Active ingredients: Piperacillin, tazobactam
Tazocin 2 g / 0.25 g powder for solution for infusion
Tazocin 4 g / 0.5 g powder for solution for infusion
Tazocin package inserts are available for pack sizes: - Tazocin 2 g / 0.25 g powder for solution for infusion, Tazocin 4 g / 0.5 g powder for solution for infusion
- Tazocin 2 g +0.25 g / 4 ml powder and solvent for solution for injection for intramuscular use
Why is Tazocin used? What is it for?
Piperacillin belongs to a group of medicines known as 'broad spectrum penicillin antibiotics' and is capable of killing 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, they can kill multiple types of bacteria.
TAZOCIN 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. TAZOCIN can be used. to treat bacterial infections in patients with low white blood cell counts (reduced resistance to infections).
TAZOCIN is used in children aged 2 to 12 years to treat infections of the abdomen, such as appendicitis, peritonitis (infection of the fluid and lining of the abdominal organs) and infections of the gallbladder (biliary). TAZOCIN can be used. to treat bacterial infections in patients with low white blood cell counts (reduced resistance to infections)
In certain severe infections, the doctor may consider using TAZOCIN in combination with other antibiotics.
Contraindications When Tazocin should not be used
Do not use TAZOCIN
- If you are allergic (hypersensitive) to piperacillin or tazobactam or any of the other ingredients of TAZOCIN.
- If you are allergic (hypersensitive) to antibiotics known as penicillins, cephalosporins or other beta-lactamase inhibitors, as you may be allergic to TAZOCIN
Precautions for use What you need to know before taking Tazocin
- If you have allergies. If you have several allergies, please tell your doctor or healthcare professional before taking this medicine.
- If you suffer from diarrhea before, or if you develop diarrhea during or after treatment. In this case you must inform your doctor or healthcare professional immediately. Do not take medicines for diarrhea without first checking with your doctor.
- If you have low levels of potassium in your blood. Your doctor may decide to check your kidney function before giving you this medicine and may order you to have periodic blood tests during your treatment.
- If you have kidney or liver problems or if you are undergoing hemodialysis. Your doctor may decide to check your kidney function before giving you this medicine and may order you to have periodic blood tests during your treatment.
- If you are taking certain medicines (called anticoagulants) to prevent "excessive blood clotting (see also section Other medicines and Tazocin in this leaflet), or if you experience unexpected bleeding during treatment. In this case, you must inform your doctor or health care professional immediately.
- If you develop convulsions during treatment. In this case, you must inform your doctor or healthcare professional.
- If you think you have developed a new infection or if the infection has worsened. In this case, you should tell your doctor or healthcare professional.
Children under 2 years old
The use of piperacillin / tazobactam is not recommended in children below 2 years of age due to insufficient data on safety and efficacy.
Interactions Which drugs or foods may change the effect of Tazocin
Tell your doctor or healthcare professional if you are taking or have recently taken any other medicines, including those obtained without a prescription. Some medicines may interact with piperacillin and tazobactam.
These include:
- Medicine for gout (probenecid). It may increase the time it takes for piperacillin and tazobactam to be cleared from the body.
- Medicines to thin the blood or to treat blood clots (e.g. heparin, warfarin or aspirin).
- Medicines used to relax muscles during surgery. Tell your doctor if you are going to have a "general anesthesia."
- Methotrexate (medicine used to treat cancer, arthritis or psoriasis). Piperacillin and tazobactam can increase the time it takes for methotrexate to be cleared from the body.
- Medicines that can reduce the level of potassium in the blood (e.g. tablets that increase urine production or some medicines for cancer).
- Medicines containing the other antibiotics tobramycin or gentamicin. Tell your doctor if you have kidney problems.
Effect on laboratory tests
Tell your doctor or laboratory staff that you are taking TAZOCIN if you need to provide a blood or urine sample.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or healthcare professional for advice before taking this medicine. Your doctor will decide whether TAZOCIN is suitable for you. Piperacillin and tazobactam can pass to the baby in the womb or through breast milk. If you are breastfeeding, your doctor will decide if TAZOCIN is suitable for you.
Driving and using machines
The use of TAZOCIN is not expected to affect the ability to drive and use machines
Important information about some of the ingredients of TAZOCIN
TAZOCIN 2 g / 0.25 g contains 5.58 mmol (128 mg) of sodium.
TAZOCIN 4 g / 0.5 g contains 11.16 mmol (256 mg) of sodium.
This should be taken into consideration if you are following a controlled sodium diet.
Dose, Method and Time of Administration How to use Tazocin: Posology
Your doctor or healthcare professional will give you this medicine as an infusion into a vein (one drip for 30 minutes
Dosage
The dose of medicine given depends on the reason for treatment, age and whether or not you have kidney problems.
Adults and adolescents over 12 years of age
The usual dose is 4 g / 0.5 g piperacillin / tazobactam, every 6-8 hours, given into a vein (directly into the bloodstream)
Children from 2 to 12 years
The usual dose for children with abdominal infections is piperacillin / tazobactam 100 mg / 12.5 mg / kg body weight, every 8 hours, given into a vein (directly into the bloodstream). The usual dose for children with low white blood cell counts is 80 mg / 10 mg / kg body weight of piperacillin / tazobactam, every 6 hours, given into a vein (directly into the bloodstream).
The doctor will calculate the dose based on the weight of the child; in any case, the daily dose will not exceed 4 g / 0.5 g of TAZOCIN.
TAZOCIN will be given to you until the signs of infection have completely disappeared (5-14 days).
Patients with kidney problems
Your doctor may need to reduce the dose of TAZOCIN or the frequency of administration. Your doctor may also perform blood tests to make sure that the dose prescribed for treatment is correct, especially if you need to take this medicine for a long time.
Overdose What to do if you have taken too much Tazocin
As TAZOCIN will be administered by a doctor or healthcare professional, it is unlikely that you will receive an incorrect dose. However, if you experience any side effects, such as seizures, or if you think you have been given an overdose of this medicine, tell your doctor immediately.
If you miss a dose of Tazocin
If you think you have not been given a dose of TAZOCIN, tell your doctor or healthcare professional immediately.
If you have any further questions on the use of TAZOCIN, ask your doctor or healthcare professional.
Side Effects What are the side effects of Tazocin
Like all medicines, TAZOCIN can cause side effects, although not everybody gets them.
The serious side effects of TAZOCIN are:
- severe skin reactions (Stevens Johnson syndrome and toxic epidermal necrolysis) which initially manifest as reddish patches or circular bumps often with central blisters on the trunk. Additional symptoms include ulcers in the mouth, throat, nose, extremities, genitals and conjunctivitis (red and swollen eyes). The rash may increase with widespread blistering or peeling of the skin which can potentially be life-threatening
- swelling of the face, lips, tongue or other parts of the body
- shortness of breath, wheezing or difficulty in breathing
- intense rash, itching or hives on the skin - yellowing of the eyes or skin
- damage to blood cells (signs include unexpected wheezing, red or brown urine, nosebleeds and bruises)
- severe or persistent diarrhea accompanied by fever or weakness
- unexpected bleeding, especially if you are taking blood thinners such as warfarin
If any of the side effects listed below get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or healthcare professional.
Possible side effects are listed according to the following frequencies:
- common: affects 1 to 10 users in 100
- uncommon: affects 1 to 10 users in 1,000
- rare: affects 1 to 10 users in 10,000
- very rare: affects less than 1 user in 10,000
Common side effects:
- diarrhea, vomiting, nausea
- skin rash
Uncommon side effects:
- thrush
- reduction (abnormal) in the number of white blood cells (leukopenia, neutropenia) and platelets (thrombocytopenia)
- allergic reaction
- headache, insomnia
- low blood pressure, inflammation of the veins (felt as tenderness or redness in the affected area)
- jaundice (yellowing of the skin or whites of the eyes), inflammation of the lining of the mouth, constipation, indigestion, stomach upset
- increase in some enzymes in the blood (increase in alanine aminotransferase, increase in aspartate aminotransferase)
- itching, hives
- increase in the product of muscle metabolism in the blood (increase in blood creatinine)
- fever, injection site reaction
- yeast infection (candida superinfection)
Rare side effects:
reduction (abnormal) in the number of red blood cells or blood pigment / hemoglobin, reduction (abnormal) in red blood cells due to premature breakdown (haemolytic anemia), bruising with small patches (purpura), nose bleeding (epistaxis) and prolonged bleeding time, (abnormal) increase in a specific type of white blood cell (eosinophilia)
severe allergic reaction (anaphylactic / anaphylactoid reaction, including shock)
reddened skin with hot flashes
some form of colon infection (pseudomembranous colitis), abdominal pain
inflammation of the liver (hepatitis), increase in the breakdown product of blood pigments (bilirubin), increase in certain blood enzymes (increase in blood alkaline phosphatase, increase in gammaglutamyltransferase)
skin reactions with redness and formation of lesions on the skin (rash, erythema multiforme), skin reactions with blistering (bullous dermatitis)
pain in the joints and muscles
poor kidney function and kidney problems
chills / stiffness
Very rare side effects:
- severe reduction in granular white blood cells (agranulocytosis), severe reduction in red blood cells, white blood cells and platelets (pancytopenia)
- prolonged time of blood clot formation (prolonged partial thromboplastin time, prolonged prothrombin time), abnormal laboratory test (positive direct Coombs test), increased platelets (thrombocythemia)
- decreased blood potassium (hypokalaemia), decreased blood sugar (glucose), decreased blood protein albumin, decreased total blood protein
- detachment of the upper layer of the skin all over the body (toxic epidermal necrolysis), severe allergic reaction all over the body with rash on the skin and mucous membranes and various rashes (Stevens-Johnson syndrome)
- increased blood urea nitrogen
Piperacillin therapy has been associated with a higher incidence of fever and rash in patients with cystic fibrosis.
Expiry and Retention
Keep TAZOCIN out of the sight and reach of children.
Do not use TAZOCIN 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 25ºC.
For single use only. Discard the unused solution.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What TAZOCIN contains
- The active ingredients are piperacillin and tazobactam. Each vial contains 2 g of piperacillin (as the sodium salt) and 0.25 g of tazobactam (as the sodium salt). Each vial contains 4 g of piperacillin (as the sodium salt) and 0.5 g of tazobactam (as the sodium salt).
- The other ingredients are citric acid monohydrate and edetate disodium (EDTA).
What TAZOCIN looks like and contents of the pack
TAZOCIN 2 g / 0.25 g is a white to off-white powder, supplied in a vial.
Packs contain 1, 5, 10, 12, 25 or 50 vials.
TAZOCIN 4 g / 0.5 g is a white to off-white powder, supplied in a vial.
Packs contain 1, 5, 10, 12, 25 or 50 vials.
Not all pack sizes may be marketed.
The following information is intended for medical or healthcare professionals only:
Instructions for use TAZOCIN will be administered by intravenous infusion (one drip over 30 minutes).
Intravenous use
Reconstitute each vial with the volume of solvent indicated in the table below, using one of the compatible solvents for reconstitution. Shake with a rotary motion until dissolved. When shaken with constant rotating motion, reconstitution usually occurs within 5-10 minutes (for handling details, see below).
Contents of the vial
* Compatible solvents for reconstitution:
- 0.9% sodium chloride (9 mg / ml) solution for injection
- sterile water for injections
- glucose 5%
The maximum recommended volume of sterile water for injections for each dose is 50 ml.
The reconstituted solution should be withdrawn from the vial with a syringe. Once reconstituted according to the instructions, the contents of the vial withdrawn with the syringe will provide the quantities of piperacillin and tazobactam indicated on the label.
The reconstituted solutions can be further diluted to the desired volume (e.g. 50ml to 150ml) with one of the following compatible solvents:
- 0.9% sodium chloride (9 mg / ml) solution for injection
- glucose 5%
- 6% dextran in 0.9% sodium chloride
- lactated Ringer's solution for injection
- Hartmann's solution
- Ringer acetate
- Ringer acetate / diseased
Incompatibility
When TAZOCIN is used concomitantly with another antibiotic (e.g. aminoglycosides), the substances must be administered separately. The mixing of beta-lactam antibiotics with aminoglycosides in vitro can cause substantial inactivation of the aminoglycoside.However, compatibility of amikacin and gentamicin with TAZOCIN has been determined in vitro in certain diluents at specific concentrations (see section Co-administration of TAZOCIN with aminoglycosides).
TAZOCIN must not be mixed with other substances in the same syringe or infusion bottle, as compatibility has not been established.
Due to chemical instability, TAZOCIN should not be used with solutions containing only sodium bicarbonate.
TAZOCIN is compatible with lactated Ringer's solution and for co-administration via a Y tubing. TAZOCIN should not be added to blood products or hydrolysed albumin.
Co-administration of TAZOCIN with aminoglycosides
Due to in vitro inactivation of the aminoglycoside by beta-lactam antibiotics, it is recommended to administer TAZOCIN and the aminoglycoside separately. When concomitant therapy with aminoglycosides is indicated, TAZOCIN and the aminoglycoside should be reconstituted and diluted separately.
In circumstances where co-administration is recommended, TAZOCIN is compatible for simultaneous co-administration, via infusion with a Y-line, only with the following aminoglycosides under the following conditions:
* The aminoglycoside dose should be based on patient weight, infection status (severe or life-threatening) and renal function (creatinine clearance).
Compatibility of TAZOCIN with other aminoglycosides has not been established. Only the concentrations and diluents of amikacin and gentamicin together with the dose of Tazocin, as reported in the previous table, have been found compatible for co-administration by infusion via a Y-line. above may lead to the inactivation of the aminoglycoside by TAZOCIN.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
TAZOCIN POWDER FOR SOLUTION FOR INFUSION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains piperacillin (as sodium salt) equivalent to 2 g and tazobactam (as sodium salt) equivalent to 0.25 g.
Each vial of Tazocin 2 g / 0.25 g contains 5.58 mmol (128 mg) of sodium.
Each vial contains piperacillin (as sodium salt) equivalent to 4 g and tazobactam (as sodium salt) equivalent to 0.5 g.
Each vial of Tazocin 4 g / 0.5 g contains 11.16 mmol (256 mg) of sodium.
Excipients:
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Powder for solution for infusion. White to off-white powder.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Tazocin is indicated for the treatment of the following infections in adults and children over 2 years (see sections 4.2 and 5.1):
Adults and adolescents
• Severe pneumonia, including hospital-acquired and mechanical ventilation 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 in association with, or suspected to be associated with, any of the infections listed above.
Tazocin can be used in the treatment of neutropenic patients with fever of suspected bacterial infection.
Children from 2 to 12 years
• Complicated intra-abdominal infections
Tazocin can be used to treat neutropenic children with fever of suspected bacterial infection.
Appropriate use of antibacterial agents must comply with official guidelines.
04.2 Posology and method of administration
Dosage
The dose and frequency of administration of Tazocin depend on the severity and location of the infection and the anticipated pathogens.
Adult and adolescent patients
Infections
The usual dose is 4 g of piperacillin / 0.5 g of tazobactam given every 8 hours.
For hospital-acquired pneumonia and bacterial infections in neutropenic patients, the recommended dose is 4 g piperacillin / 0.5 g tazobactam, given every 6 hours. This dosing regimen may also be appropriate for the treatment of patients with other infections included in the therapeutic indications, if particularly severe.
The following table summarizes the frequency of administration and the recommended dose for adult and adolescent patients, depending on the indication or disease:
Kidney failure
The intravenous dose should be adjusted according to the degree of actual renal insufficiency, according to the following schedule (each patient should be carefully monitored for signs of substance toxicity; the dose and interval of administration of the medicinal product should be adjusted accordingly) :
For hemodialysis patients, an additional dose of piperacillin / tazobactam 2 g / 0.25 g should be given after each dialysis session, as hemodialysis eliminates 30% -50% of piperacillin in 4 hours.
Hepatic insufficiency
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.
Pediatric population (2-12 years of age)
Infections
The following table summarizes the frequency of administration and dose by body weight for pediatric patients 2 to 12 years of age, depending on the indication or disease:
* Do not exceed the maximum dose of 4 g / 0.5 g in 30 minutes.
Kidney failure
The intravenous dose should be adjusted according to the degree of actual renal insufficiency, according to the following schedule (each patient should be carefully monitored for signs of substance toxicity; the dose and interval of administration of the medicinal product should be adjusted accordingly) :
For children with hemodialysis, an additional dose of 40 mg piperacillin / 5 mg tazobactam / kg should be administered after each dialysis session.
Use in children under 2 years of age
The safety and efficacy of Tazocin in children aged 0-2 years have not been established. There are no data available from controlled clinical trials.
Duration of treatment
The usual duration of treatment for most indications is between 5 and 14 days. However, the duration of treatment must be established according to the severity of the infection, the pathogen (s) and the clinical and bacteriological evolution of the patient.
Route of administration
Tazocin 2 g / 0.25 g is administered by intravenous infusion (over 30 minutes).
Tazocin 4 g / 0.5 g is administered by intravenous infusion (over 30 minutes).
For instructions on reconstitution, see section 6.6.
04.3 Contraindications
Hypersensitivity to the active substances, to any other penicillin antibacterial agent or to any of the excipients.
History of acute severe allergic reaction to any other beta-lactam active substance (e.g. cephalosporin, monobactam or carbapenem).
04.4 Special warnings and appropriate precautions for use
The choice of piperacillin / tazobactam for the individual treatment of a patient must take into account the appropriateness of the use of a broad spectrum semi-synthetic penicillin, based on factors such as the severity of the infection and the prevalence of resistance to other available antibacterial agents. .
Prior to initiating therapy with Tazocin, any previous hypersensitivity reactions to penicillins, other beta-lactam agents (e.g. cephalosporin, monobactam and carbapenem) and other allergens should be carefully investigated. Serious and occasionally fatal hypersensitivity reactions (anaphylactic / anaphylactoid [including shock]) have been reported in patients receiving penicillin therapy, including piperacillin / tazobactam. Such reactions are more likely to occur in people with a history of sensitivity to multiple allergens. Severe hypersensitivity reactions require discontinuation of the antibiotic and may require the administration of epinephrine and the adoption of other emergency measures.
Serious skin reactions such as Stevens Johnson syndrome and toxic epidermal necrolysis have been reported in patients treated with Tazocin (See Section 4.8). If patients develop skin rash they should be monitored closely and if lesions worsen Tazocin should be discontinued.
Antibiotic-induced pseudomembranous colitis can manifest as severe and persistent diarrhea, and can be life-threatening. Symptoms of pseudomembranous colitis can arise during or after antibacterial treatment. In such cases, Tazocin should be discontinued.
Therapy with Tazocin can cause the emergence of resistant organisms which can cause superinfections.
Hemorrhagic manifestations have occurred in some patients treated with beta-lactam antibiotics. These reactions have sometimes been associated with coagulation test abnormalities, such as clotting time, platelet aggregation, and prothrombin time, and are more likely to occur in patients with renal insufficiency. If bleeding occurs, the antibiotic should be discontinued and appropriate therapy instituted.
Leukopenia and neutropenia can appear, especially during prolonged therapy; therefore, periodic assessment of hematopoietic function should be performed.
As with treatment with other penicillins, neurological complications in the form of seizures may occur when high doses are administered, especially in patients with impaired renal function.
Each vial of Tazocin 2 g / 0.25 g contains 5.58 mmol (128 mg) of sodium, while Tazocin 4 g / 0.5 g contains 11.16 mmol (256 mg) of sodium. This should be taken into consideration in patients on a controlled sodium diet.
Hypokalaemia can occur in patients with low potassium stores, or in patients receiving concomitant medications that can lower potassium levels. In such patients, periodic electrolyte determinations may be appropriate.
04.5 Interactions with other medicinal products and other forms of interaction
Non-depolarizing muscle relaxants
Piperacillin, when used concomitantly with vecuronium, prolonged vecuronium neuromuscular blockade. Due to the similar mechanism of action, the neuromuscular block produced by any non-depolarising muscle relaxant is expected to be prolonged in the presence of piperacillin.
Oral anticoagulants
During concomitant 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 methotrexate excretion; therefore, patients' serum methotrexate levels should be monitored to avoid drug toxicity.
Probenecid
As with other penicillins, concomitant administration of probenecid and piperacillin / tazobactam prolongs the half-life and reduces the renal clearance of both piperacillin and tazobactam; however, this does not affect the peak plasma concentrations of the two substances.
Aminoglycosides
Piperacillin, either alone or in combination 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 metabolite M1 were not significantly altered by the administration of tobramycin.
Inactivation of tobramycin and gentamicin by piperacillin has been demonstrated in patients with severe renal insufficiency.
For information regarding the administration of piperacillin / tazobactam in combination with aminoglycosides, see sections 6.2 and 6.6.
Vancomycin
No pharmacokinetic interactions were observed between piperacillin / tazobactam and vancomycin.
Effects on laboratory tests
As with other penicillins, the adoption of non-enzymatic methods for measuring glucosuria can lead to false positives. Therefore, in the case of therapy with Tazocin, measurement of glucosuria by enzymatic methods is necessary.
Several chemical methods for measuring proteinuria can lead to false positives. The adoption of test strips (dip sticks) does not affect the measurement of proteins.
The direct Coombs test can be positive.
False positives may occur when testing Platelia Aspergillus EIA of Bio-Rad
Laboratories in patients treated with Tazocin. Cross reactions with polysaccharides and non polyfuranoses have been reported Aspergillus with the testPlatelia Aspergillus EIA from Bio-Rad Laboratories.
In patients treated with Tazocin, positive results obtained with the methods listed above must be confirmed by other diagnostic methods.
04.6 Pregnancy and lactation
Pregnancy
Data on the use of Tazocin in pregnant women do not exist or are very scarce.
Animal studies have shown developmental toxicity in the animal, but there is no evidence of teratogenic effects when the medicinal product has been used at maternally toxic doses (see section 5.3).
Piperacillin and tazobactam cross the placental barrier. Piperacillin / tazobactam should only be used during pregnancy if clearly indicated, i.e. if the expected benefit outweighs the possible risks to the pregnant woman and the fetus.
Pregnancy
Piperacillin is excreted in low concentrations in human milk; human milk concentrations of tazobactam have not been studied. Breastfeeding women should only be treated if the expected benefit outweighs the possible risks to the woman and baby.
Fertility
A fertility study in rats showed no effect on fertility and mating after intraperitoneal administration of tazobactam or the piperacillin / tazobactam combination (see section 5.3).
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed.
04.8 Undesirable effects
The most commonly reported adverse reactions (occurring in 1 to 10 patients in 100) are diarrhea, vomiting, nausea and rash.
In the table below, adverse reactions are listed by system organ class and MedDRA code terminology. Within each frequency group, undesirable effects are reported in order of decreasing severity.
Piperacillin therapy has been associated with a higher incidence of fever and rash in patients with cystic fibrosis.
04.9 Overdose
Symptoms
There have been post-marketing reports of overdose with piperacillin / tazobactam. Most of the reported events, including nausea, vomiting and diarrhea, were also reported with the usual recommended dose. Patients may experience neuromuscular excitability or convulsions if higher than recommended intravenous doses are administered (particularly in the presence of renal insufficiency).
Treatment
In the event of overdose, piperacillin / tazobactam treatment should be discontinued. No specific antidote is known.
Treatment should be supportive and symptomatic, according to the patient's clinical picture.
Excessive serum concentrations of piperacillin or tazobactam can be reduced by hemodialysis (see section 4.4).
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antibacterials for systemic use, combinations of penicillins including beta-lactamase inhibitors.
ATC code: J01C R05.
Mechanism of action
Piperacillin, a broad spectrum semi-synthetic penicillin, exerts a bactericidal action by inhibiting the synthesis of both the septum and the cell wall.
Tazobactam, a beta-lactam structurally related to penicillins, is an inhibitor of many beta-lactamases that commonly cause resistance to penicillins and cephalosporins, but 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.
Pharmacokinetic / pharmacodynamic relationship
Time above minimal inhibitory concentration (T> MIC) is believed to be the major pharmacodynamic determinant of piperacillin efficacy.
Resistance mechanism
The two main mechanisms of resistance to piperacillin / tazobactam are:
Inactivation of piperacillin by beta-lactamases that are not inhibited by tazobactam: beta-lactamases of molecular class B, C and D. Furthermore, tazobactam does not protect against extended spectrum beta-lactamases (ESBL) included in the enzyme groups of molecular class A and D.
Alteration of penicillin-binding proteins (PBPs), which results in the reduction of the affinity of piperacillin for the molecular target in bacteria.
Furthermore, alterations in bacterial membrane permeability, as well as in the expression of multi-drug efflux pumps, may cause or contribute to bacterial resistance to piperacillin / tazobactam, especially in gram-negative bacteria.
Breakpoint
Clinical MIC breakpoints defined by EUCAST for piperacillin / tazobactam (2009-12-02, v 1). For sensitivity testing purposes, the concentration of tazobactam is fixed at 4 mg / l
Sensitivity of streptococci is inferred from penicillin sensitivity.
The sensitivity of staphylococci is inferred from the sensitivity to oxacillin.
Sensitivity
The prevalence of acquired resistance may vary by geographic area and over time for particular species, therefore local information on resistance is desirable, particularly in the treatment of severe infections. If necessary, seek expert advice when the local prevalence of resistance is such that the utility of the antibiotic is questionable, at least in some types of infections.
05.2 Pharmacokinetic properties
Absorption
The peak concentrations of piperacillin and tazobactam following a dose of 4 g / 0.5 g administered over 30 minutes by intravenous infusion are 298 mcg / ml and 34 mcg / ml, respectively.
Distribution
Both piperacillin and tazobactam are approximately 30% bound to plasma proteins. The protein binding of piperacillin or tazobactam is not altered by the presence of the other compound. The protein binding of the tazobactam metabolite is negligible.
Piperacillin / tazobactam is widely distributed in body tissues and fluids, including intestinal mucosa, gallbladder, lung, bile and bone. Mean tissue concentrations are typically 50-100% of plasma concentrations. Distribution in cerebrospinal fluid is low in people with non-inflamed meninges, as is the case with other penicillins.
Biotransformation
Piperacillin is metabolised to a microbiologically active minor metabolite (desethyl metabolite). Tazobactam is metabolised to a single, microbiologically inactive metabolite.
Elimination
Piperacillin and tazobactam are eliminated renally by glomerular filtration and tubular secretion.
Piperacillin is rapidly excreted as unchanged substance, with 68% of the administered dose recovered in the urine. Tazobactam and its metabolite are eliminated primarily by renal excretion, with 80% of the administered dose recovered as unchanged substance and the remainder as a single metabolite. Piperacillin, tazobactam and desethyl piperacillin are also excreted in the bile.
After single or repeated administrations of piperacillin / tazobactam to healthy subjects, the plasma half-life of piperacillin and tazobactam ranged from 0.7 to 1.2 hours and was not affected by dose or infusion duration. The elimination half-life. of both piperacillin and tazobactam increased with decreased 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-lives of piperacillin and tazobactam increase by approximately 25% and 18%, respectively, in patients with liver cirrhosis, compared to healthy subjects.
The half-life of piperacillin and tazobactam increases with decreasing creatinine clearance. When creatinine clearance is less than 20 ml / min, the half-life of piperacillin increases two-fold and the half-life of tazobactam increases four-fold compared to patients with normal renal function.
Hemodialysis eliminates 30% to 50% of piperacillin / tazobactam, and an additional 5% of the tazobactam dose is eliminated as the metabolite of tazobactam. Peritoneal dialysis eliminates approximately 6% of the piperacillin dose and 21% of the tazobactam dose, and up to 18% of the tazobactam dose is eliminated as the tazobactam metabolite.
Pediatric population
In a "population pharmacokinetic analysis, the estimated clearance for patients aged 9 months to 12 years was comparable to that in adults, with a population mean (SE) value of 5.64 ml / min / kg. For pediatric patients aged 2 to 9 months, the estimated clearance of piperacillin was found to be 80% of this value. The population mean (SE) for piperacillin volume of distribution is 0.243 L / kg and is independent of age.
Elderly patients
The mean half-lives of piperacillin and tazobactam were prolonged by 32% and 55% respectively in the elderly compared to younger subjects. This difference may be due to age-related changes in creatinine clearance.
Race
There was no difference in piperacillin or tazobactam pharmacokinetics between Asian (n = 9) and Caucasian (n = 9) healthy volunteers treated with single 4 g / 0.5 g doses.
05.3 Preclinical safety data
Based on conventional repeated dose toxicity studies and genotoxicity studies, non-clinical data reveal no special hazard for humans. Carcinogenicity studies with piperacillin / tazobactam have not been conducted.
A fertility and general reproduction study in rats, with intraperitoneal administration of tazobactam or the piperacillin / tazobactam combination, reported a reduction in the size of the offspring and an increase in the number of fetuses with delayed ossification and rib alterations, associated to maternal toxicity. Fertility of the F1 generation and embryonic development of the F2 generation were not compromised.
Teratogenicity studies with intravenous administration of tazobactam or the piperacillin / tazobactam combination in mice and rats showed slight reductions in fetal weight in rats at maternally toxic coughs, but did not show teratogenic effects.
After intraperitoneal administration of tazobactam or the piperacillin / tazobactam combination in rats, peri / postnatal development was altered (reduced fetal weight, increased offspring mortality, increased fetal mortality) associated with maternal toxicity.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Disodium edetate (EDTA) Citric acid monohydrate
06.2 Incompatibility
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
When Tazocin is used concomitantly with another antibiotic (e.g. aminoglycosides), the substances must be administered separately. The mixing of beta-lactam antibiotics with an aminoglycoside in vitro it can cause substantial inactivation of the aminoglycoside.
Tazocin must not be mixed with other substances in the same syringe or infusion bottle, as compatibility has not been established.
Due to chemical instability, Tazocin should not be used in solutions containing only sodium bicarbonate.
Tazocin must not be added to blood products or hydrolysed albumin.
06.3 Period of validity
Reconstituted solution in vial
Chemical and physical in-use stability has been demonstrated for up to 24 hours at 25 ° C and for 48 hours when stored in a refrigerator at 2 - 8 ° C when reconstituted with one of the compatible solvents for reconstitution (see section 6.6).
Diluted solution for infusion
After reconstitution, the chemical and physical in-use stability of the diluted solutions for infusion has been demonstrated for 24 hours at 25 ° C and for 48 hours when stored in a refrigerator at 2 - 8 ° C, when reconstituted using one of the compatible solvents for the "Further dilution of the reconstituted solution to the recommended dilution volumes (see section 6.6).
From a microbiological point of view, the reconstituted and diluted solutions should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 12 hours at 2 - 8 ° C, unless reconstitution and dilution did not take place under controlled and validated aseptic conditions.
06.4 Special precautions for storage
Unopened vials: Do not store above 25 ° C.
For storage conditions of the reconstituted and diluted medicinal product, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
30 ml type I glass vial with bromobutyl rubber stopper and flip-off seal. 70 ml type I glass vial with bromobutyl rubber stopper and flip-off seal. Pack sizes: 1, 5, 10, 12, 25 or 50 vials per carton pack.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Reconstitution and dilution must be performed under aseptic conditions. The solution should be visually examined prior to administration to exclude the presence of particulates and discolouration. The solution should only be used if it is clear and free of particulates.
Intravenous use
Reconstitute each vial with the volume of solvent indicated in the table below, using one of the compatible solvents for reconstitution. Shake with a rotating motion until dissolved. When shaken with constant rolling motion, reconstitution typically occurs within 5-10 minutes (for details on
handling, see below).
* Compatible solvents for reconstitution:
• 0.9% sodium chloride (9 mg / ml) solution for injection
• sterile water for injections
• glucose 5%
The maximum recommended volume of sterile water for injections for each dose is 50 ml.
The reconstituted solution should be withdrawn from the vial with a syringe. Once reconstituted according to the instructions, the contents of the vial withdrawn with the syringe will provide the quantities of piperacillin and tazobactam indicated on the label.
Reconstituted solutions can be further diluted to the desired volume (e.g. 50ml to 150ml)
with one of the following compatible solvents:
• 0.9% sodium chloride (9 mg / ml) solution for injection
• glucose 5%
• dextran 6% in 0.9% sodium chloride
• Lactated Ringer's solution for injection
• Hartmann's solution
• Ringer acetate
• Ringer acetate / diseased
Co-administration with aminoglycosides
Due to inactivation in vitro of the aminoglycoside by beta-lactam antibiotics, it is recommended to administer Tazocin and the aminoglycoside separately. When concomitant aminoglycoside therapy is indicated, Tazocin and the aminoglycoside must be reconstituted and diluted separately.
In circumstances where co-administration is recommended, Tazocin is compatible for simultaneous co-administration, via infusion with a Y-line, only with the following aminoglycosides and under the following conditions:
* The aminoglycoside dose should be based on patient weight, infection status (severe or life-threatening) and renal function (creatinine clearance).
Compatibility of Tazocin with other aminoglycosides has not been established. Only the concentrations and diluents of amikacin and gentamicin together with the dose of Tazocin, as reported in the previous table, have been found compatible for co-administration by infusion via a Y-line. Simultaneous co-administration via a Y-tube in ways other than those listed above may result in the inactivation of the aminoglycoside by Tazocin.
For incompatibilities, see section 6.2.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
For single use only. Discard any unused solution.
07.0 MARKETING AUTHORIZATION HOLDER
Pfizer Limited, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom
Representative for Italy: Pfizer Italia S.r.l. - Via Isonzo, 71 - 04100 Latina
08.0 MARKETING AUTHORIZATION NUMBER
TAZOCIN 2 g + 0.250 g powder for solution for infusion AIC n ° 028249050;
TAZOCIN 4 g + 0.500 g powder for solution for infusion AIC n ° 028249035;
TAZOCIN 4 g + 0.500 g powder for solution for infusion AIC n ° 028249062;
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
TAZOCIN 2 g + 0.250 g powder for solution for infusion - 12 vials June 2009 / November 2009
TAZOCIN 4 g + 0.500 g powder for solution for infusion-1 Vial 29 December 1998 / November 2009
TAZOCIN 4 g + 0.500 g powder for solution for infusion -12 Vials June 17, 2008 / November 2009
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