Active ingredients: Piperacillin, Tazobactam
Piperacillin and Tazobactam Ibigen 4 g / 0.5 g powder for solution for infusion
Why are Piperacillin and Tazobactam used? What is it for?
Piperacillin belongs to the group of antibiotic drugs known as broad-spectrum penicillins, which can kill many types of bacteria. Tazobactam can prevent some bacteria from resisting piperacillin.
This means that when piperacillin and tazobactam are given together, more types of bacteria are killed.
Piperacillin and Tazobactam Ibigen is indicated in adults and adolescents for the treatment of bacterial infections, affecting the lower respiratory tract (lungs), urinary tract (kidney and bladder), abdomen, skin or blood.
Piperacillin and Tazobactam Ibigen can be used to treat infections in patients with low white blood cell counts (reduced resistance to infections).
Piperacillin and Tazobactam Ibigen is indicated in children between the ages of 2 and 12 for the treatment of abdominal infections, such as appendicitis, peritonitis (fluid infection and an "infection of the fluid and lining of the abdominal organs), and gallbladder (biliary ).
Your doctor may use Piperacillin and Tazobactam Ibigen in combination with other antibiotics in some severe infections.
Contraindications When Piperacillin and Tazobactam should not be used
Do not use Piperacillin and Tazobactam Ibigen
- If you are allergic (hypersensitive) to piperacillin or tazobactam
- If you are allergic (hypersensitive) to antibiotics known as penicillins, cephalosporins or other beta-lactamase inhibitors, so you may be allergic to Piperacillin and Tazobactam Ibigen
Precautions for use What you need to know before taking Piperacillin and Tazobactam
Talk to your doctor or healthcare professional before taking Piperacillin and Tazobactam Ibigen
- If you have allergies. If you have multiple allergies, please tell your doctor or healthcare professional before taking this product
- If you suffer from diarrhea before treatment or if you have diarrhea during or after treatment. In this case, please inform your doctor or healthcare professional immediately. Do not take any diarrhea medication until you have talked to your doctor
- If you think your infection is getting worse or you have a new infection. In this case, you must inform your doctor or healthcare professional
- If you are taking certain medicines (called anticoagulants) to prevent "excessive blood clotting (see also" Taking other medicines "in this leaflet) or unexpected bleeding occurs during treatment. In this case, you should tell your doctor or healthcare personnel immediately
- If you have liver or kidney problems, or are treated with hemodialysis. Your doctor may have your kidneys checked before giving you this medicine and may require regular blood tests during treatment.
- If you have convulsions during treatment. In this case, you must inform your doctor or healthcare professional
- If you have low levels of potassium in your blood. Your doctor may request a check of your kidneys before taking this drug and may require regular blood tests during treatment.
Children under 2 years old
The use of Piperacillin and Tazobactam Ibigen is not recommended in children less than 2 years of age due to a lack of sufficient data on safety and efficacy.
Interactions Which drugs or foods can modify the effect of Piperacillin and Tazobactam
Tell your doctor or healthcare professional if you are taking, have recently taken or might take any other medicines, including those obtained without a prescription.
Some drugs can interact with Piperacillin and Tazobactam Ibigen. These include:
- Gout medications (probenecid). It may increase the time to eliminate piperacillin and tazobactam from your body
- Medicines to thin the blood or to treat blood clots (eg, heparin, warfarin, or aspirin)
- Medicines used to relax muscles during surgery. Tell your doctor if you are about to undergo general anesthesia
- Methotrexate (drug used to treat cancer, arthritis or psoriasis). Piperacillin and tazobactam may increase the time it takes to eliminate methotrexate
- Medicines used to reduce potassium levels in the blood (such as tablets to increase diuresis or some cancer drugs
- Medicines containing other antibiotics, such as tobramycin and gentamicin. Tell your doctor if you have kidney problems
Effects on laboratory tests
Tell the laboratory staff if you are taking Piperacillin and Tazobactam Ibigen if you need to have a blood or urine test.
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. Piperacillin and tazobactam can be absorbed by the baby when it is in the womb or through breastfeeding. If you are breastfeeding, your doctor will decide whether you can use Piperacillin and Tazobactam Ibigen.
Driving and using machines
The intake of Piperacillin and Tazobactam Ibigen does not appear to affect the ability to drive or use machines
Important information about some of the ingredients of Piperacillin and Tazobactam Ibigen
This medicinal product contains 9.39 mmol (216 mg) sodium per vial of powder for solution for infusion.
This should be taken into consideration in patients on a controlled sodium diet.
Dose, Method and Time of Administration How to use Piperacillin and Tazobactam: Posology
Always take this medicine exactly as your doctor or healthcare professional has told you. If in doubt, consult your doctor or healthcare professional. Your doctor or healthcare professional will give you Piperacillin and Tazobactam Ibigen by intravenous infusion (30 minutes) into one of your veins.
The dose of drug administered depends on the cause for which you are receiving treatment, on your age and on whether or not you have kidney problems.
Use in adults and children over 12 years of age
The usual dose is 4 g / 0.5 g piperacillin / tazobactam given every 8 hours, into a vein (directly into the blood
Use in children between 2 and 12 years of age
The usual dosage in children with abdominal infections is 100 mg / 12.5 mg / kg of Piperacillin and Tazobactam Ibigen every 8 hours into a vein (directly into the blood).
The usual dosage in children with low white blood cell counts is 80 mg / 10 mg / kg of Piperacillin and Tazobactam Ibigen every 6 hours into a vein (directly into the blood).
Your doctor will calculate the dosage based on the weight of the child, but the daily dosage should not be more than 4 g / 0.5 g of Piperacillin and Tazobactam Ibigen.
Treatment should last until the infection has completely healed (5 to 14 days).
Use in patients with impaired renal function
If you have kidney problems, your doctor may need to reduce the dose of Piperacillin and Tazobactam Ibigen or the frequency of administration.
Your doctor may also order blood tests to make sure you are getting the right dosage, especially if you have to take this drug for a long time.
Overdose What to do if you have taken an overdose of Piperacillin and Tazobactam
If you take, take more Piperacillin and Tazobactam Ibigen than directed
As Piperacillin and Tazobactam Ibigen will be given to you by your doctor or healthcare professional it is unlikely that you will be given the wrong dosage. However, if you notice any side effects, such as seizures, or think you have received too much medication, tell your doctor immediately.
If you forget to take Piperacillin and Tazobactam Ibigen
If you think you have forgotten to take a dose of Piperacillin and Tazobactam Ibigen, tell your doctor or healthcare professional immediately.
If you have any further questions on the use of this medicine, ask your doctor or other healthcare professional.
Side Effects What are the side effects of Piperacillin and Tazobactam
Like all medicines, this medicine can cause side effects, although not everybody gets them.
See a doctor right away if any of these potentially serious side effects occur:
- Severe skin rashes (Stevens-Johnson syndrome, toxic epidermal necrolysis) initially manifesting as target-like reddish patches or circular patches often with central blisters on the trunk. Additional signs include ulcers in the mouth, throat, nose, extremities, genitals, and conjunctivae (red and swollen eyes). The rash can progress to widespread blistering or peeling of the skin and could potentially be life threatening.
- swelling of the face, lips, tongue or other parts of the body
- shortness of breath, difficulty in breathing
- severe rash, itching or blistering of the skin
- damage to blood cells (this includes: suddenly being out of breath, red or brown urine, nosebleeds and bruising)
- severe and persistent diarrhea accompanied by fever and weakness
- unexpected bleeding, particularly if you are taking blood thinners such as warfarin
Other possible adverse events:
Common adverse events (may affect 1 in 10 people)
- diarrhea, vomiting, nausea
- skin redness
Uncommon adverse events (may affect 1 in 100 people)
- thrush
- (abnormal) decrease in white blood cells (leukopenia, neutropenia) and platelets (thrombocytopenia)
- allergic reaction
- headache, drowsiness
- low blood pressure, inflammation of the veins (a feeling of tension or redness of 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 (increased alanine aminotransferases, increased aspartate aminotransferases)
- itching, hives
- increased muscle metabolism products (increased blood creatinine)
- fever, injection site reaction
- yeast infections (candi superinfection
Rare adverse events (may affect up to 1 in 1,000 people)
- (abnormal) decrease in red blood cells or blood pigment / hemoglobin
- (abnormal) decrease in red blood cells from premature rupture (degradation) (haemolytic anemia), small itchy papules (purpura), nosebleeds (epistaxis) and prolonged bleeding time, (abnormal) increase in a particular type of white blood cell (eosinophilia )
- severe allergic reaction (anaphylactic / anaphylactoid reaction, including shock)
- redness of the skin
- a type of colon infection (pseudomembranous colitis), abdominal pain
- inflammation of the liver (hepatitis), increased catabolism of blood pigments (bilirubin), increase in some enzymes in the blood (alkaline phosphatase, gamma-glutamyltransferase)
- skin reactions with redness and formation of skin lesions (rash, erythema multiforme), skin reactions with blisters (bullous dermatitis)
- joint and muscle pain
- reduced kidney function and kidney problems
- cramps / stiffness
Very rare adverse events (may affect up to 1 in 10,000 people)
- severe decrease in white blood cells (agranulocytosis), severe decrease in red, white blood cells and platelets (pancytopenia)
- prolonged clotting time (prolonged partial thromboplastin time, prolonged prothrombin time), abnormal blood tests (positive Coombs test), increased platelets (thrombocythemia)
- decreased blood potassium (hypokalemia), decreased blood sugar (glucose), decreased blood albumin, decreased total protein
- detachment of the upper layer of the skin throughout the body (toxic epidermal necrolysis), severe allergic reactions with extensive rashes all over the skin and mucous membranes and various rashes (Stevens-Johnson syndrome)
- nitrogen in the blood, increased urea
Piperacillin therapy has been associated with an "increased incidence of fever and flushing in patients with cystic fibrosis.
Reporting of side effects
If you get any side effects, talk to your doctor or healthcare professional. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system of the Italian Medicines Agency Website: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
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 bottle after "EXP". The expiry date refers to the last day of that month.
Unopened vial: Store at a temperature not exceeding 25 ° C. Store in the original package.
The reconstituted / diluted solution should be used within 5 hours if stored at 20 - 25 ° C and within 24 hours if 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 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 Piperacillin and Tazobactam Ibigen contains
The active ingredients are piperacillin and tazobactam.
Each vial contains:
- 4 g piperacillin (as sodium salt)
- 0.5 g of tazobactam (as sodium salt)
Description of what Piperacillin and Tazobactam Ibigen look like and contents of the pack
White - almost white powder
Clear glass vial with sealed rubber stopper with aluminum cap and flip-off
Packaging:
Piperacillin and Tazobactam Ibigen 4 g / 0.5 g powder for solution for infusion:
1 x 1 vial containing powder for solution for infusion (DE / H / 904/03 / DC)
10 x 1 vial containing powder for solution for infusion (DE / H / 904/01 / DC)
Not all pack sizes may be marketed
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
PIPERACILLIN AND TAZOBACTAM 2 G / 0.25 G 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 contains 4.70 mmol (108 mg) of sodium
Excipients: for the full list of excipients see section 6.1
03.0 PHARMACEUTICAL FORM
Powder for solution for infusion
White or almost white powder
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Piperacillin / Tazobactam IBIGEN 2 g / 0.25 g powder for solution for infusion is indicated for the 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 pneumonia associated with mechanical ventilation
• Complicated urinary tract infections (including pyelonephritis)
• Complicated intra-abdominal infections
• Complicated skin and soft tissue infections (including foot infections in the diabetic)
Treatment of patients with concomitant or suspected septicemia with any of the infections listed above.
Piperacillin / Tazobactam is indicated for the treatment of neutropenic patients with fever which may be attributable to bacterial infection.
Children between 2 and 12 years of age
• Complicated intra-abdominal infections
Piperacillin / Tazobactam is indicated for the treatment of neutropenic children with fever which may be attributable to bacterial infection.
Official guidelines on the appropriate use of antibacterial products should be considered.
04.2 Posology and method of administration
Dosage
The dosage and frequency of administration of Piperacillin / Tazobactam depend on the severity and location of the infection and suspected bacteria.
Adult and adolescent patients
Infections
The usual dosage is 4 g piperacillin / 0.5 g tazobactam every 8 hours.
For hospital pneumonias and bacterial infections in neutropenic patients, the recommended dosage is 4 g piperacillin / 0.5 g tazobactam every 6 hours. This regimen may also be applicable to treat patients in other indications, when particularly severe.
The following table gathers the dosage and frequency of treatment in adults and children by indication or condition:
Kidney failure
In patients with renal insufficiency the intravenous dosage should be adjusted according to the degree of residual renal function (each patient should be closely monitored for signs of suspected toxicity; intravenous dosages and dosing intervals should be corrected accordingly):
Since hemodialysis removes 30% to 50% of piperacillin in 4 hours, dialysis patients should receive an additional dose of Piperacillin / Tazobactam 2 g / 0.250 g after each dialysis treatment.
Patients with impaired hepatic function
No dosage adjustment is necessary (see section 5.2).
Elderly patients
No dosage adjustment is necessary in the elderly with renal function or creatinine clearance greater than 40 ml / min.
Children (2-12 years of age)
Infections
The following table gathers the dosage and frequency of treatment in children between 2 and 12 years of age in relation to weight, indication or condition:
Kidney failure
Intravenous dosing should be adjusted according to the degree of residual renal function (each patient should be closely monitored for signs of suspected toxicity; intravenous dosages and dosing intervals should be corrected accordingly):
Children undergoing dialysis should receive an additional dose of 40 mg piperacillin / 5 mg tazobactam / kg after each dialysis treatment.
Children under the age of 2
As there are no data available on the safety and efficacy of Piperacillin / Tazobactam in children under 2 years of age, the use of Piperacillin / Tazobactam is not recommended in this age group.
Duration of treatment
The duration of therapy, for most indications, is at least 5 days up to a maximum of 14 days.However, it should be adjusted according to the severity of the infection and the patient's clinical and bacteriological response.
Route of administration
Piperacillin / Tazobactam 2 g / 0.25 g should be administered by intravenous infusion (over 30 minutes).
For reconstitution, see section 6.6
04.3 Contraindications
Hypersensitivity to the active substances, to other penicillins or to excipients.
History of severe acute allergic reactions to other beta-lactam products (e.g. cephalosporins, monobactams or carbapenems).
04.4 Special warnings and appropriate precautions for use
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 compared to other products, should be considered when choosing a patient's treatment with Piperacillin / Tazobactam. antibacterials available.
Before starting treatment with Piperacillin and Tazobactam IBIGEN, a careful investigation should be made of previous hypersensitivity reactions to penicillins, other beta-lactam antibiotics (e.g. cephalosporins, monobactams or carbapenems) and other allergens.
Serious and occasional fatal hypersensitivity reactions (anaphylactic / anaphylactoid reactions [including shock]) have been reported in patients receiving treatment with penicillins, including Piperacillin / Tazobactam. These reactions occur more frequently in patients with a history of sensitization to various allergens. Severe hypersensitivity reactions require discontinuation of the antibiotic, and may require administration of epinephrine and other emergency measures.
Antibiotic-induced pseudomembranous colitis could manifest as severe, persistent, life-threatening diarrhea. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment. In such cases Piperacillin / Tazobactam should be discontinued.
Piperacillin / Tazobactam therapy can cause the development of resistant bacteria, which could cause super-infections.
Hemorrhagic manifestations have been reported in some patients treated with beta-lactam antibiotics.
These reactions have sometimes been associated with abnormal clotting tests such as bleeding time, platelet aggregation and prothrombin time; these phenomena occur more frequently in patients with renal insufficiency. In this case, discontinue piperacillin / tazobactam treatment and institute appropriate therapy.
Leukopenia and neutropenia may occur, especially in the course of prolonged therapy, therefore periodic checks of hematopoietic function are recommended.
As with other penicillins, neuromuscular excitability or convulsions may occur when higher than recommended doses are administered, especially in patients with renal insufficiency.
Each vial contains 4.70 mmol (108 mg) sodium. Therefore this information should be taken into consideration in those patients on a controlled sodium diet.
Hypokalaemia may occur in patients who have low potassium stores or in patients who are taking other medications that can lower potassium levels at the same time; in such patients periodic electrolyte determinations are advisable.
04.5 Interactions with other medicinal products and other forms of interaction
Muscle relaxants of the non-depolarizing type
Piperacillin when used concomitantly with vecuronium has been involved in the prolongation of vecuronium-induced neuromuscular blockade.
Because of their similar mechanism of action, neuromuscular blockade produced by any of the nondepolarizing muscle relaxants is expected to be prolonged in the presence of piperacillin.
Oral anticoagulants
During the simultaneous administration of heparin, oral anticoagulants and other drugs that can interfere with blood clotting, including thrombocytic function, coagulation parameters should be checked more frequently and monitored regularly.
Methotrexate
Piperacillin may reduce the elimination of methotrexate. Therefore, serum levels of methotrexate should be monitored to avoid toxic effects of the drug.
Probenecid
As with other penicillins, co-administration of probenecid and piperacillin tazobactam results in a longer half-life and lower renal clearance of piperacillin and tazobactam. However, the maximum plasma concentrations of each active substance are unchanged.
Aminoglycosides
Piperacillin either alone or with tazobactam produces no major clinical alterations on the pharmacokinetics of tobramycin in patients with normal renal function and mild or moderate renal impairment. The pharmacokinetics of piperacillin, tazobactam and metabolite M1 are not significantly changed 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 and tazobactam with aminoglycosides refer to sections 6.2 and 6.6.
Vancomycin
There were no important pharmacokinetic interactions between piperacillin and tazobactam and vancomycin in healthy subjects with normal renal function.
Effects on laboratory tests
Non-enzymatic methods of urinary glucose determination can give false positives, as with other penicillins. Therefore, enzymatic methods should be used to determine urinary glucose during piperacillin / tazobactam treatment.
Several chemical methods for determining protein in urine can give false positives. The determination of proteins with strips testit is not altered. The direct Coombs test can give a positive result.
Positive results have been reported using the Platelia® Aspergillus EIA Test from Bio-Rad Laboratories in patients treated with piperacillin / tazobactam. Cross reactions of non-aspergillus polysaccharides and polyphuranoses have been reported with the Platelia® Aspergillus EIA Test from Bio-Rad Laboratories.
Therefore, positive results in patients receiving Piperacillin and Tazobactam IBIGEN should be interpreted with caution and confirmed by other diagnostic methods.
04.6 Pregnancy and lactation
Pregnancy
There are no or limited data on the use of piperacillin / tazobactam in pregnant women.
Animal studies have shown reproductive toxicity but no evidence of teratogenicity at maternal toxic doses (see section 5.3).
Piperacillin and tazobactam cross the placenta. Piperacillin and Tazobactam IBIGEN in pregnancy should only be used if clearly indicated only if the expected benefit outweighs the possible risks to the woman or fetus.
Feeding time
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 mice showed no effects on fertility and mating after intraperitoneal administration of tazobactam or piperacillin / tazobactam (see section 5.3).
04.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
04.8 Undesirable effects
The most common side effects reported (between 1 and 10 in 100 patients) are diarrhea, vomiting, nausea and redness.
The following table lists undesirable effects for MedDRA systems and terms. In each group, undesirable effects are reported in order of decreasing severity
Piperacillin therapy has been associated with an increased incidence of fever and rash in patients with cystic fibrosis.
04.9 Overdose
Symptomatology
Cases of overdose with piperacillin and tazobactam have been reported post-marketing. The majority of those events experienced including nausea, vomiting and diarrhea occurred even with common recommended dosages. Neuromuscular overexcitability or convulsions have been reported in some patients after intravenous administration of higher than recommended doses (especially 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 in relation to the patient's clinical condition.
In an emergency, all required intensive measures are the same as those indicated for piperacillin.
Excessive plasma concentrations of piperacillin or tazobactam can be reduced by hemodialysis.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antibacterials for systemic use. Association of penicillins and beta-lactamase inhibitors.
ATC-Code: J01CR05
Mechanism of action
Piperacillin is a broad spectrum semi-synthetic penicillin whose antibacterial activity is carried out by inhibiting the synthesis of the septum and the bacterial wall.
Tazobactam, a beta-lactam structurally related to penicillins, is an inhibitor of many beta-lactamases, which commonly cause resistance to penicillins and cephalosporins but does not inhibit AmpC enzymes or metallo beta-lactamases. Tazobactam enhances the antibiotic spectrum of piperacillin against numerous other bacterial strains, producing beta-lactamases, which are normally resistant to piperacillin and other beta-lactam antibiotics.
Pharmacokinetic / Pharmacodynamic correlations
Time above minimal inhibitory concentration (T> MIC) is considered to be the major pharmacodynamic efficacy parameter for piperacillin.
Resistance mechanism
The two main mechanisms of resistance to piperacillin / tazobactam are:
• inactivation of piperacillin by those beta-lactamases not inhibited by tazobactam: beta-lactamases in Molecular class B, C and D. Furthermore, tazobactam does not give its protection against extended spectrum beta-lactamases ((ESBLs) in the of enzymes of Molecular class A and D.
• alteration of piperacillin-carrying proteins (PBPs), which results in a reduction of piperacillin's affinity for the molecular target in bacteria.
In addition, 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 breackpoints for Piperacillin / Tazobactam (2009-12-02, v 1). For the purpose of testing for sensitivity, the concentration of Tazobactam is fixed at 4 mg / l.
Sensitivity of strep is referred to sensitivity to penicillin
Sensitivity of streptococcus refers to sensitivity to oxacillin
Sensitivity
The prevalence of acquired resistance may vary geographically and with time for selected species. It is important to take into account local information on resistance, especially when treating severe infections. Refer to local guidelines for proper antibiotic susceptibility testing.
05.2 "Pharmacokinetic properties
Absorption
Piperacillin and tazobactam are well absorbed after intramuscular administration with a bioavailability of 71% for piperacillin and 84% for tazobactam.
The peak plasma concentrations of piperacillin and tazobactam after an intravenous infusion of more than 30 minutes are 298 mcg / ml and 34 mcg / ml, respectively.
Distribution
The extent of plasma protein binding is approximately 30% for both piperacillin and tazobactam.
The protein binding of piperacillin or tazobactam is not affected by the presence of other compounds. Protein binding of the tazobactam metabolite is negligible.
Piperacillin / tazobactam is widely distributed in tissues and body fluids including intestinal mucosa, gallbladder, lung, bile, and bones. Mean tissue concentrations are generally 50 to 100% of those in plasma. CSF distribution is low in people with non-inflamed meninges, as with other penicillins.
Transformation
Piperacillin is metabolised to a minor, microbiologically active ethyl metabolite.
Tazobactam is metabolised to a single, microbiologically inactive metabolite.
Excretion
Piperacillin and tazobactam are rapidly eliminated by the kidney, by glomerular filtration and active secretion.
Piperacillin is rapidly excreted in the urine as unchanged substance, accounting for 68% of the administered dose. Tazobactam and its metabolite are eliminated mainly by renal excretion, with 80% of the administered dose appearing as unchanged substance and the rest as its sole metabolite. Piperacillin, tazobactam and disethyl-piperacillin are secreted in the bile.
Following single or multiple doses of piperacillin / tazobactam to healthy subjects, the plasma half-life of piperacillin and tazobactam ranges from 0.7 to 1.2 hours and is affected by the dose or duration of the infusion. The elimination half-lives of both piperacillin and tazobactam increased with decreasing renal clearance.
There are no significant changes in piperacillin pharmacokinetics due to tazobactam.
Piperacillin appears to moderately reduce the clearance of tazobactam.
Special populations
The half-life of piperacillin and tazobactam increases 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.
The half-life increase is two-fold and four-fold for piperacillin and tazobactam, respectively, with a creatinine clearance of less than 20 ml / min compared to patients with normal renal function.
Hemodialysis removes 30% to 50% of piperacillin / tazobactam, with an additional 5% of the tazobactam dose removed as the metabolite of tazobactam. Peritoneal dialysis removes approximately 6% and 21% of the doses of piperacillin and tazobactam, respectively. up to 18% of the tazobactam dose removed as the tazobactam metabolite.
Pediatric population
In a population pharmacokinetic analysis, the estimated clearance for patients 9 months to 12 years was comparable to adults, with a population mean (SE) of 5.64 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 the volume of distribution is piperacillin 0.243 l / kg and is independent of age.
Elderly patients
The mean half-lives of piperacillin and tazobactam are 32% and 55% longer, respectively, in the elderly than in younger subjects. This difference may be due to age-related changes in creatinine clearance.
Race
No differences in piperacillin or tazobactam pharmacokinetics were observed between Asians (n = 9) and Caucasians (n = 9) of the healthy volunteers who received doses of 4 g / 0.5 g.
05.3 Preclinical safety data
Preclinical data, based on conventional repeat dose studies for toxicity and genotoxicity, showed no special hazard for humans. Carcinogenicity studies with piperacillin / tazobactam have not been conducted.
In a fertility study with the combination of piperacillin and tazobactam, a decrease in fertility and an increase in fetuses with delayed ossification and alterations of the ribs in conjunction with maternal toxicity were observed after intraperitoneal administration in rats. F1 and the embryonic development of the F2 generation were not altered.
Teratogenicity studies with intravenous administration of tazobactam or the piperacillin / tazobactam combination in mice and rats showed a slight reduction in rat fetal weight at maternally toxic doses, but did not show teratogenic effects.
In rats, effects on embryo development were observed with the combination piperacillin and tazobactam only at maternally toxic doses. Peri / postnatal development was impaired (reduced fetal weight, increased pup mortality, increased stillbirth). concurrent with maternal toxicity, following intraperitoneal administration of tazobactam or the piperacillin / tazobactam combination in rats.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Nobody.
06.2 Incompatibility
This medicinal product must not be mixed with other products except those mentioned in section 6.6.
When piperacillin and tazobactam are used concomitantly with other antibiotics, (e.g. aminoglycosides), the products should not be administered separately.
Mix beta / lactam antibiotics with an aminoglycoside in vitro it can determine the inactivation of the aminoglycoside.
Lactated Ringer's solution is not compatible with Piperacillin and Tazobactam IBIGEN.
Piperacillin and Tazobactam IBIGEN must not be mixed with other drugs in the syringe or infusion bottle if compatibility has not been established.
Due to chemical instability, Piperacillin and Tazobactam Ibigen should not be used with solutions containing only sodium bicarbonate.
Piperacillin and Tazobactam Ibigen should not be added to blood derivatives or hydrolyzed proteins.
Lactated Ringer's solution is not compatible with Piperacillin and Tazobactam Ibigen.
06.3 Period of validity
Powder in closed vial: 2 years.
Reconstituted / diluted solutions :
When prepared under aseptic conditions, chemical and physical in-use stability has been demonstrated for 5 hours at 25 ° C and for 24 hours at 2-8 ° C.
From a 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.
06.4 Special precautions for storage
Do not store above 25 ° C. Store in the original packaging.
For storage of the reconstituted / diluted product see paragraph 6.3.
Unused solutions should be discarded.
06.5 Nature of the immediate packaging and contents of the package
Type 1 clear glass vial with bromine or chlorobutyl rubber stopper and aluminum flip-off cap.
Packaging:
Piperacillin and Tazobactam IBIGEN 2 g / 0.25 g powder for solution for infusion:
1 x 1 vial containing powder for solution for infusion (DE / H / 904/01 / DC)
10 x 1 vial containing powder for solution for infusion (DE / H / 904/01 / DC)
Not all pack sizes may be marketed
06.6 Instructions for use and handling
Reconstitution / dilution must be done under aseptic conditions. The solution should be visually inspected for foreign particles and discoloration prior to administration. The solution should only be used if the solution is clear and free of particles.
Intravenous infusion
Shake the contents of the Piperacillin and Tazobactam IBIGEN 2 g / 0.25 g vial with at least 10 ml of one of the following diluents until dissolved. When stirred constantly, reconstitution occurs within 5 - 8 minutes (handling details are given below).
Compatible solvents for reconstitution dilution:
- Water for injections (the maximum recommended volume of water for preparations injectable is 50 ml per dose)
- 0.9% sodium chloride solution (9 mg / ml) for injection
- 5% glucose solution
The reconstituted solutions should be withdrawn from the vial with a syringe. When reconstituted as directed, the contents of the syringe aspirated bottle will correspond to the amount of piperacillin and tazobactam stated on the label.
The solution can be further diluted to the desired volume (e.g. 50ml up to 150ml) using the following solvents:
- 0.9% sodium chloride solution (9 mg / ml) for injection
- 5% glucose solution
- 6% dextran in 0.9% sodium chloride solution
Administration with aminoglycosides
It is recommended that Piperacillin / Tazobactam and aminoglycosides be administered separately, due to in vitro inactivation of the aminoglycoside by beta-lactam antibiotics.
Piperacillin / Tazobactam and aminoglucosides must be reconstituted and diluted separately in cases where concomitant therapy is recommended.
Any unused solutions must be disposed of in accordance with local legal requirements.
For single use. Discard the unused solution.
07.0 MARKETING AUTHORIZATION HOLDER
IBIGEN S.r.l.
Via Fossignano, 2
04011 Aprilia (LT)
08.0 MARKETING AUTHORIZATION NUMBER
038476014 / M - "2 g / 0.25 g Powder for solution for infusion" 1 glass vial
038476026 / M - "2 g / 0.25 g Powder for solution for infusion" 10 glass vials
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
January 2009
10.0 DATE OF REVISION OF THE TEXT
September 2011.