Tazolitt

A white to off white crystalline powder filled in 30 mL USP Type III flint vial with flip off seal.
Each vial contains: Piperacillin Sodium USP equivalent to Piperacillin 4 g, Tazobactam Sodium equivalent to Tazobactam 500 mg.

Pharmacotherapeutic group: Antibacterials for systemic use, Combinations of penicillins, including beta-lactamase inhibitors.
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.
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.
Pharmacokinetics: Absorption: The peak piperacillin and tazobactam concentrations after 4 g/500 mg 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 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 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 clearance of tazobactam.

For documented multidrug resistant Gram-negative infections due to organisms proven or suspected to be susceptible to piperacillin + tazobactam except CNS infections; polymicrobial infections (e.g., mixed aerobic and anaerobic infections) in which other agents have insufficient activity or are contraindicated due to toxic potential.

For serious complicated infections: adults may be given 200 to 300 mg/kg daily in divided doses intravenously: the usual dose is 3 to 4 g every 4 to 6 hours.
For mild or uncomplicated infections: 100 to 125 mg/kg daily may be given to adults; usual doses are 2 g every 6 to 8 hours, or 4 g every 12 hours, intravenously, or 2 g every 8 or 12 hour intramuscularly.
Uncomplicated gonorrhoea: single intramuscular dose of 2 g.
For prophylaxis infection during surgery: 2 g just before the procedure.
Or as prescribed by the physician.
Piperacillin/Tazobactam should be administered by intravenous infusion over 30 minutes.
Adult Patients: The usual total dose of piperacillin/tazobactam for adults is 3.375 g every six hours totaling 13.5 g (12.0 g piperacillin/1.5 g tazobactam). The usual duration of piperacillin/tazobactam treatment is from 7 to 10 days. Piperacillin/Tazobactam should be administered by intravenous infusion over 30 minutes.
Nosocomial Pneumonia: Initial presumptive treatment of patients with nosocomial pneumonia should start with piperacillin/tazobactam at a dosage of 4.5 g every six hours plus an aminoglycoside, totaling 18.0 g (16.0 g piperacillin/2.0 g tazobactam). The recommended duration of piperacillin/tazobactam treatment for nosocomial pneumonia is 7 to 14 days. Treatment with the aminoglycoside should be continued in patients from whom P. aeruginosa is isolated.
Renal Impairment: In patients with renal impairment (creatinine clearance ≤40 mL/min) and dialysis patients (hemodialysis and CAPD), the intravenous dose of piperacillin/tazobactam should be reduced to the degree of actual renal function impairment. The recommended daily of doses of piperacillin/tazobactam for patients with renal impairment are as follows: (see Table 1).

Click on icon to see table/diagram/image

For patients on hemodialysis, 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 (0.67 g piperacillin/0.08 g tazobactam) should be administered following each dialysis period on hemodialysis days. No additional dosage of piperacillin/tazobactam is necessary for CAPD patients.
Pediatric Patients: For children with appendicitis and/or peritonitis 9 months of age or older, weight up to 40 kg, and normal renal function, the recommended piperacillin/tazobactam dosage is 100 mg piperacillin/12.5 mg tazobactam per kilogram of body weight, every 8 hours.
For pediatric patients between 2 months and 9 months of age, the recommended piperacillin/tazobactam dosage based on pharmacokinetic modeling, is 80 mg piperacillin/10 mg tazobactam per kilogram of body weight, every 8 hours. Pediatric patients weighing over 40 kg with normal renal function.
It has not been determined how to adjust piperacillin/tazobactam dosage in pediatric patients with renal impairment.
Direction for Reconstitution: 4 g/500 mg should be reconstituted with 20 mL. Swirl until dissolved.
It should be used immediately after reconstitution. Discard any unused portion after 24 hours if stored at room temperature (20°C to 25°C) or after 48 hours if stored at refrigerated temperature (2°C to 8°C). Compatible Reconstitution Diluents: Sterile Water for Injection.

There have been post-marketing reports of overdose with piperacillin/tazobactam. The majority of those events experienced, including nausea, vomiting, and diarrhea, 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 should be supportive and symptomatic according the patient's clinical presentation.
Excessive serum concentrations of either piperacillin or tazobactam may be reduced by hemodialysis. Following a single 3.375 g dose of piperacillin/tazobactam, the percentage of the piperacillin and tazobactam dose removed by hemodialysis was approximately 31% and 39%, respectively.

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

Hypersensitivity Adverse Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid) reactions (including shock) have been reported in patients receiving therapy with piperacillin/tazobactam. These reactions are more likely to occur in individuals with a history of penicillin, cephalosporin, or carbapenem hypersensitivity or a history of sensitivity to multiple allergens. Before initiating therapy with piperacillin/tazobactam, careful inquiry should be made concerning previous hypersensitivity reactions. If an allergic reaction occurs, piperacillin/tazobactam should be discontinued and appropriate therapy instituted.
Severe Cutaneous Adverse Reactions: Piperacillin/Tazobactam may cause severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilic and systemic symptoms, and acute generalized exanthematous pustulosis. If patients develop a skin rash they should monitored closely and piperacillin/tazobactam discontinued if lesions progress.
Hematologic Adverse reactions: Bleeding manifestations have occurred in some patients receiving β-lactam drugs, including 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, piperacillin/tazobactam should be discontinued and appropriate therapy instituted.
The leukopenia/neutropenia associated with piperacillin/tazobactam administration appears to be reversible and most frequently associated with prolonged administration.
Periodic assessment of hematopoietic function should be performed, especially with prolonged therapy, ie, ≥21 days.
Central Nervous System Adverse Reactions: As with other penicillins, patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure).
Nephrotoxicity in Critically Ill Patients: The use of piperacillin/tazobactam was found to be an independent risk factor for renal failure and was associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs in a randomized, multicenter controlled trial in critically ill patients. Based on this study, alternative treatment drugs in a randomized, multicenter controlled trial in critically ill patients. Based on this study, alternative treatment options should be considered in the critically ill population. If alternative treatment options are inadequate or unavailable, monitor renal function during treatment with piperacillin/tazobactam.
Combined use of piperacillin/tazobactam and vancomycin may be associated with an increased incidence of acute kidney injury.
Electrolyte Effects: Piperacillin/Tazobactam contains a total of 2.84 mEq (65 mg) of Na+ (sodium) per gram of piperacillin in the combination product. This should be considered when treating patients requiring restricted salt intake. Periodic electrolyte determinations should be performed in patients with low potassium reserves, and the possibility of hypokalemia should be kept in mind with patients who have potentially low potassium reserves and who are receiving cytologic therapy or diuretics.
Clostridium difficile-associated Diarrhea: Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including piperacillin/tazobactam, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD.

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 fetus.
Breastfeeding: Piperacillin is excreted in low concentrations in breast milk; tazobactam concentrations in human milk have not been studied. Women who are breastfeeding should be treated only if the expected benefit outweighs the possible risks to the woman and child.
Fertility: A fertility study in rats showed no effect on fertility and mating after intraperitoneal administration of tazobactam or the combination Piperacillin/Tazobactam.

(See Table 2):

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Nosocomial Pneumonia Trials: (See Table 3):

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For adverse drug reactions that appeared in both studies the higher frequency is presented.
Other trials: Nephrotoxicity: In a randomized, multicenter controlled trial in 1200 adult critically ill patients, piperacillin/tazobactam was found to be a risk factor for renal failure (odds ratio 1.7, 95% Ci 1.18 to 2.43), and associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs.
Pediatrics: Studies of piperacillin/tazobactam in pediatric patients suggest a similar safety profile to that seen adults. In a prospective, randomized, comparative, open-label clinical trial of pediatric patients with severe intra-abdominal infections (including appendicitis and/or peritonitis), 273 patients were treated with piperacillin/tazobactam (112.5 mg/kg every 8 hours) and 269 patients were treated with cefotaxime (50 mg/kg) plus metronidazole (7.5 mg/kg) every 8 hours. In this trial, treatment-emergent adverse events were reported by 146 patients, 73 (26.7%) in the piperacillin/tazobactam group and 73 (27.1%) in the cefotaxime/metronidazole group. Six patients (2.2%) in the piperacillin/tazobactam group and 5 patients (1.9%) in the cefotaxime/metronidazole group discontinued due to an adverse event.
Adverse Laboratory Events: On the trials reported, including that of nosocomial lower respiratory tract infections in which a higher dose of piperacillin/tazobactam was used in combination with an aminoglycoside, changes in laboratory parameters include: Hematologic: Decrease in hemoglobin and hematocrit, thrombocytopenia, increases in platelet count, eosinophilia, leukopenia, neutropenia. These patients were withdrawn from therapy; some had accompanying systemic symptoms (e.g., fever, rigors, chills).
Coagulation: Positive direct Coombs' test, prolonged partial thromboplastin time.
Hepatic: Transient elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubin.
Renal: Increases in serum creatinine, blood urea nitrogen.
Additional laboratory events include abnormalities in electrolytes (i.e., increases and decreases in sodium, potassium, and calcium), hyperglycemia, decreases in total protein or albumin, blood glucose decreased, gamma-glutamyl transferase increased, hypokalemia, and bleeding time prolonged.

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.
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.
Oral anticoagulants: During simultaneous administration of heparin, oral anticoagulants and other drugs 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.
For information related to the administration of Piperacillin/Tazobactam with aminoglycosides.
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.

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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