Document: spc-doc_PL 04569-1644 change

• spc-doc_PL 04569-1644
• spc-doc_PL 28176-0046

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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Piperacillin/Tazobactam 4 g/0.5 g powder for solution for injection or infusion

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each vial contains piperacillin (as sodium salt) equivalent to 4 g and tazobactam (as sodium salt) equivalent to 0.5 g.

Each vial of Piperacillin/Tazobactam 4 g/0.5 g contains 9.39 mmol (216 mg) of sodium.

Excipient(s) with known effect:

For the full list of excipients, see section 6.1.

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 the treatment of the following infections in adults and children over 2 years of age (see sections 4.2 and 5.1):

Adults and Adolescents

-    Severe pneumonia including hospital-acquired and ventilator-associated pneumonia

-    Complicated urinary tract infections (including pyelonephritis)

-    Complicated intra-abdominal infections

-    Complicated skin and soft tissue infections (including diabetic foot infections)

Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above.

Piperacillin/Tazobactam may be used in the management of neutropenic patients with fever suspected to be due to a bacterial infection.

Children 2 to 12 years of age - Complicated intra-abdominal infections

Piperacillin/Tazobactam may be used in the management of neutropenic children with fever suspected to be due to a bacterial infection.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

Posology

The dose and frequency of Piperacillin/Tazobactam depends on the severity and localisation of the infection and expected pathogens.

Adult and adolescent patients

Infections

The usual dose is 4 g piperacillin/0.5 g tazobactam given every 8 hours.

For nosocomial pneumonia and bacterial infections in neutropenic patients, the recommended dose is 4 g piperacillin/0.5 g tazobactam administered every 6 hours. This regimen may also be applicable to treat patients with other indicated infections when particularly severe.

The following table summarises the treatment frequency and the recommended dose for adult and adolescent patients by indication or condition.

Treatment frequency	Piperacillin/Tazobactam 4 g/0.5 g
Every 6 hours	Severe pneumonia
	Neutropenic adults with fever suspected to be due to a bacterial infection
Every 8 hours	Complicated urinary tract infections (including pyelonephritis)
	Complicated intra-abdominal infections
	Skin and soft tissue infections (including diabetic foot infections)

Renal impairment

The intravenous dose should be adjusted to the degree of actual renal impairment as follows (each patient must be monitored closely for signs of substance toxicity; medicinal product dose and interval should be adjusted accordingly):

Creatinine clearance (ml/min)	Piperacillin/Tazobactam (recommended dose)
> 40	No dose adjustment necessary
20 - 40	Maximum dose suggested: 4 g/0.5 g every 8 hours
< 20	Maximum dose suggested: 4 g/0.5 g every 12 hours

For patients on haemodialysis, one additional dose of piperacillin/tazobactam 2 g/0.25 g should be administered following each dialysis period, because haemodialysis removes 30%-50% of piperacillin in 4 hours.

Hepatic impairment

No dose adjustment is necessary (see section 5.2).

Dose in elderly patients

No dose adjustment is required for the elderly with normal renal function or creatinine clearance values above 40 ml/min

Paediatric population (2-12 years of age)

Infections

The following table summarises the treatment frequency and the dose per body weight for paediatric patients 2-12 years of age by indication or condition:

Dose per weight and treatment frequency	Indication / condition
80 mg Piperacillin / 10 mg Tazobactam per kg body weight / every 6 hours	Neutropenic children with fever suspected to be due to bacterial infections*
100 mg Piperacillin / 12.5 mg Tazobactam per kg body weight / every 8 hours	Complicated intra-abdominal infections*

* Not to exceed the maximum 4 g/0.5 g per dose over 30 minutes.

Renal impairment

The intravenous dose should be adjusted to the degree of actual renal impairment as follows (each patient must be monitored closely for signs of substance toxicity; medicinal product dose and interval should be adjusted accordingly):

Creatinine clearance (ml/min)	Piperacillin/Tazobactam (recommended dose)
> 50	No dose adjustment needed.
< 50	70 mg piperacillin/8.75 mg tazobactam/kg every 8 hours.

For children on haemodialysis, one additional dose of 40 mg piperacillin/5 mg tazobactam/kg should be administered following each dialysis period.

Use in children aged below 2 years

The safety and efficacy of Piperacillin/Tazobactam in children 0-2 years of age has not been established.

No data from controlled clinical studies are available.

Treatment duration

The usual duration of treatment for most indications is in the range of 5-14 days. However, the duration of treatment should be guided by the severity of the infection, the pathogen(s) and the patient's clinical and bacteriological progress.

Method of administration

Piperacillin/Tazobactam 4 g/0.5 g for solution for injection or infusion may administered by intravenous infusion (over 30 minutes).

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

4.3    Contraindications

Hypersensitivity to the active substances, any other penicillin-antibacterial agent or to any of the excipients listed in section 6.1.

History of acute severe allergic reaction to any other beta-lactam active substances (e.g. cephalosporin, monobactam or carbapenem).

4.4    Special warnings and precautions for use

The selection of piperacillin/tazobactam to treat an individual patient should take into account the appropriateness of using a broad-spectrum semi-synthetic penicillin based on factors such as the severity of the infection and the prevalence of resistance to other suitable antibacterial agents.

Before initiating therapy with Piperacillin/Tazobactam, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, other beta-lactam agents (e.g. cephalosporin, monobactam or carbapenem) and other allergens. 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. Serious hypersensitivity reactions require the discontinuation of the antibiotic, and may require administration of epinephrine and other emergency measures.

Antibiotic-induced pseudomembranous colitis may be manifested by severe, persistent diarrhoea which may be life-threatening. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment. In these cases Piperacillin/Tazobactam, should be discontinued.

Therapy with Piperacillin/Tazobactam may result in the emergence of resistant organisms, which might cause super-infections.

Bleeding manifestations have occurred in some patients receiving beta-lactam antibiotics. These reactions sometimes have 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.

Leukopenia and neutropenia may occur, especially during prolonged therapy; therefore, periodic assessment of haematopoietic function should be performed.

As with treatment with other penicillins, neurological complications in the form of convulsions may occur when high doses are administered, especially in patients with impaired renal function.

Each vial of Piperacillin/Tazobactam 4 g 0.5 g contains 9.39 mmol (216 mg) of sodium. This should be taken into consideration for patients who are on a controlled sodium diet.

Hypokalaemia may occur in patients with low potassium reserves or those receiving concomitant medicinal products that may lower potassium levels; periodic electrolyte determinations may be advisable in such patients.

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 the 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 Fertility, Pregnancy and lactation

Fertility

A fertility study in rats showed no effect on fertility and mating after intraperitoneal administration of tazobactam or the combination piperacillin / tazobactam (see section 5.3).

Pregnancy

There are no or a limited amount of data from the use of piperacillin or tazobactam in pregnant women.

Studies in animals have shown developmental toxicity, but no evidence of teratogenicity, at doses that are maternally toxic (see section 5.3).

Piperacillin and tazobactam cross the placenta. Piperacillin/tazobactam should only be used during pregnancy if clearly indicated, i.e. only if the expected benefit outweighs the possible risks to the pregnant woman and foetus.

Breast-feeding

Piperacillin is excreted in low concentrations in human milk; tazobactam concentrations in human milk have not been studied. Women who are breastfeeding 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

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

System Organ Class	Common > 1/100 to < 1/10	Uncommon > 1/1,000 to < 1/100	Rare > 1/10,000 to < 1/1,000	Very rare (< 1/10,000)
disorders		a	purpura, epistaxis, bleeding time prolonged, eosinophilia	thromboplastin time prolonged, prothrombin time prolonged, Coombs direct test positive, thrombocythaemi a
Immune system disorders		hypersensitivity	anaphylactic/ anaphylactoid reaction (including shock)
Metabolism and nutrition disorders				hypokalaemia, blood glucose decreased, blood albumin decreased, blood protein total decreased
Nervous system disorders		headache, insomnia
Vascular disorders		hypotension, thrombophlebitis, phlebitis	flushing
Gastrointestin al disorders	diarrhoea, vomiting, nausea	jaundice, stomatitis, constipation, dyspepsia	pseudo membranous colitis, abdominal pain
Hepatobiliary disorders		alanine aminotransferase increased, aspartate aminotransferase increased	hepatitis, blood bilirubin increased, blood alkaline phosphatase increased, gamma- glutamyltrans- ferase increased
Skin and subcutaneous tissue disorders	rash, including maculopapul ar rash	urticaria, pruritus	erythema multiforme, dermatitis bullous, exanthema	toxic epidermal necrolysis, Stevens-Johnson syndrome
Musculoskelet			arthralgia,

System Organ Class	Common > 1/100 to < 1/10	Uncommon > 1/1,000 to < 1/100	Rare > 1/10,000 to < 1/1,000	Very rare (< 1/10,000)
al and connective tissue disorders			myalgia
Renal and urinary disorders		blood creatinine increased	renal failure, tubulointerstiti al nephritis	blood urea increased
General disorders and administration site conditions		pyrexia, injection-site reaction	chills

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

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 will be reduced by haemodialysis (for more details see section 5.2).

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Combinations of pernicillin, including beta-lactamase inhibitor

ATC Code: J01CR05

Mechanism of action:

Piperacillin, a broad spectrum, semi-synthetic 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 beta-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 beta-lactamase producing bacteria normally resistant to it and other beta-lactam antibiotics. Thus, piperacillin/tazobactam combines the properties of a broad spectrum antibiotic and a beta-lactamase inhibitor.

Mechanism of resistance:

The presence of tazobactam expands the spectrum of activity of piperacillin to include microorganisms 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:

Classification from the Clinical and Laboratory Standards Institute (CLSI) 2006:

	Equivalent MIC breakpoints (mg/L)
Pathogen	Susceptible	Intermediate	Resistant
Staphylococcus spp.	< 8/4	-	> 16/4
Enterobacteriaceae	< 16/4	32/4 to 64/4	> 128/4
Pseudomonas	< 64/4	-	> 128/4
aeruginosa
Acinetobacter spp.	< 16/4	32/4 to 64/4	> 128/4
Haemophilus influenzae & H .parainfluenzae	< 1/4		> 2/4

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.

Commonly susceptible species Gram positive aerobes Brevibacterium spp Enterococcus faecalis Listeria monocytogenes Staphylococcus spp. methicillin-sensitive Streptococcus pneumoniae

Streptococcus pyogenes Group B streptococci Streptococcus spp *

Gram negative aerobes Branhamella catarrhalis Citrobacter koseri Haemophilus influenzae *

Haemophilus spp.

Proteus mirabilis Salmonella spp.

Shigella spp.

Gram positive anaerobes Clostridium spp.

Eubacterium spp.

Peptococcus spp.

Peptostreptococcus spp.

Gram negative anaerobes Bacteroides fragilis*

Bacteroides fragilis group Fusobacterium spp.

Porphyromonas spp.

Prevotella spp*

Species for which resistance may be a problem

Gram positive aerobes

Staphylococcus aureus, methicillin-sensitive

Staphylococcus epidermis, methicillin-sensitive Enterococcus avium ($)

Enterococcus faecium (+ $)

Propionibacterium acnes ($)

Viridans streptococci

Gram negative aerobes Actinobacter spp (+ $)

Burkholderia cepacia Citrobacter freundii Enterobacter spp.

Escherichia coli *

Klebsiella spp.

Proteus, indole positive Pseudomonas aeruginosa*

Pseudomonas spp. *

Pseudomonas stutzeri $

Serratia spp.

Gram negative anaerobes Bacteroides spp. *

Inherently resistant organisms

Gram positive aerobes Corynebacterium jeikeium Staphylococcus spp. methicillin resistant

Gram negative aerobes Legionella spp

Stenotrophomonas maltophilia +$

* 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 Absorption

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

Distribution

Both piperacillin and tazobactam are approximately 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/Tazobactam is widely distributed in tissue and body fluids including intestinal mucosa, gallbladder, lung, bile and bone. Mean tissue concentrations are generally 50 to 100% of those in plasma. Distribution into cerebrospinal fluid is low in subjects with non-inflamed meninges, as with other penicillins.

Metabolism

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 the glomerular filtration and tubular secretion.

Piperacillin is excreted rapidly as unchanged substance, with 68% of the administered dose appearing in the urine. Tazobactam and its metabolite are eliminated primarily by renal excretion, with 80% of the administered dose appearing as unchanged substance 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 slightly reduce the clearance of tazobactam.

Special populations

The half-life of piperacillin and of tazobactam increases by approximately 25% and 18%, respectively, in patients with hepatic cirrhosis compared to healthy subjects.

The half-life of piperacillin and tazobactam increases with decreasing creatinine clearance. The increase in half-life 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.

Haemodialysis removes 30% to 50% of piperacillin/tazobactam, with an additional 5% of the tazobactam dose removed as the tazobactam metabolite. Peritoneal dialysis removes approximately 6% and 21% of the piperacillin and tazobactam doses, respectively, with up to 18% of the tazobactam dose removed as the tazobactam metabolite.

Paediatric population

In a population PK analysis, estimated clearance for 9 month-old to 12 year-old

patients was comparable to adults, with a population mean (SE) value of 5.64 (0.34) ml/min/kg. The piperacillin clearance estimate is 80% of this value for paediatric patients 2-9 months of age. The population mean (SE) for piperacillin volume of distribution is 0.243 (0.011) l/kg and is independent of age.

Elderly patients

The mean half-life for piperacillin and tazobactam were 32% and 55% longer, respectively, in the elderly compared with younger subjects. This difference may be due to age-related changes in creatinine clearance.

Race

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

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 to rats. 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 substances must be administered separately. The mixing of beta-lactam antibiotics with an aminoglycoside in vitro can result in substantial inactivation of the aminoglycoside.

Piperacillin/Tazobactam should not be mixed with other substances in a syringe or infusion bottle since compatibility has not been established.

Due to chemical instability, piperacillin/tazobactam should not be used with solutions containing only sodium bicarbonate.

Lactated Ringer's solution is not compatible with Piperacillin/Tazobactam.

Piperacillin/Tazobactam should not be added to blood products or albumin hydrolysates.

6.3 Shelf life

Unopened vial

24 months

Reconstituted solution in vial

Chemical and in-use stability has been demonstrated for up to 24 hours at 25°C and for 48 hours when stored in a refrigerator at 2-8°C, when reconstituted with one of the compatible solvents for reconstitution (see section 6.6).

Diluted infusion solution

After reconstitution, chemical and physical in-use stability of diluted infusion solutions has been demonstrated for 24 hours at 25°C and for 48 hours when stored in a refrigerator at 2-8°C, when reconstituted using one of the compatible solvents for further dilution of the reconstituted solution at the suggested dilution volumes (see section 6.6).

From a microbiological point of view, the reconstituted and diluted solutions should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 12 hours at 2-8°C, unless reconstitution and dilution have taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Unopened vials: Do not store above 25°C.

For storage conditions after reconstitution and dilution of the medicinal product see section 6.3.

6.5 Nature and contents of container

Type I glass vials with dark grey rubber plug and aluminium seal. Each vial is packed in a carton.

Pack sizes: 1 vial per carton.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

Intravenous use

Reconstitute each vial with the volume of solvent shown in the table below, using one of the compatible solvents for reconstitution. Swirl until dissolved. When swirled constantly, reconstitution generally occurs within 2 to 3 minutes (for details on handling, please see below).

Content of vial	Volume of solvent* to be added to vial
2 g/0.25 g (2 g piperacillin and 0.25 g tazobactam)	10 ml
4 g/0.5 g (4 g piperacillin and 0.5 g tazobactam)	20 ml

(1)

-    Sterile water for injections

-    Glucose 5%

(1)

Maximum recommended volume of sterile water for injection per dose is 50 ml.

The reconstituted solutions should be withdrawn from the vial by syringe. When reconstituted as directed, the vial contents withdrawn by syringe will provide the labelled amount of piperacillin and tazobactam.

The reconstituted solutions may be further diluted to the desired volume (e.g. 50 ml to 150 ml) with one of the following compatible solvents:

-    0.9% (9 mg/ml) sodium chloride solution for injection

-    Glucose 5%

-    Dextran 6% in 0.9% sodium chloride

Co-administration with aminoglycosides

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

See section 6.2 for incompatibilities.

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

7 MARKETING AUTHORISATION HOLDER

Generics [UK] Limited t/a Mylan

Station Close

Hertfordshire

EN6 1TL

UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 04569/1644

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

24/01/2011

10 DATE OF REVISION OF THE TEXT

02/12/2015