TAZOTUM® 1.125 Injection

Piperacillin and Tazobactam injection IP 1.125g /2.25g/ 4.5g

TAZOTUM 1.125 Each vial contains:

Piperacillin Sodium IP (Sterile) equivalent to Piperacillin 1 g

Tazobactam Sodium IP (Sterile) equivalent to Tazobactam 125 mg

TAZOTUM 2.25 Each vial contains:

Piperacillin Sodium IP (Sterile) equivalent to Piperacillin 2 g

Tazobactam Sodium IP (Sterile) equivalent to Tazobactam 250 mg

TAZOTUM 4.5 Each vial contains:

Piperacillin Sodium IP (Sterile) equivalent to Piperacillin 4 g

Tazobactam Sodium IP (Sterile) equivalent to Tazobactam 500 mg

Powder for solution for infusion.

Single Dose Vial containing 1.125g /2.25g/ 4.5g

4.1 Therapeutic indication

TAZOTUM® is indicated in adults and pediatric patients (2 months of age and older) for the treatment of Lower respiratory tract infections Urinary tract infections Intra-abdominal infections Skin and skin structure infections Bacterial septicemic polymicrobial infections      

4.2 Posology and method of administration

Adults

Dosage in Adult Patients with Nosocomial Pneumonia

Initial presumptive treatment of adult patients with nosocomial pneumonia should start with TAZOTUM at a dosage of 4.5 g every six hours plus an aminoglycoside, [totaling 18.0 g (16.0 g piperacillin and 2.0 g tazobactam)], administered by intravenous infusion over 30 minutes. The recommended duration of TAZOTUM treatment for nosocomial pneumonia is 7 to 14 days. Treatment with the aminoglycoside should be continued in patients from whom P. aeruginosa is isolated.

Dosage in Adult Patients with Indications Other Than Nosocomial Pneumonia

The usual total daily dosage of TAZOTUM for adult patients with indications other than nosocomial pneumonia is 3.375 g every six hours [totaling 13.5 g (12.0 g piperacillin and 1.5 g tazobactam)], to be administered by intravenous infusion over 30 minutes. The usual duration of TAZOTUM treatment is from 7 to 10 days.

Dosage in Adult Patients with Renal Impairment

In adult patients with renal impairment (creatinine clearance ≤ 40 mL/min) and dialysis patients (hemodialysis and CAPD), the intravenous dose of TAZOTUM should be reduced based on the degree of renal impairment. The recommended daily dosage of TAZOTUM for patients with renal impairment administered by intravenous infusion over 30 minutes is described in Table 1.

Table 1: Recommended Dosage of TAZOTUM in Patients with Normal Renal Function and Renal Impairment (As total grams piperacillin and tazobactam)#

For patients on hemodialysis, the maximum dose is 2.25 g every twelve hours for all indications other than nosocomial pneumonia and 2.25 g every eight hours for nosocomial pneumonia. Since hemodialysis removes 30% to 40% of the administered dose, an additional dose of 0.75 g TAZOTUM (0.67 g piperacillin and 0.08 g tazobactam) should be administered following each dialysis period on hemodialysis days. No additional dosage of TAZOTUM is necessary for CAPD patients.

Dosage in Pediatric Patients with Appendicitis/Peritonitis or Nosocomial Pneumonia The recommended dosage for pediatric patients with appendicitis and/or peritonitis or nosocomial pneumonia aged 2 months of age and older, weighing up to 40 kg, and with normal renal function, is described in Table 2.

Table 2: Recommended Dosage of TAZOTUM in Pediatric Patients 2 Months of Age and Older, Weighing Up to 40 kg, and with Normal Renal Function#

# Administer TAZOTUM by intravenous infusion over 30 minutes.

Directions for reconstitution and dilution for use:

Intravenous Administration

• For conventional vials, reconstitute TAZOTUM per gram of Piperacillin with 5 ml of a compatible reconstitution diluent from the list provided below.
• 1.125 g, 2.25 g, and 4.5 g TAZOTUM should be reconstituted with 5 ml, 10 ml and 20 ml, respectively. Swirl until dissolved.
• Intravenous injection should be given over at least 3 to 5 minutes.
• Compatible Reconstitution Diluents:
  • 0.9% Sodium Chloride for Injection
  • Sterile Water for Injections
  • Dextrose 5%

Intravenous infusion

• Reconstituted TAZOTUM solution should be further diluted in a compatible intravenous solution listed below.
• Recommended volume per dose is 50 ml to 150 ml.
• Administer by infusion over a period of at least 30 minutes.
• Compatible reconstitution diluents:
  • 0.9% Sodium Chloride for Injection.
  • Sterile Water for Injections (Maximum recommended volume per dose of is 50 ml).
  • Dextrose 5%. Dextran 6% in Saline

4.3 Contraindications

TAZOTUM® is contraindicated in patients with a history of allergic reactions to any of the penicillins, cephalosporins, or β-lactamase inhibitors.

4.4 Special Warnings and Precautions

Warnings:

1. Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity anaphylactic/anaphylactoid) reactions (including shock) have been reported in patients receiving therapy with penicillins including TAZOTUM. Before initiating therapy with TAZOTUM, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other β-lactams, and other allergens.
2. Clostridium difficile–Associated Diarrhea: Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including TAZOTUM, and may range in severity from mild diarrhea to fatal colitis.

If CDAD is suspected or confirmed, ongoing antibiotic use may need to be discontinued.

Precautions:

Pregnancy

Pregnancy Category B:

Piperacillin and Tazobactam cross the placenta. TAZOTUM 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 fetus.

Nursing Mothers

Piperacillin is excreted in low concentrations in human milk; Tazobactam concentrations in human milk have not been studied. Caution should be exercised when TAZOTUM is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of TAZOTUM for intra-abdominal infections, and nosocomial pneumonia have been established in pediatric patients 2 months of age and older. Use of TAZOTUM in pediatric patients 2 months of age and older with nosocomial pneumonia and intra-abdominal infections including appendicitis and/or peritonitis is supported by evidence from well-controlled studies and pharmacokinetic studies in adults and in pediatric patients. The safety and effectiveness of TAZOTUM have not been established in pediatric patients less than 2 months of age. 

Geriatric Use

• Patients over 65 years are not at an increased risk of developing adverse effects solely because of age. 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.
• In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range.
• TAZOTUM contains 64 mg (2.79 mEq) of sodium per gram of Piperacillin in the combination product. At the usual recommended doses, patients would receive between 768 and 1024 mg/day (33.5 and 44.6 mEq) of sodium. This should be taken into account by patients on a controlled sodium diet. The geriatric population may respond with a blunted natriuresis due to salt loading. This may be clinically important with regard to diseases such as congestive heart failure.

General

• Neutropenia and leucopenia may occur especially during prolonged therapy. Therefore, periodic assessment of a complete blood count should be performed.
• Periodic assessment of renal and hepatic functions during prolonged therapy is advisable.
• Bleeding manifestations have occurred in some patients receiving β-lactam antibiotics. These reactions have sometimes been associated with abnormalities of coagulation tests such as clotting time, platelet aggregation and prothrombin time, and are more likely to occur in patients with renal failure. If bleeding manifestations occur, the antibiotic should be discontinued and appropriate therapy instituted.
• The possibility of the emergence of resistant organisms should be kept in mind, particularly during prolonged treatment i.e. ≥21 days. Microbiological follow-up may be required to detect any important superinfection. If this occurs, appropriate measures should be taken.
• Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously.
• Hypokalaemia may occur in patients with low potassium reserves or who are receiving concomitant medications that may lower potassium levels; periodic electrolyte determinations should be performed in such patients. Modest elevation of AST, ALT may be observed.
• Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.
• In patients with creatinine clearance ≤ 40 mL/min and dialysis patients (hemodialysis and CAPD), the intravenous dose should be adjusted to the degree of renal function impairment.
• Prescribing TAZOTUM in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of development of drug-resistant bacteria.

4.5 Drug interactions

Aminoglycosides

The mixing of β-lactam antibiotics with aminoglycosides in vitro can result in substantial inactivation of the aminoglycoside. The inactivation of aminoglycosides in the presence of penicillin-class drugs has been recognized.

It has been postulated that penicillin-aminoglycoside complexes are formed and these complexes are microbiologically inactive and of unknown toxicity. Sequential administration of TAZOTUM with tobramycin to patients with normal renal function and mild to moderate renal impairment has been shown to decrease serum concentrations of tobramycin but does not significantly affect tobramycin pharmacokinetics.

When aminoglycosides are administered in combination with Piperacillin to patients with end-stage renal disease requiring hemodialysis, the concentrations of the aminoglycosides (especially tobramycin) may be significantly altered and should be monitored.

Probenecid

Probenecid administered concomitantly with TAZOTUM prolongs the half-life of Piperacillin by 21% and that of Tazobactam by 71%.

Heparin (oral anticoagulants)

Coagulation parameters should be tested more frequently and monitored regularly during simultaneous administration of high doses of heparin, oral anticoagulants, or other drugs that may affect the blood coagulation system or the thrombocyte function.

Vecuronium (Non-depolarising muscle relaxants)

Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. TAZOTUM could produce the same phenomenon if given along with vecuronium. Due to their similar mechanism of action, it is expected that the neuromuscular blockade produced by any of the non-depolarizing muscle relaxants could be prolonged in the presence of Piperacillin.

Methotrexate

Piperacillin may reduce the excretion of methotrexate. Therefore, serum levels of methotrexate should be monitored in patients to avoid substance toxicity.

Vancomycin

No pharmacokinetic interactions have been noted between TAZOTUM & vancomycin.

Drug/Laboratory Test Interactions

• Non-enzymatic methods of measuring urinary glucose may lead to false-positive results, as with other penicillins. It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.
• 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. Positive test results for the assays listed above in patients receiving TAZOTUM should be confirmed by other diagnostic methods.

4.6 Use in special populations

• The half-life of Piperacillin and 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.

Pediatric population

In a population pharmacokinetic analysis, estimated clearance for 9 months 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 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.

4.7 Effects on the ability to drive and use machines

The use of TAZOTUM is not expected to affect the ability to drive or use machines.

4.8 Undesirable effects

Infections and infestations:

Candidal superinfection.

Blood and lymphatic system disorders:

Leucopenia, neutropenia, thrombocytopenia, anaemia, bleeding manifestations (including purpura, epistaxis, bleeding time prolonged), eosinophilia, haemolytic anaemia, agranulocytosis, Coombs' direct test positive, pancytopenia, prolonged partial thromboplastin time, prothrombin time prolonged, thrombocytosis.

Immune system disorders: Hypersensitivity reaction, anaphylactic/anaphylactoid reaction (including shock).

Metabolism and nutritional disorders: Hypoalbuminaemia, hypoglycaemia, hypoproteinaemia, hypokalaemia.

Nervous system disorders: Headache, insomnia, muscular weakness, hallucination, convulsion.

Respiratory disorder: Bronchospasm. Vascular disorders: Hypotension, phlebitis, thrombophlebitis, flushing.

Gastrointestinal disorders: Diarrhoea, nausea, vomiting, constipation, dyspepsia, jaundice, stomatitis, abdominal pain, pseudomembranous colitis, dry mouth.

Hepatobiliary disorders: Alanine aminotransferase increased, aspartate aminotransferase increased, bilirubin increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, hepatitis.

Skin and subcutaneous tissue disorders: Rash including maculopapular rash, pruritus, urticaria, erythema, bullous dermatitis, erythema multiforme, increased sweating, eczema, exanthema, Stevens-Johnson Syndrome, toxic epidermal necrolysis and Acute Generalized Exanthematosus Pustulosis (AGEP).

Musculoskeletal, connective tissue and bone disorders: Arthralgia, myalgia. Renal and urinary disorders: Blood creatinine increased, interstitial nephritis, renal failure, blood urea nitrogen increased.

General disorders and administration site conditions: Fever, injection site reaction, rigors, tiredness, oedema. The administration of high doses of β-lactams, particularly in patients with renal insufficiency, can lead to encephalopathies (consciousness fluctuation, myoclonus and convulsions). Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.

Reporting of side effects    

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. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: http://www.zuventus.co.in/safety.aspx

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

There have been post marketing reports of overdose with Piperacillin/Tazobactam. The majority of those events experienced, including nausea, vomiting, and diarrhea, have also been reported with the usual recommended doses. Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure). Treatment should be supportive and symptomatic according to the patient's clinical presentation. Excessive serum concentrations of either Piperacillin or Tazobactam may be reduced by hemodialysis.

5.1 Mechanism of Action

Piperacillin, a broad spectrum, semi-synthetic penicillin, active against many gram-positive and gram-negative aerobic and anaerobic bacteria, exerts bactericidal activity by inhibition of both septum and cell wall synthesis. Tazobactam, a triazolylmethyl penicillanic acid sulphone, is a potent inhibitor of many β-lactamases, in particular the plasmid mediated enzymes which commonly cause resistance to penicillins and cephalosporins including third-generation cephalosporins. The presence of Tazobactam in the Piperacillin/Tazobactam formulation enhances and extends the antibiotic spectrum of Piperacillin to include many β-lactamase producing bacteria normally resistant to Piperacillin and other β-lactam antibiotics. Thus, TAZOTUM combines the properties of a broad spectrum antibiotic and a β-lactamase inhibitor.

5.2 Pharmacodynamic properties

TAZOTUM has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections.

The following in vitro data regarding the susceptibility of microorganisms to Piperacillin/Tazobactam is available.

At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for TAZOTUM.

5.3 Pharmacokinetics

Absorption

Both Piperacillin and Tazobactam are poorly absorbed after oral administration and therefore can only be administered parenterally. 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 either Piperacillin or Tazobactam is unaffected by the presence of the other compound. Protein binding of the Tazobactam metabolite is negligible.

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

Biotransformation

Piperacillin is metabolized 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 kidney 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 desethyl Piperacillin are also secreted into the bile.

• Following single or multiple doses of TAZOTUM 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.

6.1 Animal Toxicology or Pharmacology

The aminoglycosides as a class of antibiotics are known to have the potential to cause significant nephrotoxic and ototoxic effects, some of which may be irreversible. Fertility, teratogenicity and postnatal studies of netilmicin in rats and rabbits have not provided any significant evidence of toxicity of netilmicin, particularly following ocular administration.

TAZOTUM is a combination of the semi synthetic β-lactam antibiotic piperacillin sodium and the β-lactamase inhibitor tazobactam sodium. It has a broad spectrum of antibacterial activity that includes gram-positive and gram-negative aerobic and anaerobic bacteria, including many pathogens producing β-lactamases.

Piperacillin Sodium :

Chemical Name : sodium(2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazine-carboxamido)-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate

Molecular formula: C23H26N5NaO7S

Molecular weight : 539.5

Chemical structure:

Tazobactam Sodium:

Chemical Name : sodium(2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo[3.2.0] heptane-2-carboxylate-4,4-dioxide.

Molecular formula: C10H11N4NaO5S

Molecular weight : 322.3

Chemical structure:

8.1 Incompatibilities

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

• TAZOTUM should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established.
• TAZOTUM should be administered through an infusion set separately from other drugs unless compatibility is proven.
• Due to chemical instability, TAZOTUM should not be used in solutions that contain sodium bicarbonate.
• Lactated Ringer's (Hartmann's) solution is not compatible with TAZOTUM. • TAZOTUM should not be added to blood products or albumin hydrolysates.

8.2 Shelf life

Refer to the pack.

8.3 Packaging Information

Single Dose Vial

TAZOTUM 1.125: A vial of 1.125 g.

TAZOTUM 2.25:

A vial of 2.25 g.

TAZOTUM 4.5: A vial of 4.5 g.

8.4 Storage and handling instructions

Prior to reconstitution: Store at controlled room temperature.

Keep out of reach of children.

Use immediately after reconstitution.

Any unused portion must be discarded.

After reconstitution, do not use in case any foreign particulate matter is observed inside the vial.

Serious Hypersensitivity Reactions

Advise patients, their families, or caregivers that serious hypersensitivity reactions, including serious allergic cutaneous reactions, could occur with use of TAZOTUM that require immediate treatment. Ask them about any previous hypersensitivity reactions to TAZOTUM, other beta-lactams (including cephalosporins), or other allergens.

Hemophagocytic Lymphohistiocytosis

Prior to initiation of treatment with TAZOTUM, inform patients that excessive immune activation may occur with TAZOTUM and that they should report signs or symptoms such as fever, rash, or lymphadenopathy to a healthcare provider immediately.

Diarrhea

Advise patients, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs, including TAZOTUM, which usually ends when the drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the drug. If this occurs, patients should contact their physician as soon as possible.

Antibacterial Resistance

Patients should be counseled that antibacterial drugs including TAZOTUM should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When TAZOTUM is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by TAZOTUM or other antibacterial drugs in the future.

Pregnancy and Lactation

Patients should be counseled that TAZOTUM can cross the placenta in humans and is excreted in human milk.