Consumer medicine information

DBL Piperacillin and Tazobactam Injection

Piperacillin; Tazobactam

BRAND INFORMATION

Brand name

DBL Piperacillin and Tazobactam Injection

Active ingredient

Piperacillin; Tazobactam

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using DBL Piperacillin and Tazobactam Injection.

What is in this leaflet

This leaflet answers some common questions about DBL™ Piperacillin and Tazobactam for Injection. 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 DBL™ Piperacillin and Tazobactam for Injection against the benefits this medicine is expected to have for you.

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

Keep this leaflet.

You may need to read it again.

What DBL™ Piperacillin and Tazobactam for Injection is used for

This medicine 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 helps piperacillin to overcome bacteria, which have become resistant to piperacillin.

DBL™ Piperacillin and Tazobactam for Injection is active against bacteria, which cause serious infections such as:

  • Chest infections
  • Urine infections
  • Stomach infections
  • Skin infections
  • Gynaecological infections
  • Infections of the blood or blood poisoning.

It is also used to treat many other infections.

In children aged 2 to 12 years, piperacillin and tazobactam is used to treat serious infections in the abdomen.

DBL™ Piperacillin and Tazobactam for Injection is not recommended to treat abdominal infections in children under 2 years.

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

Your doctor may have prescribed piperacillin and tazobactam for another reason. Ask your doctor if you have any questions about why Medicine Name has been prescribed for you.

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

DBL™ Piperacillin and Tazobactam for Injection is not addictive.

Before you are given DBL™ Piperacillin and Tazobactam for Injection

When you must not be given it

Do not use DBL™ Piperacillin and Tazobactam for Injection if 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.

DBL™ Piperacillin and Tazobactam for Injection should not be given to children under two years of age unless directed by the child's doctor.

Before you are given it

You must tell your doctor if you have any of the following conditions:

  • allergy to penicillins or cephalosporins
  • allergy to any foods, dyes, preservatives or any other medicines
  • kidney disease
  • liver disease
  • any other health problems
  • you are on a low salt diet

Tell your doctor if you are pregnant or plan to become pregnant

Your doctor will discuss the risks and benefits of using this medicine if you are pregnant.

Tell your doctor if you are breast-feeding.

DBL™ Piperacillin and Tazobactam for Injection passes into breast milk. Therefore, if you are breast-feeding, you should discuss with your doctor whether to stop breast-feeding or stop using this medicine.

If you are being treated with DBL™ Piperacillin and Tazobactam for Injection for gonorrhoea, your doctor should test you for syphilis as well.

DBL™ Piperacillin and Tazobactam for Injection in high doses may hide early symptoms of syphilis without curing it long-term.

If you are not sure whether you should be taking DBL™ Piperacillin and Tazobactam for Injection, 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.

Some medicines and DBL™ Piperacillin and Tazobactam for Injection may interfere with each other. These include:

  • medicines used to treat gout (such as probenicid)
  • aminoglycoside antibiotics eg tobramycin
  • vancomycin antibiotics
  • medicines used for thinning blood, (such as warfarin or heparin)
  • methotrexate, a medicine used to treat cancer, rheumatoid arthritis and other inflammatory conditions
  • vecuronium, a muscle relaxant used in surgery.

These medicines may be affected by DBL™ Piperacillin and Tazobactam for Injection 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 DBL™ Piperacillin and Tazobactam for Injection.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while being treated with this medicine.

How DBL™ Piperacillin and Tazobactam for Injection is given

How much is given

Your doctor will decide what dose you will receive. This depends on your condition and other factors, such as your weight.

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

How it is given

DBL™ Piperacillin and Tazobactam for Injection is usually given as a slow infusion (drip) into a vein over 20-30 minutes.

This medicine must only be given by a nurse or doctor.

How long it is given for

Your doctor will decide how long you are to receive DBL™ Piperacillin and Tazobactam for Injection.

The length of time you will be given the medicine 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.

If you are given too much (overdose)

As DBL™ Piperacillin and Tazobactam for Injection is given under medical supervision, it is very unlikely that you will receive too much.

However, if you experience severe side effects after being given this medicine, tell your doctor immediately.

Symptoms of an overdose may include the side effects listed below in the ‘Side Effects’ section, but are usually of a more severe nature.

Please contact the Poisons Information Centre in Australia on 131 126 or in New Zealand on 0800 764 766 for advice on overdose management.

Ask your doctor if you have any concerns.

While you are receiving DBL™ Piperacillin and Tazobactam for Injection

If you are given this medicine for a long period of time, your doctor may wish to do some blood tests.

Sometimes blood disorders can occur if you take DBL™ Piperacillin and Tazobactam for Injection.

If a doctor asks you for a urine sample, tell him/her that you are receiving DBL™ Piperacillin and Tazobactam for Injection.

Antibiotics in the penicillin family, including DBL™ Piperacillin and Tazobactam for Injection, can cause interference in some tests for glucose in urine. Penicillins that are excreted in urine can affect the test result. The doctor will request a test which is not affected by penicillins.

Things you must do

If the symptoms of your infection do not improve within a few days, or if they become worse, tell your doctor.

If you develop itching or swelling or skin rash or difficulty breathing while you are being given this medicine, tell your doctor or nurse immediately.

If you develop severe diarrhoea, tell your doctor immediately. Do this even if it occurs several weeks after stopping DBL™ Piperacillin and Tazobactam for Injection.

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.

If you become pregnant while you are being given DBL™ Piperacillin and Tazobactam for Injection, tell your doctor immediately.

If you are about to start taking a new medicine tell your doctor or pharmacist that you are being given piperacillin.

Side Effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking DBL™ Piperacillin and Tazobactam for Injection.

This medicine 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.

Ask your doctor to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • increased sweating
  • eczema or rash
  • severe skin reactions
  • dry mouth
  • weakness and tiredness
  • hallucinations
  • muscle or joint pain or muscle weakness
  • fever
  • hot flushes
  • difficulty sleeping
  • swelling of the hands, feet and ankles
  • swelling or redness along a vein which is extremely tender when touched
  • yellowing of skin and eyes (called jaundice)
  • diarrhoea
  • difficulty urinating

These side effects are usually mild.

Tell your doctor as soon as possible if you experience any of the following:

  • redness or pain at the injection site
  • rash, itchy or red skin
  • nausea or vomiting
  • Severe diarrhoea or constipation
  • spasms, seizures or fits
  • allergic reactions such as hives
  • headache, dizziness or light-headedness.
  • white, furry, sore tongue and mouth (oral thrush)
  • sore and itchy vagina and/or discharge (vaginal thrush)

These are serious side effects. You may need urgent medical attention. Serious side effects are rare.

If any of the following happen, tell your doctor immediately or go to casualty at your nearest hospital:

  • 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
  • severe blisters and bleeding in the lips, eyes, mouth, nose and genitals
  • painful red areas, large blisters and peeling of layers of skin.
  • Severe rash on the face, the armpits or groin,

These are very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are rare.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything else that is making you feel unwell.

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 finishing it

Tell your doctor immediately if you notice any of the following side effects, even if they occur several weeks after stopping treatment with DBL™ Piperacillin and Tazobactam for Injection.

  • severe abdominal cramps or stomach cramps
  • watery and severe diarrhoea, which may also be bloody
  • fever, in combination with one or both of the above.

These are rare but serious side effects. You may have a serious condition affecting your bowel.

Therefore, you may need urgent medical attention. However, this side effect is rare.

Do not take any diarrhoea medicine without first checking with your doctor.

After using DBL™ Piperacillin and Tazobactam for Injection

Storage

DBL™ Piperacillin and Tazobactam for Injection will be stored in the pharmacy or on the ward.

DBL™ Piperacillin and Tazobactam for Injection is stored in a cool, dry place where it stays below 25°C.

Heat and dampness can destroy some medicines.

Product description

What it looks like

DBL™ Piperacillin and Tazobactam for Injection is a white to off white powder which is supplied as powder in glass containers (vials).

The powder is mixed with sterile liquid to give a clear, colourless solution for injection by your doctor.

Ingredients

DBL™ Piperacillin and Tazobactam for Injection vials contain piperacillin sodium and tazobactam sodium as the active ingredients and contains no inactive ingredients.

DBL™ Piperacillin and Tazobactam for Injection contains 54.28 mg of Sodium per gram of piperacillin in the combination product.

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

Australian Sponsor:

Hospira Australia Pty Ltd
ABN 58 097 064 330
Level 3
500 Collins Street
Melbourne VIC 3000
Australia

New Zealand Sponsor

Hospira NZ Limited
58 Richard Pearse Drive
Airport Oaks, Mangere 2022
Auckland
New Zealand


Australian Registration Numbers:

2 g/ 0.25 g AUST R 128752 (not marketed)

4 g/ 0.5 g AUST R 128753

This leaflet was updated in July 2016

BRAND INFORMATION

Brand name

DBL Piperacillin and Tazobactam Injection

Active ingredient

Piperacillin; Tazobactam

Schedule

S4

 

Name of the medicine

Piperacillin sodium, tazobactam sodium.

Description

Piperacillin sodium.

Chemical name: (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-carboxylate. Molecular formula: C23H26N5NaO7S. MW: 539.5. CAS: 66258-76-2. Piperacillin sodium is derived from D(-)-(α)-aminobenzyl-penicillin.

Tazobactam sodium.

Chemical name: (2S,3S,5R)-3-methyl-7-oxo-3- (1H-1,2,3-triazol-1-yl methyl)-4-thia-1-azabicyclo [3.2.0]heptane-2-carboxylate-4,4-dioxide. Molecular formula: C10H11N4NaO5S. MW: 322.3. CAS: 89786-04-9. Tazobactam sodium, a derivative of the penicillin nucleus, is a penicillanic acid sulfone.
Each 2 g/0.25 g single dose vial contains piperacillin sodium equivalent to 2 grams of piperacillin and tazobactam sodium equivalent to 250 mg of tazobactam.
Each 4 g/0.5 g single dose vial contains piperacillin sodium equivalent to 4 grams of piperacillin and tazobactam sodium equivalent to 500 mg of tazobactam.
DBL Piperacillin and Tazobactam for Injection is a monosodium salt of piperacillin and a monosodium salt of tazobactam containing a total of Na+ 2.36 mEq (54.28 mg)/gram of piperacillin in the combination product.

Pharmacology

Actions.

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 piperacillin/ tazobactam formulation enhances and extends the antibiotic spectrum of piperacillin to include many β-lactamase producing bacteria normally resistant to it. Thus piperacillin/ tazobactam combines the properties of a broad spectrum antibiotic and a β-lactamase inhibitor.

Pharmacokinetics.

Distribution and plasma levels.

Mean plasma concentrations of piperacillin and tazobactam at steady state of the combination appear in Table 1. 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/minute, compared to patients with normal renal function. Dosage adjustments are recommended when creatinine clearance is below 40 mL/minute (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 hepatic function.

Piperacillin half-life and AUC (area under the curve) 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 piperacillin 100 mg/kg plus tazobactam 12.5 mg/kg (see Table 2). 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 piperacillin 100 mg/kg plus tazobactam 12.5 mg/kg administered every eight hours is predicted to provide coverage 31 to 61% of the time for the range of MIC values of 2 to 16 microgram/mL commonly found in intra-abdominal infections in children.

Microbiology.

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

Gram negative bacteria.

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

Gram positive bacteria.

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

Anaerobic bacteria.

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

Susceptibility.

Local information of resistance is desirable, particularly when treating severe infections. This information provides guidance on microorganisms susceptible to piperacillin/ tazobactam. The following MIC90 values were reported in 1996 for clinical isolates collected in three Australian states (see Table 3).

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 concentration 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 in 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 if the antimicrobial compound in the 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.
The latest NCCLS references are the following.
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.

Clinical Trials

Paediatric.

A study was performed to compare the safety, tolerance and efficacy of piperacillin 100 mg/kg plus tazobactam 12.5 mg/kg with those of cefotaxime 50 mg/kg plus metronidazole 7.5 mg/kg administered intravenously (IV) every eight 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 analysis 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.

Indications

Treatment of serious bacterial infections caused by susceptible strains of β-lactamase producing organisms in the following conditions: lower respiratory tract infections; urinary tract infections (complicated and uncomplicated); intra-abdominal infections; skin and skin structure infections; bacterial septicaemia; gynaecological infections.

Children under the age of 12 years.

In hospitalised children aged 2 to 12 years, DBL Piperacillin and Tazobactam for Injection 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 DBL Piperacillin and Tazobactam for Injection 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 β-lactamase producing, piperacillin resistant organisms. Appropriate culture and susceptibility tests should be performed before treatment in order to identify organisms causing infection and to determine their susceptibilities to piperacillin/ tazobactam. Therapy with DBL Piperacillin and Tazobactam for Injection, however, may be initiated before results of such tests are known when there is reason to believe the infection may involve any of the β-lactamase producing organisms listed above; however, once these results become available, appropriate therapy should be continued.
In serious infections, presumptive therapy with DBL Piperacillin and Tazobactam for Injection may be initiated before susceptibility test results are available.
Combination therapy with DBL Piperacillin and Tazobactam for Injection 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

History of allergic reactions to any of the penicillins and/or cephalosporins or β-lactamase inhibitors.

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, piperacillin/ tazobactam 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.
Piperacillin/ tazobactam may cause severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalised exanthematous pustulosis. If patients develop a skin rash they should be monitored closely and piperacillin/ tazobactam 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 drug discontinuation alone. However, in moderate to severe cases, appropriate therapy with a suitable oral antibacterial agent effective against Cl. 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 (e.g. Lomotil), 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 haemopoietic 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 drug may result in overgrowth of nonsusceptible organisms, including fungi. Patients should be carefully monitored during therapy. If superinfection occurs, appropriate measures should be taken.

Use in patients with renal impairment.

In patients with renal insufficiency or dialysis patients (haemodialysis and CAPD), the intravenous dose should be adjusted to the degree of renal impairment. Measurement of serum levels of piperacillin will provide guidance for adjusting dosage (see Dosage and Administration).

Use with caution in the following circumstances.

Bleeding manifestations have occurred in some patients receiving piperacillin. These reactions have sometimes been associated with abnormalities of coagulation tests, e.g. 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 a solvent 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 effects. The incidence of increased liver enzymes in patients treated with piperacillin/ tazobactam was slightly higher than has been reported previously with the use of piperacillin alone. The potential for increased hepatic adverse effects should be borne in mind when using piperacillin/ tazobactam.
Combined use of piperacillin/ tazobactam and vancomycin may be associated with an increased risk of acute kidney injury.

Check the following before use.

Periodic assessment of organ system functions, including renal, hepatic and haemopoietic, during prolonged therapy (≥ 21 days), is advisable.
Piperacillin/ tazobactam contains 54.28 mg (2.36 mEq) of sodium per gram of piperacillin, which may increase a patient's overall sodium intake.
Periodic 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.
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 four months.

Use in pregnancy.

(Category B1) Category B1: drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage.
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 fetus. Studies with tazobactam (doses up to 3,000 mg/kg intravenously) or tazobactam and piperacillin (doses up to 750 mg/kg and 3,000 mg/kg intravenously) in mice showed no evidence of teratogenicity or harm to the fetus. Studies in rats at these dose levels showed no evidence of teratogenicity although 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 fetus.

Use in lactation.

Adequate clinical studies on the use of piperacillin/ tazobactam during lactation 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.

Use in children.

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

Carcinogenesis, mutagenesis, impairment of fertility.

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 greater than or equal to 3,200 microgram/mL and 2,500 microgram/mL, respectively. Piperacillin and tazobactam did not affect the fertility of male or female rats.

Interactions

Aminoglycosides.

If piperacillin/ tazobactam 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.
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.
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 broad spectrum beta-lactam penicillin is only clinically significant in patients with severe renal dysfunction.

Probenecid.

Concurrent administration of probenecid and piperacillin/ tazobactam produces a longer half-life and lower renal clearance for both piperacillin and tazobactam. However, peak plasma concentrations of neither drug are affected.

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.

Nondepolarizing muscle relaxants.

Piperacillin, when used concomitantly with vecuronium, has been implicated in the prolongation of the neuromuscular blockade of vecuronium. 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.

Anticoagulants.

During simultaneous administration of piperacillin/ tazobactam 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.

Effects 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 piperacillin/ tazobactam, 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.

Adverse Effects

Piperacillin/ tazobactam 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 effects.
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 CIOMS frequency categories as follows. Very common ≥ 10%; common ≥ 1%; uncommon ≥ 0.1% and < 1%; rare ≥ 0.01% and < 0.1%; very rare < 0.01%; unknown cannot be estimated from available data.

Infections and infestations.

Rare: pseudomembranous colitis.

Skin and subcutaneous tissue disorders.

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

Gastrointestinal disorders.

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

Psychiatric disorders.

Uncommon: insomnia.

Nervous system disorders.

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

Musculoskeletal, connective tissue and bone disorders.

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

Vascular disorders.

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

Respiratory, thoracic and mediastinal disorders.

Rare: epistaxis.

Blood and lymphatic system disorders.

Uncommon: leucopenia, neutropenia, thrombocytopenia.
Rare: anaemia, eosinophilia.
Very rare: disturbed thrombocyte function.

Renal and urinary disorders.

Rare: tubulointerstitial nephritis, renal failure.

Metabolism and nutrition disorders.

Very rare: hypokalaemia.
Hypokalaemia was reported in patients with liver disease and those receiving cytotoxic therapy or diuretics when given high doses of piperacillin.

General disorders and administration site conditions.

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

Investigations.

Uncommon: alanine aminotransferase increased, aspartate aminotransferase increased, blood creatinine increased.
Rare: bleeding time prolonged, blood bilirubin increased*, blood alkaline phosphatase increased*, gamma-glutamyltransferase increased*.
Very rare: Coombs direct test positive, activated partial thromboplastin time prolonged, prothrombin time prolonged, blood albumin decreased, blood glucose decreased, blood total protein decreased, blood urea increased.
*The incidence is higher than with piperacillin alone.

Postmarketing experience.

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

Blood and lymphatic system disorders.

Rare: haemolytic anaemia.
Very rare: Agranulocytosis, pancytopenia, thrombocytosis.

Immune system disorders.

Uncommon: hypersensitivity.
Rare: anaphylactoid shock, anaphylactic shock, anaphylactoid reaction, anaphylactic reaction.

Infections and infestations.

Uncommon: Candida infection (especially with prolonged treatment).

Respiratory, thoracic and mediastinal disorders.

Unknown: eosinophilic pneumonia.

Renal and urinary disorders.

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

Skin and subcutaneous tissue disorders.

Uncommon: rash maculopapular.
Rare: erythema multiforme.
Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis.
Unknown: drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalised exanthematous pustulosis (AGEP), dermatitis exfoliative.

Hepatobiliary disorders.

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

Dosage and Administration

DBL Piperacillin and tazobactam for injection may be given by slow intravenous infusion (20 to 30 minutes).

Adults, children 12 years and older.

The usual intravenous dosage for adults and children with normal renal function is piperacillin 4 g/tazobactam 0.5 g (piperacillin/ tazobactam) given every eight hours.
The total daily dose depends on the severity and localisation of the infection and can vary from piperacillin 2 g/tazobactam 0.25 g to piperacillin 4 g/tazobactam 0.5 g (piperacillin/ tazobactam) administered every six or eight 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 piperacillin 100 mg/tazobactam 12.5 mg per kg every eight hours.
For children aged 2 to 12 years, weighing over 40 kg and with normal renal function, follow the adult dose guidance, i.e. piperacillin 4 g/tazobactam 0.5 g every eight 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 five 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 of piperacillin/ tazobactam is piperacillin 8 g/tazobactam 1 g. In addition, because haemodialysis removes 30 to 50% of piperacillin in four hours, one additional dose of piperacillin 2 g/tazobactam 0.25 g 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 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 piperacillin/ tazobactam should be for a minimum of five days and continued for 48 hours beyond resolution of clinical symptoms or the fever.

Administration.

Reconstitution directions.

Diluents for reconstitution: sterile water for injections or sodium chloride injection. Product is for single use in one patient only. Discard any remaining contents.

Intravenous use.

Reconstitute each vial with the volume of diluent shown in Table 5 below, using one of the above diluents. Shake until dissolved.
The reconstituted solution may be further diluted to 50 mL with saline, glucose 5% or dextran 6% in saline.
To reduce microbiological hazard, use as soon as practicable after reconstitution. If storage is necessary, hold at 2°C to 8°C for not more than 24 hours.

Pharmaceutical incompatibilities.

DBL Piperacillin and Tazobactam for Injection should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established. Whenever DBL Piperacillin and Tazobactam for Injection is used concurrently with another antibiotic, the drugs must be administered separately.
Because of chemical instability, DBL Piperacillin and Tazobactam for Injection should not be used with lactated Ringer’s solution, solutions containing only sodium bicarbonate or having a pH in the basic range.
DBL Piperacillin and Tazobactam for Injection 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 countermeasures 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.
In case of overdose, immediately contact the Poisons Information Centre for advice (in Australia, call 131 126).

Presentation

DBL Piperacillin and Tazobactam for Injection 2 g/0.25 g* is supplied as a white to off-white lyophilised powder in 30 mL, clear Type 1 glass vial with grey elastomeric closure and flip-off top.
DBL Piperacillin and Tazobactam for Injection 4 g/0.5 g is supplied as a white to off-white lyophilised powder in 48 mL, clear Type 1 glass vial with grey elastomeric closure and flip-off top.
DBL Piperacillin and Tazobactam Injection is available in cartons containing 1 vial.
*Not currently marketed in Australia.

Storage

Store below 25°C.

Poison Schedule

S4.