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Militian Inessa Mesropovna 、薬局による医学的評価、 最終更新日:21.03.2022
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Tazip is a combination product consisting of a penicillin-class antibacterial, piperacillin, and a β-lactamase inhibitor, tazobactam, indicated for the treatment of patients with moderate to severe infections caused by susceptible isolates of the designated bacteria in the conditions listed below.
Intra-abdominal Infections
Appendicitis (complicated by rupture or abscess) and peritonitis caused by β-lactamase producing isolates of Escherichia coli or the following members of the Bacteroides fragilis group: B. fragilis, B. ovatus, B. thetaiotaomicron, or B. vulgatus. The individual members of this group were studied in fewer than 10 cases.
Skin And Skin Structure Infections
Uncomplicated and complicated skin and skin structure infections, including cellulitis, cutaneous abscesses and ischemic/diabetic foot infections caused by β-lactamase producing isolates of Staphylococcus aureus.
Female Pelvic Infections
Postpartum endometritis or pelvic inflammatory disease caused by β-lactamase producing isolates of Escherichia coli.
Community-acquired Pneumonia
Community-acquired pneumonia (moderate severity only) caused by β-lactamase producing isolates of Haemophilus influenzae.
Nosocomial Pneumonia
Nosocomial pneumonia (moderate to severe) caused by β-lactamase producing isolates of Staphylococcus aureus and by piperacillin/tazobactam-susceptible Acinetobacter baumannii, Haemophilus influenzae, Klebsiella pneumoniae, and Pseudomonas aeruginosa (Nosocomial pneumonia caused by P. aeruginosa should be treated in combination with an aminoglycoside).
Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Tazip and other antibacterial drugs, Tazip should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
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 Tazip. 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 Tazip, careful inquiry should be made concerning previous hypersensitivity reactions. If an allergic reaction occurs, Tazip should be discontinued and appropriate therapy instituted.
Severe Cutaneous Adverse Reactions
Tazip 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 Tazip 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, Tazip should be discontinued and appropriate therapy instituted.
The leukopenia/neutropenia associated with Tazip 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 Tazip 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 Tazip.
Combined use of piperacillin/tazobactam and vancomycin may be associated with an increased incidence of acute kidney injury.
Electrolyte Effects
Tazip 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 Tazip, 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 Tazip 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 Tazip and any potential adverse effects on the breastfed child from Tazip or from the underlying maternal condition.
Pediatric Use
Use of Tazip 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 Tazip 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.
Tazip 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 Tazip should be reduced to the degree of renal function impairment.
Hepatic Impairment
Dosage adjustment of Tazip 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 Tazip 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, Tazip 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 Tazip 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 Tazip 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 Tazip 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 Tazip 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 Tazip (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 Tazip group and 73 (27.1%) in the cefotaxime/metronidazole group. Six patients (2.2%) in the Tazip 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 Tazip 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 Tazip. 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 Tazip in pediatric patients suggests a similar safety profile to that seen in adults.
複数の静脈内投与後のピペラシリンとタゾバクタムの薬物動態パラメータの平均と変動係数(CV%)を表6にまとめます。.
表6:平均(CV%)ピペラシリンとタゾバクタムPKパラメーター。
ピペラシリン。 | ||||||
ピペラシリン/タゾバクタム用量。a | Cmax mcg / mL。 | AUC。b 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。 | -- |
タゾバクタム。 | ||||||
ピペラシリン/タゾバクタム用量。a | Cmax mcg / mL。 | AUC。b 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 ピペラシリンとタゾバクタムを組み合わせて投与し、30分以上注入した。. b 括 ⁇ 内の数値は変動係数(CV%)です。. |
ピペラシリンとタゾバクタムのピーク血漿濃度は、タジップの静脈内注入が完了した直後に達成されます。. Tazipの30分の注入後のピペラシリン血漿濃度は、同等の用量のピペラシリンを単独で投与した場合に達成される濃度と同様でした。. ピペラシリンとタゾバクタムの定常血漿濃度は、ピペラシリンとタゾバクタムの半減期が短いため、最初の投与後に達成されたものと同様でした。.
分布。
ピペラシリンとタゾバクタムの両方が血漿タンパク質に約30%結合しています。. ピペラシリンまたはタゾバクタムのいずれかのタンパク質結合は、他の化合物の存在による影響を受けません。. タゾバクタム代謝物のタンパク質結合は無視できます。.
ピペラシリンとタゾバクタムは、腸粘膜、胆 ⁇ 、肺、女性の生殖組織(子宮、卵巣、卵管)、間質液、胆 ⁇ などの組織と体液に広く分布しています。. 平均組織濃度は一般に血漿中の濃度の50%から100%です。. 他のペニシリンと同様に、非炎症性髄膜の被験者では、ピペラシリンとタゾバクタムの脳脊髄液への分布が低いです(表7を参照)。.
表7:タジップの単回4 g / 0.5 g 30分IV注入後の特定の組織と流体におけるピペラシリン/タゾバクタム濃度。
組織または流体。 | Na | サンプリング期間。b (h)。 | 平均PIP濃度範囲(mg / L)。 | 組織:血漿範囲。 | タゾ濃度範囲(mg / L)。 | タゾ組織:血漿範囲。 |
皮膚。 | 35 | 0.5-4.5。 | 34.8-94.2。 | 0.60-1.1。 | 4.0-7.7。 | 0.49-0.93。 |
脂肪組織。 | 37 | 0.5-4.5。 | 4.0-10.1。 | 0.097-0.115。 | 0.7-1.5。 | 0.10-0.13。 |
筋肉。 | 36 | 0.5-4.5。 | 9.4-23.3。 | 0.29-0.18。 | 1.4-2.7。 | 0.18-0.30。 |
近位腸粘膜。 | 7 | 1.5-2.5。 | 31.4。 | 0.55。 | 10.3。 | 1.15。 |
遠位腸粘膜。 | 7 | 1.5-2.5。 | 31.2。 | 0.59。 | 14.5。 | 2.1。 |
付録。 | 22 | 0.5-2.5。 | 26.5-64.1。 | 0.43-0.53。 | 9.1-18.6。 | 0.80-1.35。 |
a 各被験者は単一のサンプルを提供しました。. b 注入開始からの時間。 |
代謝。
ピペラシリンは、微生物学的に活性なデエチル代謝物に代謝されます。. タゾバクタムは、薬理学的および抗菌活性を欠く単一の代謝産物に代謝されます。.
排 ⁇ 。
健康な被験者への単一または複数のタジップ投与後、ピペラシリンとタゾバクタムの血漿半減期は0.7〜1.2時間の範囲であり、投与量または注入期間の影響を受けませんでした。.
ピペラシリンとタゾバクタムの両方が、糸球体 ⁇ 過と尿細管分 ⁇ によって腎臓から排出されます。. ピペラシリンは未変化の薬物として急速に排 ⁇ され、投与量の68%が尿中に排 ⁇ されます。. タゾバクタムとその代謝産物は主に腎排 ⁇ によって排除され、投与量の80%が未変化の薬物として排 ⁇ され、残りは単一の代謝物として排 ⁇ されます。. ピペラシリン、タゾバクタム、デセチルピペラシリンも胆 ⁇ に分 ⁇ されます。.