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Revisione medica di Fedorchenko Olga Valeryevna, Pharmacy Ultimo aggiornamento in data 02.04.2022
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Primi 20 medicinali con gli stessi componenti:
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 Tazocin 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, Tazocin 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 Tazocin 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 Tazocin 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 Tazocin 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 Tazocin 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 Tazocin (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 Tazocin group and 73 (27.1%) in the cefotaxime/metronidazole group. Six patients (2.2%) in the Tazocin 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 Tazocin 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 Tazocin. 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 Tazocin in pediatric patients suggests a similar safety profile to that seen in adults.
La media e i coefficienti di variazione (CV%) per i parametri farmacocinetici di piperacillina e tazobactam dopo dosi endovenose multiple sono riassunti nella Tabella 6.
Tabella 6: parametri medi (CV%) di piperacillina e tazobactam PK
Piperacillin | ||||||
Piperacillin / Tazobactam Dosea | 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 Dosea | 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 e tazobactam sono stati somministrati in combinazione, infusi per oltre 30 minuti. b I numeri tra parentesi sono coefficienti di variazione (CV%). |
Le concentrazioni plasmatiche di picco di piperacillina e tazobactam vengono raggiunte immediatamente dopo il completamento di un'infusione endovenosa di tazocina. Le concentrazioni plasmatiche di piperacillina, a seguito di un'infusione di Tazocin di 30 minuti, erano simili a quelle raggiunte quando dosi equivalenti di piperacillina venivano somministrate da sole. Le concentrazioni plasmatiche allo stato stazionario di piperacillina e tazobactam erano simili a quelle raggiunte dopo la prima dose a causa delle brevi emivite di piperacillina e tazobactam.
Distribuzione
Sia la piperacillina che il tazobactam sono legati per circa il 30% alle proteine plasmatiche. Il legame proteico della piperacillina o del tazobactam non è influenzato dalla presenza dell'altro composto. Il legame proteico del metabolita tazobactam è trascurabile.
Piperacillin e tazobactam sono ampiamente distribuiti nei tessuti e nei fluidi corporei tra cui mucosa intestinale, cistifellea, polmone, tessuti riproduttivi femminili (utero, ovaio e tuba di Falloppio), liquido interstiziale e bile. Le concentrazioni medie di tessuto sono generalmente dal 50% al 100% di quelle nel plasma. La distribuzione di piperacillina e tazobactam nel liquido cerebrospinale è bassa nei soggetti con meningi non infiammate, come con altre penicilline (vedere Tabella 7).
Tabella 7: Concentrazioni di piperacillina / tazobattame in tessuti e fluidi selezionati dopo singola infusione di tazocina da 4 g / 0,5 g 30 minuti IV
Tessuto o fluido | Na | Periodo di campionamentob (H) | Intervallo di concentrazione PIP medio (mg / L) | Tessuto: gamma al plasma | Tazo Concentration Range (mg / L) | Tessuto Tazo: gamma al plasma |
Pelle | 35 | 0,5 - 4,5 | 34,8 - 94,2 | 0,60 - 1,1 | 4.0 - 7.7 | 0,49 - 0,93 |
Tessuto grasso | 37 | 0,5 - 4,5 | 4.0 - 10.1 | 0,097 - 0,115 | 0,7 - 1,5 | 0,10 - 0,13 |
Muscolo | 36 | 0,5 - 4,5 | 9.4 - 23.3 | 0,29 - 0,18 | 1.4 - 2.7 | 0,18 - 0,30 |
Mucosa intestinale prossimale | 7 | 1,5 - 2,5 | 31.4 | 0,55 | 10.3 | 1.15 |
Mucosa intestinale distale | 7 | 1,5 - 2,5 | 31.2 | 0,59 | 14.5 | 2.1 |
Appendice | 22 | 0,5 - 2,5 | 26,5 - 64,1 | 0,43 - 0,53 | 9.1 - 18.6 | 0,80 - 1,35 |
a Ogni soggetto ha fornito un singolo campione. b Tempo dall'inizio dell'infusione |
Metabolismo
La piperacillina viene metabolizzata in un metabolita desetilico microbiologicamente attivo minore. Tazobactam è metabolizzato in un singolo metabolita privo di attività farmacologiche e antibatteriche.
Escrezione
Dopo dosi singole o multiple di Tazocin in soggetti sani, l'emivita plasmatica di piperacillina e di tazobactam variava da 0,7 a 1,2 ore e non era influenzata dalla dose o dalla durata dell'infusione.
Sia la piperacillina che il tazobactam vengono eliminati attraverso il rene mediante filtrazione glomerulare e secrezione tubulare. La piperacillina viene escreta rapidamente come farmaco immodificato con il 68% della dose somministrata escreta nelle urine. Tazobactam e il suo metabolita vengono eliminati principalmente per escrezione renale con l'80% della dose somministrata escreta come farmaco immodificato e il resto come singolo metabolita. Anche la piperacillina, il tazobactam e la desetil piperacillina sono secrete nella bile.