Piperacillin/Tazobactam 2 g/0.25 g Powder for Solution for Injection or Infusion.

Each vial contains 2 g piperacillin (as sodium salt) and 0.25 g tazobactam (as sodium salt).

One vial of powder for solution for injection or infusion contains 4.72 mmol (109 mg) of sodium.

For a full list of excipients see section 6.1.

Powder for solution for injection or infusion

White to off white powder.

Piperacillin/Tazobactam is indicated for the treatment of moderate to severe systemic and/or local bacterial infections in which betalactamase producing bacteria are suspected or have been detected, such as:

Adults/Adolescents and the Elderly

Nosocomial pneumonia

Complicated urinary tract infections (including pyelonephritis)

Intra-abdominal infections

Skin and soft tissue infections

Bacterial infections in neutropenic adults

Children (2-12 years)

Bacterial infections in neutropenic children

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

Piperacillin/Tazobactam may be given by slow intravenous injection (over at least three to five minutes) or by slow intravenous infusion (over 20-30 minutes). .

For reconstitution instructions, see section 6.6.

The treatment of mixed infections caused by piperacillin susceptible organisms and betalactamase producing organisms susceptible to Piperacillin/Tazobactam generally do not require the addition of another antibiotic.

In patients with nosocomial pneumonia and infections in neutropenic patients Piperacillin/Tazobactam can be used with an aminoglycoside. If the use of an aminoglycoside is needed with piperacillin/tazobactam, both Piperacillin/Tazobactam and the aminoglycoside must be used in completely therapeutic doses.

Neutropenic patients with signs of infection (e.g. fever) should receive immediate empirical antibiotic therapy before laboratory results are available.

Adults and Children Over 12 Years, Each with Normal Renal Function

The usual dosage for adults and children over 12 years is Piperacillin/Tazobactam 4000/500 mg given every eight hours.

The total daily dose of Piperacillin/Tazobactam depends on the severity and localisation of the infection and can vary fromPiperacillin/Tazobactam 2000/250 mg to Piperacillin/Tazobactam 4000/500 mg administered every six or eight hours.

In neutropenia the recommended dose is Piperacillin/Tazobactam 4000/500mg given every six hours in combination with an aminoglycoside.

Elderly with Normal Renal Function

Piperacillin/Tazobactam may be used at the same dose levels as adults except in cases of renal impairment (see below):

Renal Insufficiency in Adults, the Elderly and Children (over 40kg) Receiving the Adult Dose

In patients with renal insufficiency, the intravenous dose should be adjusted to the degree of actual renal impairment. The suggested daily doses are as follows:

For patients on haemodialysis, the maximum daily dose isPiperacillin/Tazobactam 8/1 g. In addition, because haemodialysis removes 30%-50% of piperacillin in four hours, one additional dose of Piperacillin/Tazobactam 2000/250 mg should be administered following each dialysis period.

For patients with renal failure and hepatic insufficiency, measurement of serum levels of Piperacillin/Tazobactam will provide additional guidance for adjusting dosage.

Children Aged 2-12 Years with Normal Renal Function

Piperacillin/Tazobactam is only recommended for the treatment of children with neutropenia.

Neutropenia

For children weighing less than 40kg the dose should be adjusted to 90 mg/kg (Piperacillin/ Tazobactam 80/10 mg) administered every six hours, in combination with an aminoglycoside, not exceeding Piperacillin/Tazobactam 4000/500 mg every six hours.

Renal Insufficiency in Children Aged 2-12 Years (or bodyweight less than 40kg)

In children with renal insufficiency the intravenous dosage should be adjusted to the degree of actual renal impairment as follows:

For children weighing < 50kg on haemodialysis the recommended dose is 45mg (Piperacillin/Tazobactam 40/5 mg) /kg every eight hours.

The above dosage modifications are only an approximation. Each patient must be monitored closely for signs of drug toxicity. Drug dose and interval should be adjusted accordingly.

Children under 2 years

Piperacillin/tazobactam is not recommended for use in children below 2 years old due to insufficient data on safety.

Hepatic Impairment

No dose adjustment is necessary.

Duration of Therapy

The duration of therapy should be guided by the severity of the infection and the patient's clinical and bacteriological progress.

In acute infections, treatment with Piperacillin/Tazobactam should be continued for 48 hours beyond the resolution of clinical symptoms or the fever.

Hypersensitivity to piperacillin or any of the beta-lactam antibiotics and to tazobactam or any otherbeta-lactamase inhibitor.

Warnings

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.

There have been reports of patients with a history of penicillin hypersensitivity who have experienced severe reactions when treated with a cephalosporin.

If an allergic reaction occurs during therapy with Piperacillin/Tazobactam, the antibiotic should be discontinued. Serious hypersensitivity reactions may require adrenaline and other emergency measures.

Before initiating therapy with Piperacillin/Tazobactam, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, and other allergens.

In case of severe, persistent diarrhoea, the possibility of antibiotic-induced, life threatening pseudomembranous colitis must be taken into consideration. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment. Therefore, Piperacillin/Tazobactam must be discontinued immediately in such cases, and suitable therapy should be initiated.

Precautions

Leukopenia and neutropenia may occur, especially during prolonged therapy. Therefore, periodic assessment of a full blood count should be performed.

Periodic assessment of organ system functions including renal and hepatic during prolonged therapy is advisable.

Bleeding manifestations have occurred in some patients receiving β-lactam antibiotics. These reactions have sometimes 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.

The possibility of the emergence of resistant organisms, which might cause superinfections, should be kept in mind, particularly during prolonged treatment. Microbiological follow-up may be required to detect any important superinfection. If this occurs, appropriate measures should be taken.

Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously.

This medicinal product contains 4.72 mmol (109 mg) of sodium per vial of powder for solution for injection or infusion. To be taken into account by patients on a controlled sodium diet.

Hypokalaemia may occur in patients with low potassium reserves or who are receiving concomitant medications that may lower potassium levels; periodic electrolyte determinations should be performed in such patients. Modest elevation of indices of liver function may be observed.

Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients (see also 4.8).

Until further experience is available, Piperacillin/Tazobactam should not be used in children who do not have neutropenia.

Interaction with probenecid:

Concurrent administration of probenecid and Piperacillin/Tazobactam produced a longer half-life and lower renal clearance for both piperacillin and tazobactam. However, peak plasma concentrations of either drug are unaffected.

Interaction with antibiotics:

No clinically relevant adverse pharmacokinetic interaction with tobramycin or vancomycin has been observed in healthy adults with a normal renal function. The clearance of tobramycin and gentamicin was enhanced in patients with severe renal dysfunction using Piperacillin/Tazobactam. In these patients mixing of Piperacillin/Tazobactam formulation with tobramycin and gentamicin was excluded.

For information related to the administration of Piperacillin/Tazobactam with aminoglycosides please refer to section 6.2.

Interaction with anticoagulants:

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

Interaction with vecuronium:

Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. Due to their similar mechanism of action, it is expected that the neuromuscular blockade produced by any of the non-polarizing muscle relaxants could be prolonged in the presence of piperacillin. This should be taken into account when piperacillin/tazobactam is used peri-operatively.

Interaction with methotrexate:

Piperacillin may reduce the excretion of methotrexate. Serum levels of methotrexate should be monitored in patients on methotrexate therapy.

Interaction with laboratory test results:

The administration of Piperacillin/Tazobactam may result in a false-positive reaction for glucose in the urine using a copper-reduction method. It is recommended that glucose tests based on enzymatic glucose oxidase reaction be used.

There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving Piperacillin-Tazobactam injection who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving Piperacillin-Tazobactam should be interpreted cautiously and confirmed by other diagnostic methods.

There are no adequate and well-controlled studies with Piperacillin-Tazobactam in combination or with piperacillin or tazobactam alone in pregnant women. Studies in animals have shown reproductive toxicity (see 5.3).Piperacillin and tazobactam cross the placenta. Piperacillin/Tazobactam should only be used during pregnancy if clearly indicated.

Piperacillin is excreted in low concentrations in breast milk. Tazobactam concentrations in human milk have not been studied. The effect on the suckling infant is unknown. Women who are breast-feeding should be treated only if clearly indicated. Diarrhoea and fungal infections of the mucous membranes as well as sensitisation could occur in the breast-fed infant.

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

However, side effects may occur (see also 4.8), which may influence the ability to drive and use machines.

Undesirable effects are listed by frequency as follows: Very common (1/10); common (1/100 to <1/10); uncommon (1/1 000 to 1/100); rare (1/10 000 to 1/1 000); very rare (1/10 000); not known (cannot be estimated from the available data).

The most commonly reported adverse reactions are diarrhoea, nausea, vomiting, and rash, each having a frequency of 1% but 10%.

The administration of high doses of beta-lactams, particularly in patients with renal insufficiency, can lead to encephalopathies (consciousness fluctuation, myoclonus and convulsions).

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

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 dosages. Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure).

Treatment of Intoxication

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. In the event of an emergency, all required intensive medical measures are indicated as in the case of piperacillin.

Excessive serum concentrations of either piperacillin or tazobactam will be reduced by haemodialysis (for more details see section 5.2).

Pharmacotherapeutic group: Combinations of penicillins, including beta-lactamase inhibitors.

ATCClassification: J01CR05

Mechanism of action:

Piperacillin, a broad spectrum, semisynthetic penicillin active against many Gram-positive and Gram-negative aerobic and anaerobic bacteria, exerts bactericidal activity by inhibition of both septum and cell wall synthesis. Tazobactam, a triazolylmethyl penicillanic acid sulphone, is a potent inhibitor of many beta-lactamases, in particular the plasmid mediated enzymes which commonly cause resistance to penicillins and cephalosporins including third-generation cephalosporins. The presence of tazobactam in the Piperacillin /Tazobactam formulation enhances and extends the antibiotic spectrum of piperacillin to include many beta-lactamase producing bacteria normally resistant to it and other beta-lactam antibiotics. Thus, Piperacillin/Tazobactam combines the properties of a broad spectrum antibiotic and a beta-lactamase inhibitor.

Mechanism of resistance:

The presence of tazobactam expands the spectrum of activity of piperacillin to include microorganisms that would otherwise, due to the formation of beta-lactamase, be resistant to piperacillin and other beta-lactam antibiotics. In vitro investigation has demonstrated that the type I beta-lactamase inducing ability of tazobactam is insignificant with regard to Gram-negative bacteria. In vitro studies have demonstrated a synergetic effect of Piperacillin/Tazobactam and aminoglycosides against Pseudomonas aeruginosa and other bacteria, including beta-lactamase producing strains.

Breakpoints

The minimum inhibitory concentration (MIC) breakpoints separating susceptible, intermediately susceptible and resistant organisms have been defined as follows:

EUCAST clinical MIC breakpoints 2008 (version 1.2):

For susceptibility testing purposes, the concentration of tazobactam is fixed at 4 mg/L

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.

Commonly susceptible species

Gram positive aerobes

Brevibacterium spp

Enterococcus faecalis

Listeria monocytogenes

Staphylococcus spp. methicillin-sensitive

Streptococcus pneumoniae

Streptococcus pyogenes

Group B streptococci

Streptococcus spp*

Gram negative aerobes

Branhamella catarrhalis

Citrobacter koseri

Haemophilus influenzae*

Haemophilus spp.

Proteus mirabilis

Salmonella spp.

Shigella spp.

Gram positive anaerobes

Clostridium spp.

Eubacterium spp.

Peptococcus spp.

Peptostreptococcus spp.

Gram negative anaerobes

Bacteroides fragilis*

Bacteroides fragilis group

Fusobacterium spp.

Porphyromonas spp.

Prevotella spp*

Species for which resistance may be a problem

Gram positive aerobes

Staphylococcus aureus, methicillin-sensitive

Staphylococcus epidermis, methicillin-sensitive

Enterococcus avium ($)

Enterococcus faecium (+ $)

Propionibacterium acnes ($)

Viridans streptococci

Gram negative aerobes

Actinobacter spp (+ $)

Burkholderia cepacia

Citrobacter freundii

Enterobacter spp.

Escherichia coli *

Klebsiella spp.

Proteus, indole positive

Pseudomonas aeruginosa*

Pseudomonas spp. *

Pseudomonas stutzeri $

Serratia spp.

Gram negative anaerobes

Bacteroides spp. *

Inherently resistant organisms

Gram positive aerobes

Corynebacterium jeikeium

Gram negative aerobes

Stenotrophomonas maltophilia +$

* Clinical effectiveness against this has been demonstrated in the registered indications.

($) Species showing natural intermediate susceptibility

(+) Species for which high resistance rates (more than 50%) have been observed in one or more areas/countries/regions within the EU.

Distribution

Peak piperacillin and tazobactam plasma concentrations are attained immediately after completion of an intravenous infusion or injection. Piperacillin plasma levels produced when given with tazobactam are similar to those attained when equivalent doses of piperacillin are administered alone.

There is a greater proportional (approximately 28%) increase in plasma levels of piperacillin and tazobactam with increasing dose over the dosage range of Piperacillin/Tazobactam 2000/250 mg to Piperacillin/Tazobactam 4000/500 mg .

Both piperacillin and tazobactam are 20 to 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 tissue and body fluids including intestinal mucosa, gallbladder, lung, bile and bone.

Biotransformation

Piperacillin is metabolised to a minor microbiologically active desethyl metabolite. Tazobactam is metabolised to a single metabolite, which has been found to be micro-biologically inactive.

Elimination

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

Piperacillin is excreted rapidly as unchanged drug 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 drug 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 reduce the rate of elimination of tazobactam.

Impaired Renal Function

Piperacillin and tazobactam are haemodialysable: 31% (piperacillin) and 39% (tazobactam) of administered doses are filtrated. During peritoneal dialysis, 5% of administered piperacillin and 12% of administered tazobactam are found in the dialysis liquid. Patients treated by chronic ambulatory peritoneal dialysis should receive the same dose as non dialysed patients with severe renal insufficiency.

Impaired Liver Function

Plasma concentrations of piperacillin and tazobactam are prolonged in hepatically impaired patients. The half-life of piperacillin and of tazobactam increases by approximately 25% and 18%, respectively, in patients with hepatic cirrhosis compared to healthy subjects. However, dosage adjustments in patients with hepatic impairment are not necessary.

Paediatric patients

The pharmacokinetics of Piperacillin/Tazobactam has been studied in paediatric patients with intra-abdominal infections and other kinds of infections. In every age group, renal fraction of elimination of piperacillin and tazobactam was approximately 70% and 80%, respectively, like in adults.

Mean pharmacokinetic parameters of Piperacillin/Tazobactam of paediatric patients of different age groups.

Preclinical 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 study of Piperacillin/Tazobactam reported a decrease in litter size and an increase in fetuses with ossification delays and variations of ribs following i.p. administration to rats. Fertility of the F1 generation and embryonic development of the F2 generation was not impaired. A teratogenicity study in rats, did not show teratogenic effects after i.v. administration. In the rat, effects on the embryonic development were observed at maternal toxic doses. Peri/postnatal development was impaired (reduced fetal weights, increase in pup mortality, increase in stillbirths) concurrently with maternal toxicity after i.p. administration in the rat.

None

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

Piperacillin/Tazobactam should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established.

Piperacillin/Tazobactam should be administered through an infusion set separately from any other drugs unless compatibility is proven.

Because of chemical instability, Piperacillin/Tazobactam should not be used with solutions containing only sodium bicarbonate.

Lactated Ringer's solution is not compatible with Piperacillin/Tazobactam.

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

Unopened -3 years

When reconstituted with water for injections or saline, reconstituted solutions will remain stable for 24 hours at 25°C and for 48 hours at 4°C.

From a microbiological point of view, once opened, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Unopened: Do not store above 25°C.

After reconstitution: Store at 2-8^oC (see 6.3 Shelf Life).

Packs of one two, five and ten* Type II glass vial with butyl rubber stopper and aluminium/plastic seal

*Not all pack sizes may be marketed.

Reconstitution Directions

Intravenous Injection

Each vial of Piperacillin/Tazobactam 2 g/0.25 g Powder for Solution for Injection or Infusion should be reconstituted with 10ml of one of the following diluents.

• Sterile water for injections

• 0.9% sodium chloride for injection

Swirl until dissolved. Intravenous injection should be given over at least three to five minutes.

Intravenous Infusion

Each vial of Piperacillin/Tazobactam 2 g/0.25 g Powder for Solution for Injection or Infusion should be reconstituted with 10ml of one of the above diluents. The reconstituted solution should be further diluted to at least 50ml with one of the reconstitution diluents, or with Dextrose 5% in Water.

Displacement Volume

Each gram of Piperacillin/Tazobactam 2 g/0.25 g Powder for Solution for Injection or Infusion has a displacement volume of 0.7ml.

Piperacillin/Tazobactam 2 g/0.25 g Powder for Solution for Injection or Infusion will displace 1.58ml.

For single use only. Discard any unused solution.

The reconstitution/dilution is to be made under aseptic conditions. The solution is to be inspected visually for particulate matter and discoloration prior to administration. The solution should only be used if the solution is clear and free from particles.

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

Wockhardt UK Limited

Ash Road North

Wrexham LL13 9UF

United Kingdom

PL 29831/0329

PA 1339/1/1

17 April 2009