PTZ 2.25/PTZ 4.5

Piperacillin Tazobactam (2 g/250 mg) (4 g/500 mg) Powder for Injection is a white or almost white crystalline powder.
PTZ 2.25: Each vial contains: Piperacillin (as sodium) 2 g, Tazobactam (as sodium) 250 mg.
PTZ 4.5: Each vial contains: Piperacillin (as sodium) 4 g, Tazobactam (as sodium) 500 mg.

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.
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 piperacillin or tazobactam is unaffected by the presence of the other compound. Protein binding of the tazobactam metabolite is negligible.
Piperacillin/Tazobactam is widely distributed in tissue and body fluids including intestinal mucosa, gallbladder, lung, bile and bone. Mean tissue concentrations are generally 50 to 100% of those in plasma.
Distribution into cerebrospinal fluid is low in subjects with non-inflamed meninges, as with other penicillins.
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 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 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.

Used for the treatment of the following infections in adults and children over 2 years of age: Adults and Adolescents: Severe pneumonia including hospital-acquired and ventilator-associated pneumonia.
Complicated urinary tract infections (including pyelonephritis).
Complicated intra-abdominal infections.
Complicated skin and soft tissue infections (including diabetic foot infections).
Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed previously. Piperacillin/Tazobactam may be used in the management of neutropenic patients with fever suspected to be due to a bacterial infection.
Children 2 to 12 years of age: Complicated intra-abdominal infections.
Piperacillin/Tazobactam may be used in the management of neutropenic children with fever suspected to be due to a bacterial infection.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Posology: The dose and frequency of Piperacillin/Tazobactam depends on the severity and localisation of the infection and expected pathogens.
Adult and adolescent patients: Infections: The usual dose is 4 g piperacillin/0.5 g tazobactam given every 8 hours.
For nosocomial pneumonia and bacterial infections in neutropenic patients, the recommended dose is 4 g piperacillin/0.5 g tazobactam administered every 6 hours. This regimen may also be applicable to treat patients with other indicated infections when particularly severe.
The following table summarises the treatment frequency and the recommended dose for adult and adolescent patients by indication or condition: 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 1.

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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.
Hepatic impairment: See Table 2.

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No dose adjustment is necessary.
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: See Table 3.

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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 4.

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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.
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.

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 dose. Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly 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 haemodialysis.

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

The selection of Piperacillin/Tazobactam to treat an individual patient should take into account the appropriateness of using a broad-spectrum semi-synthetic penicillin based on factors such as the severity of the infection and the prevalence of resistance to other suitable antibacterial agents.
Before initiating therapy with Piperacillin/Tazobactam, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, other beta-lactam agents (e.g. cephalosporin, monobactam or carbapenem) and other allergens. Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid [including shock]) reactions have been reported in patients receiving therapy with penicillins, including Piperacillin/Tazobactam. These reactions are more likely to occur in persons with a history of sensitivity to multiple allergens. Serious hypersensitivity reactions require the discontinuation of the antibiotic, and may require administration of epinephrine and other emergency measures.
Piperacillin/Tazobactam may cause severe cutaneous adverse reaction such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in patients receiving Piperacillin/Tazobactam. 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 may be life-threatening. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment. In these cases Piperacillin/Tazobactam, should be discontinued.
Therapy with Piperacillin/Tazobactam may result in the emergence of resistant organisms, which might cause super-infections.
Bleeding manifestations have occurred in some patients receiving beta-lactam antibiotics. These reactions sometimes have been associated with abnormalities of coagulation tests, such as clotting time, platelet aggregation and prothrombin time, and are more likely to occur in patients with renal failure. If bleeding manifestations occur, the antibiotic should be discontinued and appropriate therapy instituted.
Leukopenia and neutropenia may occur, especially during prolonged therapy. Therefore, periodic assessment of haematopoietic function should be performed.
As with treatment with other penicillins, neurological complications in the form of convulsions (seizures) may occur when high doses 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.

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 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 risks to the pregnant woman and foetus.
Breast-feeding: Piperacillin is excreted in low concentrations in breast 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.

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, undesirable effects are presented in order of decreasing seriousness. (See Table 5.)

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Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.
ADR in identified post marketing: Beta-lactam antibiotics, including piperacillin tazobactam, may lead to manifestation of encephalopathy and convulsions.

Non-depolarising muscle relaxants: Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. Due to their similar mechanisms 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.
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. studies have detected an increased incidence of acute kidney injury in patients concomitantly administered Piperacillin/Tazobactam and vancomycin as compared to vancomycin alone. Some of these studies have reported that the interaction is vancomycin dose dependent.

Direction for Reconstitution: Each vial of Piperacillin/Tazobactam 4 g/0.5 g Powder for Solution for Infusion should be reconstituted with 20 mL of one of the following diluents: Sterile water for injections; 0.9% sodium chloride for injection.
To achieve effective reconstitution, invert and shake the vial thoroughly to detach any powder adhering to the walls prior to addition of the diluent. Add the solvent and shake until complete dissolution is achieved.
The reconstituted solution should be further diluted to at least 50 mL with one of the reconstitution diluents, or with Dextrose 5% in Water.
Each vial of Piperacillin/Tazobactam 2 g/0.25 g Powder for Solution for Infusion should be reconstituted with 10 mL of one of the following diluents: Sterile water for injections; 0.9% sodium chloride for injection.
To achieve effective reconstitution, invert and shake the vial thoroughly to detach any powder adhering to the walls prior to addition of the diluent. Add the solvent and shake until complete dissolution is achieved.
The reconstituted solution should be further diluted to the concentration range of 13.33/1.67 mg/mL to 80/10 mg/mL with following diluents: Sterile Water for Injection; 9 mg/mL (0.9%) Sodium Chloride for Injection; Dextrose 50 mg/mL (5%) in water; Dextrose 5% in 0.9% Sodium chloride solution.
For single use only. Discard any unused solution.
The reconstitution/dilution is to be made under aseptic conditions. The reconstituted solution is to be inspected visually for particulate matter and discoloration prior to administration. The solution should only be used if the solution is clear and free from particles.

Store at temperatures not exceeding 30°C.

Penicillins

J01CR05 - piperacillin and beta-lactamase inhibitor ; Belongs to the class of penicillin combinations, including beta-lactamase inhibitors. Used in the systemic treatment of infections.

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