PIPERACILLIN Drug Interactions: What You Need to Know

INTERACTIONS Piperacillin and Tazobactam for Injection and Sodium Chloride Injection administration can significantly reduce tobramycin concentrations in hemodialysis patients. Monitor tobramycin concentrations in these patients. ( 7.1 ) Probenecid prolongs the half-lives of piperacillin and tazobactam and should not be co-administered with Piperacillin and Tazobactam for Injection and Sodium Chloride Injection unless the benefit outweighs the risk. ( 7.2 ) Co-administration of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection with vancomycin may increase the incidence of acute kidney injury. Monitor kidney function in patients receiving Piperacillin and Tazobactam for Injection and Sodium Chloride Injection and vancomycin. ( 7.3 ) Monitor coagulation parameters in patients receiving Piperacillin and Tazobactam for Injection and Sodium Chloride Injection and heparin or oral anticoagulants. ( 7.4 ) Piperacillin and Tazobactam for Injection and Sodium Chloride Injection may prolong the neuromuscular blockade of vecuronium and other non-depolarizing neuromuscular blockers. Monitor for adverse reactions related to neuromuscular blockade. ( 7.5 )

7.1 Aminoglycosides Piperacillin may inactivate aminoglycosides by converting them to microbiologically inert amides. In vivo inactivation : When aminoglycosides are administered in conjunction with piperacillin to patients with end-stage renal disease requiring hemodialysis, the concentrations of the aminoglycosides (especially tobramycin) may be significantly reduced and should be monitored. Sequential administration of piperacillin and tazobactam and tobramycin to patients with either normal renal function or mild to moderate renal impairment has been shown to modestly decrease serum concentrations of tobramycin but no dosage adjustment is considered necessary. In vitro inactivation : Due to the in vitro inactivation of aminoglycosides by piperacillin, piperacillin and tazobactam and aminoglycosides are recommended for separate administration. Piperacillin and Tazobactam for Injection and Sodium Chloride Injection and aminoglycosides should be reconstituted, and administered separately when concomitant therapy with aminoglycosides is indicated. Piperacillin and Tazobactam for Injection and Sodium Chloride Injection, which contains EDTA, is compatible with amikacin and gentamicin for simultaneous Y-site infusion in certain diluents and at specific concentrations. Piperacillin and Tazobactam for Injection and Sodium Chloride Injection is not compatible with tobramycin for simultaneous Y-site infusion <span class="opacity-50 text-xs">[see Dosage and Administration (2.7) ]</span>.

7.2 Probenecid Probenecid administered concomitantly with Piperacillin and Tazobactam for Injection and Sodium Chloride Injection prolongs the half-life of piperacillin by 21% and that of tazobactam by 71% because probenecid inhibits tubular renal secretion of both piperacillin and tazobactam. Probenecid should not be co-administered with Piperacillin and Tazobactam for Injection and Sodium Chloride Injection unless the benefit outweighs the risk.

7.3 Vancomycin Studies have detected an increased incidence of acute kidney injury in patients concomitantly administered piperacillin and tazobactam and vancomycin as compared to vancomycin alone <span class="opacity-50 text-xs">[see Warnings and Precautions (5.7) ]</span>. Monitor kidney function in patients concomitantly administered with Piperacillin and Tazobactam for Injection and Sodium Chloride Injection and vancomycin. No pharmacokinetic interactions have been noted between piperacillin and tazobactam and vancomycin.

7.4 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.5) ]</span>.

7.5 Vecuronium Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. Piperacillin and Tazobactam for Injection and Sodium Chloride Injection 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 neuromuscular blockers could be prolonged in the presence of piperacillin. Monitor for adverse reactions related to neuromuscular blockade (see package insert for vecuronium bromide).

7.6 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.

7.7 Effects on Laboratory Tests There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving piperacillin and 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 and tazobactam should be interpreted cautiously and confirmed by other diagnostic methods. As with other penicillins, the administration of piperacillin and tazobactam may result in a false-positive reaction for glucose in the urine using a copper-reduction method (CLINITEST ® ). It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.

Piperacillin and Tazobactam for Injection and Sodium Chloride Injection is contraindicated in patients with a history of allergic reactions to any of the penicillins, cephalosporins, or betalactamase inhibitors. Patients with a history of allergic reactions to any of the penicillins, cephalosporins, or beta-lactamase inhibitors. ( 4 )

AND PRECAUTIONS Serious hypersensitivity reactions (anaphylactic/anaphylactoid) reactions have been reported in patients receiving piperacillin and tazobactam.

Discontinue

Piperacillin and Tazobactam for Injection and Sodium Chloride Injection if a reaction occurs. ( 5.1 ) Piperacillin and tazobactam 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.

Discontinue

Piperacillin and Tazobactam for Injection and Sodium Chloride Injection for progressive rashes. ( 5.2 ) Hemophagocytic lymphohistiocytosis (HLH) has been reported with the use of piperacillin and tazobactam. If HLH is suspected, discontinue Piperacillin and Tazobactam for Injection and Sodium Chloride Injection immediately. ( 5.3 ) Rhabdomyolysis: If signs or symptoms of rhabdomyolysis are observed, discontinue Piperacillin and Tazobactam for Injection and Sodium Chloride Injection and initiate appropriate therapy. ( 5.4 ) Hematological effects (including bleeding, leukopenia and neutropenia) have occurred. Monitor hematologic tests during prolonged therapy. ( 5.5 ) As with other penicillins, piperacillin and tazobactam may cause neuromuscular excitability or seizures. Patients receiving higher doses, especially in the presence of renal impairment may be at greater risk. Closely monitor patients with renal impairment or seizure disorders for signs and symptoms of neuromuscular excitability or seizures. ( 5.6 ) Nephrotoxicity in critically ill patients has been observed; the use of piperacillin and tazobactam 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection. ( 5.7 )

High Sodium

Load and Electrolyte Effects: Piperacillin and Tazobactam for Injection and Sodium Chloride Injection contains a total of 220 mg, 256 mg, 440 mg of sodium per 2.25 g, 3.375 g, and 4.5 g product, respectively. Consider an alternative formulation of piperacillin-tazobactam in patients requiring restricted sodium intake. Periodic electrolyte determinations should be performed in patients with low potassium reserves. ( 5.8 ) Clostridioides difficile -Associated Diarrhea: Evaluate patients if diarrhea occurs. ( 5.9 )

5.1 Hypersensitivity Adverse Reactions Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid) reactions (including shock) have been reported in patients receiving therapy with piperacillin and tazobactam. 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection, careful inquiry should be made concerning previous hypersensitivity reactions. If an allergic reaction occurs, Piperacillin and Tazobactam for Injection and Sodium Chloride Injection should be discontinued and appropriate therapy instituted.

5.2 Severe Cutaneous Adverse Reactions Piperacillin and tazobactam 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection discontinued if lesions progress.

5.3 Hemophagocytic Lymphohistiocytosis Cases of hemophagocytic lymphohistiocytosis (HLH) have been reported in pediatric and adult patients treated with piperacillin and tazobactam. Signs and symptoms of HLH may include fever, rash, lymphadenopathy, hepatosplenomegaly and cytopenia. If HLH is suspected, discontinue Piperacillin and Tazobactam for Injection and Sodium Chloride Injection immediately and institute appropriate management.

5.4 Rhabdomyolysis Rhabdomyolysis has been reported with the use of piperacillin and tazobactam <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> . If signs or symptoms of rhabdomyolysis such as muscle pain, tenderness or weakness, dark urine, or elevated creatine phosphokinase are observed, discontinue Piperacillin and Tazobactam for Injection and Sodium Chloride Injection and initiate appropriate therapy.

5.5 Hematologic Adverse Reactions Bleeding manifestations have occurred in some patients receiving beta-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, Piperacillin and Tazobactam for Injection and Sodium Chloride Injection should be discontinued, and appropriate therapy instituted. The leukopenia/neutropenia associated with piperacillin and tazobactam administration appears to be reversible and most frequently associated with prolonged administration. Periodic assessment of hematopoietic function should be performed, especially with prolonged therapy, i.e., ≥ 21 days <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>.

5.6 Central Nervous System Adverse Reactions As with other penicillins, piperacillin and tazobactam may cause neuromuscular excitability or seizures. Patients receiving higher doses, especially patients with renal impairment may be at greater risk for central nervous system adverse reactions. Closely monitor patients with renal impairment or seizure disorders for signs and symptoms of neuromuscular excitability or seizures <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span>.

5.7 Nephrotoxicity in Critically Ill Patients The use of piperacillin and tazobactam 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>. 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> . Combined use of piperacillin and tazobactam and vancomycin may be associated with an increased incidence of acute kidney injury <span class="opacity-50 text-xs">[see Drug Interactions (7.3) ]</span>.

5.8 High Sodium Load and Electrolyte Effects Piperacillin and Tazobactam for Injection and Sodium Chloride Injection contains a total of 220 mg, 256 mg, and 440 mg of sodium per 2.25 g, 3.375 g, and 4.5 g product, respectively. Consider using an alternative formulation of piperacillin and tazobactam 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.

5.9 Clostridioides difficile- Associated Diarrhea Clostridioides difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including piperacillin and tazobactam, 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.

5.10 Development of Drug-Resistant Bacteria Prescribing Piperacillin and Tazobactam for Injection and Sodium Chloride Injection 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 development of drug-resistant bacteria.