A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Zosyn Side Effects, and Drug Interactions - Piperacillin and Tazobactam Inj
Zosyn Side Effects, and Drug Interactions - Piperacillin and Tazobactam Inj
SIDE EFFECTS
Adverse Events From Clinical Trials
During the initial clinical investigations, 2621 patients worldwide were treated with Zosyn (piperacillin and tazobactam for injection) in phase 3 trials. In the key North American 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, Zosyn 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%).
Adverse local reactions that were reported, irrespective of relationship to therapy with Zosyn, were phlebitis (1.3%), injection site reaction (0.5%), pain (0.2%), inflammation (0.2%), thrombophlebitis (0.2%), and edema (0.1%).
Based on patients from the North American trials (n=1063), the events with the highest incidence in patients, irrespective of relationship to Zosyn therapy, were diarrhea (11.3%); headache (7.7%); constipation (7.7%); nausea (6.9%); insomnia (6.6%); rash (4.2%), including maculopapular, bullous, urticarial, and eczematoid; vomiting (3.3%); dyspepsia (3.3%); pruritus (3.1%); stool changes (2.4%); fever (2.4%); agitation (2.1%); pain (1.7%); moniliasis (1.6%); hypertension (1.6%); dizziness (1.4%); abdominal pain (1.3%); chest pain (1.3%); edema (1.2%); anxiety (1.2%); rhinitis (1.2%); and dyspnea (1.1%).
Additional adverse systemic clinical events reported in 1.0% or less of the patients in the initial North American trials are listed below within each body system.
Autonomic nervous system—hypotension, ileus, syncope
Body as a whole—rigors, back pain, malaise
Cardiovascular—tachycardia, including supraventricular and ventricular; bradycardia; arrhythmia, including atrial fibrillation, ventricular fibrillation, cardiac arrest, cardiac failure, circulatory failure, myocardial infarction
Central nervous system—tremor, convulsions, vertigo
Gastrointestinal—melena, flatulence, hemorrhage, gastritis, hiccough, ulcerative stomatitis
Pseudomembranous colitis was reported in one patient during the clinical trials. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment. (See WARNINGS.)
Hearing and Vestibular System—tinnitus
Hypersensitivity—anaphylaxis
Metabolic and Nutritional—symptomatic hypoglycemia, thirst
Musculoskeletal—myalgia, arthralgia
Platelets, Bleeding, Clotting—mesenteric embolism, purpura, epistaxis, pulmonary embolism (See PRECAUTIONS, General).
Psychiatric—confusion, hallucination, depression
Reproductive, Female—leukorrhea, vaginitis
Respiratory—pharyngitis, pulmonary edema, bronchospasm, coughing
Skin and Appendages—genital pruritus, diaphoresis
Special senses—taste perversion
Urinary—retention, dysuria, oliguria, hematuria, incontinence
Vision—photophobia
Vascular (extracardiac)—flushing
Nosocomial Pneumonia Trials
In a completed study of nosocomial lower respiratory tract infections, 222 patients were treated with Zosyn 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.
In this study of Zosyn in combination with an aminoglycoside, adverse events that occurred in more than 1% patients and were considered by the investigator to be drug-related were: diarrhea (17.6%), fever (2.7%), vomiting (2.7%), urinary tract infection (2.7%), rash (2.3%), abdominal pain (1.8%), generalized edema (1.8%), moniliasis (1.8%), nausea (1.8%), oral moniliasis (1.8%), BUN increased (1.8%), creatinine increased (1.8%), peripheral edema (1.8%), abdomen enlarged (1.4%), headache (1.4%), constipation (1.4%), liver function tests abnormal (1.4%), thrombocythemia (1.4%), excoriations (1.4%), and sweating (1.4%).
Drug-related adverse events reported in 1% or less of patients in the nosocomial pneumonia study of Zosyn with an aminoglycoside were: acidosis, acute kidney failure, agitation, alkaline phosphatase increased, anemia, asthenia, atrial fibrillation, chest pain, CNS depression, colitis, confusion, convulsion, cough increased, thrombocytopenia, dehydration, depression, diplopia, drug level decreased, dry mouth, dyspepsia, dysphagia, dyspnea, dysuria, eosinophilia, fungal dermatitis, gastritis, glossitis, grand mal convulsion, hematuria, hyperglycemia, hypernatremia, hypertension, hypertonia, hyperventilation, hypochromic anemia, hypoglycemia, hypokalemia, hyponatremia, hypophosphatemia, hypoxia, ileus, injection site edema, injection site pain, injection site reaction, kidney function abnormal, leukocytosis, leukopenia, local reaction to procedure, melena, pain, prothrombin decreased, pruritus, respiratory disorder, SGOT increased, SGPT increased, sinus bradycardia, somnolence, stomatitis, stupor, tremor, tachycardia, ventricular extrasystoles, and ventricular tachycardia.
In a previous nosocomial pneumonia study conducted with a dosing regimen of 3.375 g given every 4 hours with an aminoglycoside, the following adverse events, irrespective of drug relationship, were observed: diarrhea (20%); constipation (8.4%); agitation (7.1%); nausea (5.8%); headache (4.5%); insomnia (4.5%); oral thrush (3.9%); erythematous rash (3.9%); anxiety (3.2%); fever (3.2%); pain (3.2%); pruritus (3.2%); hiccough (2.6%); vomiting (2.6%); dyspepsia (1.9%); edema (1.9%); fluid overload (1.9%); stool changes (1.9%); anorexia (1.3%); cardiac arrest (1.3%); confusion (1.3%); diaphoresis (1.3%); duodenal ulcer (1.3%); flatulence (1.3%); hypertension (1.3%); hypotension (1.3%); inflammation at injection site (1.3%); pleural effusion (1.3%); pneumothorax (1.3%); rash, not otherwise specified (1.3%); supraventricular tachycardia (1.3%); thrombophlebitis (1.3%); and urinary incontinence (1.3%).
Adverse events irrespective of drug relationship observed in 1% or less of patients in the above study with Zosyn and an aminoglycoside included: aggressive reaction (combative), angina, asthenia, atelectasis, balanoposthitis, cerebrovascular accident, chest pain, conjunctivitis, deafness, dyspnea, earache, ecchymosis, fecal incontinence, gastric ulcer, gout, hemoptysis, hypoxia, pancreatitis, perineal irritation/pain, urinary tract infection with trichomonas, vitamin B12 deficiency anemia, xerosis, and yeast in urine.
Post-Marketing Experience
Additional adverse events reported from worldwide marketing experience with Zosyn, occurring under circumstances where causal relationship to Zosyn is uncertain:
Gastrointestinal—hepatitis, cholestatic jaundice
Hematologic—hemolytic anemia, anemia, thrombocytosis, agranulocytosis, pancytopenia
Immune—hypersensitivity reactions, anaphylactic/anaphylactoid reactions (including shock)
Infections—candidal superinfections Renal—interstitial nephritis, renal failure
Skin and Appendages—erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis
Adverse Laboratory Events (Seen During Clinical Trials)
Of the studies reported, including that of nosocomial lower respiratory tract infections in which a higher dose of Zosyn (piperacillin and tazobactam for injection) was used in combination with an aminoglycoside, changes in laboratory parameters, without regard to drug relationship, include:
Hematologic—decreases in hemoglobin and hematocrit, thrombocytopenia, increases in platelet count, eosinophilia, leukopenia, neutropenia. The leukopenia/neutropenia associated with Zosyn administration appears to be reversible and most frequently associated with prolonged administration, ie, >21 days of therapy. These patients were withdrawn from therapy; some had accompanying systemic symptoms (eg, 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
Urinalysis—proteinuria, hematuria, pyuria
Additional laboratory events include abnormalities in electrolytes (ie, 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.
The following adverse reaction has also been reported for PIPRACILÒ
(piperacillin for injection):
Skeletal—prolonged muscle relaxation (See PRECAUTIONS, Drug Interactions.)
Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.
DRUG INTERACTIONS
Aminoglycosides: The mixing of Zosyn with an aminoglycoside in vitro can result in substantial inactivation of the aminoglycoside. (See DOSAGE AND ADMINISTRATION, Compatible Intravenous Diluent Solutions.)
When Zosyn was co-administered with tobramycin, the area under the curve, renal clearance, and urinary recovery of tobramycin were decreased by 11%, 32%, and 38%, respectively. The alterations in the pharmacokinetics of tobramycin when administered in combination with piperacillin/tazobactam may be due to in vivo and in vitro inactivation of tobramycin in the presence of piperacillin/ tazobactam. The inactivation of aminoglycosides in the presence of penicillin-class drugs has been recognized. It has been postulated that penicillin-aminoglycoside complexes form; these complexes are microbiologically inactive and of unknown toxicity. In patients with severe renal dysfunction (ie, chronic hemodialysis patients), the pharmacokinetics of tobramycin are significantly altered when tobramycin is administered in combination with piperacillin.5 The alteration of tobramycin pharmacokinetics and the potential toxicity of the penicillin-aminoglycoside complexes in patients with mild to moderate renal dysfunction who are administered an aminoglycoside in combination with piperacillin/tazobactam are unknown.
Probenecid: Probenecid administered concomitantly with Zosyn prolongs the half-life of piperacillin by 21% and that of tazobactam by 71%.
Vancomycin: No pharmacokinetic interactions have been noted between Zosyn and vancomycin.
Heparin: Coagulation parameters should be tested more frequently and monitored regularly during simultaneous administration of high doses of heparin, oral anticoagulants, or other drugs that may affect the blood coagulation system or the thrombocyte function.
Vecuronium: Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. Zosyn (piperacillin/tazobactam) could produce the same phenomenon if given along with vecuronium. Due to their similar mechanism of action, it is expected that the neuromuscular blockade produced by any of the non-depolarizing muscle relaxants could be prolonged in the presence of piperacillin. (See package insert for vecuronium bromide.)
Methotrexate : Limited data suggests that co-administration of methotrexate and piperacillin may reduce the clearance of methotrexate due to competition for renal secretion. The impact of tazobactam on the elimination of methotrexate has not been evaluated. If concurrent therapy is necessary, serum concentrations of methotrexate as well as the signs and symptoms of methotrexate toxicity should be frequently monitored.
Drug/Laboratory Test Interactions
As with other penicillins, the administration of ZosynÒ (piperacillin and tazobactam for injection) may result in a false-positive reaction for glucose in the urine using a copper-reduction method (CLINITESTÒ ). It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as DIASTIXÒ or TES-TAPEÒ ) be used.
There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving piperacillin/tazobactam injection who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with the Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported.
Therefore, positive test results in patients receiving piperacillin/tazobactam should be interpreted cautiously and confirmed by other diagnostic methods.
REFERENCES
5. Halstenson CE, Hirata CAI, Heim-Duthoy KL, Abraham PA, and Matzke GR. Effect of concomitant administration of piperacillin on the dispositions of netilmicin and tobramycin in patients with end-stage renal disease. Antimicrob Agents Chemother 34(1):128-133, 1990.
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