TAZOCIN EF
Piperacillin/tazoboctam
TAZOCIN EF ; Piperacillin sodium +
Tazobzctam
DESCRIPION
TAZOCIN EF is an
injectable antibacterial combination , consisting of the semisynthetic
antibiotic piperacillin sodium and the
lactamase inhibitor tazobactam sodium , for intravenous administration.
Piperacillin
sodium is derived from D(-)-<-aminobenzylpenicillin. The chemical name of
piperacillin sodium is sodium (2S,5R,6R)
-6-[®-2-(4-ethy1-2,3-dioxo-1—piperazine
–carboxamid)-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic
acid.
Piperacillin
sodium
Tazobactam
sodium is a derivative of the penicillin nucleus. Chemically , tazobactam is a
penicillanic acid sulfone, its chemical name is sodium (2S-(2<,3 5<)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethy1)-4-thai-1azabicyclo[3.2.0]heptane-2-carboxylic
acid 4,4-dioxide. The chemical structure of tazobactam sodium is:-
Tazobactam
sodium
TAZOCIN EF is
available as a white to off-white sterile, cryodesiccated powder of
piperacillin and tazobactam as the sodium salts packaged in glass vials. The
product contains citric acid and disodium edetate (EDTA).
PHARMACOLOGY
Piperacillin ,a
broad spectrum , semisyntheic 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 triszolylmethy1
penicillanic acid sulfone , is a potent inhibitor of many lactamases, including the plasmid and chromosomally
mediated enzymes that commonly cause resistance to penicillins. The presence of
tazobactam in the TAZOCIN EF formulation enhances and extends the antibiotic
spectrum of piperacilln to include many
lactamase producing bacteria normally resistant to it. Thus , TAZOCIN EF
combines the porperties of a broad-spectrum antibiotic and a lactamase inhibitor.
Microbiology
TAZOCIN EF is
active against most strains of the following
lactamase producing and non lactamase producing microorganisms;
Gram-negative bacteria
Escherichia coli
, Citrobacter app.,Klebsiella app. (including K. pneumonia),Enterobacter
spp.,(including E.cloacae), Proteus vulgaris , Proteus mirabilis, serratia spp.
(including S. marcescens ), pseudomonas aeruginosa and other pseudomonas spp,
Neisseria gonorrhoeae ,Neisseria meningitides , Moraxella catarrhalis ,
acinetobacter spp., haemophilus influenza.
Gram-positive bacteria
Streptococci
(S.pneumoniae , S. pyogenes, S. agalatiae, S.viridans ), Enterococci
(E.faecalis, E.faecium ) , staphylococcus aureus (not methicillin-resistant
S.aureus) , S. epidermidis
(coagulase-negative staphylococci).
Anaerobic bacteria
Bacteroides spp.
Including bacteroides fragilis group, peptostreptococcus spp. Fusobacterim spp.
Eubacterium group, clostridia ., veillonella ssp.
Susceptibility
Local
information of resistance is desirable, particularly when treating severe
infection. This information provides guidance on micro-organisms susceptible to
piperacillin/Tazobactam. The following MIC 90values were reported in 1996 for
clinical isolates collected in 3 Australian states
Table1 MIC 90 for 1,952 clinically significant isolates
|
Organism- (number )
|
|
|
E.coli (528)
|
2.0
|
|
Klebsiella spp. (180)
|
4.0
|
|
Klebsiella spp. (ESBL 44)
|
64.0
|
|
Enterobacter spp. (142)
|
16.0
|
|
Citrobacter/Serratia spp. (84)
|
8.0
|
|
Morganella/Proteus/Providencia spp. (45)
|
2.0
|
|
Proteus mirablis spp. (104)
|
|
|
Pseudomonas aeruginosa (88)
|
32.2
|
|
Acinetobacter calcoaceticus(40)
|
32.2
|
|
Staphyloccus aureus (433)
|
4.0
|
|
Coagulase-negative Staphylococcal (28)
|
16.0
|
The latest NCCL
referneces are
Methods for
Dilution antimicrobial susceptibility tests for bacteria that grow aerobicall;
approved standard-seventh edition, NCCLS document M7-a5,2006. NCCLS, wayne,pa for anaerobes:
Methods for
antimicrobial susceptibility testing of anaerobic bacteria ; approved standard
sixth edition. NCCLS document M11-a,2006 . NCCLS , wayne , pa
Phaemacokinetics
Distribution and plasma levels
Mean plasma
concentrations of piperacillin and TAzobactam at steady state of the
combination appear in tables 2. Peak piperacillin and Tazobactam plasma
concentrations are attained immediately after completion of an intravenous
infusion. When given with Tazobactam, piperacillin p;asma levels are similar to
those attained when equivalent doses of piperacillin are administered alone.
Table 2plama levels in adults after a thirty-minute intravenous infusion
of piperacillin/Tazobactam(steady stete)
PIPERACILLIN PLASMA LEVELS (μg/mL)
|
Peperacillin/Tazobactam
Dose
4g/500mg
|
30*min
298
|
1 hr
141
|
1.5 hr
87
|
2 hr
47
|
3 hr
16
|
4 hr
7
|
TAZOBACTAM PLASMA LEVELS (μg/mL)
|
Peperacillin/Tazobactam
Dose
4g/500mg
|
30*min
33.8
|
1 hr
17.3
|
1.5 hr
11.5
|
2 hr
6.8
|
3 hr
2.8
|
4 hr
1.3
|
*Comletion of 30
minute infusion
In healthy subjects piperacillin/Tazobactam plasma
elimination half lives range from 0.7 to 1.2 hours following single or multiple
doses .these half-lives are unaffected by dose or duration of infusion.
Piperacillin and Tazobactam are 21% and 23% respectively , bound to plasma
proteins the protein binding of either piperacillin or tazobactam is unaffected
by the presence of either compound. Piperacillin and Tazobactam are widely
distributed in tissues and body fluids including intestinal mucosa ,gall
bladder , bladder lung and bile.
Biotransformation
Piperacillin
does not undergo biotransformation in humans. Approximately 20% of a dose of
Tazobactam is metabolized to a single
metabolite that has been found to microbiologically inactive.
Excretion
Piperaciiln and
Tazobactam are eliminated by the kidney via glomerular filtration and tubular
secretion. Pipercillin is excreted rapidly as unchanged drug,with 69% of the
dose appearing in the urine. Piperacillin is also secreted into bile.
Tazobactam and its metabolite are eliminated primarily by renal excretion, with
80%of the dose appearing as unchanged drug and the remainder of the dose
appearing as the metabolite.
Impaired renal function
The half life of
piperacillin and Tazobactam incrases with decresing creatinine clearance. The
increase is two-fold for piperacillin and Tazobactam, respectively,at
creatinine clearance below 20 mL/min compared to patients with normal renal
function. Dosage adjustments are recommended when creatinine clearance is below 40mL/min, see DOSAGE AND ADMINISTRATION.
Piperacillin and
Tazobactam are removed from the body during haemodialysis with 31% and 39%of
the dosage of piperacillin and
Tazobactam,respectively, recovered in the dialysis fluid. Piperacillin and
Tazobactam are removed from the body by peritoneal dialysis with 5%and 12% of
the dose ,respectively , appearing in the dialysate. For dosage recommendations
in patients undergoing haemodilalysis,see DOSEGE AND ADMINISTEATION.
Impaired liver function
Piperacillin
half-life and AUC were increased by 25% and 40% respectively and tazobactum
half-life and AUC by 18% and 23% respectively in patients with hepatic impairment.
However, dosage adjustment in patients with hepatic impairment are not
necessary.
Children
The
pharmacokinetics of piperacillin and Tazobictam have been examined in 24
paediatric patients aged 2 months to 12 years receiving 100 mg/kg piperacillin/2.5mg/kg
Tazobatam (table 4). The maximum concentration (cmax)forboth piperacillin
and Tazobactam is increased relative to
the maximum adult dose but predicted time above the minimum inhibitory
concentration is slightly decreased. The dosage of 100mg/kg
piperacillin/12.5/kg Tazobactam administered every 8 hours is predicted to
provide conerage 31% to 61% of the time for the range of MIC values of 2 g/mL commonly found in intra-abdminal
infections in children.
Table 3 piperacillin and
Tazobactam pharmacokinetics in children (cv%) following single doses
|
Dose
|
Patient age
|
Cmax
(mg/L)
|
AUC
(mg.h/L)
|
CL
(mL/min/kg)
|
Vss
(L/kg)
|
T1/2
(h)
|
|
Piperacillin
100mg/kg
|
2-5 mo
6-23 mo
2-5 y
6-12 y
|
382(15)
344(15)
408(80)
394(24)
|
539(29)
373(27)
331(21)
404(17)
|
3.3(24)
4.8(29)
5.2(19)
4.2(21)
|
0.28(32)
0.25(27)
0.23(36)
0.24(42)
|
1.3(16)
1.0(24)
0.9(26)
0.8(27)
|
|
Tazobactam
12.5mg/kg
|
2-5 mo
6-23 mo
2-5 y
6-12 y
|
43(49)
35(22)
45(42)
45(25)
|
63(32)
42(23)
37(24)
57(27)
|
3.6(28)
5.2(24)
5.8(19)
3.9(36)
|
0.32(31)
0.33(29)
0.27(33)
0.28(36)
|
1.3(15)
1.1(23)
0.9(29)
1.3(57)
|
Clinical Trials
Paediatric
A study was
performed to compare the safety, tolerance, and efficacy of 100 mg/kg
piperacillin/12.5mg/kg Tazobactam with
those of 50mg/kg cefotaxime plus 7.5 mg/kg metronidazole administered
intravenously (iv) every 8hours for the treatment of hospitalized
paediatric patients (aged 2 to 12 of age
) with clinically or bacteriologically diagnosed intra-abdominal infection
(IAI).the cure rates in the efficacy evaluable (EE) population at the follow-up
visit were 90% and 91%for piperacillin/Tazobactam and cefotaxime plus
metronidazole, respectively. The result of the clinicaland microbiological
analyses in 521 patients showed that pipercillin/TAzobactam (TAZOCIN EF)
administered intravenously was at least as effective as cefotaxime plus
metronidazole in the treatment of children aged 2 to 12 years with severe IAIs.
INDICATIONS
TAZOCIN EF is
indicated for the treatment of the following systemic and /or local bacterial
infections in which susceptible organisms have been detected or are suspected:
1.
lower respiratory tract infection
2.
Urinary tract infections (complicated and
uncomplicated)
3.
Intra-abdominal infection
4.
Skin and skin structure infection
5.
Bacterial septicemia
6.
Gynaecological infection
7.
Bacterial infection in neutropenic patient. Full
therapeutic doses of TAZOCIN EF plus an aminoglycoside should be used.
8.
bone and joint infection
9.
polymicrobio infection: TAZOCIN EF is indicated for
polymicrobio infections including those where aerobic and anaerobic organism
are suspected (intra-abdominal, skin and skin structure , upper and lower
respiratory tract,gynaecological).
While TAZOCIN EF is indicated only for the conditions listed above ,infection
caused by piperacillin susceptible organisms are also amenable to TAZOCIN EF
treatment due to its piperacilllin content. Therefore, the treatment of mixed
infection caused by piperacillin susceptible organisms and lactamase producing organisms susceptible
to TAZOCIN EF should not require the addition of another antibiotic.
Appropriate culture and susceptibility tests should be performed before
treatment in order to identify organisms causing infection and to determine
their susceptibilities to TAZOCIN EF. Because of its broad-spectrum of activity
against Gram-positive and Gram-nagative aerobic
and anaerobic organisms as listed above, TAZOCIN EF is particulary useful
in the treatment of mixed infections and presumptive therapy prior to the availability of the result of sensitivity
tests.
Therapy with TAZOCIN EF may, howevr, be initiated before result of such
tests 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 TAZOCIN EF may be initiated before susceptibility test results are
available.
TAZOCIN EF acts synergistically with
aminoglycosides against certain strains of Pseudomonas aeruginosa.
Combined therapy has been successful, especially in patients with impaired host
defences. Both drugs should be used in full therapeutic doses. As soon as
results of culture and susceptibility tests become available, antimicrobial
therapy should be adjusted.
Children under the age of 12 years
In hospitalised children aged 2 to 12
years, TAZOCIN EF is indicated for the treatment of serious
intra-abdominal infections. It has
not been evaluated in this indication for paediatric patients
below the age of 2 years.
CONTRAINDICATIONS
The use of TAZOCIN EF is
contraindicated in patients with a history of allergic reactions to any
of the penicillins and/or
cephalosporins or - lactamase inhibitors.
PRECAUTIONS
Serious and occasionally fatal
hypersensitivity (anaphylactic/anaphylactoid [including shock]) reactions have
been reported in patients on penicillin/cephalosporin therapy. Although
anaphylaxis is more frequent following parenteral therapy, it has occurred in
patients on oral penicillins/cephalosporins. These reactions are more likely to
occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to
multiple allergens. There have been reports of individuals with a history of penicillin/cephalosporin
hypersensitivity who have experienced
severe reactions when treated with either a penicillin or cephalosporin. Past
history of a severe allergic reaction to penicillin/cephalosporin is a
contraindication to the use of TAZOCIN EF. Before initiating therapy with any penicillin/cephalosporin,
careful inquiry should be
made concerning previous hypersensitivity reactions to penicillins,
cephalosporins or other allergens. If an allergic reaction occurs, TAZOCIN EF
should be discontinued and the appropriate therapy instituted. Serious anaphylactoid
reactions require immediate emergency treatment with adrenaline. Oxygen,
intravenous steroids and airway management, including
intubation, should also be
administered as indicated.
TAZOCIN EF may cause severe cutaneous
adverse reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with
eosinophilia and systemic symptoms, and acute generalised exanthematous pustulosis. If patients develop a
skin rash they should be monitored
closely and TAZOCIN EF discontinued if lesions progress.
Antibiotic-associated
pseudomembranous colitis has been reported with many antibiotics including
piperacillin. A toxin produced by Clostridium difficile appears to be
the primary cause. The severity of the colitis may range from mild to life
threatening. It is important to consider this diagnosis in patients who develop diarrhoea or colitis
in association with antibiotic use (this may occur up to several weeks after cessation of antibiotic
therapy). Mild cases usually respond to drug discontinuation alone. However, in
moderate to severe cases appropriate therapy with a suitable oral antibacterial
agent effective against C. difficile should be considered. Fluids,
electrolytes and protein replacement should be provided when indicated. Drugs
that delay peristalsis eg: opiates and diphenoxylate with atropine (Lomotil)
may prolong and/or worsen the condition and should not be used.
Leucopenia and neutropenia may occur,
especially during prolonged therapy. Therefore, periodic
assessment of 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.
As with other antibiotic
preparations, use of this drug may result in overgrowth of non-susceptible organisms, including fungi. Patients should be carefully
monitored during therapy. If superinfection
occurs, appropriate measures should be taken.
Use
with caution in the following circumstances
Bleeding manifestations have occurred
in some patients receiving piperacillin. These reactions
have sometimes been associated with
abnormalities of coagulation tests such as clotting time,
platelet aggregation and prothrombin
time and are more likely to occur in patients with renal
failure. If bleeding manifestations
occur, the antibiotic should be discontinued and appropriate
therapy instituted.
The possibility of the emergence of
resistant organisms that might cause superinfections should be
kept in mind, particularly during prolonged treatment. If
this occurs, appropriate measures should
be taken.
As with other penicillins, patients
may experience neuromuscular excitability or convulsions if
higher than recommended doses are
given intravenously.
Repeated use of lignocaine as diluent
should be avoided in patients with severe liver disease or
decreased hepatic blood flow due to
the possibility of lignocaine toxicity (resulting from
decreased metabolism and
accumulation).
Combined administration of lactamase inhibitors
and lactam antibiotics may be
associated
with a slightly increased risk of
hepatic adverse reactions. The incidence of increased liver
enzymes in patients treated with
TAZOCIN EF was slightly higher than has been reported
previously with the use of
piperacillin alone. The potential for increased hepatic adverse reactions
should be borne in mind when using
TAZOCIN EF.
Check the following
before use
Periodical assessment of organ system
functions including renal, hepatic and haematopoietic
during prolonged therapy (>21
days) is advisable.
For patients with renal impairment
and/or hepatic insufficiency, measurement of serum levels of
piperacillin will provide guidance for
adjusting dosage.
The theoretical sodium content of
each vial of TAZOCIN EF
|
2.25 g vial:
|
128mg
|
Sodium(5.58mmol)
|
|
4.5 g vial:
|
256 mg
|
Sodium(11.6 mmol)
|
which may increase a patient’s overall sodium intake.
Periodical electrolyte determinations
should be made in patients with low potassium reserves and
the possibility of hypokalaemia should
be kept in mind with patients who have potentially low
potassium reserves and who are
receiving cytotoxic therapy or diuretics.
Because of its poor penetration into
the CSF, piperacillin is not advised in the treatment of
meningitis and brain abscess.
Antimicrobials used in high doses for
short periods to treat gonorrhoea may mask or delay
symptoms of incubating syphilis. Therefore, prior to
treatment, patients with gonorrhoea should
also be evaluated for syphilis. Specimens for darkfield
examination should be obtained from
patients with any suspected primary lesion and
serological tests should be made for a minimum of
months.
Use
in pregnancy
Pregnancy Category B1.
Adequate human studies on the use of TAZOCIN EF during
pregnancy are not available. Limited
studies with piperacillin alone in rats and mice
revealed no teratogenic effects or harm to the
foetus. Studies with tazobactam (doses up to 3000 mg/kg
IV) or tazobactam and piperacillin
(doses
up to 750 mg/kg and 3000 mg/kg IV) in mice showed no evidence of teratogenicity
or
harm to the foetus. Studies in rats at these dose levels
showed no evidence of teratogenicity
though maternal toxicity, in the form of decreased
weight gain, was noted at the dose levels
tested. Piperacillin has been found to cross the
placenta in rats. Pregnant women should be
treated only if the expected benefit outweighs the
possible risks to the pregnant woman and
foetus.
Use in lactation
Adequate clinical studies on the use of TAZOCIN EF
during pregnancy are not available.
Piperacillin is excreted in low concentrations in milk.
In animal studies, both piperacillin and
tazobactam were excreted in the milk of lactating rats.
Women who are breast-feeding should be
treated only if the expected benefit outweighs the
possible risks to the woman and child.
Use in children
Safety and efficacy of the use of TAZOCIN EF in children
under the age of 2 years has not yet
been established.
Carcinogenicity, mutagenicity and impairment of fertility
Long term carcinogenicity studies of TAZOCIN EF in
animals have not been performed.
Mutagenicity studies with piperacillin and tazobactam
showed no evidence of genotoxicity in
assays for chromosomal and DNA damage. One assay for
gene mutations (Mouse lymphoma
assay) was weakly positive at tazobactam and
piperacillin concentrations ≥g/ml and
2500g/ml respectively. Piperacillin and
tazobactam did not affect the fertility of male or female rats.
Interactions with other drugs
Concurrent administration of probenecid and TAZOCIN EF
produced a longer half-life and lower
renal clearance for both piperacillin and tazobactam.
However, peak plasma concentrations of
neither drug are affected. No kinetic interaction is
found between TAZOCIN EF and
vancomycin.
Concurrent administration of piperacillin and tobramycin
in patients with severe renal dysfunction
(ie chronic haemodialysis patients) has been reported to
reduce the elimination half life and
significantly increase the total body clearance of
tobramycin.
The alteration of tobramycin pharmacokinetics in
patients with mild to moderate renal dysfunction
who are taking piperacillin concomitantly is unknown.
However, reports suggest that the
aminoglycoside inactivation in patients concomitantly
taking an aminoglycoside with a broad
spectrum beta-lactam penicillin is only clinically
significant in patients with severe renal
dysfunction.
The inactivation of aminoglycosides in the presence of
penicillin class drugs has been recognised.
It has been postulated that penicillin-aminoglycoside
complexes form; these complexes are
microbiologically inactive and of unknown toxicity.
Piperacillin when used concomitantly with vecuronium has
been implicated in the prolongation of
the neuromuscular blockade of vecuronium. TAZOCIN EF
(piperacillin/tazobactam) could
produce the same phenomenon if given along with
vecuronium. Due to their similar mechanism
of action, it is expected that the neuromuscular
blockade produced by any of the non-depolarising
muscle relaxants could be prolonged in the presence of
piperacillin.
Piperacillin may reduce the excretion of methotrexate;
therefore, serum levels of methotrexate
should be monitored in patients to avoid drug toxicity.
If TAZOCIN EF is used concurrently with another
antibiotic, especially an aminoglycoside, the
drugs must not be mixed in intravenous solutions or
administered concurrently due to physical
incompatibility.
During simultaneous administration of high doses of
heparin, oral anticoagulants and other drugs
that may affect the blood coagulation system and/or the
thrombocyte function, the coagulation
parameters should be tested more frequently and
monitored regularly.
Effects on laboratory tests
As with other penicillins, the administration of
piperacillin/tazobactam may result in a false-
positive reaction for glucose in the urine using a
copper-reduction method. It is recommended
that glucose tests based on enzymatic glucose oxidase
reactions be used.
There have been reports of positive test results using
Bio-Rad Laboratories Platelia Aspergillus
EIA test in patients receiving TAZOCIN EF 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 TAZOCIN EF should be
interpreted cautiously and confirmed by
other diagnostic methods.
ADVERSE REACTIONS
TAZOCIN EF is generally well tolerated. The overall
incidence of adverse events was 15.7%
although a cause/effect relationship was not established
in all cases. This incidence was
comparable to that observed with other agents used in
the clinical studies. Treatment had to be
discontinued in only 2.9% of cases due to adverse
reactions.
The most frequently reported adverse clinical reactions
were diarrhoea, rash, erythema, pruritis,
vomiting, allergic reactions, nausea, urticaria,
superinfection, phlebitis, thrombophlebitis,
dyspepsia, and insomnia.
Adverse reactions are listed in the Table in CIOMS
frequency categories:
Very Common: ≥
Common ≥
Uncommon ≥and
<1%
Rare ≥and <0.1%
Very rare: < 0.01%
Not known: frequency could not be accurately estimated from
clinical studies
The following table of suspected undesirable effects is
based on clinical trials and/or spontaneous
postmarketing reporting rates:
Body System Adverse Reaction
Infections and infestations
Common: Candidal superinfection
Blood and lymphatic system disorders
Common: Thrombocytopenia, anaemia , Coombs direct test
positive, activated partial
thromboplastin
time prolonged
Uncommon: Leucopenia, prothrombin time prolonged
Rare: Agranulocytosis, epistaxis
Not known: Pancytopenia
, neutropenia, purpura, bleeding time prolonged, haemolytic
anaemia , eosinophilia , thrombocytosis
Immune system disorders
Not known: Hypersensitivity
, anaphylactic reaction , anaphylactoid reaction ,
anaphylactic shock , anaphylactoid shock
Metabolism and Nutrition Disorders
Common: Blood albumin decreased, blood total protein decreased
Uncommon: Hypokalaemia, blood glucose decreased
Nervous system disorders
Common: Headache, insomnia
Not known: Dizziness
Vascular disorders
Uncommon: Hypotension, phlebitis,
thrombophlebitis, flushing
Gastrointestinal disorders
Very common: Diarrhoea
Common: Abdominal pain , nausea, vomiting,
constipation, dyspepsia
Body System Adverse Reaction
Rare: Pseudomembranous colitis, stomatitis
Not known: Bloody
diarrhoea, dry mouth
Hepatobiliary disorders
Common: Alanine aminotransferase increased, aspartate
aminotransferase increased,
blood alkaline phosphatase increased
Uncommon: Blood bilirubin increased
Not known: Jaundice, gamma-glutamyltransferase increased,
hepatitis
Skin and subcutaneous tissue disorders
Common: Rash,
pruritis
Uncommon: Erythema
multiforme , urticaria, rash maculopapular
Rare: Toxic epidermal necrolysis
Not known: Dermatitis bullous, Stevens-Johnson
Syndrome , hyperhidrosis, eczema,
drug reaction with eosinophilia and systemic symptoms
(DRESS) , acute
generalised exanthematous pustulosis (AGEP)
Musculoskeletal, Connective tissue and bone disorders
Uncommon: Arthralgia,
myalgia
Not known: Muscular weakness, prolonged muscle relaxation
Renal and urinary disorders
Common: Blood creatinine increased, blood
urea increased
Not known: Tubulointerstitial
nephritis , renal failure
General disorders and administration site conditions
Common: Pyrexia, injection site reaction
Uncommon: Chills
Not known: Oedema, fatigue
Psychiatric Disorders
Not known: Hallucinations
Piperacillin therapy has been associated with an
increased incidence of pyrexia and rash in cystic
fibrosis patients.
† Adverse event identified post-marketing.
DOSAGE AND ADMINISTRATION
Dosage
TAZOCIN EF may be given by slow intravenous injection,
by infusion (20-30 minutes).
Adults and children 12 years and older
The usual intravenous dosage for adults and children with
normal renal function is 4 g
piperacillin/0.5 g tazobactam (TAZOCIN EF) given every
eight hours.
The total daily dose depends on the severity and
localisation of the infection and can vary from 2
g piperacillin/0.25 g tazobactam to 4g piperacillin
/0.5g tazobactam (TAZOCIN EF) administered
every six, eight or twelve hours.
Use in neutropenic patients -adults and children over the
age of 12:
In neutropenic patients, the usual intravenous dosage
for adults and children with normal renal
function is 4.5 g TAZOCIN EF given every eight hours as a
30 minute infusion, in conjunction with
an aminoglycoside. The total daily dose depends on the
severity and localisation of the infection and
can
vary from 2.25 g to 4.5 g TAZOCIN EF administered every six or eight hours.
Tazocin EF has been shown to have a synergistic effect
with an aminoglycoside against
Pseudomonas infection. Therefore combination therapy is
recommended for use in neutropenic
patients, in whom infection is attributed predominantly
to Pseudomonas organisms.
Children under the age of 12 years:
Recommended Intravenous Dosage
Hospitalised children with intra-abdominal
infection
For
children aged 2 to 12 years, weighing up to 40 kg, and with normal renal
function, the
recommended dosage is 100 mg piperacillin/12.5 mg
tazobactam per kilogram every 8 hours.
For children aged 2 to 12 years, weighing over 40 kg,
and with normal renal function, follow the
adult dose guidance, ie 4 g piperacillin/0.5 g
tazobactam every 8 hours.
The duration of therapy should be guided by the severity
of the infection and the patient's clinical
adult dose guidance, ie 4 g piperacillin/0.5 g
tazobactam every 8 hours.
The duration of therapy should be guided by the severity
of the infection and the patient's clinical
and bacteriological progress. Therapy is recommended to
be a minimum of 5 days and a
maximum of 14 days, considering that dose administration
should continue at least 48 hours after
the resolution of clinical signs and symptoms.
Renal insufficiency:
In patients with renal insufficiency, the intravenous
dose should be adjusted to the degree of
actual renal function impairment. The suggested daily
doses are as follows:
Intravenous dosage schedule for adults with impaired renal function
|
Creatinine
Clearance (mL/min)
>40
20-40
<20
|
Recommended piperacillin / Tazobactam
Dosage
NO DOSAGE
ADJUSTMENT NECESSARY
12 g/1.5g/day
Divided Dose
4g
piperacillin/0.5g tazobactum q 8 hr
8g /1g/day
Divided Dose
4g
piperacillin/0.5g tazobactum q 12 hr
|
For patients on haemodialysis, the maximum daily dose is
8 g/1 g/day TAZOCIN EF. In addition,
because haemodialysis removes 30%-50% of piperacillin in
4 hours, one additional dose of 2 g
piperacillin/0.25 g tazobactam (TAZOCIN EF) should be
administered following each dialysis
period. For patients with renal failure and hepatic
insufficiency, measurement of serum levels of
TAZOCIN
EF will provide additional guidance for adjusting dosage.
Children aged 2 to 12 years:
The pharmacokinetics of piperacillin/tazobactam have not
been studied in paediatric patients with
renal impairment. Each patient must be monitored closely
for signs of drug toxicity. Drug dose
and interval should be adjusted accordingly.
Duration of therapy:
In acute infections, treatment with TAZOCIN EF should be
for a minimum of five days and
continued for 48 hours beyond resolution of clinical
symptoms or the fever.
Co-administration of piperacillin/tazobactam with aminoglycosides
Due to the in vitro inactivation of the aminoglycoside
by the beta-lactam antibiotics,
piperacillin/tazobactam and the aminoglycoside are
recommended for separat e administrat ion.
Piperacillin/tazobactam and the aminoglycoside should be
reconstituted and diluted separately
when concomitant therapy with aminoglycosides is indicat
ed.
The
following compatibility information doesnot apply to the
piperacillin/tazobactam formulation
not containing EDTA.
In circumstances where co-administrat ion is preferred,
the ref ormulat ed piperacillin/tazobactam
containing
EDTA (TAZOCIN EF) supplied in vialsiscompatiblefor simultaneousco-
administration viaY-site infusion only with the following
aminoglycosidesunder the following
conditions
|
Aminoglycosides
|
Piperacillin/tazobactam
(gram) dose
|
Tazobactum Diluent volume(ml)
|
Aminoglycosides
Concentration
Range(mg/ml)
|
Acceptable
Diluent
|
|
Amikacin
|
2.25,3375,45
|
50,100,150
|
1.75-7.5
|
0.9%
Sodium Choloride of
5%
dextrose
|
|
Gentamicin
|
2.25,3375,45
|
100,150
|
0.7-3.32
|
0.9%
Sodium
Chloride
|
The dose of aminoglycoside should be based on pat ient
weight, status of infection
(serious or life threatening) and renal function (creatinine clearance).
Compatibility of piperacillin/tazobactam with other
aminoglycosides has not been established.
Only the concentration and diluents for amikacin and
gentamicin with the dosages of
piperacillin/tazobactam listed in the above table have
been established as compatible for co-
administration via Y-site infusion. Simultaneous
co-administration via Y-site in any manner other
than listed above may result in inactivation of the
aminoglycoside by piperacillin/tazobactam
Administration
Reconstitution Directions
For intravenous use
Diluents for Reconstitution:Sterile Water for Injections
Sodium
Chloride Injection
Dextrose
5% in Water
When swirled constantly, reconstitution generally occurs
within 5 to 10 minutes. The reconstituted
solution should be withdrawn from the vial by syringe.
When reconstituted as directed, the vial
contents withdrawn by syringe will provide the labelled
amount of TAZOCIN EF. Solutions of
TAZOCIN EF prepared in this manner appear clear to
slightly yellow in colour.
|
Vial Size (piperacillin/tazobactam)
4,50 g (4 g/0.5 g)
|
Minimum volume of
diluent to be added
To vial
20 ML
|
Reconstitute each vial with the volume of diluent shown
in the table below, using one of the above
Diluents.
Administration
Directons
For intravenous use:
The reconstituted solution may be further diluted to the
desired volume (e.g. 50 mL to 150 mL)
with one of the compatible diluents for intravenous use
listed below.
Compatible Intravenous Diluents:
1.0.9% Sodium Chloride for Injection.
2. Sterile Water for Injection.
3.Dextrose 5%.
4.Dextran 6% in Saline.
4.Lactated Ringer’s Solution (Only compatible with
piperacillin/tazobactam EDTA
reformulation and is compatible for co-administration
via a Y-site).
*Maximum recommended volume of Sterile Water for
Injection per dose is 50 mL.
Pharmaceutical Incompatibilities
TAZOCIN EF should not be mixed with other drugs in a
syringe or infusion bottle since
compatibility has not been established. Whenever TAZOCIN
EF is used concurrently with
another antibiotic, the drugs must be administered
separately. The mixing of TAZOCIN EF with
an aminoglycoside can result in substantial inactivation
of the aminoglycoside. However,
amikacin
and gentamicin were determined to be compatible with
TAZOCIN EF in certain diluents at
specific concentrations (see DOSAGE AND ADMINISTRATION:
Co-administration of piperacillin/tazobactam
with Aminoglycosides)
Because of chemical instability, TAZOCIN EF should not be
used with solutions containing only
sodium bicarbonate or having a pH in the basic range.
TAZOCIN
EF should not be added to blood products or albumin hydrolysates.
OVERDOSAGE
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).
No specific antidote is known. In the event of an
emergency, all required intensive medical
measures are indicated as in the case of piperacillin.
In cases of motor excitability or convulsions,
anticonvulsive agents (e.g. diazepam or barbiturates)
may be indicated. In cases of anaphylactic
reactions, the usual counter measures are to be
initiated (adrenaline, antihistamines,
corticosteroids and, if required, oxygen and airway
management).
Excessive serum concentrations of either piperacillin or
tazobactam may be reduced by
Haemodialysis.
PRESENTATION
2.25g vial containing piperacillin sodium 2.085 g
equivalent to 2 g piperacillin and tazobactam
sodium
0.2683 g equivalent to 250 mg tazobactam..
5
g vial containing piperacillin sodium 4.170 g equivalent to 4 g piperacillin and
tazobactam
sodium
0.5366 g equivalent to 500 mg tazobactam.
STORAGE AND STABILITY
Lyophilized
Vials containing sterite TAZOCIN EF lyophilized power
may be stored below
30 for to 2year.
Solution:
Diluted solution should be used immediately.
DATE OF PREPARATION
13 Oct 2015
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