1. Name Of The Medicinal Product
Piperacillin/Tazobactam 2 g / 0.25 g powder for solution for injection or infusion
2. Qualitative And Quantitative Composition
Each vial contains piperacillin sodium corresponding to 2g piperacillin and tazobactam sodium corresponding to 0.25g tazobactam.
One vial of powder for solution for injection/infusion contains 4.7 mmol (108mg) of sodium.
3. Pharmaceutical Form
Powder for solution for injection or infusion.
White to off-white powder.
4. Clinical Particulars
4.1 Therapeutic Indications
Piperacillin/Tazobactam is indicated for treatment of the moderate to severe systemic and/or local bacterial infections in which beta-lactamase producing bacteria are suspected or have been detected, such as:
Adults/ Adolescents and the Elderly
- Nosocomial pneumonia; - Complicated urinary tract infections (including pyelonephritis);
- Intra-abdominal infections;
- Skin and soft tissue infections;
- Bacterial infections in neutropenic patients.
Children (2 to 12 years)
Bacterial infections in neutropenic children.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
4.2 Posology And Method Of Administration
Piperacillin/Tazobactam may be given by slow intravenous injection (over at least 3-5 minutes) or by slow intravenous infusion (over 20-30 minutes).
For reconstitution instructions, see section 6.2 and 6.6.
The treatment of mixed infections caused by piperacillin susceptible organisms and beta-lactamase producing organisms susceptible to piperacillin/tazobactam generally do not require the addition of another antibiotic.
In patients with nosocomial pneumonia and infections in neutropenic patients piperacillin/tazobactam can be used with an aminoglycoside. If the use of an aminoglycoside is needed, with piperacillin/tazobactam, both piperacillin/tazobactam and the aminoglycoside must be used in completely therapeutic doses.
Neutropenic patients with signs of infection (e.g. fever) should receive immediate empirical antibiotic therapy before laboratory results are available.
Adults and Children Over 12 Years, Each with Normal Renal Function
The usual dosage for adults and children over 12 years is 4.5g Piperacillin/Tazobactam (4g piperacillin / 500mg tazobactam) given every 8 hours.
The total daily dose of Piperacillin/Tazobactam depends on the severity and localisation of the infection and can vary from 2.25g (2g piperacillin / 250mg tazobactam) to 4.5g (4g piperacillin / 500mg tazobactam) administered every 6 or 8 hours.
In neutropenia the recommended dose is 4.5g Piperacillin/Tazobactam (4g piperacillin / 500mg tazobactam) given every 6 hours in combination with an aminoglycoside.
Elderly with Normal Renal Function
Piperacillin/Tazobactam may be used at the same dose levels as adults except in cases of renal impairment (see below):
Renal Insufficiency in Adults, the Elderly and Children (over 40 Kg) Receiving the Adult Dose
In patients with renal insufficiency, the intravenous dose should be adjusted to the degree of actual renal impairment. The suggested daily doses are as follows:
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For patients on haemodialysis, the maximum daily dose is 8g/1g piperacillin/tazobactam. In addition, because haemodialysis removes 30%-50% of piperacillin in 4 hours, one additional dose of 2g/250mg piperacillin/tazobactam 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 with normal renal function
Piperacillin/Tazobactam is only recommended for the treatment of children with neutropenia.
Neutropenia
For children weighing less than 40 kg the dose should be adjusted to 90mg/kg (80mg piperacillin / 10mg tazobactam) administered every 6 hours, in combination with an aminoglycoside, not exceeding 4.5g (4g piperacillin / 500mg tazobactam) every 6 hours.
Renal Insufficiency in Children Aged 2-12 Years (or bodyweight less than 40 kg)
In children with renal insufficiency the intravenous dosage should be adjusted to the degree of actual renal impairment as follows:
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For children weighing < 50 kg on haemodialysis the recommended dose is 45 mg (40mg piperacillin /5mg tazobactam) /kg every 8 hours.
The above dosage modifications are only an approximation. Each patient must be monitored closely for signs of drug toxicity. Drug dose and interval should be adjusted accordingly.
Children under 2 years:
Piperacillin/Tazobactam is not recommended for use in children below 2 years old due to insufficient data on safety.
Hepatic Impairment
No dose adjustment is necessary.
Duration of Therapy
The duration of therapy should be guided by the severity of the infection and the patient's clinical and bacteriological progress.
In acute infections, treatment with Piperacillin/Tazobactam should be continued for 48 hours beyond the resolution of clinical symptoms or the fever.
4.3 Contraindications
Patients with a history of hypersensitivity to the active substances, to other beta-lactams (e.g. penicillins and cephalosporins) or to any other beta-lactamase inhibitor.
4.4 Special Warnings And Precautions For Use
Warnings
Serious and occasionally fatal hypersensitivity (anaphylactic / anaphylactoid [including shock]) reactions have been reported in patients receiving therapy with penicillins including piperacillin / tazobactam. These reactions are more likely to occur in persons with a history of sensitivity to multiple allergens.
There have been reports of patients with a history of penicillin hypersensitivity who have experienced severe reactions, when treated with cephalosporin. If an allergic reaction occurs during therapy with piperacillin / tazobactam, the antibiotic should be discontinued. Serious hypersensitivity reactions may require adrenaline and other emergency measures.
Before initiating therapy with piperacillin / tazobactam, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, and other allergens.
In case of severe, persistent diarrhoea, the possibility of antibiotic-induced, life threatening pseudomembranous colitis must be taken into consideration. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment. Therefore, piperacillin / tazobactam must be discontinued immediately in such cases, and suitable therapy should be initiated.
Precautions
Leukopenia and neutropenia may occur, especially during prolonged therapy. Therefore, periodic assessment of a full blood count should be performed.
Periodic assessment of organ system functions including renal and hepatic during prolonged therapy is advisable.
Bleeding manifestations have occurred in some patients receiving β-lactam antibiotics. These reactions have sometimes been associated with abnormalities of coagulation tests such as clotting time, platelet aggregation and prothrombin time, and are more likely to occur in patients with renal failure. If bleeding manifestations occur, the antibiotic should be discontinued and appropriate therapy instituted.
The possibility of the emergence of resistant organisms, which might cause superinfections, should be kept in mind, particularly during prolonged treatment. Microbiological follow-up may be required to detect any important superinfection. If this occurs, appropriate measures should be taken.
Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously.
This medicinal product contains 4.7 mmol (108 mg) of sodium per vial of powder for solution for injection or infusion. To be taken into consideration by patients on a controlled sodium diet
Hypokalaemia may occur in patients with low potassium reserves or who are receiving concomitant medications that may lower potassium levels; periodic electrolyte determinations should be performed in such patients. Modest elevation of indices of liver function may be observed.
Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients (see also section 4.8).
Until further experience is available, piperacillin/ tazobactam should not be used in children who do not have neutropenia.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Interaction with probenecid:
Concurrent administration of probenecid and piperacillin/tazobactam produced a longer half-life and lower renal clearance for both piperacillin and tazobactam. However, peak plasma concentrations of either drug are unaffected.
Interaction with antibiotics:
No clinically relevant adverse pharmacokinetic interaction with tobramycin or vancomycin has been observed in healthy adults with a normal renal function. The clearance of tobramycin and gentamicin was enhanced in patients with severe renal dysfunction using piperacillin/tazobactam. In these patients mixing of piperacillin/tazobactam formulation with tobramycin and gentamicin was excluded.
For information related to administration of piperacillin/tazobactam with aminoglycosides please refer to section 6.2.
Interaction with anticoagulants:
During simultaneous administration of heparin, oral anticoagulants and other drugs, which may affect the blood coagulation system including thrombocyte function, appropriate coagulation tests should be performed more frequently and monitored regularly.
Interaction with vecuronium:
Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. Due to their similar mechanism of action, it is expected that the neuromuscular blockade produced by any of the non-depolarising muscle relaxants could be prolonged in the presence of piperacillin. This should be taken into account when piperacillin/tazobactam is used peri-operatively.
Interaction with methotrexate:
Piperacillin may reduce the excretion of methotrexate. Serum levels of methotrexate should be monitored in patients on methotrexate therapy.
Interaction with laboratory test results:
The administration of piperacillin / tazobactam may result in a false-positive reaction for glucose in the urine using a copper-reduction method. It is recommended that glucose tests based on enzymatic glucose oxidase reaction be used.
There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving piperacillin-tazobactam injection who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving piperacillin-tazobactam should be interpreted cautiously and confirmed by other diagnostic methods.
4.6 Pregnancy And Lactation
Pregnancy
There are no adequate and well-controlled studies with piperacillin/tazobactam combination or with piperacillin or tazobactam alone in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Piperacillin and tazobactam cross the placenta. Piperacillin/tazobactam should only be used during pregnancy if clearly indicated.
Lactation
Piperacillin is excreted in low concentrations in breast milk. Tazobactam concentrations in human milk have not been studied. The effect on the suckling infant is unknown. Women who are breast feeding should be treated only if clearly indicated. Diarrhoea and fungal infections of the mucous membranes as well as sensitisation could occur in the breast-fed infant.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed.
However, side effects may occur (see also section 4.8), which may influence the ability to drive and use machines.
4.8 Undesirable Effects
Undesirable effects are listed by frequency as follows: Very common (
The most commonly reported adverse reactions are diarrhoea, nausea, vomiting, and rash, each having a frequency of
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The administration of high doses of beta-lactams, particularly in patients with renal insufficiency, can lead to encephalopathies (consciousness fluctuation, myoclonus and convulsions).
Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.
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 of Intoxication
In the event of an overdose, piperacillin/tazobactam treatment should be discontinued.
No specific antidote is known.
Treatment should be supportive and symptomatic according to the patient's clinical presentation. In the event of an emergency, all required intensive medical measures are indicated as in the case of piperacillin.
Excessive serum concentrations of either piperacillin or tazobactam may be reduced by haemodialysis (for more details, see section 5.2).
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Combinations of penicillins, including beta-lactamase inhibitors
ATC classification: J01CR05
Mechanism of action:
Piperacillin, a broad spectrum, semisynthetic penicillin active against many gram-positive and gram-negative aerobic and anaerobic bacteria, exerts bactericidal activity by inhibition of both septum and cell wall synthesis. Tazobactam, a triazolylmethyl penicillanic acid sulphone, is a potent inhibitor of many β-lactamases, in particular the plasmid mediated enzymes which commonly cause resistance to penicillins and cephalosporins including third-generation cephalosporins. The presence of tazobactam in the piperacillin/tazobactam formulation enhances and extends the antibiotic spectrum of piperacillin to include many β-lactamase producing bacteria normally resistant to it and other β-lactam antibiotics. Thus, piperacillin/tazobactam combines the properties of a broad spectrum antibiotic and a β-lactamase inhibitor.
PK/PD relationship:
Similar to other beta-lactam antimicrobial agents, the time that the plasma concentration of
piperacillin exceeds the MIC (%T >MIC) of the infecting organism has been shown to best
correlate with efficacy.
Mechanism of resistance
The presence of tazobactam expands the spectrum of activity of piperacillin to include micro-organisms that would otherwise, due to the formation of beta-lactamase, be resistant to piperacillin and other beta-lactam antibiotics.
In vitro investigation has demonstrated that the type I beta-lactamase inducing ability of tazobactam is insignificant with regard to Gram-negative bacteria.
In vitro studies have demonstrated a synergetic effect of piperacillin/tazobactam and aminoglycosides against Pseudomonas aeruginosa and other bacteria, including beta-lactamase producing strains
Breakpoints
The minimum inhibitory concentration (MIC) breakpoints separating susceptible, intermediately susceptible and resistant organisms have been defined as follows:
EUCAST clinical MIC breakpoints 2008 (version 1.2):
For susceptibility testing purposes, the concentration of tazobactam is fixed at 4 mg/L
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The susceptibility of streptococci is inferred from the penicillin susceptibility.
The susceptibility of staphylococci is inferred from the oxacillin susceptibility.
Susceptibility
The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
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* Clinical effectiveness against this has been demonstrated in the registered indications.
$ species showing natural intermediate susceptibility
+ species for which high resistance rates ( more than 50%) have been observed in one or more areas/countries /regions within the EU
5.2 Pharmacokinetic Properties
Distribution
Peak piperacillin and tazobactam plasma concentrations are attained immediately after completion of an intravenous infusion or injection. Piperacillin plasma levels produced when given with tazobactam are similar to those attained when equivalent doses of piperacillin are administered alone.
There is a greater proportional (approximately 28%) increase in plasma levels of piperacillin and tazobactam with increasing dose over the dosage range of 250mg tazobactam/2g piperacillin to 500mg tazobactam/4g piperacillin.
Both piperacillin and tazobactam are 20 to 30% bound to plasma proteins. The protein binding of either piperacillin or tazobactam is unaffected by the presence of the other compound. Protein binding of the tazobactam metabolite is negligible.
Piperacillin and tazobactam are widely distributed in tissue and body fluids including intestinal mucosa, gall bladder, lung, bile and bone.
Biotransformation
Piperacillin is metabolised to a minor microbiologically active desethyl metabolite. Tazobactam is metabolised to a single metabolite, which has been found to be micro-biologically inactive.
Elimination
Piperacillin and tazobactam are eliminated by the kidney via glomerular filtration and tubular secretion.
Piperacillin is excreted rapidly as unchanged drug with 68% of the administered dose appearing in the urine. Tazobactam and its metabolite are eliminated primarily by renal excretion with 80% of the administered dose appearing as unchanged drug and the remainder as the single metabolite. Piperacillin, tazobactam, and desethyl piperacillin are also secreted into the bile.
Following single or multiple doses of piperacillin / tazobactam to healthy subjects, the plasma half-life of piperacillin and tazobactam ranged from 0.7 to 1.2 hours and was unaffected by dose or duration of infusion. The elimination half-lives of both piperacillin and tazobactam are increased with decreasing renal clearance.
There are no significant changes in piperacillin pharmacokinetics due to tazobactam. Piperacillin appears to reduce the rate of elimination of tazobactam.
Impaired Renal Function
Piperacillin and tazobactam are haemodialysable: 31% (piperacillin) and 39% (tazobactam) of administered doses are filtrated. During peritoneal dialysis, 5% of administered piperacillin and 12% of administered tazobactam are found in the dialysis liquid. Patients treated by chronic ambulatory peritoneal dialysis should receive the same dose as non dialysed patients with severe renal insufficiency.
Impaired Liver Function
Plasma concentrations of piperacillin and tazobactam are prolonged in hepatically impaired patients. The half-life of piperacillin and of tazobactam increases by approximately 25% and 18%, respectively, in patients with hepatic cirrhosis compared to healthy subjects. However, dosage adjustments in patients with hepatic impairment are not necessary.
Paediatric patients
The pharmacokinetics of piperacillin/tazobactam has been studied in paediatric patients with intra-abdominal infections and other kind of infections. In every age group, renal fraction of elimination of piperacillin and tazobactam was approximately 70% and 80%, respectively, like in adults.
Mean pharmacokinetic parameters of piperacillin/tazobactam of paediatric patients of different age groups.
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5.3 Preclinical Safety Data
Preclinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity and genotoxicity. Carcinogenicity studies have not been conducted with piperacillin/tazobactam.
A fertility study of piperacillin/ tazobactam reported a decrease in litter size and an increase in fetuses with ossification delays and variations of ribs following i.p. administration. Fertility of the F1 generation and embryonic development of the F2 generation was not impaired. A teratogenicity study in rats, did not show teratogenic effects after i.v. administration. In the rat, effects on the embryonic development were observed at maternal toxic doses. Peri/postnatal development was impaired (reduced fetal weights, increase in pup mortality, increase in stillbirths) concurrently with maternal toxicity after i.p. administration in the rat.
6. Pharmaceutical Particulars
6.1 List Of Excipients
None.
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
Whenever Piperacillin / Tazobactam is used concurrently with another antibiotic (e.g. aminoglycosides), the drugs must be administered separately. The mixing of Piperacillin / Tazobactam with an aminoglycoside in vitro can result in substantial inactivation of the aminoglycoside.
Piperacillin / Tazobactam should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established.
Piperacillin/Tazobactam should be administered through an infusion set separately from any other drugs unless compatibility is proven.
Due to chemical instability, Piperacillin / Tazobactam should not be used with solutions that contain sodium bicarbonate.
Lactated Ringer's (Hartmann´s) solution is not compatible with piperacillin/tazobactam.
Piperacillin / Tazobactam should not be added to blood products or albumin hydrolysates.
6.3 Shelf Life
Vial before opening: 2 years
Vial after first opening/after reconstitution:
After reconstitution (and dilution):
Reconstituted and/or diluted Piperacillin/Tazobactam should be used immediately.
From a microbiological point of view, the product should be used immediately.
Unused solution should be discarded.
6.4 Special Precautions For Storage
Un opened: Store in the original package in order to protect from light.
Store below 25°C.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature And Contents Of Container
Clear glass vials of 30 ml stoppered with grey colour bromo butyl rubber stopper and sealed with violet colour PP/Al flip off seal.
Pack sizes: 1 and 12 vials per carton.
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
Reconstitution Directions
Intravenous Injection:
Each vial of Piperacillin / tazobactam 2g/0.25g should be reconstituted with 10ml of one of the following diluents:
• Sterile Water for Injection
• 9 mg/ml (0.9%) Sodium Chloride for Injection
• Dextrose 50 mg/ml (5%) in water
• Dextrose 50 mg/ml (5%) in sodium chloride 9 mg/ml (0.9%) solution
Swirl until dissolved. Intravenous injection should be given over at least 3-5 minutes.
Intravenous Infusion:
Each vial of Piperacillin / Tazobactam 2g/0.25g should be reconstituted with 10ml of one of the above diluents:
The reconstituted solution should be further diluted to a total volume of 50 ml to 100 ml with one of the reconstitution diluents, or with dextran 60 mg/ml (6%) in sodium chloride 9 mg/ml (0.9%) solution. Intravenous infusion should be given over 20-30 minutes.
For single use only. Discard any unused solution.
The reconstitution/dilution is to be made under aseptic conditions. The reconstituted solution is to be inspected visually for particulate matter and discoloration prior to administration. The solution should only be used if the solution is clear and free from particles.
Any unused product or waste material should be disposed of in accordance with local requirements.
7. Marketing Authorisation Holder
Milpharm Limited
Ares, Odyssey Business Park
West End Road
South Ruislip HA4 6QD
United Kingdom
8. Marketing Authorisation Number(S)
PL 16363/0220
9. Date Of First Authorisation/Renewal Of The Authorisation
06/11/2009
10. Date Of Revision Of The Text
06/11/2009
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