TAZACT Injection (Piperacillin sodium + Tazobactam sodium )

Table of Content

To be sold by retail on the prescription of Registered Medical Practitioner only

Qualitative & Quantitative Composition

TAZACT 1.125 g

Each vial contains:

Piperacillin Sodium IP equivalent to

Piperacillin………….. 1 gm

Tazobactam Sodium IP equivalent to Tazobactam………. 125 mg

(Sodium Content 54.01 mg)

TAZACT 2.25 g

Each vial contains:

Piperacillin Sodium IP equivalent to

Piperacillin………….. 2 gm

Tazobactam Sodium IP equivalent to Tazobactam………. 250 mg

(Sodium Content 108. 036 mg)

TAZACT 4.5 g

Each vial contains:

Piperacillin Sodium IP equivalent to

Piperacillin…………. 4 gm

Tazobactam Sodium IP equivalent to Tazobactam………. 500 mg

(Sodium Content 216.06 mg)

Dosage Form & Strength

Powder for reconstitution and intravenous (I.V.) use only and 1.125 gm, 2.25 gm and 4.5 gm

Clinical Particulars

Therapeutic Indications

Piperacillin/Tazobactam is indicated for the treatment of the following infections:

  • Lower respiratory tract infection
  • Urinary tract infection
  • Intra-abdominal infection
  • Skin and skin structure infection
  • Bacterial septicaemia
  • Polymicrobic infection

Posology & Method of Administration

Posology

The dose and frequency of Piperacillin/Tazobactam depends on the severity and localisation of the infection and expected pathogens.

Adult and adolescent patients

Infections

The usual dose is 4 gm piperacillin / 0.5 gm tazobactam given every 8 hours.

For nosocomial pneumonia and bacterial infections in neutropenic patients, the recommended dose is 4 gm piperacillin /0.5 gm tazobactam administered every 6 hours. This regimen may also be applicable to treat patients with other indicated infections when particularly severe.

The following table summarises the treatment frequency and the recommended dose for adult and adolescent patients by indication or condition:

Treatment Frequency

Piperacillin/Tazobactam 4 gm/0.5 gm

Every 6 hours

Pneumonia

Every 8 hours

Urinary tract infections

Intra-abdominal infections

Skin and soft tissue infections

Renal impairment

The intravenous dose should be adjusted to the degree of actual renal impairment as follows (each patient must be monitored closely for signs of substance toxicity; medicinal product dose and interval should be adjusted accordingly):

Creatinine Clearance (ml/min)

TAZACT (recommended dose)

>40

No dose adjustment necessary

20 to 40

Maximum dose suggested: 4 gm/0.5 gm every 8 hours

<20

Maximum dose suggested: 4 gm/0.5 gm every 12 hours

For patients on haemodialysis, one additional dose of piperacillin / tazobactam 2 gm / 0.25 gm should be administered following each dialysis period, because haemodialysis removes 30%-50% of piperacillin in 4 hours.

Hepatic impairment

No dose adjustment is necessary.

Elderly patients

No dose adjustment is required for the elderly with normal renal function or creatinine clearance values above 40 ml/min.

Pediatric patients

TAZACT can be administered in pediatric patients above 2 months of age.

Intra-abdominal Infections (appendicitis and/or peritonitis)

  • 2 months to 9 months of age: 80 mg piperacillin/10 mg tazobactam per kg q8 hour.
  • 9 months or older weighing up to 40 kg: 100 mg piperacillin/12.5 mg tazobactam per kg q8 hour.
  • Weighing over 40 kg: As per the adult dose.

Neutropaenia (2 to 12 years of age)

  • 80 mg piperacillin/10 mg tazobactam per kg q6 hour.

Dose not to exceed the maximum 4 gm/0.5 gm per dose over 30 minutes.

Renal impairment (2- 12 years of age)

The intravenous dose should be adjusted to the degree of actual renal impairment as follows (each patient must be monitored closely for signs of substance toxicity; medicinal product dose and interval should be adjusted accordingly):

Creatinine Clearance (ml/min)

Recommended Piperacillin/Tazobactam Dosage

>50

No dose adjustment needed

≤50

70 mg piperacillin/8.75 mg tazobactam/kg q 8 hours

For children on haemodialysis, one additional dose of 40 mg piperacillin / 5 mg tazobactam / kg should be administered following each dialysis period.

Treatment duration

The usual duration of treatment for most indications is in the range of 5-14 days. However, the duration of treatment should be guided by the severity of the infection, the pathogen(s) and the patient's clinical and bacteriological progress.

Method of Preparation and Administration  

For conventional vials, reconstitute TAZACT per gram of piperacillin with 5 mL of a compatible reconstitution diluent from the list provided below.

1.125 gm, 2.25 gm and 4.5 gm should be reconstituted with 5 mL, 10 mL and 20 mL, respectively. When swirled constantly, reconstitution generally occurs within 5 to 10 minutes. 

Use immediately after reconstitution. Discard any unused portion after 24 hours if store at controlled room temperature (20°C to 25°C ), or after 48 hours if store at refrigerated temperature (2°C to 8°C ).

Compatible Reconstitution Diluents

0.9% Sodium Chloride for Injection

Sterile Water for Injections IP

Dextrose 5% 

Piperacillin/Tazobactam for injection should be administered by intravenous infusion over 30 minutes. I.V. injection should be given over at least 3 to 5 minutes.

Reconstituted TAZACT solution should be further diluted (recommended volume per dose of 50 mL to 150 mL) with a compatible I.V. diluent solution listed below. Administer by infusion over a period of 30 minutes. During the infusion, it is desirable to discontinue the primary infusion solution.

Compatible I.V. Diluent Solutions

0.9% Sodium Chloride for Injection

Sterile Water for Injections IP

Dextrose 5%

Lactated Ringer's solution is not compatible with TAZACT.

Due to the in vitro inactivation of the aminoglycoside by beta-lactam antibiotics, TAZACT and the aminoglycoside are recommended for separate administration.

TAZACT and the aminoglycoside should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated.

TAZACT is not compatible with tobramycin for simultaneous coadministration via Y-site infusion. Compatibility of piperacillin and tazobactam with other aminoglycosides has not been established.

TAZACT should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established. The product is not chemically stable in solutions that contain only sodium bicarbonate and solutions that significantly alter the pH. It should not be added to blood products or albumin hydrolysates.

TAZACT can be used in ambulatory I.V. infusion pumps.

Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit.

Contraindication

Hypersensitivity to the active substances, any other penicillin-antibacterial agent or to any of the excipients.

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

Special Warnings & Precaution for Use

The selection of piperacillin / tazobactam to treat an individual patient should take into account the appropriateness of using a broad-spectrum semi-synthetic penicillin based on factors such as the severity of the infection and the prevalence of resistance to other suitable antibacterial agents. Before initiating therapy with Piperacillin/Tazobactam, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, other beta-lactam agents (e.g. cephalosporin, monobactam or carbapenem) and other allergens. Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid ) reactions have been reported in patients receiving therapy with penicillins, including piperacillin / tazobactam. These reactions are more likely to occur in persons with a history of sensitivity to multiple allergens. Serious hypersensitivity reactions require the discontinuation of the antibiotic, and may require administration of epinephrine and other emergency measures. 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 generalised exanthematous pustulosis. If patients develop a skin rash they should be monitored closely and piperacillin / tazobactam discontinued if lesions progress. Antibiotic-induced pseudomembranous colitis may be manifested by severe, persistent diarrhoea which may be life - threatening. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment. In these cases Piperacillin/Tazobactam should be discontinued.

Clostridium difficile-associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including piperacillin/tazobactam, and may range in severity from mild diarrhoea to fatal colitis. CDAD must be considered in all patients who present with diarrhoea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the 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.

Therapy with Piperacillin/Tazobactam may result in the emergence of resistant organisms, which might cause superinfections. Bleeding manifestations have occurred in some patients receiving β-lactam antibiotics. These reactions sometimes have 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. Leukopenia and neutropenia may occur, especially during prolonged therapy; therefore, periodic assessment of haematopoietic function should be performed. As with treatment with other penicillins, neurological complications in the form of convulsions may occur when high doses are administered, especially in patients with impaired renal function.

Electrolyte Effects

Piperacillin and tazobactam for injection contains sodium (Na+). 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 hypokalaemia should be kept in mind with patients who have potentially low potassium reserves and who are receiving cytotoxic therapy or diuretics.

Hypokalaemia may occur in patients with low potassium reserves or who are receiving concomitant medicinal products that may lower potassium levels; periodic electrolyte determinations may be advisable in such patients.

Nephrotoxicity in Critically Ill Patients

The use of piperacillin and tazobactam for injection 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 with piperacillin and tazobactam for injection.

Combined use of piperacillin/tazobactam and vancomycin may be associated with an increased incidence of acute kidney injury.

Renal Impairment

Due to its potential nephrotoxicity, piperacillin/tazobactam should be used with care in patients with renal impairment or in hemodialysis patients. Intravenous dosages and administration intervals should be adjusted to the degree of renal function impairment.

In a secondary analysis using data from a large multicenter, randomized-controlled trial when glomerular filtration rate (GFR) was examined after administration of frequently used antibiotics in critically ill patients, the use of piperacillin/tazobactam was associated with a lower rate of reversible GFR improvement compared with the other antibiotics. This secondary analysis concluded that piperacillin/tazobactam was a cause of delayed renal recovery in these patients.

Drug Interactions

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 mechanism 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. Monitor for adverse reactions related to neuromuscular blockade.

Oral anticoagulants

During simultaneous administration of heparin, oral anticoagulants and other substances , 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.

Vancomycin

Studies have detected an increased incidence of acute kidney injury in patients concomitantly administered piperacillin/tazobactam and vancomycin as compared to vancomycin alone. Some of these studies have reported that the interaction is vancomycin dose-dependent.

No pharmacokinetic interactions have been noted between piperacillin / tazobactam and vancomycin.

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.

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 above in patients receiving Piperacillin/Tazobactam should be confirmed by other diagnostic methods.

Use in Special Populations

Patients with Renal Impairment

In patients with creatinine clearance ≤ 40 mL/min and dialysis patients (hemodialysis and CAPD), the intravenous dose of piperacillin and tazobactam for injection should be reduced to the degree of renal function impairment

Patients with Hepatic Impairment

Dosage adjustment of piperacillin and tazobactam for injection is not warranted in patients with hepatic cirrhosis.

Pregnant Women

Risk Summary

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 rats 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/m ). 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/m).

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.

Animal Data

In embryo-fetal development studies in mice and rats, pregnant animals received intravenous doses of piperacillin/tazobactam up to 3000/750 mg/kg/day during the period of organogenesis. There was no evidence of teratogenicity up to the highest dose evaluated, which is 1 to 2 times and 2 to 3 times the human dose of piperacillin and tazobactam, in mice and rats respectively, based on body-surface area (mg/m ). Fetal body weights were reduced in rats at maternally toxic doses at or above 500/62.5 mg/kg/day, minimally representing 0.4 times the human dose of both piperacillin and tazobactam based on body-surface area (mg/m ).

A fertility and general reproduction study in rats using intraperitoneal administration of tazobactam or the combination piperacillin/tazobactam prior to mating and through the end of gestation, reported a decrease in litter size in the presence of maternal toxicity at 640 mg/kg/day tazobactam (4 times the human dose of tazobactam based on body-surface area), and decreased litter size and an increase in fetuses with ossification delays and variations of ribs, concurrent with maternal toxicity at ≥640/160 mg/kg/day piperacillin/tazobactam (0.5 times and 1 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area).

Peri/postnatal development in rats was impaired with reduced pup weights, increased stillbirths, and increased pup mortality concurrent with maternal toxicity after intraperitoneal administration of tazobactam alone at doses ≥320 mg/kg/day (2 times the human dose based on body surface area) or of the combination piperacillin/tazobactam at doses ≥640/160 mg/kg/day (0.5 times and 1 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area) from gestation day 17 through lactation day 21.

Lactating women

Risk Summary

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 and tazobactam for injection and any potential adverse effects on the breastfed child from piperacillin and tazobactam for injection or from the underlying maternal condition.

Pediatric Patients

Use of piperacillin and tazobactam for injection in pediatric patients 2 months of age or older with appendicitis and/or peritonitis is supported by evidence from well-controlled studies and pharmacokinetic studies in adults and in pediatric patients. This includes a prospective, randomized, comparative, open-label clinical trial with 542 pediatric patients 2-12 years of age with complicated intra-abdominal infections, in which 273 pediatric patients received piperacillin/tazobactam. Safety and efficacy in pediatric patients less than 2 months of age have not been established.

Geriatric Patients

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 impairment.

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 drug therapy. Piperacillin and tazobactam for injection contains sodium. To be taken into account by patients on a controlled sodium diet. The geriatric population may respond with a blunted natriuresis to salt loading. This may be clinically important with regard to such diseases as congestive heart failure. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Effects on Ability to Drive & Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

Undesirable Effects

The most commonly reported adverse reactions is diarrhea (occurring in patient out of 10).

Among the most serious adverse reactions pseudo-membranous colitis and toxic epidermal necrolysis occur in 1 to 10 patients in 10,000. The frequencies for pancytopenia, anaphylactic shock and Stevens-Johnson syndrome cannot be estimated from the currently available data.

In the following table, adverse reactions are listed by system organ class and MedDRA-preferred term. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class

Very common

(≥1/10)

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1,000 to

<1/100)

Rare

(≥1/10,000 to

<1/1,000)

Frequency not known (cannot be estimated from available data)

Infections and infestations

 

Candida infection*

 

Pseudomembranous

colitis

 

Blood and lymphatic system disorders

 

thrombocytopaenia, anaemia*

leukopaenia,

agranulocytosis,

pancytopaenia*, neutropenia, haemolytic anaemia*, thrombocytosis*, eosinophilia*

Immune system disorders

       

anaphylactoid reaction*, anaphylactic reaction*, anaphylactoid shock*, anaphylactic shock*, hypersensitivity*

Metabolism and nutrition disorders

   

hypokalaemia,

   

Psychiatric

Disorders

 

Insomnia

 

 

 

Nervous system disorders

 

Headache

     

Vascular disorders

   

hypotension, phlebitis, thrombophlebitis, flushing

   

Respiratory,

thoracic and

mediastinal

disorders

 

 

 

epistaxis

eosinophilic pneumonia, bronchospasm also occur

Gastrointestinal disorders

diarrhoea

abdominal pain, vomiting, nausea, constipation, dyspepsia

 

stomatitis

 

Hepatobiliary disorders

       

hepatitis*, jaundice,

Skin and subcutaneous tissue disorders

 

rash, pruritus

erythema multiforme*, urticaria, rash maculopapular*

toxic epidermal necrolysis*

Stevens-Johnson syndrome*, drug reaction with eosinophilia and systemic symptoms (DRESS)*, acute generalised exanthematous pustulosis (AGEP)*, dermatitis bullous, purpura

Musculoskeletal and connective tissue disorders

   

arthralgia, myalgia

   

Renal and urinary disorders

       

renal failure, tubulointerstitial nephritis*

General disorders and administration site conditions

 

pyrexia, injection site reaction

Chills

   

Investigations

 

Alanine

aminotransferase

increased,

aspartate

aminotransferase

increased, protein

total decreased,

blood albumin

decreased,

Coombs direct

test positive,

blood creatinine

increased, blood

alkaline

phosphatase

increased, blood

urea increased,

activated partial

thromboplastin

time prolonged

blood glucose

decreased, blood

bilirubin

increased,

prothrombin time

prolonged

 

bleeding time prolonged,

gammaglutamyltransferase

increased

*ADR identified post marketing

Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.

Studies and postmarketing experience of piperacillin/ tazobactam in pediatric patients suggest a similar safety profile to that seen in adults.

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the National Pharmacovigilance Programme of India by calling on 1800 267 7779 (Cipla number) or you can report to PvPI on 1800 180 3024. By reporting side effects, you can help provide more information on the safety of this product.

Overdose

Symptoms

There have been post-marketing reports of overdose with piperacillin/tazobactam. The majority of those events experienced including nausea, vomiting, and diarrhoea have also been reported with the usual recommended dose. Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure).

Treatment

In the event of an overdose, piperacillin/tazobactam treatment should be discontinued. No specific antidote is known. 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 haemodialysis.

Pharmacological Properties

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. Tazobactam does not induce chromosomally-mediated β-lactamases at tazobactam concentrations achieved with the recommended dosage regimen.

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 (methicillin susceptible isolates only)

Gram-negative bacteria:

Acinetobacter baumannii

Escherichia coli

Haemophilus influenzae (excluding β-lactamase negative, ampicillin-resistant isolates)

Klebsiella pneumoniae

Pseudomonas aeruginosa (given in combination with an aminoglycoside to which the isolate is susceptible)

Gram negative Anaerobic bacteria:

Bacteroides fragilis group (B. fragilis, B. ovatus, B. thetaiotaomicron, and B. vulgatus)

The following in vitro data are available, but their clinical significance is unknown.

At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for piperacillin/tazobactam. However, the safety and effectiveness of piperacillin/tazobactam in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Gram-positive bacteria:

Enterococcus faecalis (ampicillin or penicillin-susceptible isolates only)

Staphylococcus epidermidis (methicillin susceptible isolates only)

Streptococcus agalactiae

Streptococcus pneumoniae (penicillin-susceptible isolates only)

Streptococcus pyogenes

Viridans group streptococci

Gram-negative bacteria:

Citrobacter koseri

Moraxella catarrhalis

Morganella morganii

Neisseria gonorrhoeae

Proteus mirabilis

Proteus vulgaris

Serratia marcescens

Providencia stuartii

Providencia rettgeri

Salmonella enterica

Anaerobic bacteria:

Clostridium perfringens

Bacteroides distasonis

Prevotella melaninogenica

These are not β-lactamase producing bacteria and, therefore, are susceptible to piperacillin alone.

Pharmacokinetics Properties

The mean and coefficients of variation (CV%) for the pharmacokinetic parameters of piperacillin and tazobactam after multiple I.V. doses are summarized in Table 1 given below. 

Table 1: Mean (CV%) Piperacillin and Tazobactam Pharmacokinetic Parameters

Peak plasma concentrations of piperacillin and tazobactam are attained immediately after completion of an intravenous infusion of piperacillin and tazobactam for injection. Piperacillin plasma concentrations, following a 30-minute infusion of piperacillin and tazobactam for injection, 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.

Piperacillin/Tazobactam Concentrations in Selected Tissues and Fluids after Single 4gm/0.5 gm 30-min IV Infusion of Piperacillin and Tazobactam

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 piperacillin and tazobactam 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.

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 piperacillin and tazobactam for injection are recommended when creatinine clearance is below 40 mL/min in patients receiving the usual recommended daily dose of piperacillin and tazobactam for injection. See Dosage and Administration for specific recommendations for the treatment of patients with renal impairment.

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 piperacillin and tazobactam for injection 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.

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.

Drug Interactions

The potential for pharmacokinetic drug interactions between piperacillin and tazobactam for injection and aminoglycosides, probenecid, vancomycin, heparin, vecuronium, and methotrexate has been evaluated.

Non-Clinical Properties

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term carcinogenicity studies in animals have not been conducted with piperacillin/tazobactam, piperacillin, or tazobactam.

Piperacillin/Tazobactam

Piperacillin/tazobactam was negative in microbial mutagenicity assays, the unscheduled DNA synthesis (UDS) test, a mammalian point mutation (Chinese Hamster Ovary cell HPRT) assay, and a mammalian cell (BALB/c-3T3) transformation assay. In vivo, piperacillin/tazobactam did not induce chromosomal aberrations in rats.

Piperacillin/Tazobactam

Reproduction studies have been performed in rats and have revealed no evidence of impaired fertility when piperacillin/tazobactam is administered intravenously up to a dose of 1280/320 mg/kg piperacillin/tazobactam, which is similar to the maximum recommended human daily dose based on body-¬surface area (mg/m2).

Description

Piperacillin and Tazobactam for Injection is an injectable antibacterial combination product consisting of the semisynthetic antibacterial piperacillin sodium and the β-lactamase inhibitor tazobactam sodium for intravenous administration.

Piperacillin sodium is derived from D(-)-α-aminobenzyl-penicillin. The chemical name of piperacillin sodium is sodium(2S,5R,6R)-6--3,3-dimethyl-7-oxo-4-thia-1-azabicycloheptane-2-carboxylate. The chemical formula is C23H26N5NaO7S and the molecular weight is 539.5.

Tazobactam sodium, a derivative of the penicillin nucleus, is a penicillanic acid sulfone. Its chemical name is sodium(2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1- azabicycloheptane-2-carboxylate-4,4-dioxide. The chemical formula is C10H11N4NaO5S and the molecular weight is 322.3.

Pharmaceutical Particulars

Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned.

Whenever Piperacillin / Tazobactam is used concurrently with another antibiotic (e.g. aminoglycosides), the drugs must be administered separately. The mixing of Piperacillin / Tazobactam with an aminoglycoside in vitro can result in substantial inactivation of the aminoglycoside.

Piperacillin / Tazobactam should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established.

Piperacillin/Tazobactam should be administered through an infusion set separately from any other drugs unless compatibility is proven.

Due to chemical instability, Piperacillin / Tazobactam should not be used with solutions that contain sodium bicarbonate.

Lactated Ringer's (Hartmann’s) solution is not compatible with piperacillin/tazobactam.

Piperacillin / Tazobactam should not be added to blood products or albumin hydrolysates.

Shelf Life

See on pack.

Packaging Information

TAZACT 1.125 gm: Vial of 10 mL

TAZACT 2.25 gm: Vial of 20 mL

TAZACT 4.5 gm: Vial of 30 mL

Storage & Handling Instruction

Prior to Reconstitution:

Store at controlled room temperature (20ºC - 25ºC). Protect from light and moisture. Do not freeze.

After Reconstitution: Store at (2ºC - 8ºC)

Patient Counselling Information

What Piperacillin/Tazobactam is and what it is used for?

Piperacillin belongs to the group of medicines known as “broad spectrum penicillin antibiotics”, it can kill many kinds of bacteria. Tazobactam can prevent some resistant bacteria from surviving the effects of piperacillin. This means that when piperacillin and tazobactam are given together, more types of bacteria are killed.

What you need to know before you take Piperacillin/Tazobactam?

Do not use Piperacillin/Tazobactam

- if you are allergic to piperacillin or tazobactam or any of the other ingredients of this medicine

- if you are allergic to antibiotics known as penicillins, cephalosporins or other betalactamase inhibitors, as you may be allergic to Piperacillin/Tazobactam.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before using Piperacillin/Tazobactam

- if you have allergies. If you have several allergies make sure you tell your doctor or other healthcare professional before receiving this product.

- if you are suffering from diarrhoea before, or if you develop diarrhoea during or after your treatment. In this case, make sure you tell your doctor or other healthcare professional immediately. Do not take any medicine for the diarrhoea without first checking with your doctor.

- if you have low levels of potassium in your blood. Your doctor may want to check your kidneys before you take this medicine and may perform regular blood tests during treatment

- if you have kidney or liver problems, or are receiving haemodialysis. Your doctor may want to check your kidneys before you take this medicine, and may perform regular blood tests during treatment

- if you are taking certain medicines (called anticoagulants) to avoid an excess of blood clotting (see also Other medicines and Piperacillin/Tazobactam in this leaflet) or any unexpected bleeding occurs during the treatment. In this case, you should inform your doctor or other healthcare professional immediately.

- if you develop convulsions during the treatment. In this case, you should inform your doctor or other healthcare professional.

- if you think you developed a new or worsening infection. In this case, you should inform your doctor or other healthcare professional.

Other medicines and Piperacillin/Tazobactam

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Some medicines may interact with piperacillin and tazobactam. These include:

- Medicines for gout (Probenecid). This can increase the time it takes for piperacillin and tazobactam to leave your body.

Medicines to thin your blood or to treat blood clots (e.g. heparin, warfarin or aspirin).

- Medicines used to relax your muscles during surgery. Tell your doctor if you are going to have a general anaesthetic.

- Methotrexate (medicine used to treat cancer, arthritis or psoriasis). Piperacillin and tazobactam can increase the time it takes for methotrexate to leave your body.

- Medicines that reduce the level of potassium in your blood (e.g. tablets, enhancing urination or some medicines for cancer).

- medicines containing the other antibiotics tobramycin, gentamycin or vancomycin.

Tell your doctor if you have kidney problems.

Effect on laboratory tests

Tell the doctor or laboratory staff that you are taking Piperacillin / tazobactam if you have to provide a blood or urine sample.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast feeding think you may be pregnant or are planning to have a baby, ask your doctor or other healthcare professional for advice before receiving this medicine. Your doctor will decide if Piperacillin / tazobactam is right for you. Piperacillin and Tazobactam can pass to a baby in the womb or through breast milk. If you are breast-feeding, your doctor will decide if Piperacillin/Tazobactam is right for you.

Driving and using machines

The use of Piperacillin / tazobactam is not expected to affect the ability to drive or use machines.

How to take Piperacillin/Tazobactam?

Your doctor or other healthcare professional will give you this medicine through an infusion (a drip for 30 minutes) into one of your veins.

Dosage

The dose of medicine given to you depends on what you are being treated for, your age, and whether or not you have kidney problems.

Adults and adolescents aged 12 years or older

The usual dose is piperacillin 4 gm / tazobactam 0.5 gm given every 6-8 hours, which is given into one of your veins.

Children

The usual dose to treat abdominal infections in children aged 2 to 9 months is 80 mg/ 10 mg per kg of body weight while in children 9 months and above, the dose is 100 mg / 12.5 mg per kg of body weight of piperacillin / tazobactam given every 8 hours into the child’s vein (directly into the blood stream). The usual dose for children with low white blood cell counts is 80 mg / 10 mg per kg of body weight of piperacillin / tazobactam given every 6 hours.

Your doctor will calculate the dose depending on your child's weight but each individual dose will not exceed  piperacillin 4 gm / tazobactam 0.5 gm.

You will be given piperacillin / tazobactam until the sign of infection has gone completely (5 to 14 days)

Patients with kidney problems

Your doctor may need to reduce the dose of Piperacillin/Tazobactam or how often you are given it. Your doctor may also want to test your blood to make sure that your treatment is at the right dose, especially if you have to take this medicine for a long time.

If you take more Piperacillin/Tazobactam than you should

As you will receive Piperacillin/Tazobactam from a doctor or other healthcare professional, you are unlikely to be given the wrong dose. However, if you experience side effects such as convulsions, or think you have been given too much, tell your doctor immediately.

If you miss a dose of Piperacillin/Tazobactam

If you think you have not been given a dose of Piperacillin/Tazobactam, tell your doctor or other healthcare professional immediately.

If you have any further questions on the use of this medicine, ask your doctor or nurse.

Possible side effects?

Like all medicines, this medicine can cause side effects, although not everybody gets them.

See a doctor immediately if you experience any of these potentially serious side effects of Piperacillin/Tazobactam

The serious side effects of Piperacillin/Tazobactam are:

- serious skin rashes appearing initially as reddish target-like spots or circular patches often with central blisters on the trunk. Additional signs include ulcers in the mouth, throat, nose, extremities, genitals and conjunctivitis (red and swollen eyes).

The rash may progress to widespread blistering or peeling of the skin and potentially may be life threatening

- severe potentially fatal allergic condition (drug reaction with eosinophilia and systemic symptoms) that can involve the skin and most importantly other organs under the skin such as the kidney and the liver.

- a skin condition (acute generalised exanthematous pustulosis) accompanied by fever, which consists of numerous tiny fluid filled blisters contained within large areas of swollen and reddened skin

- swelling of the face, lips, tongue or other parts of the body (Not known)

- shortness of breath, wheezing or trouble breathing (Not known)

- severe rash or hives (uncommon), itching or rash on the skin (Common)

- yellowing of the eyes or skin (Not known)

- damage to blood cells ,severe decrease in white blood cells (Rare)

- severe or persistent diarrhoea accompanied by a fever or weakness (Rare)

If any of the following side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or other healthcare professional.

Very common side effects (may affect more than 1 in 10 people):

·diarrhoea

Common side effects (may affect up to 1 in 10 people)

·yeast infection

·decrease in platelets, decrease of red blood cells or blood pigment / haemoglobin,

abnormal lab test (positive direct Coombs), prolonged blood clotting time (activated

partial thromboplastin time prolonged)

·decrease in blood protein

·headache, sleeplessness

·abdominal pain, vomiting, nausea, constipation, upset stomach

·increase in blood liver enzymes

·skin rash, itching

·abnormal kidney blood tests

·fever, injection site reaction

Uncommon side effects (may affect up to 1 in 100 people)

·decrease in white blood cells (leukopenia), prolonged blood clotting time

(prothrombin time prolonged)

·decreased blood potassium, decreased blood sugar

·low blood pressure, inflammation of the veins (felt as tenderness or redness in the

affected area), reddening of skin

·increase of a blood pigment breakdown product (bilirubin)

·skin reactions with redness, formation of skin lesions, nettle rash

·joint and muscle pain

·chills

Hypokalaemia and bronchospasm

Rare side effects (may affect up to 1 in 1,000 people) are:

·severe decrease in white blood cells (agranulocytosis), bleeding of the nose

·serious infection of the colon, inflammation of the mucous lining of the mouth

·detachment of the top layer of the skin all over the body (toxic epidermal necrolysis)

Not known side effects (cannot be estimated from the available data):

·severe decrease of red blood cells, white blood cells and platelets (pancytopenia),

decrease in white blood cells (neutropenia), decrease of red blood cells due to

premature breakdown or degradation, small spot bruising, bleeding time prolonged,

increase of platelets, increase of a specific type of white blood cells (eosinophilia)

·allergic reaction and severe allergic reaction

·inflammation of the liver, yellow staining of the skin or whites of the eyes

·poor kidney functions and kidney problems

·a form of lung disease where eosinophils (a form of white blood cell) appear in the

lung in increased numbers

Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.

Experience of piperacillin/ tazobactam in children suggest a similar safety profile to that seen in adults.

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the National Pharmacovigilance Programme of India by calling on 1800 267 7779 (Cipla number) or you can report to PvPI on 1800 180 3024. By reporting side effects, you can help provide more information on the safety of this product.

How to store Piperacillin/Tazobactam?

Keep this medicine out of the sight and reach of children.

Piperacillin/Tazobactam for injection vials should be store at controlled room temperature (20ºC - 25ºC) Protect from light and moisture. Do not freeze. (prior to reconstitution)

After reconstitution: store at (2ºC - 8ºC)

Do not use Piperacillin/Tazobactam after the expiry date which is stated on the carton and the vials after Expiry. The expiry date refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use . These measures will help to protect the environment.

Details of Manufacturer

Akums Drugs & Pharmaceuticals Ltd.

2, 3, 4 & 5, Sector – 6 B I.I.E, SIDCUL

Ranipur, Haridwar- 249 403 INDIA

Marketed by : CIPLA LTD.

Cipla House, Peninsula Business Park,

Ganpatrao Kadam Marg, Lower Parel,

Mumbai – 400 013, INDIA

Details of Permission or Licence Number with Date

M.L. 29/UA/SC/P-2007 dated 20/04/2021

Date of Revision

24/05/2021