Tazovex

Tazovex

piperacillin + tazobactam

Manufacturer:

North China Pharma

Distributor:

Sannovex
Full Prescribing Info
Contents
Piperacillin sodium, tazobactam sodium.
Description
Each 2.25 g vial contains: Piperacillin Na 2 g & Tazobactam Na 250 mg.
Each 4.5 g vial contains: Piperacillin Na 4 g & Tazobactam Na 500 mg.
Piperacillin and Tazobactam for Injection is an injectable antibacterial combination, consisting of the semi-synthetic antibiotic piperacillin sodium and the β-lactamase inhibitor tazobactam sodium, for intravenous administration. It is available as a white to off-white sterile, cryodesiccated powder of piperacillin and tazobactam as the sodium salts packaged in glass vials. The product contains no excipients or preservatives.
Action
Pharmacology: Piperacillin, a broad spectrum, semisynthetic penicillin active against many Gram-positive and Gram-negative aerobic and anaerobic bacteria, exerts bactericidal activity by inhibition of both septum and cell wall synthesis. Tazobactam, a triazolylmethyl penicillanic acid sulfone, is a potent inhibitor of many β-lactamases, including the plasmid and chromosomally mediated enzymes that commonly cause resistance to penicillins. The presence of tazobactam in the piperacillin and tazobactam for injection formulation enhances and extends the antibiotic spectrum of piperacillin to include many β-lactamase producing bacteria normally resistant to it. Thus, piperacillin and tazobactam for injection combines the properties of a broad-spectrum antibiotic and a β-lactamase inhibitor.
Pharmacokinetics: Distribution and plasma levels: Mean plasma concentrations of piperacillin and tazobactam at steady state of the combination appear in Table 1. Peak piperacillin and tazobactam plasma concentrations are attained immediately after completion of an intravenous infusion. When given tazobactam, piperacillin plasma levels are similar to those attained when equivalent doses of piperacillin are administered alone. (See Table 1.)

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In healthy subjects piperacillin/tazobactam plasma elimination half lives range from 0.7 to 1.2 hours following single or multiple doses. These half-lives are unaffected by dose or duration of infusion. Piperacillin and Tazobactam are 21% and 23% respectively, bound to plasma proteins. The protein binding of either piperacillin or tazobactam is unaffected by the presence of either compound. Piperacillin and Tazobactam are widely distributed in tissues and body fluids including intestinal mucosa, gall bladder, lung and bile.
Biotransformation: Piperacillin does not undergo biotransformation in humans. Approximately 20% of a dose of tazobactam is metabolized to a single metabolite that has been found to be microbiologically inactive.
Excretion: Piperacillin and tazobactam are eliminated by the kidney via glomerular filtration and tubular secretion. Piperacillin is excreted rapidly as unchanged drug, with 69% of the dose appearing in the urine. Piperacillin is also secreted into bile. Tazobactam and its metabolite are eliminated primarily by renal excretion, with 80% of the dose appearing as unchanged drug and the remainder of the dose appearing as the metabolite.
Impaired renal function: The half-life of piperacillin and tazobactam increases with decreasing creatinine clearance. The increase 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. Dosage adjustment are recommended when creatinine clearance is below 40 mL/min (see Dosage & Administration).
Piperacillin and tazobactam are removed from the body during haemodialysis with 31% and 39% of the doses of piperacillin and tazobactam, respectively recovered in the dialysis fluid. Piperacillin and tazobactam are removed from the body by peritoneal dialysis with 5% and 12% of the dose, respectively, appearing in the dialysate. For dosage recommendations in patients undergoing haemodialysis. (see Dosage & Administration).
Impaired liver function: Piperacillin half-life and AUC were increased by 25% and 40% respectively and tazobactam half-life and AUC 18% and 23% respectively in patients with hepatic impairment. However, dosage adjustments in patients with hepatic impairment are not necessary.
Children: The pharmacokinetics of piperacillin and tazobactam have been examined in 24 pediatric patients aged 2 months to 12 years receiving 100 mg/kg piperacillin/12.5 mg/kg tazobactam (Table 2). The maximum concentration (Cmax) for both piperacillin and tazobactam is increased relative to the maximum adult dose but the predicted time above the minimum inhibitory concentration is slightly decreased. The dosage of 100 mg/kg piperacillin/12.5 mg/kg tazobactam administered every 8 hours is predicted to provide coverage 31% to 61% of the time for the rage of MIC values of 2 μg/mL to 16 μg/mL commonly found in intra-abdominal infections in children.

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Microbiology: Piperacillin and tazobactam for injection is active against most strains of the following β-lactamase producing and non β-lactamase producing microorganisms: Gram-negative bacteria: Escherichia coli, Citrobacter spp. (including K. pneumoniae), Enterobacter spp. (including E. cloacae). Proteus vulgaris, Proteus mirabilis, Serratia spp. (including S. marcescens), Pseudomonas aeruginosa and other Pseudomonas spp., Neisseria gonorrhoeae, Neisseria meningitides, Moraxella catarrhalis, Acinetobacter spp., Haemophilus influenzae.
Gram-positive bacteria: Streptococci (S. pneumoniae, S. pyogenes, S. agalactiae, S. viridans), Enterococci (E. faecalis, E. faecium), Staphylococcus aureus (not methicillin-resistant S. aureus), S. epidermidis (coagulase-negative staphylococci).
Anaerobic bacteria: Bacteroides spp. including Bacteroides fragilis group. Peptostreptococcus spp., Fusobacterium spp., Enbacterium group, Clostridia spp., Veillonella spp.
Indications/Uses
PIPERACILLIN AND TAZOBACTAM FOR INJECTION is indicated for the treatment of the following systemic and/or local bacterial infections in which susceptible organisms have been detected or are suspected: Lower respiratory tract infections, Urinary tract infections (complicated and uncomplicated), Intra-abdominal infections, Skin and skin structure infections, Bacterial septicemia, Gynecological infections, Bone and joints infections.
Bacterial infections in neutropenic patients. Full therapeutic doses of piperacillin and tazobactam for injection plus and amino glycoside should be used.
While piperacillin and tazobactam for injection is indicated only for the conditions previously listed, infections caused by piperacillin susceptible organism are also amenable to piperacillin and tazobactam for injection treatment due to its piperacillin content. Therefore, the treatment of mixed infections caused by piperacillin susceptible organisms and β-lactamase producing organism susceptible to piperacillin and tazobactam for injection should not require the addition of another antibiotic.
Appropriate culture and susceptibility test should be performed before treatment in order to identify organisms causing infections and to determine their susceptibilities to piperacillin and tazobactam for injection. Because of its broad-spectrum of activity against Gram-positive and Gram-negative aerobic and anaerobic organisms as previously listed, piperacillin and tazobactam for injection is particularly useful in the treatment of mixed infections and in presumptive therapy prior to the availability of the results of sensitivity test. Therapy with piperacillin and tazobactam for injection may, however be initiated before results of such test are known.
Modification of the treatment may be required once these results become available or if there is no clinical response.
In serious infections, presumptive therapy with piperacillin and tazobactam for injection may be initiated before susceptibility test results are available.
Piperacillin and tazobactam for injection acts synergistically with aminoglycosides against certain strains of Pseudomonas aeruginosa. Combined therapy has been successful, especially in patients with impaired host defenses. Both drugs should be used in full therapeutic doses. As soon as results of culture and susceptibility test become available, antimicrobial therapy should be adjusted.
Children under the age of 12 years: In hospitalized children aged to 2 to 12 years, piperacillin and tazobactam for injection is indicated for the treatment of serious intra-abdominal infections. It has not been evaluated in this indication for pediatric patients below the age or 2 years.
Dosage/Direction for Use
Piperacillin/Tazobactam may be given by slow intravenous injection (over at least 3-5 minutes) or by slow intravenous infusion (over a period of 20 to 30 minutes).
Piperacillin/Tazobactam should not be infused together with aminoglycosides. Neutropenic patients with sign of infection (e.g. fever) should receive immediate empirical antibiotic therapy before laboratory results are available.
Overdosage
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 of Intoxication: No specific antidote is known. In the event of an emergency, all required intensive medical measures are indicated as in the case of piperacillin. In cases of motor excitability or convulsion, anticonvulsive agent diazepam or barbiturates may be indicated. In cases of anaphylactic reactions, the usual counter measures to be initiated (adrenaline, antihistamines, corticosteroids and, if required, oxygen and airway management). Excessive serum concentrations of either piperacillin or tazobactam may be reduced by hemodialysis.
Contraindications
The used of piperacillin and tazobactam for injection is contraindicated in patients with a history of allergic reactions to any of the penicillin and/or cephalosporin or β-lactamase inhibitors.
Special Precautions
Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid [including shock]) reactions have been reported in patients on penicillin/cephalosporin therapy. Although anaphylaxis is more frequent following parental therapy, it has occurred in patients on oral penicillin/cephalosporin. These reactions are more likely to occur in individual with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin/cephalosporin hypersensitivity who have experienced severe reactions when treated with either a penicillin or cephalosporin. Past history of a severe allergic reaction to penicillin/cephalosporin is a contraindication to the use of piperacillin and tazobactam for injection. Before initiating therapy with any penicillin/cephalosporin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillin, cephalosporin or other allergens. If an allergic reaction occurs, piperacillin and tazobactam for injection should be discontinued and the appropriate therapy instituted. Serious anaphylactoid reactions require immediate emergency treatment with adrenaline. Oxygen, intravenous steroids and airway management, including intubations, should also be administered as indicated.
Antibiotic-associated pseudomembranous colitis has been reported with many antibiotics including piperacillin. A toxin produced by Clostridium difficile appears to be the primary cause. The severity of the colitis may range from mild to life threatening. It is important to consider this diagnosis in patients who develop diarrhea or colitis in association with antibiotic use (this may occur up to several weeks after cessation of antibiotic therapy). Mild cases usually respond to drug discontinuation alone. However, in moderate to severe cases appropriate with a suitable oral antibacterial agent effective against C. difficile should be considered. Fluids, electrolytes and protein replacement should be provided when indicated. Drugs that delay peristalsis eg; opiates and diphenoxylate with atropine (Lomotil) may prolong and/or worsen the condition and should not be used.
Leucopenia and neutropenia may occur, especially during prolonged therapy. Therefore, periodic assessment of hematopoietic function should be performed.
Use with caution in the following circumstances: Bleeding manifestations have occurred in some patients receiving piperacillin. These reactions have something 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.
The possibility of the emergence of resistant organisms that might cause super infection should be kept in mind, particularly during prolonged treatment. If this occurs, appropriate measures should be taken.
As with other penicillins, patients may experience neuromuscular excitability or convulsion if higher than recommended doses are given intravenously.
Repeated use of lignocaine as diluent should be avoid in patients with severe liver disease or decreased hepatic blood flow due to the possibility of lignocaine toxicity (resulting from decreased metabolism and accumulation).
Combined administration of β-lactamase inhibitors and β-lactam antibiotics may be associated with a slightly increased risk of hepatic adverse reactions. The incidence of increased liver enzymes in patients treated with piperacillin alone. The potential for increased hepatic adverse reactions should be borne in mind when using piperacillin and tazobactam for injection.
Check the following before use: Periodical assessment of organ system functions including renal, hepatic and hematopoietic during prolonged therapy (≥ 21 days) is advisable.
For patients with renal impairment and/or hepatic insufficiency, measurement of serum levels of piperacillin will provide guidance for adjusting dosage.
The theoretical sodium content of each 4.5 g vial of piperacillin and tazobactam for injection is 216 mg sodium (9.39 mmol). Which may increase a patient's overall sodium intake.
Periodical electrolyte determinations should be made 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.
Because of its poor penetration into the CSF, piperacillin is not advised in the treatment of meningitis and brain abscess.
Antimicrobials used in high doses for short periods to treat gonorrhea may mask or delay symptoms of incubating syphilis. Therefore, prior to treatment, patients with gonorrhea should also be evaluated for syphilis. Specimens for dark field examination should be obtained from patients with any suspected primary lesion and serological tests should be made for a minimum of 4 months.
Carcinogenicity, mutagenicity and impairment of fertility: Long term carcinogenicity studies of piperacillin and tazobactam for injection in animals have not been performed. Mutagenicity studies with piperacillin and tazobactam showed no evidence of genotoxicity in assays for chromosomal and DNA damage. One assay for gene mutation (Mouse lymphoma assay) was weakly positive at tazobactam and piperacillin and concentration ≥3200 μg/mL and 2500 μg/mL, respectively. Piperacillin and tazobactam did not affect the fertility of male or female rats.
Use in pregnancy: Pregnancy Category B 1.
Adequate human studies in the use of piperacillin and tazobactam for injection during pregnancy are not available. Limited studies with piperacillin alone in rats and mice revealed no teratogenic effect or harm to the fetus. Studies with tazobactam (doses up to 3000 mg/kg IV) or tazobactam and piperacillin (doses up to 750 mg/kg and 3000 mg/kg IV) in mice showed no evidence of teratogenicity or harm to the fetus. Studies in rats at these dose levels showed no evidence of teratogenicity though maternal toxicity, in the form of decreased weight gain, was noted at the dose levels tested. Piperacillin has been found to cross the placenta in rats. Pregnant women should be treated only if the expected benefit outweighs the possible risks to the pregnant woman and fetus.
Use in lactation: Adequate clinical studies on the use of piperacillin and tazobactam for injection during pregnancy are not available. Piperacillin is excreted in low concentrations in milk. In animal studies, both piperacillin and tazobactam were excreted in the milk of lactating rats. Women who are breast-feeding should be treated only of the expected benefit outweighs the possible risks to the woman and child.
Use in children: Safety and efficacy of the use of piperacillin and tazobactam for injection in children under the age of 2 years has not yet been established.
Side Effects
Piperacillin and tazobactam for injection is generally well tolerated. The overall incidence of adverse events was 15.7% although a cause/effect relationship was not established in all cases. This incidence was comparable to that observed with other agents used in the clinical studies. Treatment had to be discontinued in only 2.9% of cases due to adverse reactions.
The most frequently reported adverse clinical reactions were diarrhea, rash, erythema, pruritus, vomiting, allergic reactions, nausea, urticaria, superinfection, phlebitis, thrombophlebitis, dyspepsia and insomnia.
Additional adverse clinical reactions reported as possibly, probably or definitely drug related occurring in less than 0.1% or patients are listed within each body system in order of decreasing severity.
Skin and appendages: Skin reactions, eruption (including bullous dermatitis), increased sweating, erythema multiforme, eczema, exanthema, maculopapular rash, Stevens-Johnson Syndrome, toxic epidermal necrolysis.
Gastrointestinal: Soft/loose stools, stomatitis, constipation, bloody diarrhea, abdominal pain, very rarely pseudomembranous colitis has been reported with piperacillin.
Central nervous system: Muscular weakness, hallucination, headache, fatigue, insomnia.
Autonomic nervous system: Dry mouth.
Musculoskeletal system: Muscle pain, prolonged muscle relaxation, arthralgia.
Vascular system: Superficial phlebitis, hypotension, thrombophlebitis and flushing.
Body as a whole: Fever, hot flushes, edema, tiredness, rigors.
Local reactions: Injection site inflammation, injection site pain.
Hematological changes: Transient reduction in the white blood cell count (leucopenia), neutropenia, thrombocytopenia eosinophilia, disturbed thrombocyte function, positive Coombs' test, rarely hemorrhagic manifestation (including purpura, epistaxis and bleeding time prolonged). Anemia, hemolytic anemia, agranulocytosis, pancytopenia, prolonged partial thromboplastin time prolonged and thrombocytosis.
Hepatic: Transient rise in the serum levels of liver enzymes (ALT, AST, GGT, alkaline phosphatase), bilirubin. The incidence of such rises is higher than with piperacillin alone. Rarely cholestatic jaundice or hepatitis may occur.
Renal: Increased levels of renal function parameters in serum (urea, creatinine) may occur infrequently. Rarely, interstitial nephritis or renal failure may occur.
Hypokalaemia: This was reported rarely in patients with liver disease and those receiving cytotoxic therapy or diuretics when given high doses of piperacillin.
Superinfection: Superinfection, including candidiasis may occur especially with prolonged treatment.
Immune system disorders: Hypersensitivity reaction, anaphylactic/anaphylactoid reaction (including shock).
Metabolism and nutrition disorders: Very rarely decreases in blood albumin, blood total protein have been observed. Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.
Drug Interactions
Concurrent administration of probenecid and piperacillin and tazobactam for injection produced a longer half-life and lower renal clearance for both piperacillin and tazobactam. However, peak plasma concentrations of neither drug are affected. No kinetic interaction is found between piperacillin and tazobactam for injection and vancomycin.
Concurrent administration of piperacillin and tobramycin in patients with severe renal dysfunction (ie chronic hemodialysis patients) has been reported to reduce the elimination half life and significantly increase the total body clearance of tobramycin.
The alteration of tobramycin pharmacokinetics in patients with mild to moderate renal dysfunction who are taking piperacillin concomitantly is unknown. However, reports suggest that the aminoglycoside inactivation in patients concomitantly taking an amino glycoside with a broad spectrum beta-lactam penicillin is only clinically significant in patients with several renal dysfunction.
The inactivation of aminoglycosides in the presence of penicillin class drugs has been recognized. It has been postulated that penicillin-amino glycoside complexes form; these complexes are microbiologically inactive and of unknown toxicity.
Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. Piperacillin and tazobactam for injection (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.
Piperacillin may reduce the excretion of methotrexate, therefore, serum levels of methotrexate should be monitored in patients to avoid drug toxicity.
If piperacillin and tazobactam for injection is used concurrently with another antibiotic, especially an amino glycoside, the drug must not be mixed in intravenous solution or administered concurrently due to physical incompatibility.
During simultaneous administration of high doses of heparin, oral anticoagulants and other drugs that may affect the blood coagulation system and/or the thrombocyte function, the coagulation parameters should be tested more frequently and monitored regularly.
Effects on Laboratory Tests: As with other penicillin, the administration of piperacillin/tazobactam 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 reaction be used.
There have been reports of positive test results using Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving piperacillin and tazobactam for injection, who were subsequently found to be free of Aspergillus infection. Cross-reaction with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving piperacillin and tazobactam for injection should be interpreted cautiously and confirmed by other diagnostic methods.
Caution For Usage
Direction for Reconstitution and Dilution for Use: For intravenous use: Reconstitute each vial with the volume of solvent shown in Table 3 as follows, using one of the compatible solvents for reconstitution. Swirl until dissolved. When swirled constantly, reconstitution generally occurs within 5 to 10 minutes. (See Table 3.)

Click on icon to see table/diagram/image

Compatible solvent for Reconstitution: 0.9% Sodium Chloride for injection, Sterile water for injection, Dextrose 5%, Dextran 6% in Saline.
Maximum recommended volume of Sterile Water for injection per dose is 50 mL.
Storage
Before reconstitution, store Piperacillin/Tazobactam vials below 25°C. Piperacillin/Tazobactam vial should be used immediately 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
2 g/250 mg powd for inj (vial) 10's. 4 g/500 mg powd for inj (vial) 10's.
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