PipTaz BNM is a white to off-white powder for injection, to be administered after reconstitution. Each vial contains 4 g piperacillin (as sodium salt) and 0.5 g tazobactam (as sodium salt). Total sodium content in one vial of powder for injection is 9.4 mmol (216 mg).

Indications

PipTaz BNM is indicated for the treatment of the following systemic and/or local bacterial infections in which susceptible organisms have been detected or are suspected:

Lower respiratory tract infections
Urinary tract infections (complicated and uncomplicated)
Intra-abdominal infections
Skin and skin structure infections
Bacterial septicaemia
Gynaecological infections
Bacterial infections in neutropenic patients. Full therapeutic doses of PipTaz BNM plus an aminoglycoside should be used.
Bone and joint infections
Polymicrobic infections: PipTaz BNM is indicated for polymicrobic infections including those where aerobic and anaerobic organisms are suspected (intra-abdominal, skin and skin structure, upper and lower respiratory tract, gynaecological).

While PipTaz BNM is indicated only for the conditions listed above, infections caused by piperacillin susceptible organisms are also amenable to PipTaz BNM treatment due to its piperacillin content. Therefore, the treatment of mixed infections caused by piperacillin susceptible organisms and b-lactamase producing organisms susceptible to PipTaz BNM should not require the addition of another antibiotic. Appropriate culture and susceptibility tests should be performed before treatment in order to identify organisms causing infections and to determine their susceptibilities to PipTaz BNM. Because of its broad-spectrum of activity against Gram-positive and Gram-negative

PipTaz BNM aerobic and anaerobic organisms as listed above, PipTaz BNM is particularly useful in the treatment of mixed infections and in presumptive therapy prior to the availability of the results of sensitivity tests. Therapy with PipTaz BNM may, however, be initiated before results of such tests are known. Modification of the treatment may be required once these results become available or if there is no clinical response. In serious infections, presumptive therapy with PipTaz BNM may be initiated before susceptibility test results are available. PipTaz BNM acts synergistically with aminoglycosides against certain strains of Pseudomonas aeruginosa. Combined therapy has been successful, especially in patients with impaired host defences. Both medicines should be used in full therapeutic doses. As soon as results of culture and susceptibility tests become available, antimicrobial therapy should be adjusted.

Children under the age of 12 years

In hospitalised children aged 2 to 12 years, PipTaz BNM is indicated for the treatment of serious intra-abdominal infections. It has not been evaluated in this indication for paediatric patients below the age of 2 years.

Dosage and Administration

PipTaz BNM may be given by slow intravenous injection, by infusion (20 - 30 minutes). Recommended intravenous dosage

The usual intravenous dosage for adults and children with normal renal function is 4.5 g PipTaz BNM (4 g piperacillin/0.5 g tazobactam) given every eight hours. The total daily dose depends on the severity and localisation of the infection and can vary from 2.25 - 4.5 g PipTaz BNM (2 g piperacillin/0.25 g tazobactam to 4 g piperacillin/0.5 g tazobactam) administered every six, eight or twelve hours.

In neutropenic patients, the usual intravenous dosage for adults and children with normal renal function is 4.5 g PipTaz BNM given every eight hours as a 30-minute infusion, in conjunction with an aminoglycoside. The total daily dose depends on the severity and localisation of the infection and can vary from 2.25 g to 4.5 g PipTaz BNM administered every six or eight hours. Piperacillin/tazobactam has been shown to have a synergistic effect with an aminoglycoside against Pseudomonas infection. Therefore combination therapy is recommended for use in neutropenic patients, in whom infection is attributed predominantly to Pseudomonas organisms.

For children aged 2 to 12 years, weighing up to 40 kg, and with normal renal function, the recommended dosage is 112.5 mg PipTaz BNM (100 mg piperacillin/12.5 mg tazobactam) per kilogram every 8 hours. For children aged 2 to 12 years, weighing over 40 kg, and with normal renal function, follow the adult dose guidance, i.e. 4.5 g PipTaz BNM (4 g piperacillin/0.5 g tazobactam) every 8 hours. The duration of therapy should be guided by the severity of the infection and the patient's clinical and bacteriological progress. Therapy is recommended to be a minimum of 5 days and a maximum of 14 days, considering that dose administration should continue at least 48 hours after the resolution of clinical signs and symptoms.

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

For patients on haemodialysis, the maximum daily dose is 9 g (8 g/1 g) PipTaz BNM per day. In addition, because haemodialysis removes 30%-50% of piperacillin in 4 hours, one additional dose of 2.25 g (2 g/0.25 g) PipTaz BNM 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.

The pharmacokinetics of piperacillin/tazobactam have not been studied in paediatric patients with renal impairment. Each patient must be monitored closely for signs of medicine toxicity. Medicine dose and interval should be adjusted accordingly.

No dose adjustment is required in the elderly with normal renal function or creatinine clearance values above 40 mL/min (see Pharmacokinetics).

In acute infections, treatment with PipTaz BNM should be for a minimum of five days and continued for 48 hours beyond resolution of clinical symptoms or the fever.

Due to the in vitro inactivation of the aminoglycoside by the beta-lactam antibiotics, piperacillin/tazobactam and the aminoglycoside are recommended for separate administration. Piperacillin/tazobactam and the aminoglycoside should be reconstituted and diluted separately when concomitant therapy with aminoglycosides is indicated.

Contraindications

The use of PipTaz BNM is contraindicated in patients with a history of allergic reactions to any of the penicillins and/or cephalosporins or b-lactamase inhibitors.

Warnings and Precautions

Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid [including shock]) reactions have been reported in patients on penicillin/cephalosporin therapy. Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral penicillins/cephalosporins. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin/cephalosporin hypersensitivity who have experienced severe reactions when treated with either a penicillin or cephalosporin. Past history of a severe allergic reaction to penicillin/cephalosporin is a contraindication to the use of piperacillin/tazobactam. Before initiating therapy with any penicillin/cephalosporin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other allergens. If an allergic reaction occurs, PipTaz BNM should be discontinued and the appropriate therapy instituted. Serious anaphylactoid reactions require immediate emergency treatment with adrenaline. Oxygen, intravenous steroids and airway management, including intubation, should also be administered as indicated. Serious skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in patients receiving piperacillin/tazobactam. If patients develop a skin rash they should be monitored closely and PipTaz BNM discontinued if lesions progress. Antibiotic-associated pseudomembranous colitis has been reported with many antibiotics including piperacillin. A toxin produced by Clostridium difficile appears to be the primary cause. The severity of the colitis may range from mild to life-threatening. It is important to consider this diagnosis in patients who develop diarrhoea or colitis in association with antibiotic use (this may occur up to several weeks after cessation of antibiotic therapy). Mild cases usually respond to medicine discontinuation alone. However, in moderate to severe cases appropriate therapy with a suitable oral antibacterial agent effective against

should be considered. Fluids, electrolytes and protein replacement should be provided when indicated. Medicines that delay peristalsis eg: opiates and diphenoxylate with atropine may prolong and/or worsen the condition and should not be used.

Leucopenia 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 may occur when high doses are administered, especially in patients with impaired renal function. As with other antibiotic preparations, use of this medicine may result in overgrowth of non- susceptible organisms, including fungi. Patients should be carefully monitored during therapy. If superinfection occurs, appropriate measures should be taken.

Bleeding manifestations have occurred in some patients receiving piperacillin. 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 that might cause superinfections should be kept in mind, particularly during prolonged treatment. If this occurs, appropriate measures should be taken. As with other penicillins, patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously. Repeated use of lignocaine as diluent should be avoided in patients with severe liver disease or decreased hepatic blood flow due to the possibility of lignocaine toxicity (resulting from decreased metabolism and accumulation). Combined administration of b-lactamase inhibitors and b-lactam antibiotics may be associated with a slightly increased risk of hepatic adverse reactions. The incidence of increased liver enzymes in patients treated with PipTaz BNM was slightly higher than has been reported previously with the use of piperacillin alone. The potential for increased hepatic adverse reactions should be borne in mind when using PipTaz BNM.

Periodical assessment of organ system functions including renal, hepatic and haematopoietic during prolonged therapy (>= 21 days) is advisable. For patients with renal impairment and/or hepatic insufficiency, measurement of serum levels of piperacillin will provide guidance for adjusting dosage. The theoretical sodium content of each 4.5 g vial of PipTaz BNM is 216 mg (9.4 mmol), which may increase a patient's overall sodium intake. Periodical electrolyte determinations should be made in patients with low potassium reserves and the possibility of hypokalaemia should be kept in mind with patients who

PipTaz BNM have potentially low potassium reserves and who are receiving cytotoxic therapy or diuretics. Because of its poor penetration into the CSF, piperacillin is not advised in the treatment of meningitis and brain abscess. Antimicrobials used in high doses for short periods to treat gonorrhoea may mask or delay symptoms of incubating syphilis. Therefore, prior to treatment, patients with gonorrhoea should also be evaluated for syphilis. Specimens for darkfield examination should be obtained from patients with any suspected primary lesion and serological tests should be made for a minimum of 4 months.

Safety and efficacy of the use of piperacillin/tazobactam in children under the age of 2 years has not yet been established.

Pregnancy Category B1. Adequate human studies on the use of piperacillin/tazobactam during pregnancy are not available. Limited studies with piperacillin alone in rats and mice revealed no teratogenic effects or harm to the foetus. Studies with tazobactam (doses up to 3000 mg/kg IV) or tazobactam and piperacillin (doses up to 750 mg/kg and 3000 mg/kg IV) in mice showed no evidence of teratogenicity or harm to the foetus. Studies in rats at these dose levels showed no evidence of teratogenicity though maternal toxicity, in the form of decreased weight gain, was noted at the dose levels tested. Piperacillin has been found to cross the placenta in rats. Pregnant women should be treated only if the expected benefit outweighs the possible risks to the pregnant woman and foetus.

Adequate clinical studies on the use of piperacillin/tazobactam during pregnancy are not available. Piperacillin is excreted in low concentrations in milk. In animal studies, both piperacillin and tazobactam were excreted in the milk of lactating rats. Women who are breast-feeding should be treated only if the expected benefit outweighs the possible risks to the woman and child.

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

Long term carcinogenicity studies of piperacillin/tazobactam in animals have not been performed. Mutagenicity studies with piperacillin and tazobactam showed no evidence of genotoxicity in assays for chromosomal and DNA damage. One assay for gene mutations (mouse lymphoma assay) was weakly positive at tazobactam and piperacillin concentrations >= 3200 ug/mL and 2500 ug/mL, respectively. Piperacillin and tazobactam did not affect the fertility of male or female rats.

Adverse Effects

PipTaz BNM is generally well tolerated. The overall incidence of adverse events in piperacillin/tazobactam clinical studies was 15.7% although a cause/effect relationship was not established in all cases. This incidence was comparable to that observed with other agents used in the clinical studies. Treatment had to be discontinued in only 2.9% of cases due to adverse reactions.
The most frequently reported adverse clinical reactions were diarrhoea, rash, erythema, pruritus, vomiting, allergic reactions, nausea, urticaria, superinfection, phlebitis, thrombophlebitis, dyspepsia, and insomnia.
Adverse reactions are listed in the table in CIOMS frequency categories: Very common:>= 10%
Common:>= 1% and < 10%
Uncommon:>= 0.1% and < 1%
Rare:>= 0.01% and < 0.1%
Very rare:< 0.01%
Not known:frequency could not be accurately estimated from clinical studies
Body system	Adverse reaction
Infections and infestations
Uncommon	Candidal superinfection
Blood and lymphatic system
Uncommon	Leucopenia, neutropenia, thrombocytopenia
Rare	Anaemia, bleeding manifestations (including purpura, epistaxis, bleeding time prolonged), eosinophilia, haemolytic anaemia
Very rare	Agranulocytosis, Coombs direct test positive, pancytopenia, prolonged partial thromboplastin time, prothrombin time prolonged, disturbed thrombocyte function, thrombocytosis
Immune system disorders
Uncommon	Hypersensitivity reaction
Rare	Anaphylactic/anaphylactoid reaction (including shock)
Metabolism and nutrition disorders
Very rare	Blood albumin decreased, blood glucose decreased, blood total protein decreased, hypokalaemia
Nervous system disorders
Uncommon	Headache, insomnia
Frequency unknown	Hallucination, dizziness, dry mouth

PipTaz BNM

Body system	Adverse reaction
Vascular disorders
Uncommon	Hypotension, phlebitis, thrombophlebitis
Rare	Flushing
Gastrointestinal
Common	Diarrhoea, nausea, vomiting
Uncommon	Constipation, dyspepsia, jaundice, stomatitis
Rare	Abdominal pain, pseudomembranous colitis
Frequency unknown	Bloody diarrhoea
Hepatobiliary
Uncommon	Alanine aminotransferase increased, aspartate aminotransferase increased
Rare	Bilirubin increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, hepatitis
Skin and subcutaneous tissue disorders
Common	Rash
Uncommon	Pruritis, urticaria
Rare	Bullous dermatitis, erythema multiforme
Very rare	Stevens-Johnson syndrome, toxic epidermal necrolysis
Frequency unknown	Increased sweating, eczema, exanthema
Musculoskeletal, connective tissue and bone disorders
Rare	Arthralgia
Frequency unknown	Myalgia, muscular weakness, prolonged muscle relaxation
Renal and urinary disorders
Uncommon	Blood creatinine increased
Rare	Interstitial nephritis, renal failure
Very rare	Blood urea nitrogen increased
General disorders and administration site conditions
Uncommon	Fever, injection site reaction
Rare	Rigors
Frequency unknown	Oedema, tiredness, fatigue

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

PipTaz BNM

Interactions

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 neither medicine are affected. No kinetic interaction is found between piperacillin/tazobactam and vancomycin. Concurrent administration of piperacillin and tobramycin in patients with severe renal dysfunction (i.e. chronic haemodialysis patients) has been reported to reduce the elimination half life and significantly increase the total body clearance of tobramycin. The alteration of tobramycin pharmacokinetics in patients with mild to moderate renal dysfunction who are taking piperacillin concomitantly is unknown. However, reports suggest that the aminoglycoside inactivation in patients concomitantly taking an aminoglycoside with a broad spectrum beta-lactam penicillin is only clinically significant in patients with severe renal dysfunction. The inactivation of aminoglycosides in the presence of penicillin class medicines has been recognised. It has been postulated that penicillin-aminoglycoside complexes form; these complexes are microbiologically inactive and of unknown toxicity. Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. PipTaz BNM could produce the same phenomenon if given along with vecuronium. Due to their similar mechanism 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. Piperacillin may reduce the excretion of methotrexate; therefore, serum levels of methotrexate should be monitored in patients to avoid medicine toxicity. If PipTaz BNM is used concurrently with another antibiotic, especially an aminoglycoside, the medicines must not be mixed in intravenous solutions or administered concurrently due to physical incompatibility. During simultaneous administration of high doses of heparin, oral anticoagulants and other medicines that may affect the blood coagulation system and/or the thrombocyte function, the coagulation parameters should be tested more frequently and monitored regularly.

As with other penicillins, 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 reactions be used. 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.

PipTaz BNM There have been reports of positive test results using Bio-Rad Laboratories Platelia(tm) 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(tm) Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving PipTaz BNM should be interpreted cautiously and confirmed by other diagnostic methods.

Overdose

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). No specific antidote is known. In the event of an emergency, all required intensive medical measures are indicated, as in the case of piperacillin. In cases of motor excitability or convulsions, anticonvulsive agents (e.g. diazepam or barbiturates) may be indicated. In cases of anaphylactic reactions, the usual counter measures are to be initiated (adrenaline, antihistamines, corticosteroids and, if required, oxygen and airway management). Excessive serum concentrations of either piperacillin or tazobactam may be reduced by haemodialysis.

Further Information

Pharmacotherapeutic group: Antibacterials for systemic use, Combinations of penicillins, incl. beta-lactamase inhibitors ATC-code: J01CR05 Piperacillin and enzyme inhibitor PipTaz BNM is an injectable antibacterial combination, consisting of the semisynthetic antibiotic piperacillin sodium and the b-lactamase inhibitor tazobactam sodium, for intravenous administration.

is derived from D(-)-a-aminobenzylpenicillin. The chemical name of piperacillin sodium is sodium (2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazine- carboxamido)-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2- carboxylic acid.

is a derivative of the penicillin nucleus. Chemically, tazobactam is a penicillanic acid sulfone. Its chemical name is sodium (2S-(2a,3b,5a)-3-methyl-7-oxo-3- (1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4- dioxide. The chemical structure of tazobactam sodium is:

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 sulfone, is a potent inhibitor of many b-lactamases, including the plasmid and chromosomally-mediated enzymes that commonly cause resistance to penicillins. The presence of tazobactam in the PipTaz BNM formulation enhances and extends the antibiotic spectrum of piperacillin to include many b-lactamase producing bacteria normally resistant to it. Thus, PipTaz BNM combines the properties of a broad-spectrum antibiotic and a b-lactamase inhibitor.

PipTaz BNM is active against most strains of the following b -lactamase producing and non b -lactamase producing microorganisms:

Escherichia coli, Citrobacter spp., Klebsiella spp. (including K. pneumoniae), Enterobacter spp., (including E. cloacae), Proteus vulgaris, Proteus mirabilis, Serratia spp. (including S. marcescens), Pseudomonas aeruginosa and other Pseudomonas spp., Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella catarrhalis, Acinetobacter spp., Haemophilus influenza.

Streptococci (S. pneumoniae, S. pyogenes, S. agalactiae, S. viridans), Enterococci (E. faecalis, E. faecium), Staphylococcus aureus (not methicillin-resistant S. aureus),

Local information of resistance is desirable, particularly when treating severe infections. This information provides guidance on micro-organisms susceptible to piperacillin/tazobactam. The following MIC 90 values were reported in 1996 for clinical isolates collected in 3 Australian states1.

Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard - Ninth Edition.

Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard - Eighth Edition.

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

Mean plasma concentrations of piperacillin and tazobactam at steady state of the combination appear in Table 2. Peak piperacillin and tazobactam plasma concentrations are attained immediately after completion of an intravenous infusion. When given with tazobactam, piperacillin plasma levels are similar to those attained when equivalent doses of piperacillin are administered alone.

Plasma levels in adults after a 30-minute intravenous infusion of piperacillin/tazobactam (steady state)

Piperacillin and tazobactam are 21% and 23%, respectively, bound to plasma proteins. The protein binding of either piperacillin or tazobactam is unaffected by the presence of either compound. Piperacillin and tazobactam are widely distributed in tissues and body fluids including intestinal mucosa, gall bladder, lung and bile.

Piperacillin is metabolised to a minor microbiologically active desethyl metabolite.

Piperacillin and tazobactam are eliminated by the kidney via 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 medicine 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.

The half-life of piperacillin and tazobactam increases with decreasing creatinine clearance. At creatinine clearance below 20 mL/min, the increase is two-fold and four-fold for piperacillin and tazobactam, respectively, compared to patients with normal renal function. Dosage adjustments are recommended when creatinine clearance is below 40 mL/min, see Dosage and Administration. Piperacillin and tazobactam are removed from the body during haemodialysis with 31% and 39% of the doses of piperacillin and tazobactam, respectively, recovered in the dialysis fluid. Piperacillin and tazobactam are removed from the body by peritoneal dialysis with 5% and 12% of the dose, respectively, appearing in the dialysate. For dosage recommendations in patients undergoing haemodialysis, see Dosage and Administration.

In patients with hepatic impairment, piperacillin half-life and AUC were increased by 25% and 40%, respectively, and tazobactam half-life and AUC by 18% and 23%, respectively. However, dosage adjustments in patients with hepatic impairment are not necessary.

The pharmacokinetics of piperacillin and tazobactam have been examined in 24 paediatric patients aged 2 months to 12 years receiving 100 mg/kg piperacillin/12.5 mg/kg tazobactam (Table 3). The maximum concentration (Cmax) for both piperacillin and tazobactam is increased relative to the maximum adult dose but the predicted time above the minimum inhibitory concentration is slightly decreased. The dosage of 100 mg/kg piperacillin/12.5 mg/kg tazobactam administered every 8 hours is predicted to provide coverage 31% to 61% of the time for the range of MIC values of 2 ug/mL to 16 ug/mL commonly found in intra-abdominal infections in children.

Piperacillin and tazobactam pharmacokinetics in children (cv%) following single doses

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.

No difference in piperacillin or tazobactam pharmacokinetics was observed between Asian (n=9) and Caucasian (n=9) healthy volunteers who received single 4.5 g (4 g/0.5 g) doses.

A study was performed to compare the safety, tolerance, and efficacy of 100 mg/kg piperacillin/12.5 mg/kg tazobactam with those of 50 mg/kg cefotaxime plus 7.5 mg/kg metronidazole administered intravenously (IV) every 8 hours for the treatment of hospitalised paediatric patients (aged 2 to 12 years of age) with clinically or bacteriologically diagnosed intra-abdominal infection (IAI). The cure rates in the efficacy evaluable (EE) population at the follow-up visit were 90% and 91% for piperacillin/tazobactam and cefotaxime plus metronidazole, respectively. The results of the clinical and microbiological analyses in 521 patients showed that piperacillin/tazobactam administered intravenously was at least as effective as cefotaxime plus metronidazole in the treatment of children aged 2 to 12 years with severe IAIs.

Pharmaceutical Precautions

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

Reconstitute each vial with the volume of solvent shown in the table below, using one of the compatible solvents for reconstitution. Swirl until dissolved. When swirled constantly, reconstitution generally occurs within 5 to 10 minutes.
Vial size (piperacillin/tazobactam)	Minimum volume of solvent to be added to vial	Approximate available volume (when 20 mL is added)
4.5 g (4 g/0.5 g)	20 mL	23.4 mL

The reconstituted solutions may be further diluted to the desired volume (e.g. 50 mL to 150 mL) with one of the following compatible diluents for intravenous use listed below: Sterile water for injections

Maximum recommended volume of sterile water for injections per dose is 50 mL. For single use only. Discard any unused solution.

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

Piptaz BNM should not be mixed with other medicines in a syringe or infusion bottle since compatibility has not been established. PipTaz BNM should be administered through an infusion set separately from any other medicines unless compatibility is proven. Whenever PipTaz BNM is used concurrently with another antibiotic, the medicines must be administered separately. The mixing of PipTaz BNM with an aminoglycoside can result in substantial inactivation of the aminoglycoside. Due to chemical instability, PipTaz BNM should not be used in solutions that contain sodium bicarbonate or having a pH in the basic range. Lactated Ringer's solution is not compatible with PipTaz BNM. PipTaz BNM should not be added to blood products or albumin hydrolysates.

After reconstitution, chemical and physical in-use stability has been demonstrated for 24 hours when stored in a refrigerator at 2-8o C.

After reconstitution and dilution, chemical and physical in-use stability has been demonstrated for 72 hours when stored in a refrigerator at 2-8degC. 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 2-8degC, unless reconstitution has taken place under controlled and validated aseptic conditions.

Store below 25degC. For single use in one patient only. Discard any unused solution.

Creatinine clearance (mL/min)	Recommended PipTaz BNM (piperacillin/tazobactam) dosage
> 40	NO DOSAGE ADJUSTMENT NECESSARY
20 - 40	13.5 g (12 g/1.5 g) per day Divided dose: 4.5 g (4 g/0.5 g) every 8 hours
< 20	9 g (8 g/1 g) per day Divided doses: 4.5 g (4 g/0.5 g) every 12 hours

Organism (number)	MIC90 (mg/L)
E. coli (528)	2.0
Klebsiella spp . (180)	4.0
Klebsiella spp . (ESBL 44)	64.0
Enterobacter spp . (142)	16.0
Citrobacter/Serratia spp . (84)	8.0
Morganella/Proteus/Providencia spp . (45)	2.0
Proteus mirablis spp . (104)	2.0
Pseudomonas aeruginosa (88)	32.0
Acinetobacter calcoaceticus (40)	32.0
Staphyloccus aureus (433)	4.0
Coagulase-negative Staphylococci (28)	16.0
Streptococcus pneumoniae (45)	0.015
Enterococci (109)	4.0
Haemophilus influenzae (59)	0.094
Bacteroides fragilis gp (23)	4.0

PIPERACILLIN PLASMA LEVELS (ug/mL)
Piperacillin/tazobactam dose 4 g/0.5 g	30 *min 298	1 hr 141	1.5 hr 87	2 hr 47	3 hr 16	4 hr 7
TAZOBACTAM PLASMA LEVELS (ug/mL)
Piperacillin/tazobactam dose 4 g/0.5 g	30 *min 33.8	1 hr 17.3	1.5 hr 11.7	2 hr 6.8	3 hr 2.8	4 hr 1.3

Dose	Patient age	C max (mg/L)	AUC (mg.h/L)	CL (mL/min/kg)	V ss (L/kg)	T 1/2 (h)
Piperacillin	2-5 month	382(15)	539(29)	3.3(24)	0.28(32)	1.3(16)
100 mg/kg	6-23 month	344(15)	373(27)	4.8(29)	0.25(27)	1.0(24)
	2-5 years	408(80)	331(21)	5.2(19)	0.23(36)	0.9(26)
	6-12 years	394(24)	404(17)	4.2(21)	0.24(42)	0.8(27)
Tazobactam	2-5 month	43(49)	63(32)	3.6(28)	0.32(31)	1.3(15)
12.5 mg/kg	6-23 month	35(22)	42(23)	5.2(24)	0.33(29)	1.1(23)
	2-5 years	45(42)	37(24)	5.8(19)	0.27(33)	0.9(29)
	6-12 years	45(25)	57(27)	3.9(36)	0.28(36)	1.3(57)

PipTaz BNM

Presentations

Indications

Dosage and Administration

Contraindications

Warnings and Precautions

Adverse Effects

Interactions

Overdose

Further Information

Pharmaceutical Precautions

Package Quantities

Medicine Schedule

Sponsor Details

Date of Preparation