Pipzo

Pipzo

piperacillin + tazobactam

Manufacturer:

Alkem Lab

Distributor:

Getz Bros
Full Prescribing Info
Contents
Piperacillin sodium, tazobactam sodium.
Description
Each vial contains Piperacillin sodium USP equivalent to piperacillin 4 g and Tazobactam sodium equivalent to tazobactam 500 mg.
Action
Pharmacology: Pharmacodynamics: Pharmacological effect/mode of action: Piperacillin sodium exerts bactericidal activity by inhibiting septum formation and cell wall synthesis of susceptible bacteria. In vitro, piperacillin is active against a variety of gram-positive and gram-negative aerobic and anaerobic bacteria. Tazobactam sodium has little clinically relevant in vitro activity against bacteria due to its reduced affinity to penicillin-binding proteins. It is, however, a ß-lactamase inhibitor of the Richmond-Sykes class III (Bush class 2b & 2b') penicillinases and cephalosporinases. It varies in its ability to inhibit class II and IV (2a & 4) penicillinases. Tazobactam does not induce chromosomally-mediated ß-lactamases at tazobactam concentrations achieved with the recommended dosage regimen.
Peak plasma concentrations of piperacillin and tazobactam are attained immediately after completion of an intravenous infusion piperacillin sodium and Tazobactam sodium injection. Piperacillin plasma concentrations, following a 30-minute infusion of piperacillin sodium and Tazobactam sodium, were similar to those attained when equivalent doses of piperacillin were administered alone, with mean peak plasma concentrations of approximately 134, 242 and 298 μg/mL for the 2.25 g, 3.375 g and 4.5 g piperacillin/tazobactam doses, respectively. The corresponding mean peak plasma concentrations of tazobactam were 15, 24 and 34 μg/mL, respectively.
Following a 30-minute I.V. infusion of 3.375 g piperacillin sodium and Tazobactam sodium for injection every 6 hours, steady-state plasma concentrations of piperacillin and tazobactam were similar to those attained after the first dose. In like manner, steady-state plasma concentrations were not different from those attained after the first dose when 2.25 g or 4.5 g doses of piperacillin sodium and Tazobactam sodium for injection were administered via 30-minute infusions every 6 hours.
Following single or multiple piperacillin sodium and Tazobactam sodium for injection doses to healthy subjects, the plasma half-life of piperacillin and of tazobactam ranged from 0.7 to 1.2 hours and was unaffected by dose or duration of infusion.
Piperacillin is metabolized to a minor microbiologically active desethyl metabolite. Tazobactam is metabolized to a single metabolite that lacks pharmacological and antibacterial activities. Both piperacillin and tazobactam are eliminated via the kidney by glomerular filtration and tubular secretion. Piperacillin is excreted rapidly as unchanged drug with 68% of the administered dose excreted in the urine. Tazobactam and its metabolite are eliminated primarily by renal excretion with 80% of the administered dose excreted as unchanged drug and the remainder as the single metabolite. Piperacillin, tazobactam and desethyl piperacillin are also secreted into the bile.
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 and tazobactam are widely distributed into tissues and body fluids including intestinal mucosa, gallbladder, lung, female reproductive tissues (uterus, ovary, and fallopian tube), interstitial fluid, and bile. Mean tissue concentrations are generally 50% to 100% of those in plasma. Distribution of piperacillin and tazobactam into cerebrospinal fluid is low in subjects with non-inflamed meninges, as with other penicillins.
Piperacillin/Tazobactam: Piperacillin/tazobactam was negative in microbial mutagenicity assays at concentrations up to 14.84/1.86 µg/mL. Piperacillin/tazobactam was negative in the unscheduled DNA synthesis (UDS) test at concentrations up to 5689/711 µg/mL. Piperacillin/tazobactam was negative in a mammalian point mutation (Chinese hamster ovary cell HPRT) assay at concentrations up to 8000/1000 µg/mL. Piperacillin/tazobactam was negative in a mammalian cell (BALB/c-3T3) transformation assay at concentrations up to 8/1 µg/mL. In vivo, piperacillin/tazobactam did not induce chromosomal aberrations in rats dosed I.V. with 1500/187.5 mg/kg; this dose is similar to the maximum recommended human daily dose on a body-surface-area basis (mg/m2).
Piperacillin: Piperacillin was negative in microbial mutagenicity assays at concentrations up to 50 µg/plate. There was no DNA damage in bacteria (Rec assay) exposed to piperacillin at concentrations up to 200 µg/disk. Piperacillin was negative in the UDS test at concentrations up to 10,000 µg/mL. In a mammalian point mutation (mouse lymphoma cells) assay, piperacillin was positive at concentrations ≥2500 µg/mL. Piperacillin was negative in a cell (BALB/c-3T3) transformation assay at concentrations up to 3000 µg/mL. In vivo, piperacillin did not induce chromosomal aberrations in mice at I.V. doses up to 2000 mg/kg/day or rats at I.V. doses up to 1500 mg/kg/day. These are half (mice) or similar (rats) to the maximum recommended human daily dose based on body-surface on body-surface area (mg/m2). In another in vivo test, there was no dominant lethal effect when piperacillin was administered to rats at I.V. doses up to 2000 mg/kg/day, which is similar to the maximum recommended human daily dose based on body-surface area (mg/m2). When mice were administered piperacillin at I.V. doses up to 2000 mg/kg/day, which is half the maximum recommended human daily dose based on body-surface area (mg/m2), urine from these animals was not mutagenic when tested in a microbial mutagenicity assay. Bacteria injected into the peritoneal cavity of mice administered piperacillin at I.V. doses up to 2000 mg/kg/day did not show increased mutation frequencies.
Tazobactam: Tazobactam was negative in microbial mutagenicity assays at concentrations up to 333 µg/plate. Tazobactam was negative in the UDS test at concentrations up to 2000 µg/mL. Tazobactam was negative in a mammalian point mutation (Chinese hamster ovary cell HPRT) assay at concentrations up to 5000 µg/ml. In another mammalian point mutation (mouse lymphoma cells) assay, tazobactam was positive at concentrations ≥3000 µg/mL. Tazobactam was negative in a cell (BALB/ c-3T3) transformation assay at concentrations up to 900 µg/mL. In an in vitro cytogenetics (Chinese hamster lung cells) assay, tazobactam was negative at concentrations up to 3000 µg/ml. In vivo, tazobactam did not induce chromosomal aberrations in rats at I.V. doses up to 5000 mg/kg, which is 23 times the maximum recommended human daily dose based on body-surface area (mg/m2).
Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Long term carcinogenicity studies in animals have not been conducted with piperacillin/tazobactam, piperacillin, or tazobactam.
Indications/Uses
Piperacillin sodium and Tazobactam sodium injection is indicated for the treatment of patients with moderate to severe infections caused by piperacillin-resistant, piperacillin/tazobactam-susceptible, ß-lactamase producing strains of the designated microorganisms in the specified conditions listed as follows: Appendicitis (complicated by rupture or abscess) and peritonitis caused by piperacillin-resistant, β-lactamase producing strains of Escherichia coli or the following members of the Bacteroides fragilis group: B. fragilis, B. ovatus, B. thetaiotaomicron, or B. vulgatus. Uncomplicated and complicated skin and skin structure infections, including cellulitis, cutaneous abscesses and ischemic/diabetic foot infections caused by piperacillin-resistant, β-lactamase producing strains of Staphylococcus aureus.
Postpartum endometritis or pelvic inflammatory disease caused by piperacillin-resistant, β-lactamase producing strains of Escherichia coli.
Community-acquired pneumonia (moderate severity only) caused by piperacillin-resistant, β-lactamase producing strains of Haemophilus influenzae.
Nosocomial pneumonia (moderate to severe) caused by piperacillin-resistant, β-lactamase producing strains of Staphylococcus aureus and by piperacillin/tazobactam-susceptible Acinetobacter baumannii, Haemophilus influenzae, Klebsiella pneumoniae, and Pseudomonas aeruginosa (Nosocomial pneumonia caused by P. aeruginosa should be treated in combination with an aminoglycoside).
Dosage/Direction for Use
Piperacillin sodium and Tazobactam sodium injection should be administered by intravenous infusion over 30 minutes.
The usual total daily dose of Piperacillin sodium and Tazobactam sodium injection for adults is 3.375 g every six hours totaling 13.5 g (12 g piperacillin sodium/1.5 g tazobactam sodium).
Initial presumptive treatment of patients with nosocomial pneumonia should start with Piperacillin sodium and Tazobactam sodium injection at a dosage of 4.5 g every six hours plus an aminoglycoside, totaling 18.0 g (16.0 g piperacillin sodium/2.0 g tazobactam sodium). Treatment with the aminoglycoside should be continued in patients from whom Pseudomonas aeruginosa is isolated. If Pseudomonas aeruginosa is not isolated, the aminoglycoside may be discontinued at the discretion of the treating physician.
Renal Insufficiency: In patients with renal insufficiency (Creatinine Clearance ≤ 40 mL/min), the intravenous dose of Piperacillin sodium and Tazobactam sodium injection (piperacillin and tazobactam injection) should be adjusted to the degree of actual renal function impairment. In patients with nosocomial pneumonia receiving concomitant aminoglycoside therapy, the aminoglycoside dosage should be adjusted according to the recommendations of the manufacturer. The recommended daily doses of Piperacillin sodium and Tazobactam sodium injection for patients with renal insufficiency are as follows: see table.

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 sodium and Tazobactam sodium injection should be administered following each dialysis period on hemodialysis days. No additional dosage of Piperacillin Na & Tazobactam Na (Pipzo) is necessary for CAPD patients.
Duration of Therapy: The usual duration of Piperacillin sodium and Tazobactam sodium injection treatment is from seven to ten days. However, the recommended duration of Piperacillin sodium and Tazobactam sodium injection treatment of nosocomial pneumonia is 7 to 14 days.
In all conditions, the duration of therapy should be guided by the severity of the infection and the patient's clinical and bacteriological progress.
Directions for Reconstitution and Dilution for Use: Intravenous Administration: 2.25 g, 3.375 g, and 4.5 g Piperacillin sodium and Tazobactam sodium for injection should be reconstituted with Sterile Water for Injection 10 mL, 15 mL, and 20 mL, respectively. Swirl until dissolved.
Reconstitution diluents: IV Injection: Sterile water for Injection, 0.9% Sodium Chloride, Dextrose 5%.
IV Infusion: 0.9% Sodium Chloride, Dextrose 5% in water, Dextran 6% in saline, Sterile water for Injection.
Overdosage
There have been postmarketing 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 to 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.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Special Precautions
Bleeding manifestations have occurred in some patients receiving ß-lactam antibiotics, 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 and tazobactam injection should be discontinued and appropriate therapy instituted.
The possibility of the emergence of resistant organisms that might cause superinfections should be kept in mind. If this occurs, appropriate measures should be taken.
As with other penicillin's, patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure).
Piperacillin Na & Tazobactam Na (Pipzo) is a monosodium salt of piperacillin and a monosodium salt of tazobactam and contains a total of 2.35 mEq (54 mg) of Na+ 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 cytotoxic therapy or diuretics.
As with other semi synthetic penicillin's, piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.
In patients with creatinine clearance ≤40 mL/min and dialysis patients (hemodialysis and CAPD), the intravenous dose should be adjusted to the degree of renal function impairment.
Periodic assessment of hematopoietic function should be performed, especially with prolonged therapy, ie, ≥21 days.
Use in Children: Safety and efficacy in pediatric patients have not been established.
Use in Elderly: Patients over 65 years are not at an increased risk of developing adverse effects solely because of age. However, dosage should be adjusted in the presence of renal insufficiency.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other or other drug therapy.
Adverse Reactions
Of the studies reported, including that of nosocomial lower respiratory tract infections in which a higher dose of piperacillin and tazobactam injection was used in combination with an aminoglycoside, changes in laboratory parameters, without regard to drug relationship, include:
Hematological: decreases in hemoglobin and hematocrit, thrombocytopenia, increases in platelet count, eosinophilia, leucopenia, neutropenia. The leukopenia/neutropenia associated with Piperacillin/Tazobactam sodium injection administration appears to be reversible and most frequently associated with prolonged administration, i.e., ≥21 days of therapy.
Coagulation: positive direct Coombs' test, prolonged prothrombin time, prolonged partial thromboplastin time.
Hepatic: transient elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubin.
Renal: increases in serum creatinine, blood urea nitrogen.
Urinalysis: proteinuria, hematuria, pyuria.
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-glutamyltransferase increased, hypokalemia, and bleeding time prolonged.
The following adverse reaction has also been reported for sterile piperacillin sodium: Skeletal: prolonged muscle relaxation.
Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.
Additional adverse events reported: Gastrointestinal: hepatitis, cholestatic jaundice.
Hematological: hemolytic anemia, anemia, thrombocytosis, agranulocytosis, pancytopenia.
Immune: hypersensitivity reactions, anaphylactic/anaphylactoid reactions (including shock).
Infections: candidal superinfections.
Renal: interstitial nephritis, renal failure.
Skin and Appendages: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Drug Interactions
Aminoglycosides: The mixing of Piperacillin sodium and Tazobactam sodium injection with an aminoglycoside in vitro can result in substantial inactivation of the aminoglycoside.
When Piperacillin sodium and Tazobactam sodium injection was co-administered with tobramycin, the area under the curve, renal clearance, and urinary recovery of tobramycin were decreased by 11%, 32%, and 38%, respectively. The alterations in the pharmacokinetics of tobramycin when administered in combination with piperacillin/tazobactam may be due to in vivo and in vitro inactivation of tobramycin in the presence of piperacillin/tazobactam. The inactivation of aminoglycosides in the presence of penicillin-class drugs has been recognized. It has been postulated that penicillin-aminoglycoside complexes form; these complexes are microbiologically inactive and of unknown toxicity. In patients with severe renal dysfunction (i.e., chronic hemodialysis patients), the pharmacokinetics of tobramycin are significantly altered when tobramycin is administered in combination with piperacillin. The alteration of tobramycin pharmacokinetics and the potential toxicity of the penicillin-aminoglycoside complexes in patients with mild to moderate renal dysfunction which are occurring under circumstances where causal relationship to Piperacillin sodium and Tazobactam sodium injection is uncertain: Gastrointestinal: hepatitis, cholestatic jaundice.
Hematological: hemolyticanemia, anemia, thrombocytosis, agranulocytosis, pancytopenia.
Immune: hypersensitivity reactions, anaphylactic/anaphylactoid reactions (including shock).
Infections: candidal superinfections.
Renal: interstitial nephritis, renal failure.
Skin and Appendages: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Drug/Laboratory Test Interactions: As with other penicillin's, the administration of Piperacillin and tazobactam injection 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.
Storage
Store at temperatures not exceeding 30°C. Store in a dry place and protect from light.
Vials should be used immediately after reconstitution. Discard any unused portion after 24 hours if stored at room temperature (20°C to 25°C [68°F to 77°F]), or after 48 hours if stored at refrigerated temperature (2°C to 8°C [36°F to 46°F]). Vials should not be frozen after reconstitution.
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 inj (vial) 4.5 g x 1's.
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