Piperacillin/Tazobactam 4 g/0.5 g powder and solvent for solution for infusion

Piperacillin/Tazobactam is indicated for the treatment of the following infections in adults and children over 2 years of age (see sections 4.2 and 5.1):

Adults and adolescents

• 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 diabetic foot infections)

Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above.

Piperacillin/Tazobactam may be used in the management of neutropenic patients with fever suspected to be due to a bacterial infection.

Note: Use for bacteraemia due to extended-beta-lactamase (ESBL) producing E. coli and K. pneumoniae (ceftriaxone non-susceptible) is not recommended in adult patients, see section 5.1.

Children 2 to 12 years of age

• Complicated intra-abdominal infections

Piperacillin/Tazobactam may be used in the management of neutropenic children with fever suspected to be due to a bacterial infection.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Posology

The dose and frequency of Piperacillin/Tazobactam depends on the severity and localisation of the infection and expected pathogens.

Adult and adolescent patients

Infections

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

For nosocomial pneumonia and bacterial infections in neutropenic patients, the recommended dose is 4 g piperacillin/0.5 g tazobactam administered every 6 hours. This regimen may also be applicable to treat patients with other indicated infections when particularly severe.

The following table summarises the treatment frequency and the recommended dose for adult and adolescent patients by indication or condition:

Patients with renal impairment

The intravenous dose should be adjusted to the degree of actual renal impairment as follows (each patient must be monitored closely for signs of substance toxicity; medicinal product dose and interval should be adjusted accordingly):

For patients on haemodialysis, one additional dose of piperacillin/tazobactam 2 g/0.25 g should be administered following each dialysis period, because haemodialysis removes 30 % – 50 % of piperacillin in 4 hours.

Patients with hepatic impairment

No dose adjustment is necessary (see section 5.2).

Elderly patients

No dose adjustment is required for the elderly with normal renal function or creatinine clearance values above 40 ml/min.

Paediatric population (2 – 12 years of age)

Infections

The following table summarises the treatment frequency and the dose per body weight for paediatric patients 2 – 12 years of age by indication or condition:

* Not to exceed the maximum 4 g/0.5 g per dose over 30 minutes.

Patients with renal impairment

The intravenous dose should be adjusted to the degree of actual renal impairment as follows (each patient must be monitored closely for signs of substance toxicity; medicinal product dose and interval should be adjusted accordingly):

For children on haemodialysis, one additional dose of 40 mg piperacillin/5 mg tazobactam per kg body weight should be administered following each dialysis period.

Use in children aged below 2 years

The safety and efficacy of Piperacillin/Tazobactam in children 0 – 2 years of age has not been established.

No data from controlled clinical studies are available.

Treatment duration

The usual duration of treatment for most indications is in the range of 5 – 14 days. However, the duration of treatment should be guided by the severity of the infection, the pathogen(s) and the patient's clinical and bacteriological progress.

Method of administration

Piperacillin/Tazobactam is administered by intravenous infusion (over 30 minutes).

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substances, any other penicillin-antibacterial agent, or to any of the excipients listed in section 6.1.

History of acute severe allergic reaction to any other beta-lactam active substances (e.g. cephalosporin, monobactam or carbapenem).

The selection of piperacillin/tazobactam to treat an individual patient should take into account the appropriateness of using a broad-spectrum semi-synthetic penicillin based on factors such as the severity of the infection and the prevalence of resistance to other suitable antibacterial agents.

Before initiating therapy with Piperacillin/Tazobactam, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, other beta-lactam agents (e.g. cephalosporin, monobactam or carbapenem) and other allergens.

Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid [including shock]) reactions have been reported in patients receiving therapy with penicillins, including piperacillin/tazobactam. These reactions are more likely to occur in persons with a history of sensitivity to multiple allergens.

Serious hypersensitivity reactions require the discontinuation of the antibiotic, and may require administration of epinephrine and other emergency measures.

There have been reports of hypersensitivity reactions which progressed to Kounis syndrome (acute allergic coronary arteriospasm that can result in myocardial infarction, see section 4.8).

Piperacillin/Tazobactam may cause severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalised exanthematous pustulosis (see section 4.8). If patients develop a skin rash they should be monitored closely and Piperacillin/Tazobactam discontinued if lesions progress.

Haemophagocytic lymphohistiocytosis (HLH)

Cases of HLH have been reported in patients treated with piperacillin/tazobactam, often following treatment longer than 10 days. HLH is a life-threatening syndrome of pathologic immune activation characterised by clinical signs and symptoms of an excessive systemic inflammation (e.g. fever, hepatosplenomegaly, hypertriglyceridaemia, hypofibrinogenaemia, high serum ferritin, cytopenias and haemophagocytosis). Patients who develop early manifestations of pathologic immune activation should be evaluated immediately. If diagnosis of HLH is established, piperacillin/tazobactam treatment should be discontinued.

Rhabdomyolysis has been reported with the use of Piperacillin/Tazobactam. If signs or symptoms of rhabdomyolysis are observed, Piperacillin/Tazobactam should be discontinued and appropriate therapy initiated.

Antibiotic-induced pseudomembranous colitis may be manifested by severe, persistent diarrhoea which may be life-threatening. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment. In these cases, Piperacillin/Tazobactam should be discontinued.

Therapy with Piperacillin/Tazobactam may result in the emergence of resistant organisms, which might cause super-infections.

Bleeding manifestations have occurred in some patients receiving beta-lactam antibiotics. These reactions sometimes have been associated with abnormalities of coagulation tests, such as clotting time, platelet aggregation and prothrombin time, and are more likely to occur in patients with renal failure. If bleeding manifestations occur, the antibiotic should be discontinued, and appropriate therapy instituted.

Leukopenia and neutropenia may occur, especially during prolonged therapy; therefore, periodic assessment of haematopoietic function should be performed.

As with treatment with other penicillins, neurological complications in the form of convulsions (seizures) may occur when high doses are administered, especially in patients with impaired renal function (see section 4.8).

Hypokalaemia may occur in patients with low potassium reserves or those receiving concomitant medicinal products that may lower potassium levels; periodic electrolyte determinations may be advisable in such patients.

Renal impairment

Due to its potential nephrotoxicity (see section 4.8), piperacillin/tazobactam should be used with care in patients with renal impairment or in haemodialysis patients. Intravenous dosages and administration intervals should be adjusted to the degree of renal function impairment (see section 4.2).

In a secondary analysis using data from a large multicentre, randomized-controlled trial when glomerular filtration rate (GFR) was examined after administration of frequently used antibiotics in critically ill patients, the use of piperacillin/tazobactam was associated with a lower rate of reversible GFR improvement compared with the other antibiotics. This secondary analysis concluded that piperacillin/tazobactam was a cause of delayed renal recovery in these patients.

Combined use of piperacillin/tazobactam and vancomycin may be associated with an increased incidence of acute kidney injury (see section 4.5).

Warnings/precautions regarding excipients

This medicinal product contains 459.7 mg sodium per bag, equivalent to 22.98 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

This should be taken into consideration for patients who are on a controlled sodium diet.

Non-depolarising muscle relaxants

Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. Due to their similar mechanisms of action, it is expected that the neuromuscular blockade produced by any of the non-depolarising muscle relaxants could be prolonged in the presence of piperacillin.

Anticoagulants

During simultaneous administration of heparin, oral anticoagulants and other substances that may affect the blood coagulation system including thrombocyte function, appropriate coagulation tests should be performed more frequently and monitored regularly.

Methotrexate

Piperacillin may reduce the excretion of methotrexate; therefore, serum levels of methotrexate should be monitored in patients to avoid substance toxicity.

Probenecid

As with other penicillins, concurrent administration of probenecid and piperacillin/tazobactam produces a longer half-life and lower renal clearance for both piperacillin and tazobactam; however, peak plasma concentrations of either substances are unaffected.

Aminoglycosides

Piperacillin, either alone or with tazobactam, did not significantly alter the pharmacokinetics of tobramycin in subjects with normal renal function and with mild or moderate renal impairment. The pharmacokinetics of piperacillin, tazobactam, and the M1 metabolite were also not significantly altered by tobramycin administration.

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

For information related to the administration of piperacillin / tazobactam with aminoglycosides please refer to sections 6.2 and 6.6

Vancomycin

Studies have detected an increased incidence of acute kidney injury in patients concomitantly administered piperacillin/tazobactam and vancomycin as compared to vancomycin alone (see section 4.4). Some of these studies have reported that the interaction is vancomycin dose dependent.

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

Effects on laboratory tests

Non-enzymatic methods of measuring urinary glucose may lead to false-positive results, as with other penicillins. Therefore, enzymatic urinary glucose measurement is required under Piperacillin/Tazobactam therapy.

A number of chemical urine protein measurement methods may lead to false-positive results. Protein measurement with dip sticks is not affected.

The direct Coombs test may be positive.

Bio-Rad Laboratories Platelia Aspergillus EIA tests may lead to false-positive results for patients receiving Piperacillin/Tazobactam. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported.

Positive test results for the assays listed above in patients receiving Piperacillin/Tazobactam should be confirmed by other diagnostic methods.

Pregnancy

There are no or a limited amount of data from the use of Piperacillin/Tazobactam in pregnant women.

Studies in animals have shown developmental toxicity, but no evidence of teratogenicity, at doses that are maternally toxic (see section 5.3).

Piperacillin and tazobactam cross the placenta. Piperacillin/tazobactam should only be used during pregnancy if clearly indicated, i.e. only if the expected benefit outweighs the possible risks to the pregnant woman and foetus.

Breast-feeding

Piperacillin is excreted in low concentrations in human milk; tazobactam concentrations in human milk have not been studied. Women who are breast-feeding should be treated only if the expected benefit outweighs the possible risks to the woman and child.

Fertility

A fertility study in rats showed no effect on fertility and mating after intraperitoneal administration of tazobactam or the combination piperacillin/tazobactam (see section 5.3).

No studies on the effect on the ability to drive and use machines have been performed.

The most commonly reported adverse reaction is diarrhoea (occurring in 1 patient out of 10).

Among the most serious adverse reactions pseudo-membranous colitis and toxic epidermal necrolysis occur in 1 to 10 patients in 10,000. The frequencies for pancytopenia, anaphylactic shock and Stevens-Johnson syndrome cannot be estimated from the currently available data.

In the following table, adverse reactions are listed by system organ class and MedDRA-preferred term. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

*ADR identified post marketing

**Acute coronary syndrome associated with an allergic reaction

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

Beta-lactam antibiotic class effects

Beta-lactam antibiotics, including piperacillin/tazobactam, may lead to manifestations of encephalopathy and convulsions (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Symptoms

There have been post-marketing reports of overdose with piperacillin/tazobactam. The majority of those events experienced, including nausea, vomiting, and diarrhoea, have also been reported with the usual recommended dose. Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure).

Treatment

In the event of an overdose, piperacillin/tazobactam treatment should be discontinued. No specific antidote is known.

Treatment should be supportive and symptomatic according to the patient's clinical presentation.

Excessive serum concentrations of either piperacillin or tazobactam may be reduced by haemodialysis (see section 4.4).

Pharmacotherapeutic group: antibacterials for systemic use, combinations of penicillins incl. beta-lactamase inhibitors, ATC code: J01C R05

Mechanism of action

Piperacillin, a broad-spectrum, semi-synthetic penicillin exerts bactericidal activity by inhibition of both septum and cell-wall synthesis.

Tazobactam, a beta-lactam structurally related to penicillins, is an inhibitor of many beta-lactamases, which commonly cause resistance to penicillins and cephalosporins, but it does not inhibit AmpC enzymes or metallo beta-lactamases. Tazobactam extends the antibiotic spectrum of piperacillin to include many beta-lactamase-producing bacteria that have acquired resistance to piperacillin alone.

Pharmacokinetic/Pharmacodynamic relationship

The time above the minimum inhibitory concentration (T > MIC) is considered to be the major pharmacodynamic determinant of efficacy for piperacillin.

Mechanism of resistance

The two main mechanisms of resistance to piperacillin/tazobactam are:

• Inactivation of the piperacillin component by those beta-lactamases that are not inhibited by tazobactam: beta-lactamases in the Molecular classes B, C and D.

• Alteration of penicillin-binding proteins (PBPs), which results in the reduction of the affinity of piperacillin for the molecular target in bacteria.

Additionally, alterations in bacterial membrane permeability, as well as expression of multi-drug efflux pumps, may cause or contribute to bacterial resistance to piperacillin/tazobactam, especially in Gram-negative bacteria.

Susceptibility testing breakpoints

MIC (minimum inhibitory concentration) interpretive criteria for susceptibility testing have been established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for piperacillin/tazobactam and are listed here: https://www.ema.europa.eu/documents/other/minimum-inhibitory-concentration-mic-breakpoints_en.xlsx

Susceptibility

The prevalence of acquired resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

† Streptococci are not beta-lactamase producing bacteria; resistance in these organisms is due to alterations in penicillin-binding proteins (PBPs) and, therefore, susceptible isolates are susceptible to piperacillin alone. Penicillin resistance has not been reported in S. pyogenes.

†† Including Anaerococcus, Finegoldia, Parvimonas, Peptoniphilus, and Peptostreptococcus spp.

MerinoTrial (blood stream infections due to ESBL producers)

In a prospective, non-inferiority, parallel-group, published randomized clinical trial, definitive (i.e. based on susceptibility confirmed in vitro) treatment with piperacillin/tazobactam, compared with meropenem, did not result in a non-inferior 30-day mortality in adult patients with ceftriaxone-non-susceptible E. coli or K. pneumoniae blood stream infections.

A total of 23 of 187 patients (12.3 %) randomized to piperacillin/tazobactam met the primary outcome of mortality at 30 days compared with 7 of 191 (3.7 %) randomized to meropenem (risk difference, 8.6 % [one-sided 97.5 % CI − ∞ to 14.5 %]; P = 0.90 for non-inferiority). The difference did not meet the non-inferiority margin of 5 %.

Effects were consistent in an analysis of the per-protocol population, with 18 of 170 patients (10.6 %) meeting the primary outcome in a 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 resolution (secondary outcomes) by day 4 occurred in 121 of 177 patients (68.4 %) in the piperacillin/tazobactam group compared with 138 of 185 (74.6 %), randomized to meropenem (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 < 0.05 considered significant.

In this trial, a mortality imbalance between study groups was found. It was supposed that deaths occurred in piperacillin/tazobactam group were related to underlying diseases rather than to the concomitant infection.

Absorption

The peak piperacillin and tazobactam concentrations after 4 g/0.5 g administered over 30 minutes by intravenous infusion are 298 µg/ml and 34 µg/ml, respectively.

Distribution

Both piperacillin and tazobactam are approximately 30 % bound to plasma proteins. The protein binding of either piperacillin or tazobactam is unaffected by the presence of the other compound. Protein binding of the tazobactam metabolite is negligible.

Piperacillin/tazobactam is widely distributed in tissues and body fluids including intestinal mucosa, gallbladder, lung, bile, and bone. Mean tissue concentrations are generally 50 to 100 % of those in plasma. Distribution into cerebrospinal fluid is low in subjects with non-inflamed meninges, as with other penicillins.

Biotransformation

Piperacillin is metabolised to a minor microbiologically active desethyl metabolite. Tazobactam is metabolised to a single metabolite that has been found to be microbiologically inactive.

Elimination

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

Piperacillin is excreted rapidly as unchanged substance, with 68 % of the administered dose appearing in the urine. Tazobactam and its metabolite are eliminated primarily by renal excretion, with 80 % of the administered dose appearing as unchanged substance and the remainder as the single metabolite. Piperacillin, tazobactam, and desethyl piperacillin are also secreted into the bile.

Following single or multiple doses of piperacillin/tazobactam to healthy subjects, the plasma half-life of piperacillin and tazobactam ranged from 0.7 to 1.2 hours and was unaffected by dose or duration of infusion. The elimination half-lives of both piperacillin and tazobactam are increased with decreasing renal clearance.

There are no significant changes in piperacillin pharmacokinetics due to tazobactam. Piperacillin appears to slightly reduce the clearance of tazobactam.

Special populations

The half-life of piperacillin and of tazobactam increases by approximately 25 % and 18 %, respectively, in patients with hepatic cirrhosis compared to healthy subjects.

The half-life of piperacillin and tazobactam increases with decreasing creatinine clearance. The increase in half-life is two-fold and four-fold for piperacillin and tazobactam, respectively, at creatinine clearance below 20 ml/min compared to patients with normal renal function.

Haemodialysis removes 30 % to 50 % of piperacillin/tazobactam, with an additional 5 % of the tazobactam dose removed as the tazobactam metabolite. Peritoneal dialysis removes approximately 6 % and 21 % of the piperacillin and tazobactam doses, respectively, with up to 18 % of the tazobactam dose removed as the tazobactam metabolite.

Paediatric population

In a population PK analysis, estimated clearance for 9 month-old to 12 year-old patients was comparable to adults, with a population mean (SE) value of 5.64 (0.34) ml/min/kg. The piperacillin clearance estimate is 80 % of this value for paediatric patients 2 − 9 months of age. The population mean (SE) for piperacillin volume of distribution is 0.243 (0.011) l/kg and is independent of age.

Elderly patients

The mean half-life for piperacillin and tazobactam were 32 % and 55 % longer, respectively, in the elderly compared with younger subjects. This difference may be due to age-related changes in creatinine clearance.

Race

No difference in piperacillin or tazobactam pharmacokinetics was observed between Asian (n = 9) and Caucasian (n = 9) healthy volunteers who received single 4 g/0.5 g doses.

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity and genotoxicity. Carcinogenicity studies have not been conducted with piperacillin/tazobactam.

A fertility and general reproduction study in rats using intraperitoneal administration of tazobactam or the combination piperacillin/tazobactam reported a decrease in litter size and an increase in foetuses with ossification delays and variations of ribs, concurrent with maternal toxicity. Fertility of the F1 generation and embryonic development of F2 generation were not impaired.

Teratogenicity studies using intravenous administration of tazobactam or the combination piperacillin/tazobactam in mice and rats resulted in slight reductions in rat foetal weights at maternally toxic doses but did not show teratogenic effects.

Peri/postnatal development was impaired (reduced pup weights, increase in stillbirths, increase in pup mortality) concurrent with maternal toxicity after intraperitoneal administration of tazobactam or the combination piperacillin/tazobactam in the rat.

Solvent

Sodium chloride

Water for injections

Powder

Sodium citrate dihydrate

Disodium edetate dihydrate

This medicinal product must not be mixed with other medicinal products.

Whenever Piperacillin/Tazobactam is used concurrently with another antibiotic (e.g. aminoglycosides), the substances must be administered separately. The mixing of beta-lactam antibiotics with an aminoglycoside in vitro can result in substantial inactivation of the aminoglycoside.

Piperacillin/Tazobactam should neither be mixed nor administered with other substances in a syringe, Y-site infusion, infusion bottle, or the two-chamber bag, since compatibility has not been established.

Piperacillin/Tazobactam should not be added to blood products or albumin hydrolysates.

Shelf life before reconstitution

2 years

Shelf life after reconstitution

The reconstituted drug product is intended for single use only.

Chemical and physical in-use stability has been demonstrated for 24 hours at 25 °C or 7 days at 2 – 8 °C.

From a microbiological point of view, unless the method of opening and reconstitution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Shelf life after first opening

The opened two-chamber bag should be used immediately.

This medicinal product does not require any special storage conditions regarding temperature.

Do not freeze the reconstituted solution.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Piperacillin/Tazobactam is provided in colourless multilayer plastic two-chamber bags of PET/Alu/polypropylene copolymer/SEBS thermoplastic elastomers with a set-port. One side is opaque, the other side is transparent.

The diluent chamber contains 100 ml sterile sodium chloride solution (0.45 %).

The two-chamber bags are packed in cartons with 24 units.

Do not cover any portion of foil strip with patient label.

Do not use in series connection.

Discard unit if foil strip of container is damaged.

Peel foil strip only when ready for use.

Visually inspect medicinal product prior to reconstitution. The solution should only be used if it is clear, colourless and practically free from particles.

Instructions for reconstitution of the Piperacillin/Tazobactam two-chamber bag

1. Peel stickers halfway off and unfold container.
2. Peel foil strip from drug powder chamber.
3. Fold container just below diluent meniscus and squeeze until seal between diluent and powder pops open.
4. Shake the diluent-powder mixture until the drug powder is completely dissolved.
5. Visually inspect the reconstituted solution for particulate matter. Do not use unless the solution is clear, colourless and practically free from particles.
6. Squeeze folded container just below the solution meniscus to pop the second seal and release liquid into the port.
7. Remove foil tab cover from set port and attach sterile administration set. Hang bag on IV pole for administration of the whole dose, or only a fraction of it (e.g. for children).

Co-administration with aminoglycosides

Due to the in vitro inactivation of the aminoglycoside by beta-lactam antibiotics, Piperacillin/Tazobactam and the aminoglycoside are recommended for separate administration.

In circumstances where co-administration is recommended, Piperacillin/Tazobactam is compatible for simultaneous co-administration via Y-site infusion only with the following aminoglycosides under the following conditions:

The mixed solutions can be stable up to 4 hours when stored at 25 °C with Amikacin, whereas it can be stable up to 60 minutes when stored at 25 °C with Gentamicin.

See section 6.2 for incompatibilities.

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

For single use only. Discard any unused solution.