TAZO-PIP AVENIR 4.5 G

אפורל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה ןכדועמ(

05.2013

)

__________ ךיראת

22.7.14

םושירה רפסמו תילגנאב רישכת םש

Tazo-Pip Avenir 4.5g 146-80-33342-00

__

_____________ םושירה לעב םש

BioAvenir

Ltd

.

_______________________

! דבלב תורמחהה טורפל דעוימ הז ספוט תושקובמה תורמחהה ןולעב קרפ יחכונ טסקט שדח טסקט

Posology

,

dosage

&

Administer

ation

Tazo-Pip Avenir 4.5g may be given by slow intravenous

injection (over at least three to five minutes) or by slow

intravenous infusion (over 20-30 minutes).

For reconstitution instructions, see section 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 Tazo-Pip Avenir can be used with an aminoglycoside.

If the use of an aminoglycoside is needed with piperacillin/tazobactam,

both Tazo-Pip Avenir 4.5g 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 Tazo-Pip

Avenir 4.5 g given every eight hours.

Posology

The dose and frequency of Tazo-Pip Avenir 4.5g

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:

The total daily dose of piperacillin/tazobactam depends on

the severity and localisation of the infection and can vary from piperacillin/

tazobactam 2000/250 mg to piperacillin/tazobactam 4000/500 mg

administered every six or eight hours.

In neutropenia the recommended dose is piperacillin/tazobactam

4000/500mg given every six hours in combination with an

aminoglycoside.

Elderly with Normal Renal Function

Tazo-Pip Avenir 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 40kg) 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:

Creatinine

Clearance

(ml/min)

Recommended Tazo-Pip Avenir 4.5 g

(piperacillin/tazobactam Dosage

Total

Divided doses

20 - 80

12/1.5 g/day

4000/500mg q8H

< 20

8/1 g/day

4000/500mg q 12H

For patients on haemodialysis, the maximum daily dose is

piperacillin/tazobactam 8/1 g. In addition, because haemodialysis

removes 30%-50% of piperacillin in four hours, one additional

dose of piperacillin/tazobactam 2000/250 mg 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 2-12 Years with Normal Renal Function

Tazo-Pip Avenir is only recommended for the treatment

of children with neutropenia.

Neutropenia

For children weighing less than 40kg the dose should be

adjusted to 90 mg/kg (piperacillin/tazobactam 80/10 mg)

administered every six hours, in combination with an

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

. the maximum dose is 2.25 g every twelve hours

for all indications other than nosocomial

pneumonia and 2.25 g every eight hours for

nosocomial pneumonia. Since hemodialysis

removes 30% to 40% of the administered dose,

an additional dose of 0.75 g piperacillin-Tazobactam

should be administered following each dialysis

period on hemodialysis days.

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

aminoglycoside, not exceeding piperacillin/tazobactam

4000/500 mg every six hours.

In children with renal insufficiency the intravenous dosage

should be adjusted to the degree of actual renal impairment

as follows:

Creatinine

Renal

Insufficiency

in Children

Aged 2-12

Years

(or bodyweight

less than 40kg)

Clearance

(ml/min)

Recommended

Tazo-Pip Avenir

(piperacillin

/ tazobactam)

Dosage

Frequency

Maximum

Daily

Dose

No adjustment necessary

20-39

90 mg

(piperacillin

/ tazobactam 80/10 mg)

q 8H

12/1.5

g/day

< 20

90mg

(piperacillin

/ tazobactam 80/10 mg)

q 12H

g/day

For children weighing < 50kg on haemodialysis the recommended dose is

45mg (piperacillin/tazobactam 40/5 mg) /kg every eight 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

Tazo-Pip Avenir 4.5 g 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 Tazo-Pip Avenir 4.5g should be

continued for 48 hours beyond the resolution of clinical symptoms

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.

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.

Route of administration

Piperacillin/tazobactam 4 g / 0.5 g is administered by

intravenous infusion (over 30 minutes).

or the fever.

For reconstitution instructions, see section 6.6.

Special

Warnings and

Special

Precautions

for Use

Before initiating therapy with Tazo-Pip Avenir 4.5g, careful inquiry

should be made concerning previous hypersensitivity reactions to

penicillins.cephalosporins, and other allergens.

Serious and occasionally fatal hypersensitivity (anaphylactic 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.

Patients may experience neuromuscular excitability or convulsions if

higher than recommended doses are given intravenously

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 Tazo-Pip Avenir 4.5g,

careful inquiry should be made concerning previous

hypersensitivity reactions to penicillins, other beta lactam

agents (e.g.cephalosporins,monobactam or carbapenem)

and other allergens.

Serious and occasionally fatal hypersensitivity sitivity

(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 skin reactions, such as Stevens-Johnson syndrome

and toxic epidermal necrolysis, have been reported in

patients receiving piperacillin/tazobactam (see section 4.8).

If patients develop a skin rash they should be monitored

closely and piperacillin/tazobactam discontinued if lesions

progress

Patients may experience neuromuscular excitability or

convulsions if higher than recommended doses are given

intravenously.

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.

Interactions

with other

medicinal

products and

other forms

of interaction

A number of chemical urine protein measurement methods

may lead to false-positive results. Protein measurement

with dip sticks is not affected.

The direct Coombs test may be positive.

Adverse

events

Body System

Frequency

Adverse Reaction

Blood and

lymphatic system

disorders

Uncommon

Leucopenia,

neutropenia,

thrombocytopenia

Rare

Anaemia,

bleeding

manifestations, (including

purpura, epistaxis,

bleeding time prolonged,)

eosinophilia,

haemolytic anaemia

Very rare

Agranulocytosis, Coombs'

direct test positive,

pancytopenia, prolonged

activated partial thromboplastin

Body System

Frequency Adverse Reaction

Blood and

lymphatic

system

disorders

Uncommo

Leucopenia,

neutropenia,

thrombocytopenia

Rare

Anaemia, haemolytic

anaemia bleeding

manifestations,

(including

purpura, epistaxis,

bleeding time

prolonged,

eosinophilia,

haemolytic anaemia

Very rare

Agranulocytosis,

time prolonged, prothrombin

time prolonged,

thrombocytosis

Blood and lymphatic

system disorders

Uncommon

Leucopenia, neutropenia,

thrombocytopenia

Rare

Anaemia, bleeding

manifestations,

(including purpura, epistaxis,

bleeding time prolonged,

eosinophilia, haemolytic

anaemia

Very rare

Agranulocytosis, Coombs'

direct test positive,

pancytopenia, prolonged partial

thromboplastin

time, prothrombin time

prolonged, thrombocytosis

Hepatobiliary

disorders

Uncommon

Alanine aminotransferase

increased, aspartate

aminotransferase increased

Rare

Bilirubin increased, blood

alkaline phosphatase increased,

gamma

glutamyltransferase

increased, hepatitis

Renal and urinary

disorders

Uncommon

Blood creatinine increased

Rare

Interstitial nephritis,

renal failure

Very rare

Blood urea nitrogen increased

General disorders and

administration site

conditions

Uncommon

FeverPyrexia, injection site

reaction

Rare

Rigors, tiredness, oedema

Coombs'

direct test positive,

pancytopenia, prolonged

activated partial

thromboplastin

time prolonged,

prothrombin

time prolonged,

thrombocytosis

thrombocythaemia

Blood and

lymphatic

system disorders

Uncommo

Leucopenia, neutropenia,

thrombocytopenia

Rare

Anaemia, haemolytic

anaemia

bleeding manifestations,

(including purpura,

epistaxis, bleeding time

prolonged, eosinophilia,

haemolytic anaemia

Very rare

Agranulocytosis,

Coombs' direct

test positive,

pancytopenia,

prolonged activated

partial thromboplastin

time prolonged,

prothrombin time

prolonged,

thrombocytosis

thrombocythaemia

Hepatobiliary

disorders

Uncommo

Alanine aminotransferase

increased, aspartate

aminotransferase

increased

Rare

Blood bilirubin

increased, blood

alkaline phosphatase

increased, gamma

glutamyltransferase

increased, hepatitis

Renal and

urinary

disorders

Uncommo

Blood creatinine

increased

Rare

Tublointerstitial

nephritis,

renal failure

Very rare

Blood urea nitrogen

increased

General

disorders and

administration

site

conditions

Uncommo

FeverPyrexia, injection

site reaction

Rare

Rigors, tiredness,

oedema Chills

תושקובמה תורמחהה תונמוסמ ובש ,ןולעה ב"צמ בוהצ עקר לע

.

ונמוס תורמחה רדגב םניאש םייוניש )ןולעב( םייוניש אלו יתוהמ ןכות קר ןמסל שי .הנוש עבצב .טסקטה םוקימב

1. NAME OF THE MEDICINAL PRODUCT

Tazo-Pip Avenir 4.5 g

Powder for Solution for Injection or Infusion.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

One vial of powder for solution for injection or infusion contains 9.44 mmol (217 mg) of

sodium.

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3. PHARMACEUTICAL FORM

Powder for solution for injection or infusion.

White to off white powder.

Tazo-Pip Avenir 4.5g (Piperacillin/Tazobactam for Injection) is an injectable antibacterial

combination product consisting of the semisynthetic antibiotic piperacillin sodium and the beta-

lactamase inhibitor tazobactam sodium for intravenous administration.

Piperacillin sodium is derived from D( - )-α-aminobenzyl-penicillin. The chemical name of

piperacillin sodium is sodium (2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-

piperazinecarboxamido)-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-

azabicyclo[3.2.0]heptane-2-carboxylate. The chemical formula is C

S and the

molecular weight is 539.5. The chemical structure of piperacillin sodium is:

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

chemical name is sodium (2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-methyl)-4-thia-1-

azabicyclo[3.2.0]heptane-2-

carboxylic acid 4,4-dioxide. The chemical formula is C

S and the molecular weight

is 322.3.

The chemical structure of tazobactam sodium is:

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4. CLINICAL PARTICULARS

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4.1 Therapeutic indications

Antibiotic for the treatment of moderate to severe systemic and/or local bacterial

infections caused by susceptible organisms.

Piperacillin/Tazobactam in combination with an aminoglycoside, is indicated for the

treatment of suspected bacterial infections in neutropenic adults and children.

Appendicitis complicated by rupture with peritonitis and/or abscess formation in children

aged 2-12 years.

This indication of the medicine has not been evaluated in pediatric patients under two

years.

Appropriate culture and susceptibility tests should be performed before treatment in order

to identify organisms causing infections and to determine their susceptibilities to

piperacillin/tazobactam. Because of its broad spectrum of activity against Gram-positive

and Gram-negative aerobic and anaerobic organisms, piperacillin/tazobactam is

particularly useful in the treatment of mixed infections and in presumptive therapy prior to

the availability of the results of sensitivity tests.

Therapy with piperacillin/tazobactam may, however, be initiated before results of such

test are known. Modification of the treatment may be required once these results become

available or if there is no clinical response.

In serious infections presumptive therapy with piperacillin/tazobactam may be initiated

before susceptibility test results are available.

piperacillin/tazobactam acts synergistically with aminoglycosides against certain strains of

Pseudomonas aeruginosa. Combined therapy has been successful, especially in patients

with impaired host defenses. Both drugs should be used in full therapeutic doses. As

soon as results of culture and susceptibility test become available, antimicrobial therapy

should be adjusted.

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4.2 Posology and method of administration

Posology

dose

frequency

piperacillin/tazobactam

depends

severity

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, the maximum dose is 2.25 g every twelve hours for all

indications other than nosocomial pneumonia and 2.25 g every eight hours for

nosocomial pneumonia. Since hemodialysis removes 30% to 40% of the administered

dose, an additional dose of 0.75 g piperacillin-Tazobactam should be administered

following each dialysis period on hemodialysis days.

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.

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.

Route of administration

Piperacillin/tazobactam 4 g / 0.5 g is administered by intravenous infusion (over 30

minutes).

For reconstitution instructions, see section 6.6.

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4.3 Contraindications

Hypersensitivity to piperacillin or any of the beta-lactam antibiotics and to tazobactam or

any other beta-lactamase inhibitor.

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4.4 Special warnings and precautions for use

Warnings

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 Tazo-Pip Avenir 4.5g, careful inquiry should be made

concerning previous hypersensitivity reactions to penicillins, other beta lactam agents

(e.g.cephalosporins,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.

Serious skin reactions, such as Stevens-Johnson syndrome and toxic epidermal

necrolysis, have been reported in patients receiving piperacillin/tazobactam (see section

4.8). If patients develop a skin rash they should be monitored closely and

piperacillin/tazobactam discontinued if lesions progress.

Antibiotic-induced pseudomembranous colitis may be manifested by severe, persistent

diarrhoea

which

life-threatening.

onset

pseudomembranous

colitis

symptoms

occur

during

after

antibacterial

treatment.

these

cases

piperacillin/tazobactam, should be discontinued.

Precautions

Periodic assessment of organ system functions including renal and hepatic during

prolonged therapy is advisable.

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 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

Leukopenia and neutropenia may occur, especially during prolonged therapy. Therefore,

periodic assessment of

haematopoietic (a full blood count) should be performed.

Patients may experience neuromuscular excitability or convulsions if higher than

recommended doses are given intravenously.

with

treatment

with

other

penicillins,

neurological

complications

form

convulsions may occur when high doses are administered, especially in patients with

impaired renal function.

This medicinal product contains 9.44 mmol (217 mg) of sodium per vial of powder for

solution for injection or infusion. 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 who are receiving

concomitant medications that may lower potassium levels; periodic electrolyte

determinations may be advisable 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 4.8).

Until further experience is available, Tazo-Pip Avenir 4.5g should not be used in children

who do not have neutropenia.

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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-depolarizing 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.

A number of chemical urine protein measurement methods may lead to false-positive

results. Protein measurement with dip sticks is not affected.

The direct Coombs test may be positive.

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.

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4.6 Pregnancy and lactation

There are no adequate and well-controlled studies with piperacillin/tazobactam in

combination or with piperacillin or tazobactam alone in pregnant women. Studies in

animals have shown reproductive toxicity (see 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.

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.

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).

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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 4.8), which may influence the ability to drive

and use machines.

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4.8 Undesirable effects

Undesirable effects are listed by frequency as follows: Very common (

1/10); 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); not known (cannot be estimated from the available data).

The most commonly reported adverse reactions are diarrhoea, nausea, vomiting, and

rash, each having a frequency of

1% but

10%.

Body System

Frequency

Adverse Reaction

Infections and

infestations

Uncommon

Candidal superinfection

Blood and lymphatic

system disorders

Uncommon

Leucopenia, neutropenia,

thrombocytopenia

Rare

Anaemia, haemolytic anaemia, purpura,

epistaxis, bleeding time prolonged,

eosinophilia

Very rare

Agranulocytosis, Coombs' direct test

positive, pancytopenia, activated partial

thromboplastin time prolonged,

prothrombin time prolonged,

thrombocythaemia

Immune system

disorders

Uncommon

Hypersensitivity reaction

Rare

Anaphylactic/anaphylactoid reaction

(including shock)

Metabolism and

nutritional disorders

Very rare

Hypoalbuminaemia, hypoglycaemia,

hypoproteinaemia, hypokalaemia

Nervous system

disorders

Uncommon

Headache, insomnia

Vascular disorders

Uncommon

Hypotension, phlebitis, thrombophlebitis

Rare

Flushing

Gastrointestinal

disorders

Common

Diarrhoea, nausea, vomiting

Uncommon

Constipation, dyspepsia, jaundice,

stomatitis

Rare

Abdominal pain, pseudomembranous

colitis, dry mouth

Hepatobiliary disorders

Uncommon

Alanine aminotransferase increased,

aspartate aminotransferase increased

Rare

Blood bilirubin increased, blood alkaline

phosphatase increased, gamma

glutamyltransferase increased, hepatitis

Skin and subcutaneous

tissue disorders

Common

Rash including maculopapular rash

Uncommon

Pruritus, urticaria

Rare

Bullous dermatitis, erythema multiforme,

exanthema

Very rare

Stevens-Johnson Syndrome, toxic

epidermal necrolysis

Musculoskeletal,

connective tissue and

bone disorders

Rare

Arthralgia, myalgia

Renal and urinary

disorders

Uncommon

Blood creatinine increased

Rare

Tublointerstitial nephritis, renal failure

Very rare

Blood urea increased

General disorders and

administration site

conditions

Uncommon

Pyrexia, injection site reaction

Rare

Chills

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.

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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).

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5. PHARMACOLOGICAL PROPERTIES

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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 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:

EUCAST clinical MIC breakpoints 2008 (version 1.2):

For susceptibility testing purposes, the concentration of tazobactam is fixed at 4

mg/L

Pathogen

Species-related breakpoints (S</R>)

Enterobacteriaceae

8/16

Pseudomonas

16/16

Gram-negative and Gram-positive anaerobes

8/16

Non-species related breakpoints

4/16

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.

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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

piperacillin/tazobactam 2000/250 mg to piperacillin/tazobactam 4000/500 mg.

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/Tazobactam is widely distributed in tissue and body fluids including intestinal

mucosa, gallbladder, 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 kinds 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.

Piperacillin

Tazobactam

Age group

Half-life

Clearance

(ml/min/kg)

Half-life

Clearance

(ml/min/kg)

2-5 years

6-12 years

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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 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.

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6. PHARMACEUTICAL PARTICULARS

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6.1 List of excipients

None

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6.2 Incompatibilities

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.

Tazo-Pip Avenir 4.5g should not be mixed with other drugs in a syringe or infusion bottle

since compatibility has not been established.

Tazo-Pip Avenir 4.5g should be administered through an infusion set separately from any

other drugs unless compatibility is proven.

Because of chemical instability, Tazo-Pip Avenir 4.5g should not be used with solutions

containing only sodium bicarbonate.

Lactated Ringer's solution is not compatible with Tazo-Pip Avenir 4.5g.

Tazo-Pip Avenir 4.5g should not be added to blood products or albumin hydrolysates

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6.3 Shelf life

Unopened - 3 years

When Tazo-Pip Avenir 4.5g is reconstituted with water for injections or saline,

reconstituted solutions will remain stable for 24 hours at 25°C and for 48 hours under

refrigeration 2-8 °C.

From a microbiological point of view, once opened, the product 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 24 hours at 2-8°C,

unless reconstitution has taken place in controlled and validated aseptic conditions.

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6.4 Special precautions for storage

Unopened: Store at room temperature up to 25°C.

After reconstitution: Store at 2-8

C (see 6.3 Shelf Life).

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6.5 Nature and contents of container

Packs of one Type II glass vial with butyl rubber stopper and aluminium/plastic seal

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6.6 Special precautions for disposal and other handling

Intravenous Injection

Each vial of Tazo-Pip Avenir 4.5g Powder for Solution for Injection or Infusion should be

reconstituted with 20ml of one of the following diluents:

Sterile water for injections

0.9% sodium chloride for injection

Swirl until dissolved. Intravenous injection should be given over at least three to five

minutes.

Intravenous Infusion

Each vial of Tazo-Pip Avenir 4.5g Powder for Solution for Injection or Infusion should be

reconstituted with 20ml of Sterile water for injection or 0.9% sodium chloride for injection.

The reconstituted solution should be further diluted to at least 50ml with one of the

reconstitution diluents, or with Dextrose 5% in Water or Dextrose 5% in saline or Dextrose

6% in saline.

Displacement Volume

Each gram of Tazo-Pip Avenir 4.5g Powder for Solution for Injection or Infusion has a

displacement volume of 0.7ml.

Tazo-Pip Avenir 4.5g Powder for Solution for Injection or Infusion will displace 3.15ml.

The reconstitution/dilution is to be made under aseptic conditions. The 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.

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7. MANUFACTURER

Laboratory Reige Jofre, Spain.

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8. LICENSE HOLDER

BioAvenir Ltd.,

Kibutz Glil-Yam 46905

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9. Registration Number

146 80

-33342 -00

The format of this leaflet was determined by the Ministry of Health and the

content thereof was checked and approved in 07.2014

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