Tapimycin

Piperacillin and Tazobactam for injection is a white or almost white powder in vial.
Each vial contains: Piperacillin (as sodium), USP 4 g (potency), Tazobactam (as sodium) 500 mg (potency).

Pharmacology: Pharmacodynamics and Pharmacokinetics: Peak plasma concentrations of Piperacillin and Tazobactam are attained immediately after completion of an intravenous infusion of Piperacillin/Tazobactam.
Steady state plasma concentrations were not different from those attained after the first dose when 2.25 g or 4.5 g doses of Piperacillin/Tazobactam were administered via 30 minute infusions every 6 hours.
Piperacillin is metabolized to a minor microbiologically active desethyl metabolite. Tazobactam is metabolized to a single metabolite that lacks pharmacological and antibacterial activities.
Both Piperacillin and Tazobactam are eliminated via the kidney by glomerular filtration and tubular secretion.
Piperacillin is excreted rapidly as unchanged drug with 68% of the administered dose excreted in the urine. Tazobactam and its metabolite are eliminated primarily by renal excretion with 80% of the administered dose excreted as unchanged drug and the remainder as the single metabolite. Piperacillin, Tazobactam and desethyl Piperacillin are also secreted into the bile.
Both Piperacillin and Tazobactam are approximately 30% bound to plasma proteins.
Piperacillin and Tazobactam are widely distributed into tissues and body fluids including intestinal mucosa, gallbladder, lungs, female reproductive tissues (uterus, ovary, and fallopian tube), interstitial fluid, and bile.

For short-term treatment of bacterial infections caused by susceptible organisms: Lower respiratory tract infections, urinary tract infections (complicated and uncomplicated), intra-abdominal infections, skin and soft tissue infections, bacterial septicemia, and gynecological infections.

Piperacillin and Tazobactam for injection should be administered by intravenous infusion over 30 minutes.
The usual total daily dose of Piperacillin and Tazobactam for injection for adults is 3.375 g every 6 hours totaling 13.5 g (12.0 g Piperacillin/1.5 g Tazobactam).
For children with appendicitis and/or peritonitis 9 months of age or older, weighing up to 40 kg, and with normal renal function, the recommended Piperacillin and Tazobactam for injection dosage is 100 mg Piperacillin/12.5 mg Tazobactam per kilogram of body weight, every 8 hours.
For pediatric patients between 2 months and 9 months of age, the recommended Piperacillin and Tazobactam for injection dosage based on pharmacokinetic modeling, is 80 mg Piperacillin/10 mg Tazobactam per kilogram of body weight, every 8 hours.
Pediatric patients weighing over 40 kg and with normal renal function should receive the adult dose. There are no dosage recommendations for Piperacillin and Tazobactam for injection in pediatric patients with impaired renal function.
Impaired renal function: In patients with renal insufficiency the intravenous dose should be adjusted to the degree of actual renal function impairment. The suggested daily doses are: See table.

Click on icon to see table/diagram/image

For patients on haemodialysis, the maximum dose is 2.25 g every 12 hours for all indications. Since hemodialysis removes 30% to 40% of the administered dose, an additional dose of 0.75 g Piperacillin and Tazobactam for injection should be administered following each dialysis period on hemodialysis days. No additional dosage of Piperacillin and Tazobactam for injection is necessary for CAPD patients.
The reconstituted solution may be further diluted to 50 mL with water for injection, 5% dextrose injection, 0.9% sodium chloride injection.
The diluted solutions should be used immediately.
To be dispensed on Physician's prescription.

The majority of overdose events experienced, including nausea, vomiting, and diarrhea, have also been reported with the usual recommended dosages. Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure).
Treatment should be supportive and symptomatic according to the patient's clinical presentation. Excessive serum concentrations of either Piperacillin or Tazobactam may be reduced by hemodialysis. Following a single 3.375 g dose of Piperacillin/Tazobactam, the percentage of the Piperacillin and Tazobactam dose removed by hemodialysis was approximately 31% and 39%, respectively.

Penicillin hypersensitivity.
Attention should be given for possible cross-sensitivity with other β-lactam antibiotics, e.g. cephalosporins.

Hypersensitivity Adverse Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid) reactions (including shock) have been reported in patients receiving therapy with Piperacillin and Tazobactam for injection. 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, careful inquiry should be made concerning previous hypersensitivity reactions. If an allergic reaction occurs, Piperacillin and Tazobactam for injection should be discontinued and appropriate therapy instituted.
Severe Cutaneous Adverse Reactions: Piperacillin and Tazobactam for injection 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 discontinued if lesions progress.
Hemophagocytic Lymphohistiocytosis: Cases of hemophagocytic lymphohistiocytosis (HLH) have been reported in pediatric and adult patients treated with Piperacillin and Tazobactam for injection. Signs and symptoms of HLH may include fever, rash, lymphadenopathy, hepatosplenomegaly and cytopenia. If HLH is suspected, discontinue Piperacillin and Tazobactam for injection immediately and institute appropriate management.
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 should be discontinued and appropriate therapy instituted.
The leukopenia/neutropenia associated with Piperacillin and Tazobactam for injection 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.
Central Nervous System Adverse Reactions: As with other penicillins, Piperacillin and Tazobactam for injection 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.
Nephrotoxicity in Critically ill Patients: The use of Piperacillin and Tazobactam for injection 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.
Combined use of Piperacillin/Tazobactam and vancomycin may be associated with an increased incidence of acute kidney injury.
Electrolyte Effects: Piperacillin and Tazobactam for injection contains a total of 2.35 mEq (54 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.
Clostridioides difficile-Associated Diarrhea: Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Piperacillin and Tazobactam for injection, 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 Piperacillin and Tazobactam for 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.

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) [see Data as follows].
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 to 4% and 15 to 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 breast-fed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Piperacillin and Tazobactam for injection and any potential adverse effects on the breastfed child from Piperacillin and Tazobactam for injection or from the underlying maternal condition.

Dermatological: skin reactions, eruptions, increased sweating, erythema multiforme, eczema, maculopapular rash.
Gastrointestinal: soft/loose stools, stomatitis, constipation, bloody diarrhea, pseudomembranous colitis.
Central nervous system: muscular weakness, hallucination, headache, dizziness, fatigue.
Autonomic nervous system: dry mouth, hypotension.
Musculoskeletal system: muscle pain, prolonged muscle relaxation.
Peripheral vascular system: superficial phlebitis.
Hematological: leucopenia, eosinophilia, rarely hemorrhagic manifestations.
Hepatic: transient rise in the serum levels of liver enzymes (ALT, AST, alkaline phosphatase), bilirubin.
Renal: increased levels of renal function parameters in serum (urea, creatinine), interstitial nephritis.
Local: injection site inflammation, injection site pain.

Aminoglycosides: The mixing of beta-lactam antibiotics with aminoglycosides in vitro can result in substantial inactivation of the aminoglycoside.
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. Sequential administration of Piperacillin and Tazobactam for injection with tobramycin to patients with normal renal function and mild to moderate renal impairment has been shown to modestly decrease serum concentrations of tobramycin but does not significantly affect tobramycin pharmacokinetics. When aminoglycosides are administered in combination with Piperacillin to patients with end-stage renal disease requiring hemodialysis, the concentrations of the aminoglycosides (especially tobramycin) may be significantly altered and should be monitored. Since aminoglycosides are not equally susceptible to inactivation by Piperacillin, consideration should be given to the choice of the aminoglycoside when administered in combination with Piperacillin to these patients.
Probenecid: Probenecid administered concomitantly with Piperacillin and Tazobactam for injection prolongs the half-life of Piperacillin by 21% and that of Tazobactam by 71%.
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. Piperacillin and Tazobactam for 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 muscle relaxants could be prolonged in the presence of Piperacillin.
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.

Store at temperatures not exceeding 30°C. Protect from light and moisture.

Penicillins

J01CR05 - piperacillin and beta-lactamase inhibitor ; Belongs to the class of penicillin combinations, including beta-lactamase inhibitors. Used in the systemic treatment of infections.

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