Consumer medicine information

PiperTaz Sandoz

Piperacillin; Tazobactam

BRAND INFORMATION

Brand name

PiperTaz Sandoz

Active ingredient

Piperacillin; Tazobactam

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using PiperTaz Sandoz.

What is in this leaflet

This leaflet answers some common questions about PiperTaz Sandoz.

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 having this medicine against the benefits they expect it will have for you.

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

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

What PiperTaz Sandoz is used for

This medicine is used to treat serious bacterial 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, PiperTaz Sandoz is used to treat serious infections in the abdomen. It is not recommended to treat abdominal infections in children under 2 years.

It contains the active ingredients piperacillin and tazobactam.

Piperacillin and tazobactam belong to a group of medicines called penicillins.

Piperacillin works by killing many types of bacteria. Tazobactam does not have activity against bacteria, but helps piperacillin to overcome bacteria which have become resistant to piperacillin.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is not addictive.

Before you are given PiperTaz Sandoz

When you must not receive it

Do not have this medicine if you have an allergy to:

  • piperacillin , tazobactam, or any other penicillin antibiotics
  • any antibiotics 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,

  • shortness of breath
  • wheezing or difficulty breathing

PiperTaz Sandoz should not be given to children under 2 years of age unless directed by the child's doctor.

Do not have this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start having this medicine, talk to your doctor.

Before you start to receive it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes or any other medicines.

Tell your doctor if you have or have had any of the following medical conditions:

  • cystic fibrosis
  • kidney disease
  • liver disease
  • are on a low salt diet
  • you are being treated for gonorrhoea, as your doctor should test you for syphilis as well.

PiperTaz Sandoz in high doses may hide early symptoms of syphilis without curing it long-term.

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding. Your doctor can discuss with you the risks and benefits of using this medicine if you are pregnant. This medicine passes into breast milk. Therefore if you are breastfeeding, you should discuss with your doctor whether to stop breastfeeding while having or to stop having PiperTaz Sandoz.

If you have not told your doctor about any of the above, tell him/her before you start having PiperTaz Sandoz.

Taking other medicines

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

Some medicines and PiperTaz Sandoz may interfere with each other. These include:

  • probenecid, a medicine used for gout
  • aminoglycoside antibiotics such as tobramycin
  • vancomycin, an antibiotic
  • preparations used for thinning blood such as warfarin or 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 PiperTaz Sandoz or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

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

How PiperTaz Sandoz will be given

How much you will be given

The dose is generally 4.5 g every eight hours. The dose may vary between 2.25 g 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 problems, the dose will be adjusted to suit you.

How it will be given

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

How long you will receive PiperTaz Sandoz

The length of time you will be given this 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 receive too much (overdose)

It is unlikely that you will ever receive an overdose of this medicine because it will be given by a trained nurse or doctor. However, if you are:

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have received too much PiperTaz Sandoz. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of an overdose may include nausea, vomiting, diarrhoea or convulsions.

While you are receiving PiperTaz Sandoz

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are having PiperTaz Sandoz.

Tell any other doctors, dentists, and pharmacists who treat you that you are receiving this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are receiving this medicine. It may affect other medicines used during surgery.

If you become pregnant while having this medicine, tell your doctor immediately.

If you are asked to provide a urine sample, tell your doctor that you are receiving this medicine. Antibiotics in the penicillin family, including PiperTaz Sandoz, 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.

If you develop severe diarrhoea, tell your doctor immediately. Do this even if it occurs several weeks after stopping PiperTaz Sandoz. 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 receiving PiperTaz Sandoz.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

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

  • 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 PiperTaz Sandoz (superinfection)
  • difficulty sleeping
  • headache, dizziness or light-headedness.

These are the more common side effects of the medicine, and are usually mild and short-lived.

Rare side effects include:

  • increased sweating
  • eczema
  • flaking or peeling of the skin
  • inflammation of the mouth
  • dry mouth
  • weakness and tiredness
  • hallucinations or severe confusion
  • 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 given in high doses
  • short-term changes in kidney function
  • cough, fever, chills, shortness of breath and chest pain
  • thrush, especially with prolonged treatment.

Less often, serious effects have occurred in people taking PiperTaz Sandoz

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

  • severe blisters and bleeding in the lips, eyes, mouth, nose or genitals
  • itchy spots accompanied by fever and feeling unwell
  • 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
  • swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing.

The above list includes serious side effects that may require medical attention. Serious side effects are rare.

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

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

After having PiperTaz Sandoz

Storage

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

Keep your medicine in the original container.

If you take it out of its original container it may not keep well.

Keep your medicine in a cool dry place where the temperature stays below 25°C.

Do not store PiperTaz Sandoz or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car.

Heat and dampness can destroy some medicines.

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

Disposal

If your doctor tells you to stop having this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product Description

What it looks like

PiperTaz Sandoz comes in one strength:

PiperTaz Sandoz 4.5 g - white to off-white powder for injection, contained in 50 or 100 mL glass infusion bottles.

Pack size of one and ten infusion bottles.

Not all presentations may be marketed.

Ingredients

Active ingredients:

  • PiperTaz Sandoz 4.5 g - 4 g piperacillin (as sodium) and 0.5 g tazobactam (as sodium).

There are no inactive ingredients.

Supplier

PiperTaz Sandoz is supplied in Australia by:

Sandoz Pty Ltd
100 Pacific Highway
North Sydney, NSW 2060
Australia
Tel 1800 726 369

This leaflet was revised in March 2024.

Australian Register Number(s)

4.5g powder for injection: AUST R 140840 (bottles)

® Registered Trade Mark. The trade marks mentioned in this material are the property of their respective owners.

Published by MIMS May 2024

BRAND INFORMATION

Brand name

PiperTaz Sandoz

Active ingredient

Piperacillin; Tazobactam

Schedule

S4

 

1 Name of Medicine

Piperacillin sodium/tazobactam sodium.

2 Qualitative and Quantitative Composition

PiperTaz Sandoz contains piperacillin (as the sodium salt) 4 g and tazobactam (as the sodium salt) 500 mg.
PiperTaz Sandoz 4 g/0.5 g powder for injection is white to off white, sterile lyophilised powder, 4.5 g (equivalent to piperacillin 4 g, tazobactam 500 mg).
The product contains no excipients or preservatives.

3 Pharmaceutical Form

PiperTaz Sandoz is available as a white to off-white sterile, cryodesiccated powder of piperacillin and tazobactam as the sodium salts packaged in glass bottles. Each bottle of PiperTaz Sandoz contains a total of 2.35 mEq (54 mg) of Na+ per gram of piperacillin.

4 Clinical Particulars

4.1 Therapeutic Indications

PiperTaz Sandoz (piperacillin/tazobactam) is indicated in the treatment of serious bacterial infections caused by susceptible strains of β-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;
gynaecological infections.

Children under the age of 12 years.

In hospitalised children aged 2 to 12 years, PiperTaz Sandoz (piperacillin/tazobactam) 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.
While PiperTaz Sandoz (piperacillin/tazobactam) 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 to determine their susceptibilities to PiperTaz Sandoz (piperacillin/tazobactam). Therapy with PiperTaz Sandoz (piperacillin/tazobactam), 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 PiperTaz Sandoz (piperacillin/tazobactam) may be initiated before susceptibility test results are available.
Combination therapy with PiperTaz Sandoz (piperacillin/tazobactam) 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.

4.2 Dose and Method of Administration

Dosage.

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 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 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 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 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.

Method of administration.

PiperTaz Sandoz (piperacillin/tazobactam) may be given by slow intravenous infusion (20-30 minutes).

Reconstitution directions.

Diluents for reconstitution: sterile water for injections or sodium chloride injection.

For intravenous use.

Reconstitute each bottle with the volume of diluent shown in Table 1, using one of the above diluents. Shake until dissolved.
The reconstituted solution may be further diluted to 50 mL with saline, 5% glucose or dextran 6% in saline.

Dosage adjustment.

Renal impairment.

In patients with renal insufficiency or in haemodialysis patients, the intravenous dose and administration interval should be adjusted to the degree of actual renal function impairment. The suggested daily doses are shown in Table 2.
For patients on haemodialysis, the maximum daily dose is 8 g piperacillin/1 g tazobactam/day PiperTaz Sandoz (piperacillin/tazobactam). In addition, because haemodialysis removes 30%-50% of piperacillin in 4 hours, one additional dose of 2 g piperacillin/0.25 g tazobactam should be administered following each dialysis period. For patients with renal failure and hepatic insufficiency, measurement of serum levels of PiperTaz Sandoz (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 PiperTaz Sandoz (piperacillin/tazobactam) should be for a minimum of five days and continued for 48 hours beyond resolution of clinical symptoms or the fever.

Co-administration of piperacillin/tazobactam with aminoglycosides.

Due to the in vitro inactivation of the aminoglycoside by β-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.
In circumstances where co-administration is preferred, PiperTaz Sandoz (piperacillin/tazobactam) is compatible for simultaneous co-administration via Y-site infusion only with the following aminoglycosides under the following conditions.
Compatibility of PiperTaz Sandoz (piperacillin/tazobactam) with other aminoglycosides has not been established. Only the concentration and diluents for amikacin and gentamicin with the dosages of PiperTaz Sandoz (piperacillin/tazobactam) listed in Table 3 have been established as compatible for co-administration via Y-site infusion. Simultaneous coadministration via Y-site in any manner other than listed above may result in inactivation of the aminoglycoside by piperacillin/tazobactam.

4.3 Contraindications

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

4.4 Special Warnings and Precautions for Use

Hypersensitivity reactions.

Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid [including shock]) reactions have been reported in patients on penicillin/cephalosporin therapy, including piperacillin/tazobactam. 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 anaphylactic/anaphylactoid reactions (including shock) require immediate emergency treatment with adrenaline. Oxygen, intravenous steroids and airway management, including intubation, should also be administered as indicated.
Severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalised exanthematous pustulosis (AGEP) have been reported in patients taking β-lactam antibiotics. When SCAR is suspected, piperacillin/tazobactam should be discontinued immediately and an alternative treatment should be considered.

Haemophagocytic lymphohistiocytosis.

Rare cases of haemophagocytic lymphohistiocytosis (HLH) have been observed following therapy (> 10 days) with piperacillin/tazobactam, often as a complication of DRESS. HLH is a pathologic immune activation which leads to excessive systemic inflammation and can be life threatening and early diagnosis and rapid initiation of immunosuppressive therapy is essential. Characteristic signs and symptoms include fever, hepatosplenomegaly, cytopenias, hyperferritinaemia, hypertriglyceridaemia, hypofibrinogenaemia, and haemophagocytosis. If piperacillin/tazobactam is suspected as possible trigger, treatment should be discontinued.

Rhabdomyolysis.

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

Pseudomembranous colitis.

Antibiotic associated pseudomembranous colitis has been reported with many antibiotics including piperacillin. A toxin produced by Clostridiodes 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 (Lomotil) 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.
As with treatment with other penicillins, neurological complications in the form of convulsions (seizures) may occur when high doses are administered, especially in patients with impaired renal function (see Section 4.8 Adverse Effects (Undesirable Effects)).
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 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.

Superinfections, particularly during prolonged treatment.

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.

Neuromuscular excitability or convulsions.

As with other penicillins, patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously, especially in patients with impaired renal function.

Patients with severe liver disease or decreased hepatic blood flow.

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).

Increased hepatic adverse reactions.

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 piperacillin/tazobactam 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 piperacillin/tazobactam.
Combined use of piperacillin/tazobactam and vancomycin may be associated with an increased risk of acute kidney injury (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Check the following before use.

Organ system functions.

Periodical assessment of organ system functions including renal, hepatic and haematopoietic during prolonged therapy (≥ 21 days) is advisable.

Patients with renal impairment and/or hepatic insufficiency.

For patients with renal impairment and/or hepatic insufficiency, measurement of serum levels of piperacillin will provide guidance for adjusting dosage.

Patients requiring sodium restriction; 2.35 mEq of sodium per gram.

The theoretical sodium content of each 4.5 g bottle of PiperTaz Sandoz (piperacillin/tazobactam) is 216 mg sodium (9.39 mmol), which may increase a patient's overall sodium intake.

Patients with low potassium.

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.

Treatment of meningitis and brain abscess is not advisable.

Because of its poor penetration into the CSF, piperacillin is not advised in the treatment of meningitis and brain abscess.

Patients with gonorrhoea.

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.

Cystic fibrosis patients; increased risk for fever and rash.

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

Use in renal impairment.

Due to its potential nephrotoxicity (see Section 4.8 Adverse Effects (Undesirable Effects)), piperacillin/tazobactam should be used with care in patients with renal insufficiency or dialysis patients (haemodialysis and CAPD). The intravenous dose and administration interval should be adjusted to the degree of renal impairment. Measurement of serum levels of piperacillin will provide guidance for adjusting dosage (see Section 4.2 Dose and Method of Administration).
In a secondary analysis using data from a large multicenter, randomized-controlled trial when glomerular filtration rate (GFR) was examined after administration of frequently used antibiotics in critically ill patients, the use of piperacillin/tazobactam was associated with a lower rate of reversible GFR improvement compared with the other antibiotics. This secondary analysis concluded that piperacillin/tazobactam was a cause of delayed renal recovery in these patients.
Combined use of piperacillin/tazobactam and vancomycin may be associated with an increased incidence of acute kidney injury (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in the elderly.

No data available.

Paediatric use.

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

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

4.5 Interactions with Other Medicines and Other Forms of Interactions

Aminoglycosides.

If PiperTaz Sandoz (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 mixing of β-lactam antibiotics with aminoglycosides in vitro can result in substantial inactivation of the aminoglycoside. However, amikacin and gentamicin were determined to be compatible in vitro with piperacillin/tazobactam in certain diluents at specific concentrations for a simultaneous Y-site infusion (see Section 4.2 Dose and Method of Administration).
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 a broad-spectrum β-lactam penicillin is only clinically significant in patients with severe renal dysfunction.

Probenecid.

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

Vancomycin.

Studies have detected an increased incidence of acute kidney injury in patients concomitantly administered piperacillin/tazobactam and vancomycin as compared to vancomycin alone (see Section 4.4 Special Warnings and Precautions for Use). Some of these studies have reported that the interaction is vancomycin dose-dependent. Expert guidelines recommend intensive vancomycin dosing and maintenance of trough levels between 15 mg/L and 20 mg/L which is an increase from previously published recommendations of target trough concentrations of 5-10 mg/L. Attaining these trough concentrations often requires practitioners to prescribe vancomycin doses which exceed manufacturers' recommendations. Therefore, it is possible that in addition to the increased risk of vancomycin-induced nephrotoxicity reported with adherence to these guidelines the risk of nephrotoxicity may also increase due to an interaction with piperacillin/tazobactam.

Vecuronium.

Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. PiperTaz Sandoz (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 heparin, oral anticoagulants and other medicines that may affect the blood coagulation system including the thrombocyte function, appropriate coagulation tests should be performed more frequently and monitored regularly.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Piperacillin and tazobactam did not affect the fertility of male or female rats.
(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 although maternal toxicity, in the form of decreased weight gain, was noted at the dose levels tested. Piperacillin and tazobactam cross the placenta in humans. 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 lactation are not available. Piperacillin is excreted in low concentrations in human milk; tazobactam concentrations in human milk have not been studied. 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.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable 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 Council for International Organisations of Medical Sciences (CIOMS) frequency categories as follows:
Very common: ≥ 10%; common: ≥ 1% and < 10%; 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 bullous dermatitis), purpura.
Unknown: increased sweating, eczema, exanthema.

Gastrointestinal disorders.

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

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, myalgia, 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, 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.

Hepatobiliary disorders.

Uncommon: alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased.
Rare: bilirubin increased, blood alkaline phosphatase increased, gamma glutamyltransferase (GGT) increased. The incidence of such rises is higher than with piperacillin alone.

Renal and urinary disorders.

Uncommon: blood creatinine increased.
Rare: tubulointerstitial nephritis, renal failure.
Very rare: blood urea nitrogen increased.

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.

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.

Post-marketing 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 reaction.
Rare: anaphylactoid shock, anaphylactic shock, anaphylactoid reaction, anaphylactic reaction.
Not known: Kounis syndrome*.
*Acute coronary syndrome associated with an allergic reaction.

Psychiatric disorders.

Not known: delirium.

Nervous system disorders.

Uncommon: seizure.

Infections and infestations.

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

Musculoskeletal and connective tissue disorders.

Not known: rhabdomyolysis.

Hepatobiliary disorders.

Uncommon: cholestatic jaundice.
Rare: hepatitis.

Cystic fibrosis patients; increased risk for fever and rash.

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

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

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

Treatment.

No specific antidote is known. Treatment should be supportive and symptomatic according to the patient's clinical presentation. In the event of an emergency, all required intensive medical measures are indicated as in the case of piperacillin. 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 information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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

Mechanism of action.

Piperacillin, a broad-spectrum, semisynthetic penicillin active against many Gram-positive and Gram-negative aerobic and anaerobic bacteria, exerts bactericidal activity by inhibition of both septum and cell wall synthesis. Tazobactam, a triazolylmethyl penicillanic acid 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.

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 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 influenzae.

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.
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 medicines, the test should be repeated. This category implies possible clinical applicability in body sites where the medicine is physiologically concentrated or in situations where high dosage of the medicine 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. This information provides guidance on microorganisms susceptible to piperacillin/tazobactam. The following MIC90 values were reported in 1996 for clinical isolates collected in 3 Australian states1 (see Table 4).
1 Daley, D., Mulgrave, L., Munro, S., Smith, H. and Dimech, W. An evaluation of the in vitro activity of piperacillin/tazobactam. Pathology 28: 167-172, 1996.
The latest NCCL references are: Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Seventh Edition, NCCLS document M7-A5, 2006. NCCLS, Wayne, PA.
For anaerobes: Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard-Sixth Edition. NCCLS document M11-A, 2006. NCCLS, Wayne, PA.

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 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.

5.2 Pharmacokinetic Properties

Absorption.

Mean plasma concentrations of piperacillin and tazobactam at steady-state of the combination appear in Table 5. 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.

Distribution.

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.

Metabolism.

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.
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.

Impaired renal function.

The half-life of piperacillin and tazobactam increases with decreasing creatinine clearance. The increase is two-fold and four-fold for piperacillin and tazobactam, respectively, at creatinine clearance below 20 mL/min compared to patients with normal renal function. Dosage adjustments are recommended when creatinine clearance is below 40 mL/min (see Section 4.2 Dose and Method of 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 Section 4.2 Dose and Method of 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 100 mg/kg piperacillin/12.5 mg/kg tazobactam (see Table 6). 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.

5.3 Preclinical Safety Data

Genotoxicity.

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 microgram/mL and 2500 microgram/mL, respectively.

Carcinogenicity.

Long-term carcinogenicity studies of piperacillin/tazobactam in animals have not been performed.

6 Pharmaceutical Particulars

6.1 List of Excipients

The product contains no excipients or preservatives.

6.2 Incompatibilities

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

6.3 Shelf Life

Lyophilized powder.

Bottles containing sterile PiperTaz Sandoz lyophilized powder may be stored below 25°C for up to 2 years.

Solutions.

Diluted solutions should be used immediately. Product is for single use in one patient only. Discard any residue.
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

PiperTaz Sandoz 4 g/0.5 g Powder for Injection packed in 50 mL or 100 mL bottle (Glass Type II clear) closed with rubber stopper (bromobutyl, latex-free) and flip-off aluminium crimp caps.
Pack size of 1 or 10 bottles per carton.
Not all presentations may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Piperacillin sodium.

Piperacillin sodium is derived from D(-)-alpha-aminobenzylpenicillin.

Chemical structure.


Chemical formula: 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.
Molecular weight: 539.54.

Tazobactam sodium.

Tazobactam sodium is a derivative of the penicillin nucleus. Chemically, tazobactam is a penicillanic acid sulfone.

Chemical structure.


Chemical formula: 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.
Molecular weight: 322.28.

CAS number.

Piperacillin sodium: 59703-84-3.
Tazobactam sodium: 89785-84-2.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes