TazoPlus
-
Chemical Name:
Piperacillin (sodium)+ Tazobactam (sodium) -
Therapeutic Category:
Antimicrobial -
Pharmacologic Category:
Penicillin with beta-lactam inhibitor -
Pharmaceutical Form:
Vial -
Composition:
Piperacillin(sodium) 4000mg +Tazobactam (sodium)500mg
TAZO PLUS
powder for solution for infusion (vial)
Piperacillin (sodium)+ Tazobactam (sodium)
Broad Spectrum Antibiotic
1-COMPOSITION:
TAZO PLUS– powder for solution for infusion: Each vial contains Piperacillin (sodium) 4 g+ Tazobactam (sodium) 0.5g.
2-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.
Spectrum Of Activity:
Piperacillin/tazobactam has been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections.
- Gram-positive Bacteria: Staphylococcus aureus.
- Gram-negative Bacteria: Acinetobacter baumannii, Escherichia coli, Haemophilus influenzae (excluding β-lactamase negative, ampicillin-resistant isolates), Klebsiella pneumonia, Pseudomonas aeruginosa (given in combination with an aminoglycoside).
- Anaerobic Bacteria: Bacteroides fragilis group (B. fragilis, B. ovatus, B. thetaiotaomicron, and B. vulgatus).
3-PHARMACOKINETICS:
Peak plasma concentrations of piperacillin and tazobactam are attained immediately after completion of an intravenous infusion of TAZO PLUS. Piperacillin plasma concentrations, following a 30-minute infusion of TAZO PLUS, were similar to those attained when equivalent doses of piperacillin were administered alone.
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.
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:
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 for TAZO PLUS are recommended when creatinine clearance is below 40 mL/min in patients receiving the usual recommended daily dose of TAZO PLUS.
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. For dosage recommendations for patients undergoing hemodialysis.
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 of TAZO PLUS 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.
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 piperacilln 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.
Race:
The effect of race on piperacillin and tazobactam was evaluated in healthy male volunteers. No difference in piperacillin or tazobactam pharmacokinetics was observed between Asian (n=9) and Caucasian (n=9) healthy volunteers who received single 4/0.5 g doses.
4-INDICATIONS:
TAZO PLUS 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 below.
- Intra-abdominal Infections: Appendicitis 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.
- Skin Infections: Uncomplicated and complicated skin 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).
5-CONTRAINDICATIONS:
- Hypersensitivity to piperacillin or tazobactam or to any of the excipients.
- Hypersensitivity to antibiotics known as penicillins, cephalosporins or other beta-lactamase inhibitors.
6-WARNING and PRECAUTION:
Hypersensitivity Adverse Reactions:
Serious and occasionally fatal hypersensitivity anaphylactic reactions (including shock) have been reported in patients receiving therapy with TAZO PLUS. 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 TAZO PLUS, careful inquiry should be made concerning previous hypersensitivity reactions. If an allergic reaction occurs, TAZO PLUS should be discontinued and appropriate therapy instituted.
Severe Cutaneous Adverse Reactions:
TAZO PLUS 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 TAZO PLUS 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, TAZO PLUS should be discontinued and appropriate therapy instituted.
The leukopenia/neutropenia associated with TAZO PLUS 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 TAZO PLUS 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. 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 TAZO PLUS.
Combined use of piperacillin/tazobactam and vancomycin may be associated with an increased incidence of acute kidney injury.
Electrolyte Effects:
TAZO PLUS contains a total of 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 TAZO PLUS, 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.
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 TAZO PLUS 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.
Serious Hypersensitivity Reactions:
Advise patients, their families, or caregivers that serious hypersensitivity reactions, including serious allergic cutaneous reactions, could occur that require immediate treatment. Ask them about any previous hypersensitivity reactions to TAZO PLUS, other beta-lactams (including cephalosporins), or other allergens.
Diarrhea:
Advise patients, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs which usually ends when the drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the drug. If this occurs, patients should contact their physician as soon as possible.
Antibacterial Resistance:
Counsel patients that antibacterial drugs including TAZO PLUS should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When TAZO PLUS is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may decrease the effectiveness of the immediate treatment and increase the likelihood that bacteria will develop resistance and will not be treatable by TAZO PLUS or other antibacterial drugs in the future.
7-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 TAZO PLUS 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, TAZO PLUS and aminoglycosides are recommended for separate administration .TAZO PLUS, which contains EDTA, is compatible with amikacin and gentamicin for simultaneous Y-site infusion in certain diluents and at specific concentrations. and it is not compatible with tobramycin for simultaneous Y-site infusion
Probenecid:
Probenecid administered concomitantly with TAZO PLUS 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 TAZO PLUS 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
and it may be useful to 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. 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
Effects On Laboratory Tests:
- There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving piperacillin/tazobactam injection who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with the Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving piperacillin/tazobactam should be interpreted cautiously and confirmed by other diagnostic methods.
- As with other penicillins, the administration of TAZO PLUS 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.
8-PREGNANCY& LACTATION:
PREGNANCY:
Piperacillin and tazobactam cross the placenta. 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. Ask your doctor before taking this medicine.
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. caution should be exercised when TAZO PLUS is administered to a nursing woman.
9-PEDIATRIC USE:
Safety and efficacy of TAZO PLUS in pediatric patients less than 2 months of age have not been established.It has not been determined how to adjust TAZO PLUS dosage in pediatric patients with renal impairment.
10-GERIATRIC USE:
Patients over 65 years are not at an increased risk of developing adverse effects solely because of age. Because elderly patients are more likely to have decreased renal function, Dosage should be adjusted in the presence of renal impairment. and it may be useful to monitor renal function.
Renal Impairment:
In patients with creatinine clearance ≤ 40 mL/min and dialysis patients (hemodialysis and CAPD), the intravenous dose of TAZO PLUS should be reduced to the degree of renal function impairment.
Patients With Cystic Fibrosis:
As with other semisynthetic penicillins, piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.
11-DOSAGE and ADMINISTRATION:
TAZO PLUS should be administered by intravenous infusion over 30 minutes.
Adult Patients:
The usual total daily dose of TAZO PLUS 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 TAZO PLUS treatment is from 7 to 10 days.
Nosocomial Pneumonia:
Initial presumptive treatment of patients with nosocomial pneumonia should start with TAZO PLUS 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 TAZO PLUS treatment for nosocomial pneumonia is 7 to 14 days.
Renal Impairment:
In patients with renal impairment (creatinine clearance ≤ 40 mL/min) and dialysis patients (hemodialysis and CAPD), the intravenous dose of TAZO PLUS should be reduced to the degree of actual renal function impairment. The recommended daily doses of TAZO PLUS for patients with renal impairment are as follows:
|
Renal Function
(creatinine clearance, mL/min)
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All Indications
(except nosocomial pneumonia)
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Nosocomial Pneumonia
|
|
> 40 mL/min
|
3.375 q 6 h
|
4.5 q 6 h
|
|
20-40 mL/min*
|
2.25 q 6 h
|
3.375 q 6 h
|
|
< 20 mL/min*
|
2.25 q 8 h
|
2.25 q 6 h
|
|
Hemodialysis**
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2.25 q 12 h
|
2.25 q 8 h
|
|
CAPD
|
2.25 q 12 h
|
2.25 q 8 h
|
|
* Creatinine clearance for patients not receiving hemodialysis
**0.75g (0.67 g piperacillin/0.08 g tazobactam) should be administered following each hemodialysis session on hemodialysis days
|
||
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 TAZO PLUS 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 TAZO PLUS 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 and with normal renal function should receive the adult dose.
It has not been determined how to adjust TAZO PLUS dosage in pediatric patients with renal impairment.
Intravenous use:
|
Content of vial
|
Volume of solvent to be added to vial
|
|
4 g/ 0.5 g (4 g piperacillin and 0.5 g tazobactam)
|
20 ml
|
The solvents used for reconstitution:
- 0.9% (9 mg/ml) sodium chloride solution for injection.
- Sterile water for injections (Maximum recommended volume of sterile water for injection per dose is 50 ml).
- Dextrose 5%.
- Bacteriostatic saline/parabens.
- Bacteriostatic water/parabens.
- Bacteriostatic saline/benzyl alcohol.
- Bacteriostatic water/benzyl alcohol.
Reconstituted TAZO PLUS 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 solution listed below. Administer by infusion over a period of at least 30 minutes. During the infusion it is desirable to discontinue the primary infusion solution.
Compatible Intravenous Solutions for Single Dose Vials:
- 0.9% sodium chloride for injection.
- Sterile water for injection (Maximum recommended volume per dose of sterile water for injection is 50ml).
- Dextran 6% in saline.
- Dextrose 5%.
- Lactated Ringer's Solution (compatible only with reformulated TAZO PLUS containing EDTA and is compatible for co-administration via a Y-site).
TAZO PLUS should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established.
TAZO PLUS is not chemically stable in solutions that contain only sodium bicarbonate and solutions that significantly alter the pH.
TAZO PLUS should not be added to blood products or albumin hydrolysates. Parenteral drug products should be inspected visually for particulate matter or discoloration prior to administration, whenever solution and container permit.
- When reconstituted with water for injections or saline, reconstituted solutions will remain stable for 24 hours at 25°C and for 48 hours at 4°C.
12-UNDESIRABLE EFFECTS:
Gastrointestinal disorders: Diarrhea, Constipation, Vomiting, Dyspepsia, Abdominal pain.
General disorders and administration site conditions: Fever, Injection site reaction, Rigors.
Immune system disorders: Anaphylaxis.
Infections and infestations: Candidiasis, Pseudomembranous colitis.
Metabolism and nutrition disorders: Hypoglycemia.
Musculoskeletal and connective tissue disorders: Myalgia, Arthralgia.
Nervous system disorders: Headache.
Psychiatric disorders: Insomnia.
Skin and subcutaneous tissue disorders: Rash including maculopapular, bullous, and urticarial, Pruritus, Purpura.
Vascular disorders: Phlebitis, Thrombophlebitis, Hypotension, Flushing.
Respiratory, thoracic and mediastinal disorders: Epistaxis.
13-OVERDOSE:
Symptom: nausea, vomiting, and diarrhea (it's 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.
14-PACKAGING:
TAZO PLUS– powder for solution for infusion: Carton package of 1 vial of 20ml.
15-STORAGE CONDITIONS:
Store TAZO PLUS– powder for solution for infusion at temperature below 25°C. After reconstitution: Store at temperature between (2-8)°C.
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