Piperacillin sodium warnings and precautions

# Warnings and Precautions

## Warnings
SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC/ANAPHYLACTOID) REACTIONS HAVE BEEN REPORTED IN PATIENTS ON PENICILLIN THERAPY. THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY AND/OR A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH CEPHALOSPORINS. BEFORE INITIATING THERAPY WITH PIPRACIL, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, PIPRACIL SHOULD BE DISCONTINUED AND APPROPRIATE THERAPY INSTITUTED. SERIOUS ANAPHYLACTIC/ANAPHYLACTOID REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED.
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including PIPRACIL, 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 antibiotic 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 antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

## Precautions
- General
Bleeding manifestations have occurred in some patients receiving -lactam antibiotics, 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, the antibiotic should be discontinued and appropriate therapy instituted.
The possibility of the emergence of resistant organisms which might cause superinfections should be kept in mind, particularly during prolonged treatment. If this occurs, appropriate measures should be taken.
As with other penicillins, patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously.
PIPRACIL is a monosodium salt containing 1.85 mEq of Na+ per g (42.5 mg of Na+ per g). This should be considered when treating patients requiring restricted salt intake. Periodic electrolyte determinations should be made 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.
Leukopenia and neutropenia may occur during prolonged therapy.
As with other semisynthetic penicillins, PIPRACIL therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.
Prescribing PIPRACIL in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
- Information for Patients
Patients should be counseled that antibacterial drugs including PIPRACIL should only be used to treat bacterial infections. They do not treat viral infections (eg, the common cold). When PIPRACIL is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by PIPRACIL or other antibacterial drugs in the future.
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of antibiotic. If this occurs, patients should contact their physician as soon as possible.
- Laboratory Tests
While piperacillin possesses the characteristic low toxicity of the penicillin group of antibiotics, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, during prolonged therapy is advisable.
All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with piperacillin should have a follow-up serologic test for syphilis after 3 months.
- Drug Interactions
Aminoglycosides
The mixing of piperacillin with an aminoglycoside in vitro can result in substantial inactivation of the aminoglycoside.
Vecuronium
When used in the perioperative period, piperacillin has been implicated in the prolongation of the neuromuscular blockade of vecuronium. Caution is indicated when piperacillin is used perioperatively. In one controlled clinical study, the ureidopenicillins, including piperacillin, were reported to prolong the action of 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.
Probenecid
The oral combination of probenecid before intramuscular injection of PIPRACIL produces an increase in piperacillin peak serum level of about 30%.
Anticoagulants
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.
Methotrexate
Piperacillin sodium may reduce the excretion of methotrexate. Therefore, serum levels of methotrexate should be monitored in patients to avoid drug toxicity.
- Drug/Laboratory Test Interactions
As with other penicillins, the administration of PIPRACIL may result in a false-positive reaction for glucose in the urine using a copper-reduction method. It is recommended that glucose tests based on enzymatic glucose oxidase reactions 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 should be interpreted cautiously and confirmed by other diagnostic methods.
- Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Long-term studies in animals have not been performed to evaluate carcinogenic potential.
Mutagenesis
Piperacillin was negative in the Ames Salmonella reversion test at concentrations up to 10 g/plate. There was no DNA damage in bacteria (Rec assay) exposed to piperacillin at concentrations up to 200 g/disc. In a mammalian point mutation (mouse lymphoma cells) assay, piperacillin was positive at concentrations  2500 g/mL. Piperacillin was negative in a cell (BALB/c-3T3) transformation assay at concentrations up to 3000 g/mL. In vivo, piperacillin did not induce chromosomal aberrations in the bone marrow cells of mice at I.V. doses up to 2000 mg/kg/day or rats at I.V. doses up to 1500 mg/kg/day. These doses are half (mice) or threefourths (rats) the maximum recommended human daily dose based on body-surface area (mg/m2). In another in vivo test, there was no dominant lethal effect when piperacillin was administered to rats at I.V. doses up to 2000 mg/kg/day, which is similar to the maximum recommended human daily dose based on body-surface area (mg/m2). When piperacillin was administered to mice at I.V. doses up to 2000 mg/kg/day, which is half the maximum recommended human daily dose based on body-surface area (mg/m2), urine from these animals was not mutagenic when tested in the Ames assay using Salmonella strain TA-98 in the absence of -glucuronidase.
Impairment of Fertility
Reproduction studies have been performed in mice (SQ) and rats (I.P.) and have revealed no evidence of impaired fertility due to piperacillin administered up to a dose which is half (mice) or similar (rats) to the maximum recommended human daily dose based on body-surface area (mg/m2). The plasma/serum concentrations at the highest daily dose administered to rats in reproduction studies were comparable to the maximum serum concentration seen in man, based on a toxicology study in rats in which similar doses of piperacillin (in combination with a betalactamase inhibitor, tazobactam) were administered I.P.and based on extrapolations from an animal pharmacokinetic study using lower doses of piperacillin alone.
- Pregnancy
Teratogenic effectsPregnancy Category B
Teratology studies have been performed in mice (I.V.) and rats (I.V., I.P. and SQ) and have revealed no evidence of harm to the fetus due to piperacillin administered up to a dose which is approximately half the maximum recommended human daily dose based on body-surface area (mg/m2). In pharmacokinetic studies in pregnant and nonpregnant rats, in which piperacillin was administered I.V. at a dose which is half the maximum daily dose administered in teratology studies, serum concentrations in rats were approximately 10 times the maximum serum concentration seen in man. In other studies in mice and rats, in which piperacillin (in combination with a beta-lactamase inhibitor, tazobactam) was administered I.V. at approximately half the maximum daily dose administered in teratology studies, plasma concentrations of piperacillin were approximately 2 times (mice) and 5 times (rats) the serum concentrations seen in man.
There are, however, no adequate and well-controlled studies with piperacillin in pregnant women. Because animal reproduction studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed.
- Nursing Mothers
Piperacillin is excreted in low concentrations in human milk. Caution should be exercised when PIPRACIL is administered to nursing mothers.
- Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Data from published pharmacokinetics studies indicate that the elimination half-life of piperacillin in neonates is twofold to fourfold longer than that seen in pediatric patients 1 month of age and above as well as in adults. In infants, children, and adolescents, the elimination half-life of piperacillin is shorter than that observed in adults. As in adults, the elimination of piperacillin is decreased in pediatric patients with renal impairment. (See CLINICAL PHARMACOLOGY.)
- Geriatric Use
Clinical studies of PIPRACIL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
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.
PIPRACIL contains 42.5 mg (1.85 mEq) of sodium per gram. At the usual recommended doses, patients would receive between 255 and 765 mg/day (11.1 and 33.3 mEq) of sodium. The geriatric population may respond with a blunted natriuresis to salt loading. The total sodium content from dietary and non-dietary sources 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.