Tazokab

Tazokab

piperacillin + tazobactam

Manufacturer:

Fresenius Kabi

Distributor:

Fresenius Kabi
Full Prescribing Info
Contents
Piperacillin sodium, tazobactam sodium.
Description
Each vial contains 2 g of piperacillin (as sodium salt) and 250 mg of tazobactam (as sodium salt).
One vial of powder for solution for infusion contains 4.9 mmol (112 mg) of sodium.
Each vial contains 4 g of piperacillin (as sodium salt) and 500 mg of tazobactam (as sodium salt).
One vial of powder for solution for infusion contains 9.7 mmol (224 mg) of sodium.
Action
Pharmacotherapeutic group: Antibacterials for systemic use, Combinations of penicillins incl. beta-lactamase inhibitors. ATC code: J01C R05.
Pharmacology: Pharmacodynamics: Mechanism of action: Piperacillin, a broad-spectrum, semisynthetic penicillin exerts bactericidal activity by inhibition of both septum and cell-wall synthesis.
Tazobactam, a beta-lactam structurally related to penicillins, is an inhibitor of many beta-lactamases, which commonly cause resistance to penicillins and cephalosporins but it does not inhibit AmpC enzymes or metallo beta-lactamases. Tazobactam extends the antibiotic spectrum of piperacillin to include many beta-lactamase-producing bacteria that have acquired resistance to piperacillin alone.
Pharmacokinetic/Pharmacodynamic relationship: The time above the minimum inhibitory concentration (T>MIC) is considered to be the major pharmacodynamic determinant of efficacy for piperacillin.
Mechanism of resistance: The two main mechanisms of resistance to piperacillin/tazobactam are: Inactivation of the piperacillin component by those beta-lactamases that are not inhibited by tazobactam: beta-lactamases in the Molecular class B, C and D. In addition, tazobactam does not provide protection against extended-spectrum beta-lactamases (ESBLs) in the Molecular class A and D enzyme groups.
Alteration of penicillin-binding proteins (PBPs), which results in the reduction of the affinity of piperacillin for the molecular target in bacteria.
Additionally, alterations in bacterial membrane permeability, as well as expression of multi-drug efflux pumps, may cause or contribute to bacterial resistance to piperacillin/tazobactam, especially in Gram-negative bacteria.
Breakpoints: See Table 1.

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The susceptibility of streptococci is inferred from the penicillin susceptibility.
The susceptibility of staphylococci is inferred from the oxacillin susceptibility.
Susceptibility: The prevalence of acquired resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. (See Table 2.)

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Pharmacokinetics: Absorption: The peak piperacillin and tazobactam concentrations after 4 g/0.5 g administered over 30 minutes by intravenous infusion are 298 μg/ml and 34 μg/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 tissues 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.
Biotransformation: Piperacillin is metabolized to a minor microbiologically active desethyl metabolite. Tazobactam is metabolized to a single metabolite that has been found to be microbiologically inactive.
Elimination: Piperacillin and tazobactam are eliminated via the kidney by 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.
Toxicology: Preclinical safety data: Non-clinical 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 and general reproduction study in rats using intraperitoneal administration of tazobactam or the combination piperacillin/tazobactam reported a decrease in litter size and an increase in fetuses with ossification delays and variations of ribs, concurrent with maternal toxicity. Fertility of the F1 generation and embryonic development of F2 generation were not impaired. Teratogenicity studies using intravenous administration of tazobactam or the combination piperacillin/tazobactam in mice and rats resulted in slight reductions in rat fetal weights at maternally toxic doses but did not show teratogenic effects.
Peri/postnatal development was impaired (reduced pup weights, increase in stillbirths, increase in pup mortality) concurrent with maternal toxicity after intraperitoneal administration of tazobactam or the combination piperacillin/tazobactam in the rat.
Indications/Uses
Piperacillin/tazobactam is indicated for the treatment of the following infections in adults and children over 2 years of age.
Adults and adolescent: 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 bactaeremia that occurs in associated with, or is suspected to be associated with, any of the infections listed previously. Piperacillin/tazobactam may be used in the management of neutropenic children 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.
Dosage/Direction for Use
The dose and frequency of Piperacillin/Tazobactam depends on the severity and localization 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 summarizes the treatment frequency and the recommended dose for adult and adolescent patients by indication or condition: See Table 3.

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Patients with 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): See Table 4.

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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.
Patients with hepatic impairment: No dose adjustment is necessary.
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 summarizes the treatment frequency and the dose per body weight for paediatric patients 2-12 years of age by indication or condition: See Table 5.

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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): See Table 6.

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For children on haemodialysis, one additional dose of 40 mg piperacillin/5 mg tazobactam/kg should be administered following each dialysis period.
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.
Reconstitution: Reconstitute each vial with the volume of solvent shown in the following table, using one of the compatible solvents for reconstitution. Shake until dissolved. When shaken constantly, reconstitution generally occurs within 5 to 10 minutes.
2 g/250 mg: See Table 7.

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4 g/500 mg: See Table 8.

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Method of administration: Piperacillin/Tazobactam 2 g/0.25 g or 4 g/0/5 gis administered by intravenous infusion (over 30 minutes).
Overdosage
Symptoms: There have been post-marketing reports of overdose with piperacillin/tazobactam. The majority of those events experience, including nausea, vomiting, and diarrhea, have also been reported with usual recommended dose. Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particular in the presence of renal failure).
Treatment: 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. Excessive serum concentrations of either piperacillin or tazobactam may be reduced by hemodialysis.
Contraindications
Hypersensitivity to the active substances, any other penicillin-antibacterial agent or to any of the excipients.
History of acute severe allergic reaction to any other beta-lactam active substances (e.g. cephalosporin, monobactam, or carbapenem).
Special Precautions
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 prevalence of resistance to the other suitable antibacterial agents.
Before initiating therapy with piperacillin/tazobactam, careful inquiry should be made concerning previous hypersensitivity reactions to penicillin's, 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 penicillin's, 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.
Piperacillin/Tazobactam may cause severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis (See Adverse Reactions). If patients develop a skin rash they should be monitored closely and Piperacillin/Tazobactam discontinued if lesions progress.
Antibiotic-induced pseudo-membranous colitis may be manifested by severe, persistent diarrhea 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 appropriated 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 convulsion may occur when high-dosed are administered, especially in patients with impaired renal function.
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.
Renal Impairment: Due to its potential nephrotoxicity piperacillin/tazobactam should be used with care in patients with renal impairment or in hemodialysis patients. Intravenous dosages and administration intervals should be adjusted to the degree of renal function impairment. In a secondary analysis using data from a large multicenter, randomized-controlled trial when glomerular filtration rate (GFR) was examined after administration of frequently used antibiotics in critically ill patients, the use of piperacillin/tazobactam was associated with a lower rate of reversible GFR improvement compared with the other antibiotics. This secondary analysis concluded that piperacillin/tazobactam was a cause of delayed renal recovery in these patients.
Effects on Ability to Drive and Use Machines: No studies on the effect on the ability to drive and use machines have been performed.
2 g/250 mg: Each vial of Piperacillin/Tazobactam 2 g/0.25 g contains 4.9 mmol (112 mg) of sodium and Piperacillin/Tazobactam 4 g/0.5 g contains 9.7 mmol (224 mg) of sodium). This should be taken into consideration for patients who are on a controlled sodium diet.
4 g/500 mg: Each vial of Piperacillin/Tazobactam 4 g/0.5 g contains 9.7 mmol (224 mg) of sodium. This should be taken into consideration for patients who are on a controlled sodium diet.
Use In Pregnancy & Lactation
Pregnancy: There are no or a limited amount of data from the use of Piperacillin/Tazobactam in pregnant women. Studies in animals have shown developmental toxicity, but no evidence of teratogenicity, at doses that are a maternally toxic. 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 risk 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 breast-feeding should be treated only if the expected benefit outweighs the possible risks to the woman and child.
Fertility: A fertility study in rats showed no effect on fertility and mating after intraperitoneal administration of tazobactam or the combination piperacillin/tazobactam.
Adverse Reactions
The most commonly reported adverse reaction is diarrhoea (occurring in 1 patient out of 10).
Among the most serious adverse reactions pseudo-membranous colitis and toxic epidermal necrolysis occur in 1 to 10 patients in 10,000. The frequencies for pancytopenia, anaphylactic shock and Stevens-Johnson syndrome cannot be estimated from the currently available data.
In the following table, adverse reactions are listed by system organ class and MedDRA-preferred term. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. (See Table 9.)

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Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.
Drug Interactions
Non-depolarizing muscle relaxants: Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockage of vecuronium. Due to their similar mechanisms 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.
Oral anticoagulants: During simultaneous administration of heparin, oral anticoagulants and other substances that may affect the blood coagulation system including thrombocyte function, appropriate coagulation tests should be performed more frequently and monitored regularly.
Methotrexate: Piperacillin may reduce the excretion of methotrexate; therefore, serum levels of methotrexate should be monitored in patients to avoid substance toxicity.
Probenecid: As with other penicillins, concurrent administration of probenecid and piperacillin/tazobactam produces a longer half-life and lower renal clearance for both piperacillin and tazobactam; however, peak plasma concentrations of either substances are unaffected.
Aminoglycosides: Piperacillin, either alone or with tazobactam, did not significantly alter the pharmacokinetics of tobramycin in subjects with normal renal function and with mild or moderate renal impairment. The pharmacokinetics of piperacillin, tazobactam, and the M1 metabolite were also not significantly altered by tobramycin administration. The inactivation of tobramycin and gentamicin by piperacillin has been demonstrated in patients with severe renal impairment.
Vancomycin: No pharmacokinetic interactions have been noted between piperacillin/tazobactam and vancomycin. However, a limited number of retrospective studies have detected an increased incidence of acute kidney injury in patients concomitantly administered piperacillin/tazobactam and vancomycin as compared to vancomycin alone.
Effects on laboratory tests: Non-enzymatic methods of measuring urinary glucose may lead to false-positive results, as with other penicillins. Therefore, enzymatic urinary glucose measurement is required under Piperacillin/Tazobactam therapy.
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.
Bio-Rad Laboratories Platelia-Aspergillus EIA tests may lead to false-positive results for patients receiving Piperacillin/Tazobactam. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported.
Positive test results for the assays listed previously in patients receiving Piperacillin/Tazobactam should be confirmed by other diagnostic methods.
Caution For Usage
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. Piperacillin/tazobactam should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established. Piperacillin/Tazobactam (Tazokab) should be administered through an infusion set separately from any other drugs unless compatibility is proven. Piperacillin/tazobactam should be administered through an infusion set separately from any other drugs unless compatibility is proven. Piperacillin/tazobactam should not be added in solutions that contain sodium bicarbonate, lactated Ringer's (Hartmann's), blood products or albumin hydrolysates.
Instructions and Special Precautions for Handling and 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.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
For single use only. Discard any unused solution.
Storage
Store at temperatures not exceeding 30°C. Keep the vials in the outer carton.
For storage conditions after reconstitution/dilution of the medicinal product, see Cautions for Usage.
Shelf life: Sterile powder for injection packed for sale: 3 years.
Reconstituted/diluted Piperacillin/Tazobactam (Tazokab): Chemical and physical in use stability has been demonstrated for 24 hours at 2-8°C.
From the microbiological point of view, 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 to 8°C, unless reconstitution/dilution has be taken place in controlled and validation conditions.
Unused solution should be discarded.
MIMS Class
ATC Classification
J01CR05 - piperacillin and beta-lactamase inhibitor ; Belongs to the class of penicillin combinations, including beta-lactamase inhibitors. Used in the systemic treatment of infections.
Presentation/Packing
Powd for soln for IV infusion (vial) 2 g/250 mg (white to off-white) x 50 mL x 10's. 4 g/500 mg x 50 mL x 10's.
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