Consumer medicine information

Piptaz

Piperacillin; Tazobactam

BRAND INFORMATION

Brand name

Piptaz

Active ingredient

Piperacillin; Tazobactam

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Piptaz.

What is in this leaflet

This leaflet answers some common questions about PIPTAZ. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking PIPTAZ against the benefits this medicine is expected to have for you.

If you have any questions about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet. You may need to read it again.

What PIPTAZ is used for

The name of your medicine is PIPTAZ. It contains the active ingredients piperacillin and tazobactam. They belong to a group of antibiotics called penicillins that work by killing bacteria.

Piperacillin is an antibiotic that kills many types of bacteria. Tazobactam belongs in the penicillin group but does not have activity against bacteria. It helps piperacillin to overcome bacteria which have become resistant to piperacillin.

PIPTAZ is active against bacteria which cause serious infections such as: -

  • Chest infections
  • Urine infections
  • Stomach infections
  • Skin infections
  • Gynaecological infections
  • Septicaemia (blood poisoning).

It is also used to treat many other infections.

In hospitalised children aged 2 to 12 years, PIPTAZ is used to treat serious infections in the abdomen. PIPTAZ is not recommended to treat abdominal infections in children under 2 years.

PIPTAZ will not work against infections caused by viruses such as colds or flu.

This medicine is available only with a doctor's prescription.

PIPTAZ is not addictive.

Before you are given PIPTAZ

When you must not receive PIPTAZ

Do not have PIPTAZ if:

  1. you have ever had an allergic reaction to:
  • piperacillin, tazobactam, or any other penicillin antibiotics
  • any antibiotic in the cephalosporin group
  • medicines called beta-lactamase inhibitors.

Some of the symptoms of an allergic reaction may include rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or troubled breathing.

  1. PIPTAZ should not be given to children under two years of age unless directed by the child's doctor.

Before you start to receive PIPTAZ

You must tell your doctor if:

  1. you are allergic to any foods, dyes, preservatives or any other medicines
  2. you have any other health problems, including kidney or liver disease
    The dose of PIPTAZ will be altered, depending on blood tests.
  3. you are on a low salt diet
  4. you are pregnant or plan to become pregnant
    Your doctor will discuss the risks and benefits of using PIPTAZ if you are pregnant.
  5. you are breastfeeding
    PIPTAZ passes into breast milk. Therefore, if you are breast- feeding, you should discuss with your doctor whether to stop breast- feeding while or stop using PIPTAZ.
  6. you are being treated with PIPTAZ for gonorrhoea, your doctor should test you for syphilis as well.
    PIPTAZ in high doses may hide early symptoms of syphilis without curing it long-term.

If you are not sure whether you should be taking PIPTAZ, talk to your doctor.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines you buy without a prescription from a pharmacy, supermarket or health food shop.

There may be interference between PIPTAZ and some other medicines, including:

  • medicines for gout (probenicid)
  • aminoglycoside antibiotics including tobramycin
  • vancomycin, an antibiotic
  • preparations used for thinning blood (warfarin, heparin)
  • methotrexate, used to treat cancer, rheumatoid arthritis and other inflammatory conditions
  • vecuronium, a muscle relaxant used in surgery

These medicines may be affected by PIPTAZ or may affect how well it works. You may need to be given different amounts of your medicine or you may need to be given different medicines.

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking PIPTAZ.

How PIPTAZ will be given to you

How much you will be given

The dosage of PIPTAZ is generally 4.5g every eight hours. The dose may vary between 2.25g and 4.5 g and may also be given every six hours. For children aged 2 to 12 years, weighing up to 40 kg, and with normal kidney function, the recommended dosage is 112.5 mg/kg (100 mg piperacillin/12.5 mg tazobactam) every 8 hours. For children aged 2 to 12 years, weighing over 40 kg, and with normal kidney function, the recommended dose is 4.5 g (4 g piperacillin/0.5 g tazobactam) every 8 hours.

Your doctor may change these dosages.

If you have kidney disease your doctor will adjust the dose to suit you.

How PIPTAZ will be given

A doctor or nurse in hospital will always give PIPTAZ to you. It will usually be given to you as a slow injection into a vein over 20-30 minutes.

How long you will receive PIPTAZ

The length of time you will be given PIPTAZ depends on the type and severity of your infection. It should be given for at least five days, and for 48 hours after all signs of illness and fever have gone.

Overdose

It is unlikely that you will ever receive an overdose of PIPTAZ because it will be given by a trained nurse or doctor.

While you are receiving PIPTAZ

If you receive PIPTAZ for a prolonged time, your doctor may wish to do some blood tests. Sometimes blood disorders can occur if you take PIPTAZ.

If a doctor asks you for a urine sample, tell him/her that you are receiving PIPTAZ. Antibiotics in the penicillin family, including PIPTAZ, can cause interference in some tests for glucose in urine. Penicillins that are excreted in urine can cause a false-positive result. The doctor will request a test, which is not affected by penicillins.

Things you must do

If you develop severe diarrhoea, tell your doctor immediately. Do this even if it occurs several weeks after stopping PIPTAZ. This may be a sign of a serious side effect that affects the bowel. You may need urgent medical care. Do not take any medicines to treat this diarrhoea without checking with your doctor.

Side Effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking PIPTAZ.

PIPTAZ is effective in most people, but may have unwanted side effects in some. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

The more common side effects are:

  • nausea or indigestion
  • vomiting
  • diarrhoea or constipation
  • rash, itchy or red skin
  • allergic reactions such as hives (urticaria)
  • a new infection caused by bacteria that are resistant to PIPTAZ (superinfection)
  • difficulty sleeping
  • headache, dizziness or light- headedness

Rare side effects are:

  • increased sweating
  • eczema
  • severe skin reactions
  • inflammation of the mouth
  • dry mouth
  • weakness and tiredness
  • hallucinations
  • muscle or joint pain or prolonged muscle relaxation
  • fever
  • hot flushes
  • swelling of the hands, feet and ankles
  • swelling or redness along a vein which is extremely tender when touched
  • changes in liver function including jaundice (yellowing of skin and eyes) or hepatitis
  • injection site pain or inflammation
  • severe diarrhoea caused by a certain superinfection in the gut
  • convulsions ('fits') if PIPTAZ is given in high doses
  • short-term changes in kidney function
  • thrush, especially with prolonged treatment.

Less often, serious effects have occurred in people taking PIPTAZ.

Tell your doctor immediately if you notice any of the following:

  • tiredness, being short of breath and looking pale
  • frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • bleeding or bruising more easily than normal, nose bleeds

This is not a complete list of all possible side effects. Others may occur in some people and there may be some side effects not yet known.

Tell your doctor if you notice anything on this list or anything else that is making you feel unwell.

Importantly, tell your doctor if you have severe diarrhoea in the next few weeks after PIPTAZ treatment.

Do not try to treat it yourself with medicines that you can buy without a prescription.

Ask your doctor or pharmacist if you do not understand anything in this list.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After using PIPTAZ

Storage

It is unlikely that you will be asked to store this medication. If you are:

Keep this medicine where young children cannot reach it. A locked cupboard at least 1and a half metres above the ground is a good place to store medicines.

Keep PIPTAZ in a cool, dry place where it stays below 25°C. Do not store it, or any other medicine, in a bathroom or near a sink.

Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking PIPTAZ, or it has passed its expiry date, ask your pharmacist what to do with any left over.

Product description

What it looks like and how it is supplied

PIPTAZ is a white powder, which is supplied 4.5 grams of powder in glass containers (vials). The powder containing 4 g of piperacillin and 500 mg (0.5 g) of tazobactam is mixed with sterile liquid to give a solution for injection by your doctor.

Ingredients

PIPTAZ vials contain piperacillin and tazobactam as the active ingredients.

Supplier

PIPTAZ is supplied in Australia by:

Juno Pharmaceuticals Pty Ltd
Level 2, 6 Bond Street,
South Yarra,
VIC 3141

Australian Registration Number:
PIPTAZ 4.5 g: AUST R 143494

Date of preparation

This leaflet was prepared in January 2019.

Published by MIMS April 2019

BRAND INFORMATION

Brand name

Piptaz

Active ingredient

Piperacillin; Tazobactam

Schedule

S4

 

Name of the medicine

Piperacillin sodium 4 g, tazobactam sodium 500 mg.

Excipients.

Contains no excipients or preservatives.

Description

Piptaz is an injectable antibacterial combination, consisting of the semisynthetic antibiotic piperacillin sodium and the β-lactamase inhibitor tazobactam sodium, for intravenous administration.

Piperacillin sodium.

Chemical name: 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. Molecular formula: C23H26N5NaO7S. MW: 539.55. CAS: 59703-84-3. Piperacillin sodium is derived from D-(-)- α-aminobenzyl-penicillin.

Tazobactam sodium.

Chemical name: sodium (2S-(2α,3β,5α)-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. Molecular formula: C10H11N4NaO5S. MW: 322.3. CAS: 89785-84-2. Tazobactam sodium, a derivative of the penicillin nucleus, is a penicillanic acid sulfone.
Each vial of Piptaz contains a total of 2.35 mEq (54 mg) of Na+ per g of piperacillin.

Pharmacology

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

Microbiology.

Piptaz is active against most strains of the following β-lactamase producing and non-β-lactamase producing microorganisms.

Gram negative bacteria.

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.

Gram positive bacteria.

Streptococci (S. pneumoniae, S. pyogenes, S. agalactiae, S. viridans), Enterococci (E. faecalis, E. faecium), Staphylococcus aureus (not methicillin resistant S. aureus), S. epidermidis (coagulase negative Staphylococci).

Anaerobic bacteria.

Bacteroides spp. including Bacteroides fragilis group, Peptostreptococcus spp., Fusobacterium spp., Eubacterium group, Clostridia spp., Veillonella spp.

Susceptibility.

Disc susceptibility test.

Dilution or diffusion techniques, either quantitative (MIC) or breakpoint, should be used following a regularly updated, recognised and standardised method (e.g. NCCLS). Standardised susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.
A report of susceptible indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable.
A report of intermediate indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation.
A report of resistant indicates that the pathogen is not likely to be inhibited of the antimicrobial compound in blood reaches the concentrations usually achievable; other therapy should be selected.

Note.

The prevalence of resistance may vary geographically for selected species and local information on resistance is desirable, particularly when treating severe infections.
Local information of resistance is desirable, particularly when treating severe infections. This information provides guidance on microorganisms susceptible to piperacillin/ tazobactam. The following MIC 90 values were reported in 1996 for clinical isolates collected in 3 Australian states (see Table 1).
The latest NCCL references are: Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Fifth Edition, NCCLS document M7-A5, Vol. 20 No. 2. 2000. NCCLS, Wayne, PA.
For anaerobes: Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard-Fourth Edition. NCCLS document M1 l-A4, Vol. 17 No. 22. 1997. NCCLS, Wayne, PA.

Pharmacokinetics.

Distribution and plasma levels.

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.
In healthy subjects piperacillin/tazobactam plasma elimination half-lives range from 0.7 to 1.2 hours following single or multiple doses. These half-lives are unaffected by dose or duration of infusion. 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.

Biotransformation.

Piperacillin does not undergo biotransformation in humans. Approximately 20% of a dose of tazobactam is metabolised to a single metabolite that has been found to be microbiologically inactive.

Excretion.

Piperacillin and tazobactam are eliminated by the kidney via glomerular filtration and tubular secretion. Piperacillin is excreted rapidly as unchanged drug, with 69% of the dose appearing in the urine. Piperacillin is also secreted into bile. Tazobactam and its metabolite are eliminated primarily by renal excretion, with 80% of the dose appearing as unchanged drug and the remainder of the dose appearing as the metabolite.

Impaired renal function.

The half-life of piperacillin and tazobactam increases with decreasing creatinine clearance. The increase is twofold and fourfold for piperacillin and tazobactam, respectively at creatinine clearance below 20 mL/min 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.

Impaired liver function.

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

Children.

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 (see 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 microgram/mL to 16 microgram/mL commonly found in intra-abdominal infections in children.

Clinical Trials

Paediatric.

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 hospitalized 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 (Piptaz) administered intravenously was at least as effective as cefotaxime plus metronidazole in the treatment of children aged 2 to 12 years with severe IAIs.

Indications

Piptaz is indicated for the treatment of serious bacterial infections caused by susceptible strains of beta-lactamase producing organisms in the conditions listed below:
lower respiratory tract infections;
urinary tract infections (complicated and uncomplicated);
intra-abdominal infections;
skin and skin structure infections;
bacterial septicaemia; and
gynaecological infections.

Children under the age of 12 years.

In hospitalized children aged 2-12 years, Piptaz 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 two years.
While Piptaz is indicated only for the conditions listed above, it may be used as a single agent in the treatment of mixed infections caused by piperacillin susceptible and beta-lactamase producing, piperacillin resistant organisms. Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing infection and to determine their susceptibility to Piptaz. Therapy with Piptaz, however, may be initiated before results of such tests are known when there is reason to believe the infection may involve any of the beta-lactamase producing organisms listed above; however once results become available, appropriate therapy should be continued.
In serious infections, presumptive therapy with Piptaz may be initiated before susceptibility test results are available.
Combination therapy with Piptaz and aminoglycosides may be used in the treatment of serious infections caused by Pseudomonas aeruginosa. Both drugs should be used in full therapeutic doses. As soon as results of culture and susceptibility tests become available, antimicrobial therapy should be adjusted.

Contraindications

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

Precautions

Hypersensitivity reactions.

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 that 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 Piptaz. 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 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.

Pseudomembranous colitis.

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 drug discontinuation alone. However, in moderate to severe cases appropriate therapy with a suitable oral antibacterial agent effective against C. difficile should be considered. Fluids, electrolytes and protein replacement should be provided when indicated. Drugs that delay peristalsis, e.g. opiates and diphenoxylate with atropine may prolong and/or worsen the condition and should not be used.

Leucopenia and neutropenia.

Leucopenia and neutropenia may occur, especially during prolonged therapy. Therefore, periodic assessment of haematopoietic function should be performed.

Use with caution in the following circumstances.

Bleeding manifestations (especially in patients with renal impairment).

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.

Liver disease.

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 β-lactamase inhibitors and β-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 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.

General.

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.
Combined use of piperacillin/tazobactam and vancomycin may be associated with an increased risk of acute kidney injury.

Check the following before use.

Periodical assessment of organ system functions including renal, hepatic and haematopoietic during prolonged therapy (greater than or equal to 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 is 216 mg sodium (9.39 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 have potentially low potassium reserves and who are receiving cytotoxic therapy or diuretics.
Due to 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 gonorrhea may mask or delay symptoms of incubating syphilis. Therefore, prior to treatment, patients with gonorrhea 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.

Use in pregnancy.

(Category B1)
Adequate human studies on the use of Piptaz 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.

Use in lactation.

Adequate clinical studies on the use of Piptaz 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 breastfeeding should be treated only if the expected benefit outweighs the possible risks to the woman and child.

Paediatric use.

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

Carcinogenicity, mutagenicity and impairment of fertility.

Long-term carcinogenicity studies of Piptaz 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 greater than or equal to 3200 microgram/mL and 2500 microgram/mL, respectively. Piperacillin and tazobactam did not affect the fertility of male or female rats.

Use in patients with renal impairment.

In patients with renal insufficiency and dialysis patients (hemodialysis and CAPD), the intravenous dose should be adjusted to the degree of renal function impairment (see Dosage and Administration).

Interactions

Probenecid.

Concurrent administration of probenecid and Piptaz produced a longer half-life and lower renal clearance for both piperacillin and tazobactam. However, peak plasma concentrations of neither drug are affected. No kinetic interaction is found between Piptaz and vancomycin.

Tobramycin.

Concurrent administration of piperacillin and tobramycin in patients with severe renaldysfunction (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.

Aminoglycosides.

The inactivation of aminoglycosides in the presence of penicillin class drugs has been recognised. It has been postulated that penicillin aminoglycoside complexes form; these complexes are microbiologically inactive and of unknown toxicity. If Piptaz is used concurrently with another antibiotic, especially an aminoglycoside, the drugs must not be mixed in intravenous solutions or administered concurrently due to physical incompatibility.

Vancomycin.

A limited number of retrospective studies have detected an increased incidence of acute kidney injury in patients concomitantly administered piperacillin/tazobactam and vancomycin as compared to vancomycin alone.

Vecuronium.

Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. Piptaz (piperacillin/ tazobactam) 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 nondepolarising muscle relaxants could be prolonged in the presence of piperacillin.

Methotrexate.

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

Heparin and anticoagulants.

During simultaneous administration of Piptaz and high doses of heparin, oral anticoagulants and other drugs that may affect the blood coagulation system and/or the thrombocyte function, the coagulation parameters should be tested more frequently and monitored regularly.

Effect on laboratory tests.

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.
There have been reports of positive test results using Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving Piptaz 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 Piptaz should be interpreted cautiously and confirmed by other diagnostic methods.

Adverse Effects

Piptaz is generally well tolerated. The overall incidence of adverse events 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.
The following adverse reactions have been reported in clinical trials and are listed in Council for International Organisations of Medical Sciences (CIOMS) frequency category as follows.
Very common ≥ 10%; common ≥ 1%; uncommon ≥ 0.1% and < 1%; rare ≥ 0.01% and < 0.1%; very rare < 0.01%.

Blood and lymphatic system disorders.

Uncommon: leucopenia, neutropenia, thrombocytopenia. Rare: anaemia, bleeding manifestations (including purpura, epistaxis and bleeding time prolonged), eosinophilia. Very rare: Coombs' direct test positive, disturbed thrombocyte function, prolonged partial thromboplastin time, prothrombin time prolonged.

Gastrointestinal disorders.

Common: diarrhoea, including soft/ loose stools, nausea, vomiting. Uncommon: constipation, dyspepsia, stomatitis. Rare: abdominal pain, pseudomembranous colitis.

General disorders and administration site conditions.

Uncommon: fever, injection site reaction (pain, inflammation). Rare: rigors. Unknown: hot flushes, oedema, tiredness.

Hepatobilary disorders.

Uncommon: alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased. Rare: bilirubin increased, blood alkaline phosphatase increased, gamma glutmyltransferase increased. The incidence of such reactions is higher then with piperacillin alone.

Metabolism and nutrition disorders.

Very rare: blood albumin decreased, blood glucose decreased, blood total protein decreased, hypokalaemia. Hypokalaemia was reported in patients with liver disease and those receiving cytotoxic therapy or diuretics when given high doses of piperacillin.

Musculoskeletal, connective tissue and bone disorder.

Rare: arthralgia. Unknown: muscular weakness, muscle pain, prolonged muscle relaxation.

Nervous system disorders.

Uncommon: headache, insomnia. Unknown: hallucination, dizziness, dry mouth.

Skin and subcutaneous tissue disorders.

Common: rash. Uncommon: pruritus, urticaria. Rare: eruption (including bullous dermatitis). Unknown: increased sweating, eczema, exanthema.

Vascular disorders.

Uncommon: phlebitis, hypotension, thrombophlebitis. Rare: interstitial nephritis, renal failure. Unknown: tachycardia including supraventricular and ventricular, bradycardia, arrhythmia including atrial fibrillation, ventricular fibrillation, cardiac arrest, cardiac failure, circulatory failure, myocardial infarction.

Postmarketing experience.

Additional adverse events reported from worldwide marketing experience with piperacillin/ tazobactam, occurring under circumstances where causal relationship is uncertain.

Blood and lymphatic system.

Unknown: agranulocytosis, haemolytic anaemia, pancytopenia, thrombocytosis.

Hepatobilary disorders.

Unknown: hepatitis, cholestatic jaundice. Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.

Immune system disorders.

Unknown: anaphylactic/ anaphylactoid reaction (including shock), hypersensivity reaction.

Infections and infestations.

Unknown: candidal superinfection, especially with prolonged treatment.

Renal and urinary disorders.

Rare: interstitial nephritis, renal failure. Unknown: acute renal injury.

Skin and subcutaneous tissue disorders.

Unknown: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Dosage and Administration

Dosage.

Piptaz may be given by slow intravenous injection, by infusion (20-30 minutes).

Adults and children 12 years and older.

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

Children under the age of 12 years.

Recommended intravenous dosage for hospitalised children with intra-abdominal infection.

For children aged 2 to 12 years, weighing up to 40 kg, and with normal renal function, the recommended dosage is 100 mg piperacillin/12.5 mg tazobactam per kg 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 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.

Renal insufficiency.

In patients with renal insufficiency, the intravenous dose should be adjusted to the degree of actual renal function impairment. The suggested daily doses are shown in Table 4.
For patients on haemodialysis, the maximum daily dose is 8 g/1 g/day Piptaz. For patients with renal failure and hepatic insufficiency, measurement of serum levels of Piptaz will provide additional guidance for adjusting dosage.

Children aged 2 to 12 years.

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

Duration of therapy.

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

Administration.

Reconstitution directions.

For intravenous use only. For single use in one patient only. Diluent for Reconstitution: sterile water for injections or sodium chloride injection.

For intravenous use.

Reconstitute each vial with the volume of diluent shown in Table 5, using one of the above diluents. Shake until dissolved.
The reconstituted solution may be further diluted to the desired volume (e.g. 50 to 150 mL) with sterile water for injections*, saline, glucose 5% or dextran 6% in saline.
*Maximum recommended volume of sterile water for injections per dose is 50 mL.

Pharmaceutical incompatibilities.

Piptaz should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established. Whenever Piptaz is used concurrently with another antibiotic, the drugs must be administered separately.
Because of chemical instability, Piptaz should not be used with lactated Ringer's solution, solutions containing only sodium bicarbonate or having a pH in the basic range.
Piptaz should not be added to blood products or albumin hydrolysates.

Overdosage

Symptoms.

There have been postmarketing 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.

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.
For further advice on management contact Poisons Information Centre (131 126).

Presentation

Powder for injection, 4.5 g (piperacillin 4 g (≡ 9.4 mEq (216 mg) sodium), 500 mg tazobactam) (white to almost white, sterile, lyophilized powder sealed with a rubber closure and a flip off top): 10's (50 mL vial).

Storage

Lyophilized powder.

Store below 25°C.

Solutions.

Diluted solutions should be used immediately.

Poison Schedule

S4.