tazobactam at steady state are shown in tables 2–3. Maximum plasma concentrations of piperacillin and tazobactam are achieved immediately after completion of intravenous administration. The plasma concentration of piperacillin administered in combination with tazobactam is similar to that observed when piperacillin is administered as monotherapy at an equivalent dose.

Plasma concentration levels in adults following 5-minute intravenous infusion of piperacillin and tazobactam are shown in Table 2.

Table 2

Plasma concentration levels of piperacillin (mcg/ml)

Dose of piperacillin/tazobactam	5 min*	0.5 hour	1 hour	2 hours	3 hours	4 hours
4.5 g	364	165	92	37	16	7

Tazobactam plasma concentration level (mcg/ml)

Piperacillin/tazobactam dose	5 min*	0.5 hour	1 hour	2 hours	3 hours	4 hours
4.5 g	34.3	17.9	10.8	4.8	2.0	0.9

*End of 5-minute infusion.

Plasma concentration levels in adults following 30-minute intravenous administration of piperacillin and tazobactam are shown in Table 3.

Table 3

Plasma concentration of piperacillin (mcg/mL)

Piperacillin/tazobactam dose	30 min*	1 hour	1.5 hours	2 hours	3 hours	4 hours
4.5 g	298	141	87	47	16	7

Tazobactam plasma concentration level (mcg/ml)

Piperacillin/tazobactam dose	30 min*	1 hour	1.5 hours	2 hours	3 hours	4 hours
4.5 g	33.8	17.3	11.7	6.8	2.8	1.3

* End of 30-minute infusion.

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

Metabolism. Piperacillin is metabolized to desethylpiperacillin, a weakly active metabolite; tazobactam is metabolized to an inactive metabolite.

Excretion. Piperacillin and tazobactam are eliminated by the kidneys via glomerular filtration and tubular secretion. Piperacillin is rapidly excreted unchanged, 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 Tazpen in healthy volunteers, the elimination half-life of piperacillin and tazobactam in plasma ranged from 0.7 to 1.2 hours and was independent of dose or duration of infusion. When creatinine clearance is reduced, the elimination half-life of piperacillin and tazobactam is prolonged.

Renal impairment. The elimination half-lives of piperacillin and tazobactam increase as creatinine clearance decreases. When creatinine clearance falls below 20 mL/min, the half-lives of piperacillin and tazobactam increase by approximately 2-fold and 4-fold, respectively, compared to those in patients with normal renal function. During hemodialysis, 30% to 50% of the administered piperacillin dose and 5% of the tazobactam dose (as metabolite) are removed. During peritoneal dialysis, approximately 6% of piperacillin and 21% of tazobactam are excreted, with 18% of tazobactam excreted as its metabolite.

Hepatic impairment. Although the elimination half-lives of piperacillin and tazobactam are prolonged in patients with hepatic dysfunction, dose adjustment is not required.

Clinical characteristics.

Indications.

Treatment of infections caused by Gram-positive and Gram-negative aerobic and anaerobic bacteria sensitive to piperacillin or piperacillin/tazobactam.

In adults and elderly patients:

lower respiratory tract infections (including hospital-acquired pneumonia);
complicated urinary tract infections (including pyelonephritis);
complicated skin and soft tissue infections (abscess, infected trophic ulcers);
complicated intra-abdominal infections;
bacterial septicemia;
in combination with aminoglycosides, used in the treatment of patients with fever associated with neutropenia.

In children aged 2 to 12 years:

in combination with aminoglycosides, used in the treatment of patients with fever associated with neutropenia;
intra-abdominal infections, including complicated forms of acute appendicitis with generalized peritonitis; appendiceal infiltrate associated with abscess formation.

Contraindications.

Hypersensitivity to the active substances or to any other penicillin antibiotics. Severe allergic reaction to another beta-lactam antibiotic (e.g., cephalosporin, monobactam, or carbapenem) in medical history.

Interaction with other medicinal products and other forms of interaction.

Aminoglycosides.

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

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

Due to in vitro inactivation of aminoglycosides by piperacillin in the same solution, Tazpen and aminoglycosides should be administered separately. Piperacillin-containing products and aminoglycosides must be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is prescribed. A Y-type catheter should be used for administration. Provided all the above conditions are met, Tazpen may be administered via a Y-type catheter only with the aminoglycosides listed in Table 4.

Table 4

Aminoglycoside

Dose (mg/ml)

Required volume of solution

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*

57–12 ml

0.7–3.32

0.9% sodium chloride solution or

5% glucose solution

*Duration of administration see instructions for medical use of the drug.

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

When administering intravenously in combination, medical personnel must comply with certain requirements, namely:

observe aseptic conditions and use an intravenous administration set for no longer than 24 hours;
label the container with the patient's surname, time, and date of administration;
periodically check the solution for clarity, color, and presence of visible foreign particles.

Compatibility of Tazpen with other aminoglycosides has not been established.

Tazpen is incompatible with tobramycin for simultaneous infusion via a Y-type catheter.

Probenecid.

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

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

Vancomycin.

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

However, limited studies have shown an increased incidence of acute kidney injury in patients receiving piperacillin/tazobactam and vancomycin concomitantly, compared to vancomycin monotherapy.

Renal function monitoring is required when piperacillin/tazobactam and vancomycin are used concomitantly.

Anticoagulants.

When used concomitantly with heparin, oral anticoagulants, and other agents affecting the blood coagulation system, including platelet function, coagulation tests should be performed more frequently and monitored dynamically.

Non-depolarizing muscle relaxants.

When piperacillin and vecuronium are administered concomitantly, piperacillin may prolong neuromuscular blockade induced by vecuronium. Due to their similar mechanisms of action, neuromuscular blockade caused by any depolarizing muscle relaxant may be prolonged in the presence of piperacillin. Concomitant use of any non-depolarizing muscle relaxant with piperacillin should be anticipated. Monitoring for adverse reactions related to neuromuscular blockade is required.

Methotrexate.

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

Effect on laboratory parameters.

As with other penicillins, false-positive results in the detection of Aspergillus species have been reported in patients receiving piperacillin/tazobactam injections. Positive results from such tests should be interpreted with caution and confirmed by other diagnostic methods.

During treatment with Tazpen, false-positive results in urine glucose testing may occur when using copper ion reduction-based methods. Therefore, glucose testing based on enzymatic oxidation is recommended.

Pharmaceutical compatibility with other medicinal products.

Tazpen should not be mixed in the same syringe or infusion solution with other medicinal products except for the specified diluents, due to lack of compatibility data.

Special precautions.

Before initiating treatment with Tazpen, it is essential to carefully review the patient’s history of hypersensitivity reactions to penicillins and cephalosporins, as well as to other allergens.

Severe and, rarely, fatal hypersensitivity reactions (anaphylaxis) have been reported in patients receiving penicillin therapy. Severe allergic reactions may require discontinuation of antibiotics, administration of epinephrine, and other emergency measures.

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, Tazpen therapy should be discontinued.

Resistance of microorganisms may develop during Tazpen therapy, potentially leading to superinfection.

Bleeding has occurred in some patients receiving beta-lactam antibiotics.

These reactions have sometimes been associated with changes in laboratory coagulation parameters such as blood clotting time, platelet aggregation, and prothrombin time; they occur more frequently in patients with renal impairment. If signs of bleeding occur, antibiotic therapy should be discontinued and appropriate treatment initiated.

During Tazpen therapy, a false-positive result in the urine glucose test may occur when using methods based on copper ion reduction. Therefore, it is recommended to perform glucose testing using an enzymatic glucose oxidation method.

The sodium content in a Tazpen 4 g/0.5 g vial is 217 mg (9.44 mmol), which may increase the patient’s total body sodium load. Hypokalemia may develop in patients with low potassium stores or in those concurrently receiving medications capable of reducing potassium levels; in such patients, periodic monitoring of blood electrolyte levels is recommended.

During prolonged treatment, leukopenia and neutropenia may develop; therefore, the patient’s hematological status should be monitored periodically.

Empirical therapy with Tazpen may be initiated in severe infections before results of culture and antibiotic susceptibility testing are available.

Renal impairment

Due to the potential nephrotoxicity of tazobactam, caution should be exercised when administering the drug to patients with impaired renal function, as well as to those undergoing hemodialysis. Intravenous doses and dosing intervals should be adjusted according to the degree of renal impairment.

In a secondary analysis using data from a large multicenter randomized study on glomerular filtration rate following administration of commonly used antibiotics in critically ill patients, the use of piperacillin/tazobactam was associated with a lower glomerular filtration rate compared to other antibiotics. Based on this secondary analysis, piperacillin/tazobactam use was identified as a cause of delayed renal function recovery in these patients.

Hemophagocytic lymphohistiocytosis (HLH)

Cases of HLH have been reported in patients receiving piperacillin/tazobactam or piperacillin, often after treatment lasting 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, elevated serum ferritin, cytopenia, and hemophagocytosis). Patients who develop early signs of pathological immune activation should be evaluated immediately. If the diagnosis of HLH is confirmed, treatment with piperacillin/tazobactam or piperacillin should be discontinued.

Use during pregnancy or breastfeeding.

Pregnancy. There are no adequate and well-controlled studies of piperacillin/tazobactam, piperacillin, or tazobactam alone in pregnant women. Tazpen crosses the placenta. The drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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

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

Ability to affect reaction speed when driving or operating machinery.

No data available.

During treatment, the possibility of dizziness and seizures affecting psychomotor performance should be considered.

Method of Administration and Dosage

Tazpen must be administered by intravenous infusion over approximately 20–30 minutes or by slow intravenous bolus injection over at least 3–5 minutes.

In neutropenic patients, fever is most commonly a sign of infection. In such cases, empirical therapy with Tazpen may be initiated before the results of antibiotic susceptibility testing are available.

Adults and children aged 12 years and older with normal renal function.

The recommended daily dose is 12 g of piperacillin/1.5 g of tazobactam, i.e., 4 g/500 mg of Tazpen every 8 hours (3 times daily). The total daily dose of Tazpen depends on the severity and extent of the infection and may range from 2 g/250 mg (2 g piperacillin/250 mg tazobactam) to 4 g/500 mg (4 g piperacillin/500 mg tazobactam) every 6–8 hours (3–4 times daily).

For patients with fever associated with neutropenia, the recommended dose is 4 g/500 mg of Tazpen (4 g piperacillin/500 mg tazobactam) every 6 hours (4 times daily) in combination with aminoglycosides.

Elderly patients with normal renal function: the recommended daily dose of Tazpen may be the same as for adults (except in cases of impaired liver function).

Patients (adults, elderly patients, and children aged 12 years and older) with renal impairment.

When prescribing Tazpen to patients with renal impairment or those undergoing hemodialysis, dosage and dosing intervals must be adjusted according to the degree of renal impairment.

For patients with renal impairment, the recommended doses are listed in Table 5.

Table 5

Creatinine clearance (mL/min)	Recommended dose of Tazpen
20– 80	4.5 g every 8 hours
< 20	4.5 g every 12 hours

For patients undergoing hemodialysis, the maximum daily dose is 8 g/1 g of piperacillin/tazobactam. Since 30–50% of piperacillin is removed during a 4-hour hemodialysis session, an additional dose of 2 g/250 mg piperacillin/tazobactam should be administered after each dialysis session. Dose adjustment in patients with renal or hepatic impairment can be guided by monitoring serum concentrations of Tazpen.

Children aged 2 to 12 years with normal renal function

Tazpen is recommended only for neutropenic patients or those with complicated acute appendicitis.

In neutropenia. For febrile neutropenic patients, in combination with aminoglycosides: children with normal renal function and body weight less than 50 kg should receive 90 mg (80 mg piperacillin/10 mg tazobactam)/kg body weight every 6 hours, in combination with an appropriate dose of aminoglycoside, not exceeding 4.5 g (4 g piperacillin/500 mg tazobactam) every 6 hours (4 times daily).

For children with body weight above 50 kg, the adult dose should be used, administered in combination with an appropriately dosed aminoglycoside.

In complicated acute appendicitis

For children with body weight up to 40 kg and normal renal function, the recommended dose is 112.5 mg of Tazpen (100 mg piperacillin/12.5 mg tazobactam)/kg body weight every 8 hours, not exceeding 4.5 g (4 g piperacillin/500 mg tazobactam) every 8 hours (3 times daily).

For children with body weight above 40 kg and normal renal function, the adult dose should be used.

Children aged 2 to 12 years with renal impairment

When administering the drug to patients with renal impairment, doses and dosing intervals should be adjusted according to the degree of renal impairment.

Recommended doses for patients with renal impairment are listed in Table 6.

Table 6

Creatinine clearance (mL/min)	Recommended dose of piperacillin/tazobactam	Frequency of administration	Maximum daily dose
≥ 40	No dose adjustment required
20–39	90 mg (80 mg piperacillin/10 mg tazobactam) per kg body weight	Every 8 hours	Total daily dose not exceeding 12 g /1.5 g per day
<20	90 mg (80 mg piperacillin/10 mg tazobactam) per kg body weight	Every 12 hours	Total daily dose not exceeding 8 g /1 g per day

Recommended dosage for children undergoing hemodialysis with body weight < 50 kg is 45 mg (40 mg piperacillin/5 mg tazobactam)/kg of body weight per day, administered every 8 hours. The dosage adjustments mentioned above are only approximate. Careful monitoring of each patient is required to detect signs of drug toxicity. The dose and frequency of administration should be adjusted accordingly.

Patients with hepatic impairment.

Dosage adjustment is not required for patients with hepatic impairment receiving Tazpen.

Duration of therapy. In febrile neutropenic patients, administration of the drug should be continued for at least 48 hours after disappearance of clinical signs and symptoms of infection. For other indications, duration of therapy depends on the severity of the infectious process and the clinical and bacteriological response.

In complicated forms of acute appendicitis in children aged 2 to 12 years, treatment is recommended for a minimum of 5 days and a maximum of 14 days.

Instructions for mixing and dilution

For intravenous use only.

For intravenous bolus injection, the contents of a vial containing 2 g/250 mg or 4 g/500 mg of the drug should be reconstituted with 10 mL or 20 mL, respectively, of one of the following diluents (using a sterile needle and syringe, non-destructive method). To prepare the solution for intravenous administration, the following diluents may be used: 0.9% sodium chloride solution, 5% glucose solution, or sterile water for injection. The drug and diluent should be shaken until complete dissolution. The substance dissolves completely, leaving no undissolved residue; a clear, colorless or slightly yellow solution is obtained. The dose should be administered over 3–5 minutes.

For intravenous infusion, the contents of a vial containing 2 g/250 mg or 4 g/500 mg of the drug should first be reconstituted with 10 mL or 20 mL, respectively, of 0.9% sodium chloride solution. The resulting solution may then be further diluted to the desired volume (e.g., from 50 mL to 150 mL) with one of the compatible intravenous diluents.

Table 7

Dosage/ vial (piperacillin/ tazobactam)	Required volume of diluent	Required volume of 0.9% sodium chloride for intravenous infusion over 30 minutes	Tazpen, resulting concentration
2 g/250 mg	10 ml	100 ml	23 mg/ml
2 g/250 mg	10 ml	150 ml	15 mg/ml
4 g/500 mg	20 ml	100 ml	45 mg/ml
4 g/500 mg	20 ml	150 ml	30 mg/ml

Shake the medication with the solvent until complete dissolution. The substance dissolves completely, leaving no undissolved residue; a clear, colorless or slightly yellowish solution is obtained. The dose should be administered within 30 minutes.

The solution must be prepared under sterile conditions.

Children.

Can be used in children aged 2 years and older.

Overdose.

Most adverse symptoms observed in overdose (including nausea, vomiting, and diarrhea) have also been reported with usual doses. Patients may experience increased neuromuscular excitability or seizures when doses exceeding the recommended amount are administered (especially in the presence of renal impairment). Treatment is supportive and symptomatic, depending on the clinical presentation.

Excessive concentrations of either piperacillin or tazobactam in blood serum can be reduced by hemodialysis. After a single 3.375 g dose of piperacillin/tazobactam, the percentage of piperacillin and tazobactam removed by hemodialysis was approximately 31% and 39%, respectively.

Adverse reactions.

In most cases, adverse effects associated with the use of Tazpen were not severe (diarrhea, vomiting, nausea, rash) and were well tolerated by patients, without requiring discontinuation of the drug. The frequency of occurrence of these adverse effects is (≥ 1/100 – < 1/10).

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

Table 8

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

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

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

Effect on results of laboratory and other diagnostic tests.

Administration of Tazpen may lead to false-positive glucose reactions in urine when using copper salt-based tests, which is also characteristic for other penicillins. It is recommended to use methods for glucose determination based on enzymatic glucose oxidation. Some chemical methods for measuring urinary protein may yield false-positive results. The use of Tazpen does not affect protein measurement in urine using diagnostic test strips.

The direct Coombs test may be falsely positive.

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

Positive test results for the above-mentioned analyses in patients treated with Tazpen should be confirmed by other diagnostic methods.

Shelf life. 2 years.

Storage conditions.

Store in a dry, protected from light place at a temperature not exceeding 25 °C.

Keep out of reach of children.

Freshly prepared solution for intravenous administration is stable for use for 24 hours when stored at a temperature not exceeding 25 °C, or for 48 hours when stored at 2–8 °C.

Incompatibility.

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

When Tazpen is used concomitantly with other antibiotics, the agents should be administered separately.

Due to the chemical instability of Tazpen, it should not be used in combination with solutions containing sodium bicarbonate.

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

Packaging.

2 g/0.25 g or 4 g/0.5 g in a vial made of glass, stoppered with a rubber stopper and sealed with an aluminum crimp cap.

1 vial per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Astral SteriTech Private Limited

Manufacturer's address and place of business.

911, G.I.D.C., Makarpura, Vadodara, Gujarat, 390 010, India

911, Gidc, Makarpura, Vadodara, Gujarat 390 010, India (IND)

Marketing Authorization Holder.

M.Biotech Ltd.

Address of the Marketing Authorization Holder.

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom