Iztam-2.25/Iztam-4.5

Iztam-2.25/Iztam-4.5

piperacillin + tazobactam

Manufacturer:

Penmix

Distributor:

Bellus Life Solutions

Marketer:

Ildong Pharm
Full Prescribing Info
Contents
Piperacillin sodium, tazobactam sodium.
Description
Each Iztam 2.25 vial contains: Piperacillin (as sodium) 2 g and Tazobactam (as sodium) 250 mg.
Each Iztam 4.5 vial contains: Piperacillin (as sodium) 4 g and Tazobactam (as sodium) 500 mg.
Action
Pharmacology: Pharmacodynamics: Mechanism 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 β-lactamase inhibitor of the Molecular class A enzymes, including 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.
Pharmacokinetics: Peak plasma concentrations of piperacillin and tazobactam are attained immediately after completion of an intravenous infusion. Piperacillin plasma concentrations, following a 30-minute infusion, were similar to those attained when equivalent doses of piperacillin were administered alone. Steady-state plasma concentrations of piperacillin and tazobactam were similar to those attained after the first dose due to the short half-lives of piperacillin and tazobactam.
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 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.
Metabolism: Piperacillin is metabolized to a minor microbiologically active desethyl metabolite. Tazobactam is metabolized to a single metabolite that lacks pharmacological and antibacterial activities.
Excretion: Following single or multiple 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.
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.
Specific Populations: Renal impairment: After the administration of single doses of piperacillin/tazobactam to subjects with renal impairment, the half-life of piperacillin and of tazobactam increases with decreasing creatinine clearance. At creatinine clearance below 20 mL/min, the increase in half-life is twofold for piperacillin and fourfold for tazobactam compared to subjects with normal renal function. Dosage adjustments are recommended when creatinine clearance is below 40 mL/min in patients receiving the usual recommended daily dose.
Hemodialysis removes 30% to 40% of a piperacillin/tazobactam dose 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 16% of the tazobactam dose removed as the tazobactam metabolite.
Hepatic Impairment: The half-life of piperacillin and of tazobactam increases by approximately 25% and 18%, respectively, in patients with hepatic cirrhosis compared to healthy subjects. However, this difference does not warrant dosage adjustment due to hepatic cirrhosis.
Pediatrics: Piperacillin and tazobactam pharmacokinetics were studied in pediatric patients 2 months of age and older. The clearance of both compounds is slower in the younger patients compared to older children and adults.
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 pediatric patients 2-9 months old. In patients younger than 2 months of age, clearance of piperacillin is slower compared to older children; however, it is not adequately characterized for dosing recommendations. The population mean (SE) for piperacillin distribution volume is 0.243 (0.011) L/kg and is independent of age.
Geriatrics: The impact of age on the pharmacokinetics of piperacillin and tazobactam was evaluated in healthy male subjects, aged 18-35 years (n=6) and aged 65 to 80 years (n=12). Mean half-life for piperacillin and tazobactam was 32% and 55% higher, respectively, in the elderly compared to the younger subjects. This difference may be due to age-related changes in creatinine clearance.
Indications/Uses
Piperacillin + Tazobactam is a combination product consisting of a penicillin-class antibacterial, piperacillin, and a β-lactamase inhibitor, tazobactam, indicated for the treatment of patients with moderate to severe infections caused by susceptible isolates of the designated bacteria in the conditions listed as follows.
Intra-abdominal Infections: Appendicitis (complicated by rupture or abscess) and peritonitis caused by β-lactamase producing isolates of Escherichia coli or the following members of the Bacteroides fragilis group: B. fragilis, B. ovatus, B. thetaiotaomicron, or B. vulgatus. The individual members of this group were studied in fewer than 10 cases.
Skin and Skin Structure Infections: Uncomplicated and complicated skin and skin structure infections, including cellulitis, cutaneous abscesses and ischemic/diabetic foot infections caused by β-lactamase producing isolates of Staphylococcus aureus.
Female Pelvic Infections: Postpartum endometritis or pelvic inflammatory disease caused by β-lactamase producing isolates of Escherichia coli.
Community-acquired Pneumonia: Community-acquired pneumonia (moderate severity only) caused by β-lactamase producing isolates of Haemophilus influenzae.
Nosocomial Pneumonia: Nosocomial pneumonia (moderate to severe) caused by β-lactamase producing isolates 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).
Usage: To reduce the development of drug-resistant bacteria and maintain the effectiveness of Piperacillin + Tazobactam and other antibacterial drugs. Piperacillin + Tazobactam should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Dosage/Direction for Use
Piperacillin + Tazobactam should be administered by intravenous infusion over 30 minutes.
Adult Patients: The usual total daily dose for adults is 3.375 g every six hours totaling 13.5 g (12.0 g piperacilin/1.5 g tazobactam). The usual duration 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 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 patient (hemodialysis and CAPD), the intravenous dose should be reduced to the degree of actual renal function impairment. The recommended daily doses 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 (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, weighing up to 40 kg, and with normal renal function, the recommended dosage of Piperacillin + Tazobactam is 100 mg piperacillin/12.5 mg tazobactam per kilogram of body weight every 8 hours. For pediatric patients between 2 months and 9 montsh of age, the recommended of Piperacillin + Tazobactam dosage is 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 and with normal renal function should receive the adult dose. It has not been determined how to adjust dosage in pediatric patients with renal impairment.
Overdosage
There have been postmarketing reports of overdose with piperacillin/tazobactam. The majority of those events experience, including nausea, vomiting, and diarrhea, have also been reported with the usual recommended dosages. Patients may experience neuromuscular excitability or convulsion 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 approximatedly 31% and 39%, respectively.
Contraindications
Piperacillin + Tazobactam is contraindicated in patients with a history of allergic reactions to any of the penicillins, cephalosporins, or β-lactamase inhibitors.
Special Precautions
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 careful inquiry should be made concerning previous hypersensitivity reactions. If an allergic reaction occurs, it 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 eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis. If patients develop a skin rash they should be monitored closely and 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, 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 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 neuromusuclar 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 options should be considered in the critically ill population. If alternative treatment options are inadequate or unavailable, monitor renal function during treatment.
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 cytotoxic 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 the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile caused increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Development of Drug-Resistant Bacteria: Prescribing in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of development of drug-resistant bacteria.
Use In Pregnancy & Lactation
Pregnancy: Piperacillin and tazobactam cross the placenta in humans. However, there are insufficient data with piperacillin and/or tazobactam in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. No fetal structural abnormalities were observed in rates or mice when piperacillin/tazobactam was administered intravenously during organogenesis at doses 1 to 2 times and 2 to 3 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area (mg/m2). However, fetotoxicity in the presence of maternal toxicity was observed in developmental toxicity and peri/postnatal studies conducted in rats (intraperitoneal administration prior to mating and throughout gestation or from gestation day 17 through lactation day 21) at doses less than the maximum recommended human daily dose based on body-surface area (mg/m2).
The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Lactation: Piperacillin is excreted in human milk; tazobactam concentrations in human milk have not been studied. No information is available on the effects of piperacillin and tazobactam on the breastfed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Piperacillin + Tazobactam and any potential adverse effects on the breastfed child from Piperacillin + Tazobactam or from the underlying maternal condition.
Adverse Reactions
See Table 2 and Table 3.

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Other trials: Nephrotoxicity: Piperacillin may inactivate aminoglycosides by converting them to microbiologically inert amides.
Pediatrics: Piperacillin may inactivate aminoglycosides by converting them to microbiologically inert amides.
Adverse Laboratory Events: Of 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: decreases 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., fevers, rigors, chills).
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.
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.
Drug Interactions
Aminoglycosides: Piperacillin may inactivate aminoglycosides by converting them to microbiologically inert amides.
In vivo inactivation: When aminoglycosides are administered in conjunction with piperacillin to patients with endstage renal disease requiring hemodialysis, the concentrations of the aminoglycosides (especially tobramycin) may be significantly reduced and should be monitored. Sequential administration of Piperacillin + Tazobactam and tobramycin to patients with either normal renal function or mild to moderate renal impairment has been shown to modestly decrease serum concentrations of tobramycin but no dosage adjustment is considered necessary.
In vitro inactivation: Due to the in vitro inactivation of aminoglycosides by Piperacillin + Tazobactam and aminoglycosides are recommended for separate administration. Piperacillin + Tazobactam and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated. Piperacillin + Tazobactam, which containds EDTA, is compatible with amikacin and gentamicin for simultaneous Y-site infusion in certain diluents and at specific concentrations. Piperacillin + Tazobactam is not compatible with tobramycin for simultaneous Y-site infusion.
Probenecid: Probenecid administered concomitantly with Piperacillin + Tazobactam prolongs the half-life of piperacillin by 21% and that of tazobactam by 71% because probenecid inhibits tubular renal secretion of both piperacillin and tazobactam. Probenecid should not be co-administered with Piperacillin + Tazobactam unless the benefit outweighs the risk.
Vancomycin: Studies have detected an increased incidence of acute kidney injury in patients concomitantly administered piperacillin/tazobactam and vancomycin as compared to vancomycin alone.
Monitor kidney function in patients concomitantly administered with piperacillin/tazobactam and vancomycin.
No pharmacokinetic interactions have been noted between piperacillin/tazobactam and vancomycin.
Anticoagulants: Coagulation parameters should be tested more frequently and monitored regularly during simultaneous administration of high doses of heparin, oral anticoagulants, or other drugs that may affect the blood coagulation system or the thrombocyte function.
Vecuronium: Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. 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-depolarizing muscle relaxants could be prolonged in the presence of piperacillin. Monitor for adverse reactions related to neuromuscular blockade.
Methotrexate: Limited data suggests that co-administration of methotrexate and piperacillin may reduce the clearance of methotrexate due to competition for renal secretion. The impact of tazobactam on the elimination of methotrexate has not been evaluated. If concurrent therapy is necessary, serum concentrations of methotrexate as well as the signs and symptoms of methotrexate toxicity should be frequently monitored.
Caution For Usage
Direction for Reconstitution: Single dose vials: Reconstitute vials with a compatible reconstitution diluent from the list provided as follows.
2.25 g and 4.5 g should be reconstituted with 10 mL and 20 mL respectively. Swirl until dissolved.
Compatible Reconstitution Diluents for Pharmacy and Single Dose Vials: 0.9% Sodium Chloride for Injection, Sterile Water for Injection, Dextrose 5%.
Reconstituted solutions for both bulk and single dose vials should be further diluted (recommended volume per dose of 50 mL to 150 mL) in a compatible intravenous solutions listed as follows. Adminstered by infusion over a period of at least 30 minutes. During the infusion it is desirable to discontinue the primary infusion solution.
Storage
Store at temperatures not exceeding 30°C.
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
Iztam-2.25: Powd for inj for IV infusion 2.25 g (white lyophilized) x 20 mL x 10's.
Iztam-4.5: Powd for inj for IV infusion 4.5 g (white lyophilized) x 50 mL x 10's.
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