Piperacillin and Tazobactam for Injection USP 2.25g (PIPRANEM) Taj Pharma

  1. Name of the medicinal product

Piperacillin and Tazobactam for Injection USP 2.25g (PIPRANEM) Taj Pharma
Piperacillin and Tazobactam for Injection USP 4.5g (PIPRANEM) Taj Pharma

2. Qualitative and quantitative composition

Each vial contains piperacillin (as sodium salt) equivalent to 2g and tazobactam (as sodium salt) equivalent to 0.25g.

Each vial contains piperacillin (as sodium salt) equivalent to 4g and tazobactam (as sodium salt) equivalent to 0.5g.

  1. Pharmaceutical form

Powder for solution for infusion.

White to off-white powder.

  1. Clinical particulars

4.1 Therapeutic indications

Piperacillin/Tazobactam 2 g/0.25 g Powder for Solution for Infusion is indicated for treatment of the following infections in adults and children over 2 years of age (see sections 4.2 and 5.1):

Adults and adolescents

  • Severe pneumonia including hospital-acquired and ventilator-associated pneumonia
  • Complicated urinary tract infections (including pyelonephritis)
  • Complicated intra-abdominal infections
  • Complicated skin and soft tissue infections (including diabetic foot infections)

Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with any of the infections listed above.

Piperacillin/Tazobactam may be used in the management of neutropenic patients with fever suspected to be due to a bacterial infection.

Children aged 2-12 years

  • Complicated intra-abdominal infections

Piperacillin/Tazobactam may be used in the management of neutropenic children with fever suspected to be due to a bacterial infection.

Consideration should be given to official guidance on the appropriate use of anti-bacterial agents.

4.2 Posology and 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 g piperacillin / 0.5 g tazobactam given every 8 hours.

For nosocomial pneumonia and bacterial infections in neutropenic patients, the recommended dose is 4 g piperacillin / 0.5 g 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 4g/0.5g
Every 6 hours Severe pneumonia
Neutropenic adults with fever suspected to be due to a bacterial infection.
Every 8 hours Complicated urinary tract infections (including pyelonephritis)
Complicated intra-abdominal infections
Skin and soft tissue infections (including diabetic foot 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)

Recommended dose
> 40 No dose adjustment necessary
20-40 Maximum dose suggested: 4 g / 0.5 g every 8 hours
< 20 Maximum dose suggested: 4 g / 0.5 g every 12 hours

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

Hepatic impairment

No dose adjustment is necessary (see section 5.2).

Dose in elderly patients

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

Paediatric population (2-12 years of age)

Infections

The following table summarises the treatment frequency and the dose per body weight for paediatric patients 2-12 years of age by indication or condition:

Dose per weight and treatment frequency Indication / condition
80 mg Piperacillin / 10 mg Tazobactam per kg body weight / every 6 hours Neutropenic children with fever suspected to be due to bacterial infections*
100 mg Piperacillin / 12.5 mg Tazobactam per kg body weight / every 8 hours Complicated intra-abdominal infections*

* Not to exceed the maximum 4 g / 0.5 g per dose over 30 minutes.

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)

Recommended dose
> 50 No dose adjustment necessary
≤ 50 70 mg piperacillin / 8.75 mg tazobactam / kg every 8 hours.

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

Use in children aged below 2 years

The safety and efficacy of Piperacillin/Tazobactam in children 0- 2 years of age has not been established. No data from controlled clinical studies are available.

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.

Route of administration

Piperacillin/Tazobactam 2 g / 0.25 g is administered by intravenous infusion (over 30 minutes).

Method of administration

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

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

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

4.4 Special warnings and precautions 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 treatment with Piperacillin/Tazobactam careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, other beta-lactam agents (e.g cephalosporins, monobactam or carbapenem) and other allergens. Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid [including shock]) reactions have been reported in patients receiving treatment 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.

Serious skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in patients receiving piperacillin tazobactam (see section 4.8). 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.

Therapy with Piperacillin/Tazobactam may result in the emergence of resistant organisms, which might cause superinfections.

Bleeding manifestations have occurred in some patients receiving beta-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.

Each vial contains 4.70 mmol (108 mg) of sodium. This should be taken into account by patients on a controlled sodium diet.

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

4.5 Interaction with other medicinal products and other forms of interaction

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 mechanisms 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.

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 of piperacillin and tazobactam; however peak plasma concentrations of either active substance 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.

For information related to the administration of piperacillin / tazobactam with aminoglycosides please refer to sections 6.2 and 6.6.

Vancomycin

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.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or a limited amount of data from the use of piperacillin / tazobactam in pregnant women.

Studies in animals have shown developmental toxicity, but no evidence of teratogenicity, at doses that are maternally toxic (see section 5.3).

Piperacillin and tazobactam cross the placenta. Piperacillin/Tazobactam should only be used during pregnancy if clearly indicated i.e. only if the expected benefit outweighs the possible risks to the pregnant woman and foetus.

Breast-feeding

Piperacillin is excreted in low concentrations in human milk; tazobactam concentrations in human milk have not been studied. Women who are breast-feeding should be treated only if the expected benefit outweighs the possible risks to the woman and child.

Fertility

A fertility study in rats showed no effect on fertility and mating after intraperitoneal administration of tazobactam or the combination piperacillin / tazobactam (see section 5.3).

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Frequencies are defined as follows:

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)

Very rare (<1/10,000)

Not known (can not be estimated from the 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.

MedDRA

System Organ Class

Frequency Undesirable Effects
Infections and infestations Uncommon Candidal superinfection
Blood and lymphatic system disorders Uncommon Leukopenia, neutropenia, thrombocytopenia
Rare Anaemia, haemolytic anaemia, purpura, epistaxis, bleeding time prolonged, eosinophilia
Very rare Agranulocytosis, pancytopenia, activated partial thromboplastin time prolonged, Coombs’ direct test positive, pancytopenia, thrombocythaemia
Immune system disorders Uncommon Hypersensitivity
Rare Anaphylacticanaphylactoid reaction (including shock)
Metabolism and nutritional disorders Very rare Hypokalaemia, blood glucose decreased, blood albumin decreased, blood protein total decreased
Nervous system disorders Uncommon Headache, insomnia
Vascular disorders Uncommon Hypotension, thrombophlebitis, phlebitis
Rare Flushing
Gastrointestinal disorders Common Diarrhoea, nausea, vomiting
Uncommon Jaundice, constipation, dyspepsia, stomatitis
Rare Abdominal pain, pseudomembranous colitis
Hepatobiliary disorders Uncommon Alanine aminotransferase increased, aspartate aminotransferase increased
Rare Hepatitis, blood bilirubin increased, blood alkaline phosphatase increased, gammaglutamiltransferase increased
Skin and subcutaneous tissue disorders Common Rash including maculopapular rash
Uncommon Pruritus, urticaria
Rare Erythema multiforme, dermatitis bullous, exanthema
Very rare Stevens-Johnson-Syndrome, toxic epidermal necrolysis
Musculo-skeletal and connective tissue disorders Rare Arthralgia, myalgia
Renal and urinary disorders Uncommon Blood creatinine increased
Rare Tubulonterstitial nephritis, renal failure
Very rare Blood urea increased
General disorders and administration site conditions Uncommon Pyrexia, injection site reactions
Rare Chills

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

4.9 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 (see section 4.4).

  1. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, Combinations of penicillins, incl beta-lactamase inhibitors.

Mechanism of action

Piperacillin, a broad-spectrum, semisynthetic penicillin exerts bactericidal activity by inhibition of both septum and cell-wall synthesis.

Tazobactam, a beta-lactam structurally related to penicillins, is an inhibitor of many beta-lactamases, which commonly cause resistance to penicillins and cephalosporinsbut it does not inhibit AmpC enzymes or metallo beta-lactamases. Tazobactam extends the antibiotic spectrum of piperacillin to include many beta-lactamase-producing bacteria that have acquired resistance to piperacillin alone.

Mechanism of resistance

The two main mechanisms of resistance to piperacillin / tazobactam are:

  • Inactivation of the piperacillin component by those beta-lactamases that are not inhibited by tazobactam: beta-lactamases in the Molecular class B, C and D. In addition, tazobactam does not provide protection against extended-spectrum beta-lactamases (ESBLs) in the Molecular class A and D enzyme groups.
  • Alteration of penicillin-binding proteins (PBPs), which results in the reduction of the affinity of piperacillin for the molecular target in bacteria.

Additionally, alterations in bacterial membrane permeability, as well as expression of multi-drug efflux pumps, may cause or contribute to bacterial resistance to piperacillin / tazobactam, especially in Gram-negative bacteria.

Breakpoints

EUCAST Clinical MIC Breakpoints for Piperacillin / Tazobactam (2009-12-02, v1).

For Susceptibility Testing Purposes, the Concentration of Tazobactam is Fixed at 4 mg/l

Pathogen Species related breakpoints (S</R>)
Enterobacteriaceae 8/16
Pseudomonas 16/16
Gram-negative and Gram-positive aerobes 8/16
Non-species related breakpoints 4/16

The susceptibility of streptococci is inferred from the penicillin susceptibility.

The susceptibility of staphylococci is inferred from the oxacillin susceptibility.

Susceptibility

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Groupings of relevant species according to piperacillin / tazobactam susceptibility
COMMONLY SUSCEPTIBLE SPECIES
Aerobic Gram-positive micro-organisms

Enterococcus faecalis

Listeria monocytogenes

Staphylococcus aureus, methicillin-susceptible£

Staphylococcus species, coagulase negative, methicillin-susceptible

Streptococcus pyogenes

Group B streptococci

Aerobic Gram-negative micro-organisms

Citrobacter koseri

Haemophilus influenza

Moraxella catarrhalis

Proteus mirabilis

Anaerobic Gram-positive micro-organisms

Clostridium species

Eubacterium species

Peptostreptococcus species

Anaerobic Gram-negative micro-organisms

Bacteroides fragilis group

Fusobacterium species

Porphyromonas species

Prevotella species

SPECIES FOR WHICH ACQUIRED RESISTANCE MAY BE A PROBLEM
Aerobic Gram-positive micro-organisms

Enterococcus faecium$,+

Streptococcus pneumonia

Streptococcus viridans group

Aerobic Gram-negative micro-organisms

Acinetobacter baumannii$

Burkholderia cepacia

Citrobacter freundii

Enterobacter species

Escherichia coli

Klebsiella pneumonia

Morganella morganii

Proteus vulgaris

Providencia ssp.

Pseudomonas aeruginosa

Serratia species
INHERENTLY RESISTANT ORGANISMS
Aerobic Gram-positive micro-organisms

Corynebacterium jeikeium

Aerobic Gram-negative micro-organisms

Legionella species

Stenotrophomonas maltophilia+,$

Other microorganisms
Chlamydophilia pneumonia
Mycoplasma pneumonia
$ Species showing natural intermediate susceptibility.

+ Species for which high-resistance rates (more than 50%) have been observed in one or more areas/countries/regions within the EU.

£ All methicillin-resistant staphylococci are resistant to piperacillin / tazobactam.

5.2 Pharmacokinetic properties

Absorption

The peak piperacillin and tazobactam concentrations after 4 g / 0.5 g administered over 30 minutes by intravenous infusion are 298 μg/ml and 34 μg/ml respectively.

Distribution

Both piperacillin and tazobactam are approximately 30% bound to plasma proteins. The protein binding of piperacillin or tazobactam is unaffected by the presence of the other compound.

Protein binding of the tazobactam metabolite is negligible.

Piperacillin/Tazobactam is widely distributed in tissues and body fluids, including intestinal mucosa, gallbladder, lungs, bile and bone. Mean tissue concentrations are generally 50-100% of those in plasma. Distribution into cerebrospinal fluid is low in subjects with non-inflamed meninges, as with other penicillins

Biotransformation

Piperacillin is metabolised to a minor microbiologically active desethyl-metabolite. Tazobactam is metabolised to a single metabolite that has been found to be microbiologically inactive.

Elimination

Piperacillin and Tazobactam are eliminated via the kidneys by glomerular filtration and tubular secretion.

Piperacillin is excreted rapidly as unchanged substance with 68% of the administered dose appearing in the urine. Tazobactam and its metabolite are eliminated primarily by renal excretion, with 80 % of the administered dose appearing as unchanged substance and the remainder as the single metabolite. Piperacillin, tazobactam and desethylpiperacillin are also secreted in the bile.

Following single or multiple doses of piperacillin/tazobactam to healthy subjects, the plasma half-life of piperacillin and tazobactam ranged from 0.7 to 1.2 hours and was unaffected by dose or duration of infusion. The elimination half-lives of both piperacillin and tazobactam are increased with decreasing renal clearance.

There are no significant changes in piperacillin pharmacokinetics due to tazobactam. Piperacillin appears to slightly reduce the clearance of tazobactam.

Special populations:

The half-life of piperacillin and of tazobactam increases by approximately 25% and 18%, respectively, in patients with hepatic cirrhosis compared to healthy subjects.

The half-life of piperacillin and tazobactam increases with decreasing creatinine clearance. The increase in half-life 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.

Haemodialysis removes 30% to 50% of piperacillin / tazobactam, 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 18% of the tazobactam dose removed as the tazobactam metabolite.

Paediatric population

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 paediatric patients 2-9 months of age. The population mean (SE) for piperacillin volume of distribution is 0.243 (0.011) l/kg and is independent of age.

Elderly patients

The mean half-life for piperacillin and tazobactam were 32% and 55% longer, respectively, in the elderly compared with younger subjects. This difference may be due to age-related changes in creatinine clearance.

Race

No difference in piperacillin or tazobactam pharmacokinetics was observed between Asian (n=9) and Caucasian (n=9) healthy volunteers who received single 4 g / 0.5 g doses.

Phamacokinetic / Pharmacodynamic relationship

The time above the minimum inhibitory concentration (T>MIC) is considered to be the major pharmacodynamic determinant of efficacy for piperacillin.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity and genotoxicity. Carcinogenicity studies have not been conducted with piperacillin/tazobactam.

A fertility and general reproduction study in rats using intraperitoneal administration of tazobactam or the combination piperacillin / tazobactam reported a decrease in litter size and an increase of foetuses with ossification delays and variations of ribs, concurrent with maternal toxicity. Fertility of the F1 generation and embryonic development of the F2 generation were not impaired.

Teratogenicity studies using intravenous administration of tazobactam or the combination piperacillin / tazobactam in mice and rats resulted in slight reductions in rat foetal weights at maternally toxic doses but did not show teratogenic effects.

Peri/postnatal development was impaired (reduced pup weights, increase in stillbirths, increase in pup mortality) concurrent with maternal toxicity after intraperitoneal administration of tazobactam or the combination piperacillin / tazobactam in the rat.

  1. Pharmaceutical particulars

6.1 List of excipients

None

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Whenever piperacillin/tazobactam is used concurrently with another antibiotic (e.g. aminoglycosides), the substances must be administered separately. The mixing of beta-lactam antibiotics with an aminoglycoside in vitro can result in substantial inactivation of the aminoglycoside.

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

Lactated Ringer’s solution is not compatible with Piperacillin/Tazobactam.

Due to chemical instability, piperacillin/tazobactam should not be used in solutions containing only sodium bicarbonate.

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

6.3 Shelf life

Unopened vial: 3 years.

Reconstituted/Diluted solution:

When prepared under aseptic conditions chemical and physical in use stability has been demonstrated for 5 hours at 20-25°C and for 24 hours at 2-8°C.

From the microbiological point of view, the product should be used immediately.

If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

6.4 Special precautions for storage

Do not store above 25°C. Store in the original package.

For storage conditions after reconstitution/dilution of the medicinal product see section 6.3.

Unused solutions should be discarded.

6.5 Nature and contents of container

Clear type 1 glass vial with a bromo or chlorobutyl rubber stopper and an aluminium flip-off seal.

Pack sizes:

1 x 1 vial containing powder for solution for infusion

10 x 1 vial containing powder for solution for infusion

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

The reconstitution and dilution is to be made under aseptic conditions. The solution is to be inspected visually for particulate matter and discoloration prior to administration. The solution should only be used if the solution is clear and free from particles.

Intravenous use

Reconstitute each vial with the volume of solvent shown in the table below, using one of the compatible solvents for reconstitution. Swirl until dissolved. When swirled constantly, reconstitution generally occurs within 5 to 8 minutes (for details on handling, please see below).

Content of vial Volume of solvent* to be added to vial
2g/0.25g (2g piperacillin and 0.25g tazobactam) 10 ml
4g/0.5g (4g piperacillin and 0.5g tazobactam) 20ml

* Compatible solvents for reconstitution/dilution:

– Sterile water for injection (1)

– Sodium chloride 9 mg/ml (0.9%) solution for injection

– Glucose solution 5 mg/ml (5%)

(1) Maximum recommended volume of sterile water for injection per dose is 50 ml.

The reconstituted solutions should be withdrawn from the vial by syringe. When reconstituted as directed, the vial contents withdrawn by syringe will provide the labelled amount of piperacillin and tazobactam.
The reconstituted solutions can be further diluted to the desired volume (e.g. 50 ml to 150 ml) with one of the following compatible solvents:

– Glucose solution 5 mg/ml (5%)

– Sodium chloride 9 mg/ml (0.9%) solution for infusion

Co-administration with aminoglycosides

Due to the in vitro inactivation of the aminoglycoside by beta-lactam antibiotics, piperacillin/tazobactam and the aminoglycoside are recommended for separate administration. Piperacillin/tazobactam and the aminoglycoside should be reconstituted and diluted separately when concomitant therapy with aminoglycosides is indicated.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
For single use only. Discard any unused solution.

  1. Manufactured in India by:
    TAJ PHARMACEUTICALS LTD.

    At: 615, GIDC, Kerala, Bavla Dist., Ahmedabad-438225, Gujarat, INDIA

PACKAGE LEAFLET: INFORMATION FOR THE USER

Piperacillin and Tazobactam for Injection USP 2.25g / 4.5g (PIPRANEM) Taj Pharma

Piperacillin and tazobactam

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

•   Keep this leaflet. You may need to read it again.

  • If you have any further questions, ask your doctor or
  • This medicine has been prescribed for you Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
  • If you get any side effects talk to your doctor or healthcare This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet:

  1. What Piperacillin / Tazobactam is and what it is used for
  2. What you need to know before you use Piperacillin / Tazobactam
  3. How to use Piperacillin / Tazobactam
  4. Possible Side Effects
  5. How to store Piperacillin / Tazobactam
  6. Contents of the pack and other information

 

  1. 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 types 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.

Piperacillin / Tazobactam is used in adults and adolescents to treat bacterial infections, such as those affecting the lower respiratory tract (lungs), urinary tract (kidneys and bladder), abdomen, skin or blood. Piperacillin / Tazobactam may be used to treat bacterial infections in patients with low white blood cell counts (reduced resistance to infections).

Piperacillin / Tazobactam is used in children aged 2-12 years to treat infections of the abdomen such as appendicitis, peritonitis (infection of the fluid and lining of the abdominal organs), and gallbladder (biliary) infections. Piperacillin / Tazobactam may be used to treat bacterial infections in patients with low white blood cell counts (reduced resistance to infections).

In certain serious infections, your doctor may consider using Piperacillin / Tazobactam in combination with other antibiotics.

  1. WHAT YOU NEED TO KNOW BEFORE YOU USE PIPERACILLIN/TAZOBACTAM

Do not use Piperacillin / Tazobactam

  • if you are allergic (hypersensitive) to piperacillin or tazobactam
  • if you are allergic (hypersensitive) to antibiotics known as penicillins, cephalosporins, or other betalactamase inhibitors, as you may be allergic to Piperacillin / Tazobactam

Warning and precautions:

Talk to your doctor or other healthcare professional before using Piperacillin / Tazobactam:

if you have allergies. If you have several allergies, make sure you tell your doctor or other healthcare professional beforereceiving this product.

  • if you are suffering from diarrhoea before, or if you develop diarrhoea during or after your 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 think you developed a new or worsening In this case, you should inform your doctor or other healthcare professional
  • if you are taking certain medicines (called anticoagulants) to avoid an excess of blood clotting (see also Using other medicines in this leaflet) or any unexpected bleeding occurs during the In this case, you should inform your doctor or other healthcare professional immediately
  • 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 develop convulsions during the treatment. In this case, you should inform your doctor or other healthcare professional
  • if you have low levels of potassium in your Your doctor may want to check your kidneys before you take this medicine and may perform regular blood tests during treatment.

Children below 2 years

Piperacillin / Tazobactam is not recommended for use in children below the age of 2 years due to insufficient data on safety and effectiveness.

Other medicines and Piperacillin / Tazobactam

Tell your doctor or other healthcare professional if you are taking or have recently taken or might take any other medicines, including medicines obtained without a prescription.

Some medicines may interact with piperacillin and tazobactam.

These include:

  • medicine for gout (probenecid). This can increase the time it takes for piperacillin and tazobactam to leave your
  • 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

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 or gentamycin. Tell your doctor if you have kidney problems.

Effect on laboratory tests

Tell your doctor or laboratory staff that you are taking Piperacillin/Tazobactam if you had to provide a blood or urine sample.

Pregnancy and breast-feeding

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 taking this medicine.

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.

Important information about some of the ingredients of Piperacillin / Tazobactam

Piperacillin / Tazobactam 2g/0.25g contains 4.70 mmol (108 mg) of sodium. Piperacillin / Tazobactam 4g/0.5g contains 9.39 mmol (216 mg) of sodium.

This should be taken into consideration if you are on a controlled sodium diet.

  1. HOW TO USE PIPERACILLIN/TAZOBACTAM

Take this medicine exactly as your doctor or healthcare professional has told you. Check with your doctor or healthcare professional if you are not sure. Your doctor or other healthcare professional will give you this medicine through an infusion (a drip for 30 minutes) into one of your veins.

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.

Use in adults and adolescents aged 12 years or older)

The usual dose is 4g/0.5g Piperacillin / Tazobactam given every 6-8 hours, which is given into one of your veins (directly into the blood stream).

Use in children aged 2 to 12 years The usual dose for children with abdominal infections is 100 mg / 12.5 mg / kg of body weight of Piperacillin / Tazobactam given every 8 hours into one of your veins (directly into the blood stream).

The usual dose for children with low

white blood cell counts is 80 mg / 10 mg

/ kg of body weight of Piperacillin / Tazobactam given every 6 hours into one of your veins (directly into the blood stream).

Your doctor will calculate the dose depending on your child’s weight but the daily dose will not exceed 4 g / 0.5 g of Piperacillin / Tazobactam.

You will be given Piperacillin / Tazobactam until the sign of infection has gone completely (5 to 14 days).

Use in 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 forgot to take 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 other healthcare professional.

  1. 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:

  • Serious skin rashes (Stevens-Johnson syndrome, toxic epidermal necrolysis) 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
  • swelling of the face, lips, tongue or other parts of the body
  • shortness of breath, wheezing or trouble breathing
  • severe rash, itching or hives on the skin
  • yellowing of the eyes or skin
  • damage to blood cells (the signs include: being breathless when you do not expect it, red or brown urine, nosebleeds and bruising)
  • severe or persistent diarrhoea accompanied by a fever or weakness
  • unexpected bleeding, particularly if you are taking anticoagulants such as warfarin

Other possible side effects:

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

  • diarrhoea, vomiting, nausea
  • skin rashes

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

  • thrush
  • (abnormal) decrease in white blood cells (leukopenia, neutropenia) and platelets (thrombocytopenia)
  • allergic reaction
  • headache, sleeplessness
  • low blood pressure, inflammation of the veins (felt as tenderness or redness in the affected area)
  • jaundice (yellow staining of the skin or

whites of the eyes), inflammation of the mucous lining of the mouth, constipation, indigestion, stomach upset

  • increase of certain enzymes in the blood (alanine aminotransferase increased, aspartate aminotransferase increased
  • itching, nettle rash
  • increase of muscle metabolism product in the blood (blood creatinine increased)
  • fever, injection site reaction
  • yeast infection (candidal superinfection)

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

  • (abnormal) decrease of red blood cells or blood pigment / haemoglobin, (abnormal) decrease of red blood cells due to premature breakdown (degradation) (haemolytic anaemia), small spot bruising (purpura), bleeding of the nose (epistaxis) and bleeding time prolonged, (abnormal) increase of a specific type of white blood cells (eosinophilia)
  • severe allergic reaction (anaphylactic/anaphylactoid reaction, including shock)
  • flushed red skin
  • a certain form of infection of the colon (pseudomembranous colitis), abdominal pain
  • inflammation of the liver (hepatitis),

increase of a blood pigments breakdown product (bilirubin), increase of certain enzymes in the blood (blood alkaline phosphatase increased, gamma- glutamiltransferase increased)

  • skin reactions with redness and formation of skin lesions (exanthema, erythema multiforme), skin reactions with blistering (bullous dermatitis)
  • joint and muscle pain
  • poor kidney functions and kidney problems
  • rigors chill / rigidity

Very rare side effects (may affect up to 1 in 10,000 people)

  • severe decrease of granular white blood cells (agranulocytosis), severe decrease of red blood cells, white blood cells and platelets (pancytopenia)
  • prolonged time for blood clot formation (prolonged partial thromboplastin time, prothrombin time prolonged), abnormal lab test (positive direct Coombs), increase of platelets (thrombocythaemia)
  • decrease of potassium in the blood (hypokalaemia), decrease of blood sugar (glucose), decrease of the blood protein albumin, decrease of blood total protein

detachment of the top layer of the skin all over the body (toxic epidermal necrolysis), serious bodywide allergic reaction with skin and mucous lining rashes and various skin eruptions (Stevens-Johnson Syndrome)

  • blood urea nitrogen increased

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

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

  1. HOW TO STORE PIPERACILLIN/TAZOBACTAM

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

Do not use this medicine after the expiry date which is stated on the carton and vial after “Exp”. The expiry date refers to the last day of that month.

Unopened vials: Do not store above 25°C. Store in the original package.

The reconstituted/diluted solution should be used within 5 hours when stored at 20-25°C and within 24 hours when stored at 2 – 8°C.

Only clear solutions, free of visible particles should be used.

For single use only.

Discard any unused solution.

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.

  1. CONTENTS OF THE PACK AND OTHER INFORMATION

What Piperacillin / Tazobactam contains

The active substances are Piperacillin and Tazobactam.

Each vial contains 2 g piperacillin (as sodium salt) and 0.25 g tazobactam (as sodium salt). Each vial contains 4 g piperacillin (as sodium salt) and 0.5 g tazobactam (as sodium salt).

What Piperacillin / Tazobactam looks like and contents of the pack

White to off-white powder. Clear glass vial with a rubber stopper sealed with an aluminium flip-off seal.

Pack sizes:

1 x 1 vial containing powder for solution for infusion.

10 x 1 vial containing powder for solution for infusion.

Not all pack sizes may be marketed.

  1. Manufactured in India by:

TAJ PHARMACEUTICALS LTD.

At: 615, GIDC, Kerala, Bavla Dist., Ahmedabad-438225, Gujarat, INDIA

Related Products

Taj Generics (Taj Pharma) provides a wide range of products to the Indian market, including an extensive range of generics and specialty products; Our products cover a vast array of therapeutic categories, and we offer an extensive range of dosage forms and delivery systems including oral solids, controlled-release, steriles, injectables, topicals, liquids, transdermals, semi-solids and high-potency products. Our Generics portfolio offers over 1500 products in the major therapeutic areas of gastro-intestinal, cardiovascular, pain management, oncology, anti-infectives, paediatrics and dermatology.