Komposition:
Anwendung:
Wird bei der Behandlung verwendet:
Medizinisch geprüft von Kovalenko Svetlana Olegovna, Apotheke Zuletzt aktualisiert am 12.03.2022
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Lazopip ist ein Kombinationsprodukt, das aus einem antibakteriellen Penicillin-Klass, Piperacillin, und einem β-Lactamase-Inhibitor, Tazobactam, besteht, der zur Behandlung von Patienten mit mittelschweren bis schweren Infektionen angezeigt ist, die durch anfällige Isolate der bezeichneten Bakterien unter den nachstehend aufgeführten Bedingungen verursacht werden.
Intraabdominale Infektionen
Blinddarmentzündung (kompliziert durch Bruch oder Abszess) und Peritonitis, verursacht durch β-Lactamase produzierende Isolate von Escherichia coli oder die folgenden Mitglieder der Bacteroides fragilis-Gruppe: B. fragilis, B. ovatus, B. thetaiotaomicron, oder B. vulgatus Die einzelnen Mitglieder dieser Gruppe wurden in weniger als 10 Fällen untersucht.
Infektionen der Haut- und Hautstruktur
Unkomplizierte und komplizierte Haut- und Hautstrukturinfektionen, einschließlich Cellulitis, Hautabszesse und ischämische / diabetische Fußinfektionen, die durch β-Lactamase produzierende Isolate von verursacht werden Staphylococcus aureus.
Weibliche Beckeninfektionen
Postpartale Endometritis oder entzündliche Beckenerkrankung, verursacht durch β-Lactamase, die Isolate von Escherichia coli produziert.
Von der Gemeinschaft erworbene Lungenentzündung
In der Gemeinschaft erworbene Lungenentzündung (nur mittlerer Schweregrad), verursacht durch β-Lactamase produzierende Isolate von Haemophilus influenzae.
Nosokomiale Lungenentzündung
Nosokomiale Lungenentzündung (mäßig bis schwer), verursacht durch β-Lactamase produzierende Isolate von Staphylococcus aureus und durch Piperacillin / Tazobactam-anfällig Acinetobacter baumannii, Haemophilus influenzae, Klebsiella pneumoniae, und Pseudomonas aeruginosa (Nosokomiale Lungenentzündung verursacht durch P. aeruginosa sollte in Kombination mit einem Aminoglycosid behandelt werden).
Verwendung
Um die Entwicklung arzneimittelresistenter Bakterien zu verringern und die Wirksamkeit von Lazopip und anderen antibakteriellen Arzneimitteln aufrechtzuerhalten, sollte Lazopip nur zur Behandlung oder Vorbeugung von Infektionen angewendet werden, bei denen nachgewiesen wurde oder stark vermutet wird, dass sie durch Bakterien verursacht werden. Wenn Informationen zu Kultur und Anfälligkeit verfügbar sind, sollten sie bei der Auswahl oder Änderung der antibakteriellen Therapie berücksichtigt werden. In Ermangelung solcher Daten können lokale Epidemiologie- und Anfälligkeitsmuster zur empirischen Auswahl der Therapie beitragen.
Lazopip should be administered by intravenous infusion over 30 minutes.
Adult Patients
The usual total daily dose of Lazopip for adults is 3.375 g every six hours totaling 13.5 g (12.0 g piperacillin/1.5 g tazobactam). The usual duration of Lazopip treatment is from 7 to 10 days.
Lazopip should be administered by intravenous infusion over 30 minutes.
Nosocomial Pneumonia
Initial presumptive treatment of patients with nosocomial pneumonia should start with Lazopip at a dosage of 4.5 g every six hours plus an aminoglycoside, totaling 18.0 g (16.0 g piperacillin/2.0 g tazobactam). The recommended duration of Lazopip treatment for nosocomial pneumonia is 7 to 14 days. Treatment with the aminoglycoside should be continued in patients from whom P. aeruginosa is isolated.
Renal Impairment
In patients with renal impairment (creatinine clearance ≤ 40 mL/min) and dialysis patients (hemodialysis and CAPD), the intravenous dose of Lazopip should be reduced to the degree of actual renal function impairment. The recommended daily doses of Lazopip for patients with renal impairment are as follows:
Table 1: Recommended Dosing of Lazopip in Patients with Normal Renal Function and Renal- Impairment (As total grams piperacillin/tazobactam)
Renal Function (creatinine clearance, mL/min) | All Indications (except nosocomial pneumonia) | Nosocomial Pneumonia |
> 40 mL/min | 3.375 q 6 h | 4.5 q 6 h |
20-40 mL/min* | 2.25 q 6 h | 3.375 q 6 h |
< 20 mL/min* | 2.25 q 8 h | 2.25 q 6 h |
Hemodialysis** | 2.25 q 12 h | 2.25 q 8 h |
CAPD | 2.25 q 12 h | 2.25 q 8 h |
* Creatinine clearance for patients not receiving hemodialysis ** 0.75 g (0.67 g piperacillin/0.08 g tazobactam) should be administered following each hemodialysis session on hemodialysis days |
For patients on hemodialysis, the maximum dose is 2.25 g every twelve hours for all indications other than nosocomial pneumonia and 2.25 g every eight hours for nosocomial pneumonia. Since hemodialysis removes 30% to 40% of the administered dose, an additional dose of 0.75 g Lazopip (0.67 g piperacillin/0.08 g tazobactam) should be administered following each dialysis period on hemodialysis days. No additional dosage of Lazopip is necessary for CAPD patients.
Pediatric Patients
For children with appendicitis and/or peritonitis 9 months of age or older, weighing up to 40 kg, and with normal renal function, the recommended Lazopip dosage is 100 mg piperacillin/12.5 mg tazobactam per kilogram of body weight, every 8 hours. For pediatric patients between 2 months and 9 months of age, the recommended Lazopip dosage based on pharmacokinetic modeling, is 80 mg piperacillin/10 mg tazobactam per kilogram of body weight, every 8 hours. Pediatric patients weighing over 40 kg and with normal renal function should receive the adult dose.
It has not been determined how to adjust Lazopip dosage in pediatric patients with renal impairment.
Reconstitution And Dilution Of Powder Formulations
Pharmacy Bulk Vials
Reconstituted stock solution must be transferred and further diluted for intravenous infusion.
The pharmacy bulk vial is for use in a hospital pharmacy admixture service only under a laminar flow hood. After reconstitution, entry into the vial must be made with a sterile transfer set or other sterile dispensing device, and contents should be dispensed as aliquots into intravenous solution using aseptic technique. Use entire contents of pharmacy bulk vial promptly. Discard unused portion after 24 hours if stored at room temperature (20°C to 25°C [68°F to 77°F]), or after 48 hours if stored at refrigerated temperature (2°C to 8°C [36°F to 46°F]).
Reconstitute the pharmacy bulk vial with exactly 152 mL of a compatible reconstitution diluent, listed below, to a concentration of 200 mg/mL of piperacillin and 25 mg/mL of tazobactam. Shake well until dissolved. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to and during administration whenever solution and container permit.
Single Dose Vials
Reconstitute Lazopip vials with a compatible reconstitution diluent from the list provided below. 2.25 g, 3.375 g, and 4.5 g Lazopip should be reconstituted with 10 mL, 15 mL, and 20 mL, respectively. Swirl until dissolved.
Compatible Reconstitution Diluents for Pharmacy and Single Dose Vials
0.9% sodium chloride for injection
Sterile water for injection
Dextrose 5%
Bacteriostatic saline/parabens
Bacteriostatic water/parabens
Bacteriostatic saline/benzyl alcohol
Bacteriostatic water/benzyl alcohol
Reconstituted Lazopip solutions for both bulk and single dose vials should be further diluted (recommended volume per dose of 50 mL to 150 mL) in a compatible intravenous solution listed below. Administer by infusion over a period of at least 30 minutes. During the infusion it is desirable to discontinue the primary infusion solution.
Compatible Intravenous Solutions for Pharmacy and Single Dose Vials
0.9% sodium chloride for injection
sterile water for injection‡
Dextran 6% in saline
Dextrose 5%
Lactated Ringer's Solution (compatible only with reformulated Lazopip containing EDTA and is compatible for co-administration via a Y-site)
‡ Maximum recommended volume per dose of sterile water for injection is 50 mL.
Lazopip should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established.
Lazopip is not chemically stable in solutions that contain only sodium bicarbonate and solutions that significantly alter the pH.
Lazopip should not be added to blood products or albumin hydrolysates. Parenteral drug products should be inspected visually for particulate matter or discoloration prior to administration, whenever solution and container permit.
Stability of Lazopip Powder Formulations Following Reconstitution
Lazopip reconstituted from bulk and single vials is stable in glass and plastic containers (plastic syringes, I.V. bags and tubing) when used with compatible diluents. The pharmacy bulk vial should NOT be frozen after reconstitution. Discard unused portions after storage for 24 hours at room temperature or after storage for 48 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]).
Single dose or pharmacy vials should be used immediately after reconstitution. Discard any unused portion after 24 hours if stored at room temperature (20°C to 25°C [68°F to 77°F]), or after 48 hours if stored at refrigerated temperature (2°C to 8°C [36°F to 46°F]). Vials should not be frozen after reconstitution.
Stability studies in the I.V. bags have demonstrated chemical stability (potency, pH of reconstituted solution and clarity of solution) for up to 24 hours at room temperature and up to one week at refrigerated temperature. Lazopip contains no preservatives. Appropriate consideration of aseptic technique should be used.
Lazopip reconstituted from bulk and single vials can be used in ambulatory intravenous infusion pumps. Stability of Lazopip in an ambulatory intravenous infusion pump has been demonstrated for a period of 12 hours at room temperature. Each dose was reconstituted and diluted to a volume of 37.5 mL or 25 mL. One-day supplies of dosing solution were aseptically transferred into the medication reservoir (I.V. bags or cartridge). The reservoir was fitted to a preprogrammed ambulatory intravenous infusion pump per the manufacturer's instructions. Stability of Lazopip is not affected when administered using an ambulatory intravenous infusion pump.
Directions For Use Of Lazopip In GALAXY Containers
Lazopip Injection is to be administered using sterile equipment, after thawing to room temperature.
Lazopip containing EDTA is compatible for co-administration via a Y-site intravenous tube with Lactated Ringer's injection, USP.
Do not add supplementary medication.
Unused portions of Lazopip should be discarded.
CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.
Thawing Of Plastic Container
Thaw frozen container at room temperature 20°C to 25°C [68°F to 77°F] or under refrigeration (2°C to 8°C [36°F to 46°F]). Do not force thaw by immersion in water baths or by microwave irradiation.
Check for minute leaks by squeezing container firmly. If leaks are detected, discard solution as sterility may be impaired.
The container should be visually inspected. Components of the solution may precipitate in the frozen state and will dissolve upon reaching room temperature with little or no agitation. Potency is not affected. Agitate after solution has reached room temperature. If after visual inspection, the solution remains cloudy or if an insoluble precipitate is noted or if any seals or outlet ports are not intact, the container should be discarded.
Administer by infusion over a period of at least 30 minutes. During the infusion it is desirable to discontinue the primary infusion solution.
Storage
Store in a freezer capable of maintaining a temperature of -20°C (-4°F).
For GALAXY containers, the thawed solution is stable for 14 days under refrigeration (2°C to 8°C [36°F to 46°F]) or 24 hours at room temperature 20°C to 25°C [68°F to 77°F]. Do not refreeze thawed Lazopip.
Compatibility With Aminoglycosides
Due to the in vitro inactivation of aminoglycosides by piperacillin, Lazopip and aminoglycosides are recommended for separate administration. Lazopip and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated.
In circumstances where co-administration via Y-site is necessary, Lazopip formulations containing EDTA are compatible for simultaneous co-administration via Y-site infusion only with the following aminoglycosides under the following conditions:
Table 2: Compatibility with Aminoglycosides
Aminoglycoside | Lazopip Dose (grams) | Lazopip Diluent Volumea (mL) | Aminoglycoside Concentration Rangeb (mg/mL) | Acceptable Diluents |
Amikacin | 2.25 | 50 | 1.75 - 7.5 | 0.9% sodium chloride or 5% dextrose |
3.375 | 100 | |||
4.5 | 150 | |||
Gentamicin | 2.25 | 50 | 0.7 - 3.32 | 0.9% sodium chloride or 5% dextrose |
3.375c | 100 | |||
4.5 | 150 | |||
a Diluent volumes apply only to single vials and bulk pharmacy containers b The concentration ranges in Table 2 are based on administration of the aminoglycoside in divided doses (10-15 mg/kg/day in two daily doses for amikacin and 3-5 mg/kg/day in three daily doses for gentamicin). Administration of amikacin or gentamicin in a single daily dose or in doses exceeding those stated above via Y-site with Lazopip containing EDTA has not been evaluated. See package insert for each aminoglycoside for complete Dosage and Administration instructions. c Lazopip 3.375 g per 50 mL GALAXY containers are NOT compatible with gentamicin for coadministration via a Y-site due to the higher concentrations of piperacillin and tazobactam. |
Only the concentration and diluents for amikacin or gentamicin with the dosages of Lazopip listed above have been established as compatible for co-administration via Y-site infusion. Simultaneous co-administration via Y-site infusion in any manner other than listed above may result in inactivation of the aminoglycoside by Lazopip.
Lazopip is not compatible with tobramycin for simultaneous co-administration via Y-site infusion. Compatibility of Lazopip with other aminoglycosides has not been established.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Lazopip is contraindicated in patients with a history of allergic reactions to any of the penicillins, cephalosporins, or β-lactamase inhibitors.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Hypersensitivity Adverse Reactions
Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid) reactions (including shock) have been reported in patients receiving therapy with Lazopip. These reactions are more likely to occur in individuals with a history of penicillin, cephalosporin, or carbapenem hypersensitivity or a history of sensitivity to multiple allergens. Before initiating therapy with Lazopip, careful inquiry should be made concerning previous hypersensitivity reactions. If an allergic reaction occurs, Lazopip should be discontinued and appropriate therapy instituted.
Severe Cutaneous Adverse Reactions
Lazopip may cause severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis. If patients develop a skin rash they should be monitored closely and Lazopip discontinued if lesions progress.
Hematologic Adverse Reactions
Bleeding manifestations have occurred in some patients receiving β-lactam drugs, including piperacillin. These reactions have sometimes been associated with abnormalities of coagulation tests such as clotting time, platelet aggregation and prothrombin time, and are more likely to occur in patients with renal failure. If bleeding manifestations occur, Lazopip should be discontinued and appropriate therapy instituted.
The leukopenia/neutropenia associated with Lazopip administration appears to be reversible and most frequently associated with prolonged administration.
Periodic assessment of hematopoietic function should be performed, especially with prolonged therapy, ie, ≥ 21 days.
Central Nervous System Adverse Reactions
As with other penicillins, patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure).
Nephrotoxicity In Critically Ill Patients
The use of Lazopip was found to be an independent risk factor for renal failure and was associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs in a randomized, multicenter, controlled trial in critically ill patients. Based on this study, alternative treatment options should be considered in the critically ill population. If alternative treatment options are inadequate or unavailable, monitor renal function during treatment with Lazopip.
Combined use of piperacillin/tazobactam and vancomycin may be associated with an increased incidence of acute kidney injury.
Electrolyte Effects
Lazopip contains a total of 2.84 mEq (65 mg) of Na+ (sodium) per gram of piperacillin in the combination product. This should be considered when treating patients requiring restricted salt intake. Periodic electrolyte determinations should be performed in patients with low potassium reserves, and the possibility of hypokalemia should be kept in mind with patients who have potentially low potassium reserves and who are receiving cytotoxic therapy or diuretics.
Clostridium Difficile Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Lazopip, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Development Of Drug-Resistant Bacteria
Prescribing Lazopip in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of development of drug-resistant bacteria.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term carcinogenicity studies in animals have not been conducted with piperacillin/tazobactam, piperacillin, or tazobactam.
Piperacillin/Tazobactam
Piperacillin/tazobactam was negative in microbial mutagenicity assays, the unscheduled DNA synthesis (UDS) test, a mammalian point mutation (Chinese hamster ovary cell HPRT) assay, and a mammalian cell (BALB/c-3T3) transformation assay. In vivo, piperacillin/tazobactam did not induce chromosomal aberrations in rats.
Piperacillin/tazobactam
Reproduction studies have been performed in rats and have revealed no evidence of impaired fertility when piperacillin/tazobactam is administered intravenously up to a dose of 1280/320 mg/kg piperacillin/tazobactam, which is similar to the maximum recommended human daily dose based on body-surface area (mg/m²).
Use In Specific Populations
Pregnancy
Risk Summary
Piperacillin and tazobactam cross the placenta in humans. However, there are insufficient data with piperacillin and/or tazobactam in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. No fetal structural abnormalities were observed in rats or mice when piperacillin/tazobactam was administered intravenously during organogenesis at doses 1 to 2 times and 2 to 3 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area (mg/m²). However, fetotoxicity in the presence of maternal toxicity was observed in developmental toxicity and peri/postnatal studies conducted in rats (intraperitoneal administration prior to mating and throughout gestation or from gestation day 17 through lactation day 21) at doses less than the maximum recommended human daily dose based on body-surface area (mg/m²).
The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
In embryo-fetal development studies in mice and rats, pregnant animals received intravenous doses of piperacillin/tazobactam up to 3000/750 mg/kg/day during the period of organogenesis. There was no evidence of teratogenicity up to the highest dose evaluated, which is 1 to 2 times and 2 to 3 times the human dose of piperacillin and tazobactam, in mice and rats respectively, based on body-surface area (mg/m²). Fetal body weights were reduced in rats at maternally toxic doses at or above 500/62.5 mg/kg/day, minimally representing 0.4 times the human dose of both piperacillin and tazobactam based on body-surface area (mg/m²).
A fertility and general reproduction study in rats using intraperitoneal administration of tazobactam or the combination piperacillin/tazobactam prior to mating and through the end of gestation, reported a decrease in litter size in the presence of maternal toxicity at 640 mg/kg/day tazobactam (4 times the human dose of tazobactam based on body-surface area), and decreased litter size and an increase in fetuses with ossification delays and variations of ribs, concurrent with maternal toxicity at ≥ 640/160 mg/kg/day piperacillin/tazobactam (0.5 times and 1 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area).
Peri/postnatal development in rats was impaired with reduced pup weights, increased stillbirths, and increased pup mortality concurrent with maternal toxicity after intraperitoneal administration of tazobactam alone at doses ≥ 320 mg/kg/day (2 times the human dose based on body surface area) or of the combination piperacillin/tazobactam at doses ≥ 640/160 mg/kg/day (0.5 times and 1 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area) from gestation day 17 through lactation day 21.
Lactation
Risk Summary
Piperacillin is excreted in human milk; tazobactam concentrations in human milk have not been studied. No information is available on the effects of piperacillin and tazobactam on the breastfed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Lazopip and any potential adverse effects on the breastfed child from Lazopip or from the underlying maternal condition.
Pediatric Use
Use of Lazopip in pediatric patients 2 months of age or older with appendicitis and/or peritonitis is supported by evidence from well-controlled studies and pharmacokinetic studies in adults and in pediatric patients. This includes a prospective, randomized, comparative, open-label clinical trial with 542 pediatric patients 2-12 years of age with complicated intra-abdominal infections, in which 273 pediatric patients received piperacillin/tazobactam. Safety and efficacy in pediatric patients less than 2 months of age have not been established.
It has not been determined how to adjust Lazopip dosage in pediatric patients with renal impairment.
Geriatric Use
Patients over 65 years are not at an increased risk of developing adverse effects solely because of age. However, dosage should be adjusted in the presence of renal impairment.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Lazopip contains 65 mg (2.84 mEq) of sodium per gram of piperacillin in the combination product. At the usual recommended doses, patients would receive between 780 and 1040 mg/day (34.1 and 45.5 mEq) of sodium. The geriatric population may respond with a blunted natriuresis to salt loading. This may be clinically important with regard to such diseases as congestive heart failure.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Renal Impairment
In patients with creatinine clearance ≤ 40 mL/min and dialysis patients (hemodialysis and CAPD), the intravenous dose of Lazopip should be reduced to the degree of renal function impairment.
Hepatic Impairment
Dosage adjustment of Lazopip is not warranted in patients with hepatic cirrhosis.
Patients With Cystic Fibrosis
As with other semisynthetic penicillins, piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
During the initial clinical investigations, 2621 patients worldwide were treated with Lazopip in phase 3 trials. In the key North American monotherapy clinical trials (n=830 patients), 90% of the adverse events reported were mild to moderate in severity and transient in nature. However, in 3.2% of the patients treated worldwide, Lazopip was discontinued because of adverse events primarily involving the skin (1.3%), including rash and pruritus; the gastrointestinal system (0.9%), including diarrhea, nausea, and vomiting; and allergic reactions (0.5%).
Table 3: Adverse Reactions from Lazopip Monotherapy Clinical Trials
System Organ Class/ Adverse Reaction | |
Gastrointestinal disorders | |
Diarrhea | (11.3%) |
Constipation | (7.7%) |
Nausea | (6.9%) |
Vomiting | (3.3%) |
Dyspepsia | (3.3%) |
Abdominal pain | (1.3%) |
General disorders and administration site conditions | |
Fever | (2.4%) |
Injection site reaction | ( ≤ 1%) |
Rigors | ( ≤ 1%) |
Immune system disorders | |
Anaphylaxis | ( ≤ 1%) |
Infections and infestations | |
Candidiasis | (1.6%) |
Pseudomembranous colitis | ( ≤ 1%) |
Metabolism and nutrition disorders | |
Hypoglycemia | ( ≤ 1%) |
Musculoskeletal and connective tissue disorders | |
Myalgia | ( ≤ 1%) |
Arthralgia | ( ≤ 1%) |
Nervous system disorders | |
Headache | (7.7%) |
Psychiatric disorders | |
Insomnia | (6.6%) |
Skin and subcutaneous tissue disorders | |
Rash including maculopapular, bullous, and urticarial | (4.2%) |
Pruritus | (3.1%) |
Purpura | ( ≤ 1%) |
Vascular disorders | |
Phlebitis | (1.3%) |
Thrombophlebitis | ( ≤ 1%) |
Hypotension | ( ≤ 1%) |
Flushing | ( ≤ 1%) |
Respiratory, thoracic and mediastinal disorders | |
Epistaxis | ( ≤ 1%) |
Nosocomial Pneumonia Trials
Two trials of nosocomial lower respiratory tract infections were conducted. In one study, 222 patients were treated with Lazopip in a dosing regimen of 4.5 g every 6 hours in combination with an aminoglycoside and 215 patients were treated with imipenem/cilastatin (500 mg/500 mg q6h) in combination with an aminoglycoside. In this trial, treatment-emergent adverse events were reported by 402 patients, 204 (91.9%) in the piperacillin/tazobactam group and 198 (92.1%) in the imipenem/cilastatin group. Twenty-five (11.0%) patients in the piperacillin/tazobactam group and 14 (6.5%) in the imipenem/cilastatin group (p > 0.05) discontinued treatment due to an adverse event.
The second trial used a dosing regimen of 3.375 g given every 4 hours with an aminoglycoside.
Table 4: Adverse Reactions from Lazopip Plus Aminoglycoside Clinical Trialsa
System Organ Class Adverse Reaction | |
Blood and lymphatic system disorders | |
Thrombocythemia | (1.4%) |
Anemia | ( ≤ 1%) |
Thrombocytopenia | ( ≤ 1%) |
Eosinophilia | ( ≤ 1%) |
Gastrointestinal disorders | |
Diarrhea | (20%) |
Constipation | (8.4%) |
Nausea | (5.8%) |
Vomiting | (2.7%) |
Dyspepsia | (1.9%) |
Abdominal pain | (1.8%) |
Stomatitis | ( ≤ 1%) |
General disorders and administration site conditions | |
Fever | (3.2%) |
Injection site reaction | ( ≤ 1%) |
Infections and infestations | |
Oral candidiasis | (3.9%) |
Candidiasis | (1.8%) |
Investigations | |
BUN increased | (1.8%) |
Blood creatinine increased | (1.8%) |
Liver function test abnormal | (1.4%) |
Alkaline phosphatase increased | ( < 1%) |
Aspartate aminotransferase increased | ( ≤ 1%) |
Alanine aminotransferase increased | ( ≤ 1%) |
Metabolism and nutrition disorders | |
Hypoglycemia | ( ≤ 1%) |
Hypokalemia | ( ≤ 1%) |
Nervous system disorders | |
Headache | (4.5%) |
Psychiatric disorders | |
Insomnia | (4.5%) |
Renal and urinary disorders | |
Renal failure | ( ≤ 1%) |
Skin and subcutaneous tissue disorders | |
Rash | (3.9%) |
Pruritus | (3.2%) |
Vascular disorders | |
Thrombophlebitis | (1.3%) |
Hypotension | (1.3%) |
a For adverse drug reactions that appeared in both studies the higher frequency is presented. |
Other Trials: Nephrotoxicity
In a randomized, multicenter, controlled trial in 1200 adult critically ill patients, piperacillin/tazobactam was found to be a risk factor for renal failure (odds ratio 1.7, 95% CI 1.18 to 2.43), and associated with delayed recovery of renal function as compared to other betalactam antibacterial drugs.1.
Pediatrics
Studies of Lazopip in pediatric patients suggest a similar safety profile to that seen in adults. In a prospective, randomized, comparative, open-label clinical trial of pediatric patients with severe intra-abdominal infections (including appendicitis and/or peritonitis), 273 patients were treated with Lazopip (112.5 mg/kg every 8 hours) and 269 patients were treated with cefotaxime (50 mg/kg) plus metronidazole (7.5 mg/kg) every 8 hours. In this trial, treatment-emergent adverse events were reported by 146 patients, 73 (26.7%) in the Lazopip group and 73 (27.1%) in the cefotaxime/metronidazole group. Six patients (2.2%) in the Lazopip group and 5 patients (1.9%) in the cefotaxime/metronidazole group discontinued due to an adverse event.
Adverse Laboratory Events (Seen During Clinical Trials)
Of the trials reported, including that of nosocomial lower respiratory tract infections in which a higher dose of Lazopip was used in combination with an aminoglycoside, changes in laboratory parameters include:
Hematologic - decreases in hemoglobin and hematocrit, thrombocytopenia, increases in platelet count, eosinophilia, leukopenia, neutropenia. These patients were withdrawn from therapy; some had accompanying systemic symptoms (e.g., fever, rigors, chills)
Coagulation - positive direct Coombs' test, prolonged prothrombin time, prolonged partial thromboplastin time
Hepatic - transient elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubin
Renal - increases in serum creatinine, blood urea nitrogen
Additional laboratory events include abnormalities in electrolytes (i.e., increases and decreases in sodium, potassium, and calcium), hyperglycemia, decreases in total protein or albumin, blood glucose decreased, gamma-glutamyltransferase increased, hypokalemia, and bleeding time prolonged.
Post-Marketing Experience
In addition to the adverse drug reactions identified in clinical trials in Table 3 and Table 4, the following adverse reactions have been identified during post-approval use of Lazopip. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hepatobiliary - hepatitis, jaundice
Hematologic - hemolytic anemia, agranulocytosis, pancytopenia
Immune - hypersensitivity reactions, anaphylactic/anaphylactoid reactions (including shock)
Renal - interstitial nephritis
Respiratory - eosinophilic pneumonia
Skin and Appendages - erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, (DRESS), acute generalized exanthematous pustulosis (AGEP), dermatitis exfoliative
Additional Experience With piperacillin
The following adverse reaction has also been reported for piperacillin for injection:
Skeletal - prolonged muscle relaxation.
Post-marketing experience with Lazopip in pediatric patients suggests a similar safety profile to that seen in adults.
Nach dem Inverkehrbringen gab es Berichte über eine Überdosierung mit Piperacillin / Tazobactam. Die Mehrzahl dieser Ereignisse, einschließlich Übelkeit, Erbrechen und Durchfall, wurde ebenfalls mit den üblichen empfohlenen Dosierungen berichtet. Bei Patienten kann es zu neuromuskulären Erregbarkeiten oder Krämpfen kommen, wenn höhere als die empfohlenen Dosen intravenös verabreicht werden (insbesondere bei Vorhandensein eines Nierenversagens).
Die Behandlung sollte je nach klinischem Erscheinungsbild des Patienten unterstützend und symptomatisch sein. Übermäßige Serumkonzentrationen von Piperacillin oder Tazobactam können durch Hämodialyse verringert werden. Nach einer Einzeldosis von 3,375 g Piperacillin / Tazobactam betrug der Prozentsatz der durch Hämodialyse entfernten Piperacillin- und Tazobactam-Dosis ungefähr 31% bzw. 39%.
Der pharmakodynamische Parameter für Piperacillin / Tazobactam, der die klinische und mikrobiologische Wirksamkeit am besten vorhersagt, liegt zeitlich über dem MIC
Der Mittelwert und die Variationskoeffizienten (CV%) für die pharmakokinetischen Parameter von Piperacillin und Tazobactam nach mehreren intravenösen Dosen sind in Tabelle 6 zusammengefasst.
Tabelle 6: Mittlere (CV%) Piperacillin- und Tazobactam PK-Parameter
Piperacillin | ||||||
Piperacillin / Tazobactam-Dosisa | Cmax mcg / ml | AUCb mcg • h / ml | CL ml / min | VL | T½h | CLR ml / min |
2,25 g | 134 | 131 (14) | 257 | 17.4 | 0,79 | -- |
3,375 g | 242 | 242 (10) | 207 | 15.1 | 0,84 | 140 |
4,5 g | 298 | 322 (16) | 210 | 15.4 | 0,84 | -- |
Tazobactam | ||||||
Piperacillin / Tazobactam-Dosisa | Cmax mcg / ml | AUCb mcg • h / ml | CL ml / min | VL | T½ | CLR% ml / min |
2,25 g | 15 | 16,0 (21) | 258 | 17.0 | 0,77 | -- |
3,375 g | 24 | 25,0 (8) | 251 | 14.8 | 0,68 | 166 |
4,5 g | 34 | 39,8 (15) | 206 | 14.7 | 0,82 | -- |
a Piperacillin und Tazobactam wurden in Kombination über 30 Minuten infundiert. b Zahlen in Klammern sind Variationskoeffizienten (CV%). |
Die maximalen Plasmakonzentrationen von Piperacillin und Tazobactam werden unmittelbar nach Abschluss einer intravenösen Infusion von Lazopip erreicht. Die Piperacillin-Plasmakonzentrationen waren nach einer 30-minütigen Infusion von Lazopip ähnlich denen, die erreicht wurden, wenn äquivalente Dosen von Piperacillin allein verabreicht wurden. Die Steady-State-Plasmakonzentrationen von Piperacillin und Tazobactam waren ähnlich wie nach der ersten Dosis aufgrund der kurzen Halbwertszeiten von Piperacillin und Tazobactam.
Verteilung
Sowohl Piperacillin als auch Tazobactam sind zu etwa 30% an Plasmaproteine gebunden. Die Proteinbindung von Piperacillin oder Tazobactam wird durch das Vorhandensein der anderen Verbindung nicht beeinflusst. Die Proteinbindung des Tazobactam-Metaboliten ist vernachlässigbar.
Piperacillin und Tazobactam sind weit verbreitet in Geweben und Körperflüssigkeiten wie Darmschleimhaut, Gallenblase, Lunge, weiblichem Fortpflanzungsgewebe (Uterus, Eierstock und Eileiter), interstitieller Flüssigkeit und Galle. Die mittleren Gewebekonzentrationen betragen im Allgemeinen 50% bis 100% der im Plasma befindlichen. Die Verteilung von Piperacillin und Tazobactam in Liquor cerebrospinalis ist bei Patienten mit nicht entzündeten Meningen wie bei anderen Penicillinen gering (siehe Tabelle 7).
Tabelle 7: Piperacillin / Tazobactam-Konzentrationen in ausgewählten Geweben und Flüssigkeiten nach einmaliger 4 g / 0,5 g 30-min IV-Infusion von Lazopip
Gewebe oder Flüssigkeit | Na | Probenahmezeitb (h) | Mittlerer PIP-Konzentrationsbereich (mg / l) | Gewebe: Plasma-Bereich | Tazo-Konzentrationsbereich (mg / l) | Tazo-Gewebe: Plasma-Bereich |
Haut | 35 | 0,5 - 4,5 | 34,8 - 94,2 | 0,60 - 1,1 | 4,0 - 7,7 | 0,49 - 0,93 |
Fettgewebe | 37 | 0,5 - 4,5 | 4,0 - 10,1 | 0,097 - 0,115 | 0,7 - 1,5 | 0,10 - 0,13 |
Muskel | 36 | 0,5 - 4,5 | 9,4 - 23,3 | 0,29 - 0,18 | 1,4 - 2,7 | 0,18 - 0,30 |
Proximale Darmschleimhaut | 7 | 1,5 - 2,5 | 31.4 | 0,55 | 10.3 | 1.15 |
Distale Darmschleimhaut | 7 | 1,5 - 2,5 | 31.2 | 0,59 | 14.5 | 2.1 |
Anhang | 22 | 0,5 - 2,5 | 26,5 - 64,1 | 0,43 - 0,53 | 9,1 - 18,6 | 0,80 - 1,35 |
a Jedes Subjekt lieferte eine einzige Probe. b Zeit vom Beginn der Infusion |
Stoffwechsel
Piperacillin wird zu einem kleinen mikrobiologisch aktiven Desethylmetaboliten metabolisiert. Tazobactam wird zu einem einzelnen Metaboliten metabolisiert, dem pharmakologische und antibakterielle Aktivitäten fehlen.
Ausscheidung
Nach einmaligen oder mehrfachen Lazopip-Dosen für gesunde Probanden lag die Plasma-Halbwertszeit von Piperacillin und Tazobactam zwischen 0,7 und 1,2 Stunden und wurde von der Dosis oder Dauer der Infusion nicht beeinflusst.
Sowohl Piperacillin als auch Tazobactam werden durch glomeruläre Filtration und tubuläre Sekretion über die Niere ausgeschieden. Piperacillin wird schnell als unverändertes Arzneimittel ausgeschieden, wobei 68% der verabreichten Dosis im Urin ausgeschieden werden. Tazobactam und sein Metabolit werden hauptsächlich durch renale Ausscheidung eliminiert, wobei 80% der verabreichten Dosis als unverändertes Arzneimittel und der Rest als einzelner Metabolit ausgeschieden werden. Piperacillin, Tazobactam und Desethylpiperacillin werden ebenfalls in die Galle ausgeschieden.