Composition, form of production and packaging
Powder for the preparation of a solution for intravenous administration is white or almost white, hygroscopic.
1 f.
piperacillin 4000 mg
which corresponds to piperacillin sodium 4170 mg
tazobactam 500 mg
which corresponds to tazobactam sodium 536.6 mg
Vials of colorless glass with a capacity of 30 ml (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2013.
PHARMACHOLOGIC EFFECT
Piperacillin is a semisynthetic bactericidal broad-spectrum antibiotic that is active against many gram-positive and gram-negative aerobic and anaerobic bacteria.Piperacillin inhibits the synthesis of the membrane of the cell wall of the microorganism.
Tazobactam is a sulfonic derivative of triazolmethylpenicillanic acid, a potent inhibitor of many beta-lactamases (including plasmid and chromosomal beta-lactamases), which often cause resistance to penicillins and cephalosporins, including cephalosporins, of the third generation. The presence of tazobactam in the combination drug enhances antimicrobial activity and expands the spectrum of piperacillin action by including bacteria that form beta-lactamases, which are usually resistant to piperacillin and other beta-lactam antibiotics.
The drug is active against:
Gram-negative bacteria: producing and non-producing beta-lactamase strains of Escherichia coli, Citrobacter spp. (including Citrobacter freundii, Citrobacter diversus), Klebsiella spp. (including Klebsiella oxytoca, Klebsiella pneumoniae), Enterobacter spp. (including Enterobacter cloaca, Enterobacter aerogenes), Proteus vulgaris, Proteus mirabilis, Providencia rettgery, Providencia stuartii, Plesiomonas shigelloides, Morganella morganii, Serratia spp. (including Serratia marcescens, Serratia liquifaciens), Salmonella spp., Shigella spp., Pseudomonas aeruginosa and other Pseudomonas spp. (including Pseudomonas cepacia, Pseudomonas fluorescens), Xanthamonas maltophilia, Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella spp. (including Branhamella catarrhalis), Acinetobacter spp., Haemophilus influenzae, Haemophilus parainfluenza, Pasteurella multocida, Yersinia spp., Campylobacter spp., Gardnerella vaginalis.
Gram-positive bacteria: producing and non-producing beta-lactamase strains of Streptococcus spp. (including Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus bovis, Streptococcus agalactiae, Streptococcus spp., viridans of subgroup C and G), Enterococcus spp. (Enterococcus faecalis, Enterococcus faecium), Staphylococcus aureus (susceptible to methicillin), Staphylococcus saprophyticus, Staphylococcus epidermidis (coagulase negative), Listeria monocytogenes, Nocardia spp.
Anaerobic bacteria: producing and non-producing beta-lactamase strains of Bacteroides spp. (Bacteroides bivius, Bacteroides disiens, Bacteroides capillosus, Bacteroides melaninogenicus, Bacteroides oralis), subgroups of Bacteroides fragilis (Bacteroides fragilis, Bacteroides vulgatus, Bacteroides fragility, Bacteroides uniformis, Bacteroides thetaiotaomicron), Bacteroides uniformis, Bacteroides asaccharolyticus), Peptostreptococcus spp., Fusobacterium spp ., Eubacterium spp., Clostridium spp. (including Clostridium difficile, Clostridium perfringens), Veilonella spp. and Actynomyces spp.
PHARMACOKINETICS
C max piperacillin and tazobactam in plasma are reached immediately after completion of IV administration.
With an increase in the dose of a combination of piperacillin 2 g / tazobactam 250 mg to 4 g / 500 mg, respectively, a disproportionate increase (approximately 28%) in the concentration of piperacillin and tazobactam is observed.
The connection with the plasma proteins of both piperacillin and tazobactam is approximately 30%, with the presence of tazobactam not affecting this parameter of piperacillin, and the presence of piperacillin - tazobactam.
Piperacillin and tazobactam are widely distributed in tissues and body fluids, including in the intestinal mucosa, gall bladder, lungs, bile, female genitalia (uterus, ovaries and fallopian tubes) and bones. The average concentrations in tissues are from 50 to 100% of the concentration in the plasma.
Piperacillin is metabolized to a low-activity deshetylmetabolite; tazobactam - to an inactive metabolite. Piperacillin and tazobactam are excreted by the kidneys through, glomerular filtration and tubular secretion. Piperacillin is rapidly excreted unchanged, 68% of the administered dose is found in the urine. Tazobactam and its
Metabolite is rapidly excreted by renal excretion, 80% of the dose is detected unchanged, and the remaining amount is in the form of a metabolite. Piperacillin, tazobaktam idezetilpiperacillin are also excreted with bile and excreted by the intestine.
T 1/2 of piperacillin and tazobactam from plasma is approximately 0.7-1.2 hours. With a decrease in the creatinine clearance, T 1/2 of piperacillin and tazobactam is elongated.
Impaired renal function
As the clearance of creatinine (CC) decreases, T 1/2 piperacillin and tazobactam increase. With a decrease in CK of less than 20 ml / min, T 1/2 piperacillin and tazobactam, compared with patients with normal renal function, increase 2 and 4 times, respectively.
During hemodialysis, 30 to 50% of piperacillin and 5% of the dose of tazobactam in the form of a metabolite are excreted. When peritoneal dialysis is performed, respectively, about 6 and 21% of piperacillin and tazobactam, with 18% of the tazobactam excreted as its metabolite.
Impaired liver function
Although in patients with impaired liver function, T 1/2 piperazillin and tazobactam increase, dose adjustment is not required.
INDICATIONS
Infectious-inflammatory diseases caused by microorganisms sensitive to piperacillin.
Adults and children over 12 years of age:
- Lower respiratory tract infection;
- urinary tract infections (complicated and uncomplicated);
- intra-abdominal infections;
- skin and soft tissue infections;
- septicemia;
- gynecological infections (including endometritis and adnexitis in the postpartum period);
- bacterial infections in patients with neutropenia (in combination with aminoglycosides);
- infections of bones and joints;
- mixed infections (caused by Gram-positive / Gram-negative aerobic and anaerobic microorganisms).
Children between the ages of 2 and 12:
- intra-abdominal infections;
- infections against neutropenia (in combination with aminoglycosides).
DOSING MODE
In / in slowly struino for at least 3-5 minutes or drip for 20-30 minutes.
Doses of the drug and the duration of treatment is determined by the severity of the infectious process and the dynamics of clinical and bacteriological indicators.
Adults and children over 12 years with normal renal function
The recommended dose of the drug, which is prescribed every 8 hours, is 4.5 g (4 g piperacillin / 0.5 g tazobactam).
The total daily dose depends on the severity and localization of the infection and can vary from 2.25 g (2 g piperacillin / 0.25 g tazobactam) to 4.5 g (4 g piperacillin / 0.5 g tazobactam) of the drug administered every 6 or 8 h.
Children from 2 to 12 years old
For neutropenia:
In patients with normal kidney function and body weight less than 50 kg with a fever resulting from neutropenia, the dose of the drug is 90 mg (80 mg piperacillin / 10 mg tazobactam) per kilogram of body weight, which is administered every 6 hours in combination with a corresponding dose of aminoglycoside .
In children with a body weight of more than 50 kg, the dose corresponds to an adult, and is administered in combination with aminoglycosides.
With intra-abdominal infection: In children with a body weight of up to 40 kg and normal kidney function, the recommended dose is 112.5 mg / kg (100 mg piperacillin / 12.5 mg tazobactam) every 8 hours.
Children with a body weight of more than 40 kg and normal kidney function are given the same dose as an adult, i.e. 4.5 g of the preparation (4 g piperacillin / 0.5 g tazobactam) every 8 hours.
Treatment should be conducted for at least 5 days and not more than 14 days, taking into account that the administration of the drug is continued for at least 48 hours after the disappearance of clinical signs of infection.
Impaired renal function
Patients with chronic renal failure or a patient on hemodialysis, dose and frequency of administration should be adjusted to the degree of impaired renal function.
Recommended doses of the drug for adults and children (body weight> 50 kg) with renal failure
Creatinine clearance (ml / min) Recommended dosage of piperacillin / tazobactam
> 40 No dose adjustment required
20-40 12 g / 1.5 g / day (4 g / 0.5 g every 8 hours)
<20 8 g / 1 g / day (4 g / 0.5 g every 12 h)
For patients on hemodialysis, the maximum daily dose is 8 g / 1 g of piperacillin / tazobactam. In addition, since 30-50% piperacillin is withdrawn from the hemodialysis within 4 hours, one additional dose of 2 g / 0.25 g of piperacillin / tazobactam should be given after each dialysis session.
Children 2-12 years with renal insufficiency:
The pharmacokinetics of piperacillin + [tazobactam] in children with renal insufficiency has not been studied. There are no data on doses with a combination of renal failure and neutropenia. For children aged 2-12 years with renal insufficiency, it is recommended to adjust the dose as follows:
Recommended doses of the drug for children (body weight <50 kg) with renal failure
Creatinine clearance The dose of piperacillin / tazobactam
> 50 ml / min 112.5 mg / kg (100 mg piperacillin / 12.5 mg tazobactam) every 8 hours
<50 ml / min 78.75 mg / kg (70 mg piperacillin / 8.75 mg tazobactam) every 8 hours
Such a change in dose is only indicative. Each patient should be monitored for the timely detection of signs of an overdose. It is necessary to adjust the dose of the drug and the interval between the administration of the next dose accordingly.
There is no need for dose adjustments for liver function disorders.
In elderly patients, dose adjustment is necessary only if there is a violation of kidney function.
Method of solution preparation
Dosage / vial (piperacillin / tazobactam) Required volume of solvent
4.50 g (4 g / 500 mg) 20 ml
The preparation is dissolved in one of the following solvents in accordance with the indicated volumes. The vial is rotated in a circular motion until the content is completely dissolved (with constant rotation, usually for 5-10 min). The prepared solution is a colorless or pale yellow liquid.
Solvents compatible with the preparation: 0.9% solution of sodium chloride; sterile water for injection; 5% dextrose solution.
Then, the prepared solution can be diluted to the required volume for the IV volume (for example, from 50 ml to 150 ml) by one of the following compatible solvents: 0.9% sodium chloride solution; Sterile water for injection (maximum recommended volume - 50 ml); 5% dextrose solution.
SIDE EFFECT
Allergic reactions: urticaria, skin itch, rash, bullous dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylactic / anaphylactoid reactions (including anaphylactic shock).
On the part of the digestive system: diarrhea, nausea, vomiting, constipation, dyspepsia, jaundice, stomatitis, abdominal pain, pseudomembranous colitis, hepatitis.
On the part of the hematopoiesis: leukopenia, neutropenia, thrombocytopenia, anemia, bleeding (including purpura, epistaxis, increased time, bleeding), hemolytic anemia, agranulocytosis, false positive Coombs test, pancytopenia, partial thromboplastin time increase, prothrombin time, thrombocytosis.
From the side of the urinary system: interstitial nephritis, kidney failure.
From the nervous system: headache, insomnia, cramps.
From the cardiovascular system: a decrease in blood pressure, "tides" of blood to the skin of the face.
Laboratory indicators: hypoalbuminemia, hypoglycemia, hypoproteinemia, hypokalemia, eosinophilia, increased activity of "hepatic" transaminases (alanine aminotransferase, aspartate aminotransferase), hyperbilirubinemia, increased activity of alkaline phosphatase, gamma-glutamyltransferase, increased serum creatinine and urea concentration.
Local reactions: phlebitis, thrombophlebitis, hyperemia and compaction at the site of administration.
Other: fungal superinfections, fever, arthralgia.
CONTRAINDICATIONS
- hypersensitivity, to piperacillin, tazobactam, beta-lactam antibiotics (including penicillins, cephalosporins), to inhibitors of beta-lactamases.
- Children under 2 years.
With caution: severe bleeding (including history), cystic fibrosis (increased risk of hyperthermia and skin, rash), pseudomembranous colitis, children over 2 years of age, chronic renal failure (CC less than 20 ml / min), patients who are on hemodialysis, with the joint application of high doses of anticoagulants, with hypokalemia.
PREGNANCY AND LACTATION
There is insufficient data on the use of a combination of piperacillin + [tazobactam] in pregnant women. Piperacillin and tazobactam penetrate the placental barrier.Pregnant women drug can be prescribed only in those cases when the expected benefit for the mother exceeds the possible risk to the fetus.
Piperacillin in low concentrations is secreted with breast milk; the isolation of tazobactam in milk has not been studied. If it is necessary to use the drug during lactation, it is necessary to stop breastfeeding during the treatment.
APPLICATION FOR FUNCTIONS OF THE LIVER
With caution: chronic renal failure (CC less than 20 ml / min), patients on hemodialysis.
APPLICATION FOR CHILDREN
Contraindicated in children under 2 years.
With caution: children age over 2 years, chronic renal failure (CC less than 20 ml / min), patients on hemodialysis.
SPECIAL INSTRUCTIONS
Before starting treatment, the patient should be interviewed in detail to identify possible reactions of hypersensitivity to penicillins, cephalosporins or other allergens.Severe allergic reactions are more likely to develop in patients with increased sensitivity to several allergens. Similar
reactions require discontinuation of the drug and the introduction of epinephrine (Adrenaline) and other emergency measures.
The pseudomembranous colitis caused by antibiotics can be manifested by severe, persistent diarrhea, which poses a threat to life. Pseudomembranous colitis can develop both during antibiotic therapy and after its completion. In such cases, the drug should be discontinued immediately and appropriate therapy should be prescribed (eg, inside metronidazole, vancomycin). Preparations that inhibit intestinal motility are contraindicated.
In the treatment, especially long-term, the development of leukopenia and neutropenia, so you need to periodically monitor the peripheral blood.
In a number of cases (most often in patients with renal insufficiency), the appearance of increased bleeding and concomitant changes in the laboratory parameters of the blood coagulation system (clotting time, platelet aggregation and prothrombin time) is likely. When bleeding occurs, it is necessary to cancel the administration of the drug and prescribe appropriate therapy.
It should be borne in mind the possibility of the emergence of resistant microorganisms, which can cause superinfection, especially with a long course of treatment.This preparation contains 2.79 mEq (64 mg) of sodium per gram of piperacillin, which can lead to a general increase in sodium intake. In patients with hypokalemia or taking drugs that contribute to the excretion of potassium, during the treatment period, hypokalemia may develop (it is necessary to check the electrolyte content in the blood serum regularly).
No experience in children under 2 years of age.
In patients with chronic renal failure who are on hemodialysis, the dose of the drug and the frequency of administration need to be adjusted depending on the CK.
During the use of the drug, a false positive result can be obtained for glucose in the urine using a method based on the reduction of copper ions. Therefore, it is recommended to carry out a test based on enzymatic oxidation of glucose (glucose oxidase method).
Impact on ability to drive or move vehicles
Given the potential for side effects from the nervous system in drug treatment, care should be taken when working with mechanisms and driving vehicles.
OVERDOSE
Symptoms: nausea, vomiting, diarrhea, increased neuromuscular excitability and convulsions.
Treatment: depending on the clinical manifestations, symptomatic treatment is prescribed. To reduce high concentrations of piperacillin or tazobactam in the serum, hemodialysis can be prescribed.
DRUG INTERACTION
The combined use of the drug with probenecid increases T 1/2 and decreases the renal clearance of both piperacillin and tazobactam, but C max in plasma of both drugs remains unchanged.
The simultaneous use of the drug and vecuronium bromide can lead to a longer neuromuscular blockade caused by the latter (a similar effect can be observed with a combination of piperacillin with other nondepolarizing muscle relaxants).
With the simultaneous use of high doses of heparin, indirect anticoagulants or other drugs that affect the blood clotting system, including the function of platelets, it is necessary to more often monitor the state of the blood coagulation system.
Piperacillin may delay the excretion of methotrexate (in order to avoid a toxic effect, it is necessary to control the concentration of methotrexate in the blood serum).
There was no pharmacokinetic interaction with vancomycin.
Piperacillin, including when combined with tazobactam, did not have a significant effect on the pharmacokinetics of tobramycin. The pharmacokinetics of piperacillin, tazobactam and metabolites also did not significantly change with simultaneous use of stobramycin.
Pharmaceutical compatibility with other drugs
The drug should not be mixed in one syringe or dropper with other medicines, including. with aminoglycosides. When used in conjunction with other antibiotics, the drugs should be administered separately; most preferably administering piperacillin + [tazobactam] aminoglycosides and differentiate over time.
The drug should not be used together with solutions containing sodium bicarbonate and add blood products or albumin hydrolysates.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug is stored in reach of children, in a dry and dark place, at a temperature not higher than 25 В° C.
Shelf life - 2 years. Do not use after the expiration date printed on the package.
