Composition, form of production and packaging
Powder for the preparation of solution for intravenous administration 1 vial.
piperacillin (in the form of the sodium salt) 2 g
tazobactam (in the form of a sodium salt) 250 mg
bottles (12) - packs cardboard.
bottles (1) - packs of cardboard.
bottles (10) - packs of cardboard.
bottles (100) - cardboard boxes.
bottles (25) - cardboard boxes.
bottles (48) - cardboard boxes.
Powder for the preparation of solution for intravenous administration 1 vial.
piperacillin (in the form of a sodium salt) 4 g
tazobactam (in the form of the sodium salt) 500 mg
bottles (12) - packs cardboard.
bottles (1) - packs of cardboard.
bottles (10) - packs of cardboard.
bottles (100) - cardboard boxes.
bottles (25) - cardboard boxes.
bottles (48) - cardboard boxes.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2010.
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 triazolmethylpenicillic acid, a potent inhibitor of many beta-lactamases (including plasmid and chromosomal beta-lactamases), which often cause resistance to penicillins and cephalosporins, including third-generation cephalosporins. 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), Enlerobacter spp. (including Enlerobacter cloaca, Enlerobacter aerogenes), Proteus vulgaris, Proteus mirabilis, Providencia reltgery, Providencia stuarlii, 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 parainfluenzae, Pasteurella mullocida, 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 agalacliae, Streptococcus spp., viridans of subgroup C and G), Enterococcus spp. (Enlerococcus faecalis, Enterococcus faecium), Staphylococcus aureus (susceptible to methicillin), Staphylococcus saprophytics, Staphylococcus epidermidis (coagulase negative), Listeria monocytogenes, Nocardia spp.
Anaerobic bacteria: producing and non-producing beta-lactamase strains of Bacleroides spp. (Bacteroides bivius, Bacteroides disiens, Bacteroides capillosus, Bacteroides melaninogenicus, Bacteroides oralis), subgroups of Bacleroides fragilis (Bacteroides fragilis, Bacteroides vulgatus, Bacleroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides asaccharolyticus), Peptostreplococcus spp., Fusobacterium spp. , Eubacterium spp., Clostridium spp. (including Clostridium difficile, Clostridium perfringens), Veilonella spp. and Actynomyces spp.
PHARMACOKINETICS
The mean concentrations of piperacillin and tazobactam in plasma in equilibrium are presented in Tables 1-2. The maximum concentrations of piperacillin and tazobactam in plasma are reached immediately after completion of intravenous administration.
Table 1
Equilibrium plasma concentrations in adults after a five-minute intravenous injection of piperacillin / tazobactam.
Concentrations of piperacillin in plasma (Ојg / ml)
The dose of piperacillin / tazobactam 5 ** min 30 min 1 h 2 h 3 h 4 h
2g / 250mg 237 76 38 13 6 3
4g / 500mg 364 165 92 37 16 7
Concentrations of tazobactam in plasma (Ојg / ml)
The dose of piperacillin / tazobactam 5 ** min 30 min 1 h 2 h 3 h 4 h
2g / 250mg 23.4 8.0 4.5 1.7 0.9 0.7
4g / 500mg 34.3 17.9 10.8 4.8 2.0 0.9
The end of the 5-minute introduction.
table 2
Equilibrium plasma concentrations in adults after a thirty-minute intravenous injection of piperacillin / tazobactam
Concentrations of piperacillin in plasma (Ојg / ml)
The dose of piperacillin / tazobactam 30 ** min 1 h 1.5 h 2 h 3 h 4 h
2g / 250mg 134 57 29 17 5 2
4g / 500mg 298 141 87 47 16 7
Concentrations of tazobactam in plasma (Ојg / ml)
The dose of piperacillin / tazobactam 30 ** min 1 h 1.5 h 2 h S h 4 h
2g / 250mg 14.8 7.2 4.2 2.6 1.1 0.7
4g / 500mg 33.8 17.3 11.7 6.8 2.8 1.3
End of 30 minute injection
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 binding to plasma proteins of both piperacillin and tazobactam is approximately 30%, while the presence of tazobactam does not affect this parameter of piperacillin, and the presence of piperacillin is tazobactam.
Piperacillin / tazobactam is 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 - before the inactive metabolite. Piperacillin and tazobactam are excreted by the kidneys through glomerular filtration and tubular secretion. Piperacillin is rapidly excreted unchanged, 68% of the dose is detected in the urine. Tazobactam and its metabolite are rapidly excreted by renal excretion, 80% of the dose taken is unchanged, and the remaining amount is in the form of a metabolite. Piperacillin, tazobactam and deseptipiperacillin are also excreted with bile and excreted by the intestine.
The half-life of piperacillin and tazobactam from plasma is 0.7-1.2 hours. With a decrease in creatinine clearance, the half-life of piperacillin and tazobactam is prolonged.
Impaired renal function
As the creatinine clearance decreases, the half-lives of piperacillin and tazobactam increase. With a decrease in creatinine clearance below 20 ml / min, the half-lives of piperacillin and tazobactam are 2 and 4 times higher, respectively, than in patients with normal renal function.
During hemodialysis, 30 to 50% of piperacillin and 5% of the dose of tazobactam in the form of a metabolite are excreted. When carrying out peritoneal dialysis, respectively, about 6 and 21% of piperacillin and tazobactam are excreted, with 18% of the tazobactam being excreted in the form of its metabolite.
Impaired liver function
Although in patients with impaired liver function, the half-lives of piperacillin and tazobactam increase, dose adjustment is not required.
INDICATIONS
Infectious-inflammatory diseases caused by microorganisms sensitive to piperacillin / tazobactam.
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
Intravenously slowly run for at least 3-5 minutes or drip for 20-30 minutes.
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) drug administered every 6 or 8 h.
Children between the ages of 2 and 12:
For neutropenia:
In patients with normal kidney function and body weight less than 50 kg with a fever resulting from neutropenia, the dose is 90 mg (80 mg piperacillin / 10 mg tazobactam) per kilogram of body weight, which is administered every 6 hours in combination with the appropriate dose 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 renal 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 renal insufficiency or a patient on hemodialysis, dose and frequency of administration should be adjusted for 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 h
<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 have not been studied. 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 recommended dosage 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.
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.
Dosage / vial (piperacillin / tazobactam) Required volume of solvent
2.25 g (2 g / 250 mg) 10 ml
4.50 g (4 g / 500 mg) 20 ml
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 volume required for intravenous administration (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, nasal bleeding, increased bleeding time), hemolytic anemia, agranulocytosis, false-positive direct Coombs test, pancytopenia, increased activated partial thromboplastin time, increased prothrombin time, platelets.
From the side of the urinary system: interstitial nephritis, kidney failure.
From the nervous system: headache, insomnia, cramps.
From the cardiovascular system: lowering blood pressure, "hot flashes".
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, hyperthermia at the injection site, hyperemia and compaction at the site of administration.
Other: fungal superinfections, fever, arthralgia.
CONTRAINDICATIONS
- Children under 2 years;
- Hypersensitivity to beta-lactam antibiotics (including penicillins, cephalosporins), other components of the drug or to inhibitors of beta-lactamases.
With caution: severe bleeding (including history), cystic fibrosis (increased risk of hyperthermia and skin rashes), pseudomembranous colitis, childhood, kidney failure (CC less than 20 ml / min), patients on hemodialysis, when combined use of high doses of anticoagulants, with hypokalemia.
PREGNANCY AND LACTATION
There is insufficient data on the use of a combination of piperacillin / tazobactam or both drugs separately 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
Patients with renal insufficiency or a patient on hemodialysis should be administered with caution, the 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 h
<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 have not been studied. 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 recommended dosage 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.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
There is no need for dose adjustments for liver function disorders.
APPLICATION FOR CHILDREN
No experience in children under 2 years of age. Use with caution in children older than 2 years.
APPLICATION IN ELDERLY PATIENTS
In elderly patients, dose adjustment is necessary only if there is a violation of kidney function.
SPECIAL INSTRUCTIONS
Before starting treatment, the patient should be interviewed in detail in order to identify possible hypersensitivity reactions to penicillins, cephalosporins or other allergens. Severe allergic reactions are more likely to develop in patients with increased sensitivity to several allergens. Such reactions require the cessation of the administration of the drug and the appointment 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 some cases (most commonly in patients with renal insufficiency) is probably the appearance of increased bleeding and associated changes in laboratory parameters of blood coagulation (clotting time, platelet aggregation and prothrombin time). When the bleeding should abolish drug treatment and prescribe appropriate therapy.
It is necessary to bear in mind the possibility of the emergence of resistant organisms, which can cause superinfection, especially during long-term course of treatment. This preparation contains 2.79 mEq. (64 mg) per gram of piperacillin sodium which can lead to an overall increase in sodium Incoming. In patients with hypokalemia or taking drugs that promote excretion of potassium in the period of treatment may develop hypokalemia (you should regularly check the content of electrolytes in blood serum).
No experience of the use of children under the age of 2 years of age.
During use of the drug possible false positive samples for glucose in urine using a method based on the reduction of ions grounded. Therefore, it is recommended to carry out assays based on enzymatic oxidation of glucose (glucose oxidase method).
OVERDOSE
Symptoms of overdose include nausea, vomiting, diarrhea, increased neuromuscular excitability and seizures. Depending on the clinical manifestations symptomatic treatment assigned. To reduce high concentrations of piperacillin and tazobactam in the serum can be assigned to hemodialysis.
DRUG INTERACTION
The combined use of the drug with probenecid increases the half-life and reduces renal clearance of both piperacillin and tazobactam, but the maximum plasma concentration of both drugs remain unchanged.
Simultaneous use of the drug and vecuronium bromide, can lead to a more prolonged neuromuscular blockade caused by the latter (a similar effect may be observed when piperacillin combined with other non-depolarizing muscle relaxants).
With the simultaneous application of high doses of heparin, anticoagulants or other agents affecting the blood clotting system, including platelet function must frequently monitor the status of the blood coagulation system.
Piperacillin may delay the excretion of methotrexate (to avoid the toxic effect it is necessary to control blood serum concentration of methotrexate).
Pharmaceutical compatibility with other drugs
The drug should not be mixed in the same syringe or dropper with other drugs including the aminoglycosides. When used in conjunction with other antibiotics, drugs should be administered separately; most preferably, administration of piperacillin / tazobactam and aminoglycosides delineate in 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
On prescription.
TERMS AND CONDITIONS OF STORAGE
In the dark place at a temperature not higher than 25 В° C. Keep out of the reach of children. Shelf life - 3 years.
