Tribact-PZ (Piperacillin and Tazobactam)

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Tribact-PZ (piperacillin and tazobactam) injection and other antibacterial drugs, Tribact-PZ (piperacillin and tazobactam) should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

CLINICAL PHARMACOLOGY

Adults

Peak plasma concentrations of piperacillin and tazobactam are attained immediately after completion of an intravenous infusion of Tribact-PZ. Piperacillin plasma concentrations, following a 30-minute infusion of Tribact-PZ, were similar to those attained when equivalent doses of piperacillin were administered alone, with mean peak plasma concentrations of approximately 134, 242 and 298 μg/mL for the 2.25 g, 3.375 g and 4.5 g Tribact-PZ (piperacillin/tazobactam) doses, respectively. The corresponding mean peak plasma concentrations of tazobactam were 15, 24 and 34 μg/mL, respectively.

Following a 30-minute I.V. infusion of 3.375 g Tribact-PZ every 6 hours, steady-state plasma concentrations of piperacillin and tazobactam were similar to those attained after the first dose. In like manner, steady-state plasma concentrations were not different from those attained after the first dose when 2.25 g or 4.5 g doses of Tribact-PZ were administered via 30-minute infusions every 6 hours. Steady-state plasma concentrations after 30-minute infusions every 6 hours are provided in Table 1.

Following single or multiple Tribact-PZ doses to healthy subjects, the plasma half-life of piperacillin and of tazobactam ranged from 0.7 to 1.2 hours and was unaffected by dose or duration of infusion.

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. The protein binding of either piperacillin or tazobactam is unaffected by the presence of the other compound. Protein binding of the tazobactam metabolite is negligible.

Piperacillin and tazobactam are widely distributed into tissues and body fluids including intestinal mucosa, gallbladder, lung, female reproductive tissues (uterus, ovary, and fallopian tube), interstitial fluid, and bile. Mean tissue concentrations are generally 50% to 100% of those in plasma. Distribution of piperacillin and tazobactam into cerebrospinal fluid is low in subjects with non-inflamed meninges, as with other penicillins.

After the administration of single doses of piperacillin/tazobactam to subjects with renal impairment, the half-life of piperacillin and of tazobactam increases with decreasing creatinine clearance. At creatinine clearance below 20 mL/min, the increase in half-life is twofold for piperacillin and fourfold for tazobactam compared to subjects with normal renal function. Dosage adjustments for Tribact-PZ are recommended when creatinine clearance is below 40 mL/min in patients receiving the usual recommended daily dose of Tribact-PZ (piperacillin and tazobactam for injection, USP).

Hemodialysis removes 30% to 40% of a piperacillin/tazobactam dose with an additional 5% of the tazobactam dose removed as the tazobactam metabolite. Peritoneal dialysis removes approximately 6% and 21% of the piperacillin and tazobactam doses, respectively, with up to 16% of the tazobactam dose removed as the tazobactam metabolite. For dosage recommendations for patients undergoing hemodialysis.

The half-life of piperacillin and of tazobactam increases by approximately 25% and 18%, respectively, in patients with hepatic cirrhosis compared to healthy subjects. However, this difference does not warrant dosage adjustment of Tribact-PZ due to hepatic cirrhosis.

Pediatrics

Piperacillin and tazobactam pharmacokinetics were studied in pediatric patients 2 months of age and older. The clearance of both compounds is slower in the younger patients compared to older children and adults.

In a population PK analysis, estimated clearance for 9 month-old to 12 year-old patients was comparable to adults, with a population mean (SE) value of 5.64 (0.34) mL/min/kg. The piperacillin clearance estimate is 80% of this value for pediatric patients 2 - 9 months old. In patients younger than 2 months of age, clearance of piperacillin is slower compared to older children; however, it is not adequately characterized for dosing recommendations. The population mean (SE) for piperacillin distribution volume is 0.243 (0.011) L/kg and is independent of age.

Microbiology

Piperacillin sodium exerts bactericidal activity by inhibiting septum formation and cell wall synthesis of susceptible bacteria. In vitro, piperacillin is active against a variety of gram-positive and gram-negative aerobic and anaerobic bacteria. Tazobactam sodium has little clinically relevant in vitro activity against bacteria due to its reduced affinity to penicillin-binding proteins. It is, however, a β lactamase inhibitor of the Richmond-Sykes class III (Bush class 2b & 2b') penicillinases and cephalosporinases. It varies in its ability to inhibit class II and IV (2a & 4) penicillinases. Tazobactam does not induce chromosomally-mediated β-lactamases at tazobactam concentrations achieved with the recommended dosage regimen.

Piperacillin/tazobactam has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections.

Aerobic and facultative Gram-positive microorganisms: Staphylococcus aureus (excluding methicillin and oxacillin-resistant isolates)

Aerobic and facultative Gram-negative microorganisms:

• Acinetobacter baumanii
• Escherichia coli
• Haemophilus influenzae (excluding β-lactamase negative, ampicillin-resistant isolates)
• Klebsiella pneumoniae
• Pseudomonas aeruginosa (given in combination with an aminoglycoside to which the isolate is susceptible)

Gram-negative anaerobes:

• Bacteroides fragilis group (B. fragilis, B. ovatus, B. thetaiotaomicron, and B. vulgatus)
• The following in vitro data are available, but their clinical significance is unknown.
• At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for piperacillin/tazobactam. However, the safety and effectiveness of piperacillin/tazobactam in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Aerobic and facultative Gram-positive microorganisms:

• Enterococcus faecalis (ampicillin or penicillin-susceptible isolates only)
• Staphylococcus epidermidis (excluding methicillin and oxacillin-resistant isolates)
• Streptococcus agalactiae†
• Streptococcus pneumoniae† (penicillin-susceptible isolates only)
• Streptococcus pyogenes†
• Viridans group streptococci†

Aerobic and facultative Gram-negative microorganisms: Citrobacter koseri ,Moraxella catarrhalis ,Morganella morganii, Neisseria gonorrhoeae, Proteus mirabilis, Proteus vulgaris ,Serratia marcescens, Providencia stuartii ,Providencia rettgeri ,Salmonella enterica.

Gram-positive anaerobes:Clostridium perfringens

Gram-negative anaerobes:

• Bacteroides distasonis
• Prevotella melaninogenica
• † These are not β-lactamase producing bacteria and, therefore, are susceptible to piperacillin alone.

INDICATIONS AND USAGE Tribact-PZ (piperacillin and tazobactam for injection, USP) is indicated for the treatment of patients with moderate to severe infections caused by piperacillin-resistant, piperacillin/tazobactam-susceptible, β-lactamase producing strains of the designated microorganisms in the specified conditions listed below:

• Appendicitis (complicated by rupture or abscess) and peritonitis caused by piperacillin-resistant, β-lactamase producing strains 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 less than 10 cases.
• Uncomplicated and complicated skin and skin structure infections, including cellulitis, cutaneous abscesses and ischemic/diabetic foot infections caused by piperacillin-resistant, β lactamase producing strains of Staphylococcus aureus.
• Postpartum endometritis or pelvic inflammatory disease caused by piperacillin-resistant, β lactamase producing strains of Escherichia coli.
• Community-acquired pneumonia (moderate severity only) caused by piperacillin-resistant, β lactamase producing strains of Haemophilus influenzae.
• Nosocomial pneumonia (moderate to severe) caused by piperacillin-resistant, β-lactamase producing strains of Staphylococcus aureus and by piperacillin/tazobactam-susceptible Acinetobacter baumanii, Haemophilus influenzae, Klebsiella pneumoniae, and Pseudomonas aeruginosa (Nosocomial pneumonia caused by P. aeruginosa should be treated in combination with an aminoglycoside).
• Tribact-PZ (piperacillin and tazobactam for injection, USP) is indicated only for the specified conditions listed above. Infections caused by piperacillin-susceptible organisms, for which piperacillin has been shown to be effective, are also amenable to Tribact-PZ treatment due to its piperacillin content. The tazobactam component of this combination product does not decrease the activity of the piperacillin component against piperacillin-susceptible organisms. Therefore, the treatment of mixed infections caused by piperacillin-susceptible organisms and piperacillin-resistant, β-lactamase producing organisms susceptible to Tribact-PZ should not require the addition of another antibiotic.
• Tribact-PZ is useful as presumptive therapy in the indicated conditions prior to the identification of causative organisms because of its broad spectrum of bactericidal activity against gram-positive and gram-negative aerobic and anaerobic organisms.
• Appropriate cultures should usually be performed before initiating antimicrobial treatment in order to isolate and identify the organisms causing infection and to determine their susceptibility to Tribact-PZ. Antimicrobial therapy should be adjusted, if appropriate, once the results of culture(s) and antimicrobial susceptibility testing are known.
• To reduce the development of drug-resistant bacteria and maintain the effectiveness of Tribact-PZ (piperacillin and tazobactam) injection and other antibacterial drugs, Tribact-PZ (piperacillin and tazobactam) should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible 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.

CONTRAINDICATIONS Tribact-PZ is contraindicated in patients with a history of allergic reactions to any of the penicillins, cephalosporins, or β-lactamase inhibitors.

WARNINGS

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC/ANAPHYLACTOID) REACTIONS (INCLUDING SHOCK) HAVE BEEN REPORTED IN PATIENTS RECEIVING THERAPY WITH PENICILLINS INCLUDING TRIBACT-PZ. THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY 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 TRIBACT-PZ, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, TRIBACT-PZ SHOULD BE DISCONTINUED AND APPROPRIATE THERAPY INSTITUTED. SERIOUS ANAPHYLACTIC/ANAPHYLACTOID REACTIONS (INCLUDING SHOCK) 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 Tribact-PZ, 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.

Alpha Lipoic Acid

Alpha Lipoic Acid (also known as lipoic acid, thioctic acid, or ALA) is one of the good fatty acids produced in every one of our cells. One of its main functions is to help convert glucose (blood sugar) into energy. About forty years ago, biologists discovered that ALA is also an antioxidant—a powerful substance that combats potentially harmful chemicals called free radicals which may cause heart and liver disease, cancer, cell aging, and many other conditions.

There are other very effective antioxidants, including vitamins C and E. But what's special about ALA is that it is both water and fat soluble. Scientists believe that ALA operates in conjunction with vitamins C and E, and the antioxidant glutathione, recycling them when they're used up. Many studies have been conducted confirming the health benefits of alpha-lipoic acid, including recent findings that ALA offers neuroprotective and possibly cognitive enhancing effects

PRECAUTIONS

General

Bleeding manifestations have occurred in some patients receiving β-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, Tribact-PZ (piperacillin and tazobactam for injection, USP) should be discontinued and appropriate therapy instituted.

The possibility of the emergence of resistant organisms that might cause superinfections should be kept in mind. 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 (particularly in the presence of renal failure). Tribact-PZ contains a total of 2.79 mEq (64 mg) of Na+ 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. As with other semisynthetic penicillins, piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients. In patients with creatinine clearance ≤ 40 mL/min and dialysis patients (hemodialysis and CAPD), the intravenous dose should be adjusted to the degree of renal function impairment. Prescribing Tribact-PZ (piperacillin and tazobactam) 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. Drug Interactions

Aminoglycosides

The mixing of beta-lactam antibiotics with aminoglycosides in vitro can result in substantial inactivation of the aminoglycoside. However, amikacin and gentamicin have been shown to be compatible in vitro with reformulated Tribact-PZ containing EDTA supplied in vials or bulk pharmacy containers in certain diluents at specific concentrations for a simultaneous Y-site infusion. Reformulated Tribact-PZ containing EDTA is not compatible with tobramycin for simultaneous coadministration via Y-site infusion. 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 Tribact-PZ 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 Tribact-PZ prolongs the half-life of piperacillin by 21% and that of tazobactam by 71%.

Vancomycin

No pharmacokinetic interactions have been noted between Tribact-PZ 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.

DOSAGE AND ADMINISTRATION

TRIBACT-PZ should be administered by intravenous infusion over 30 minutes.

The usual total daily dose of TRIBACT-PZ for adults is 3.375 g every six hours totaling 13.5 g (12.0 g piperacillin/1.5 g tazobactam).

Nosocomial Pneumonia

Initial presumptive treatment of patients with nosocomial pneumonia should start with TRIBACT-PZ at a dosage of 4.5 g every six hours plus an aminoglycoside, totaling 18.0 g (16.0 g piperacillin/2.0 g tazobactam). Treatment with the aminoglycoside should be continued in patients from whom Pseudomonas aeruginosa is isolated. If Pseudomonas aeruginosa is not isolated, the aminoglycoside may be discontinued at the discretion of the treating physician. Due to the in vitro inactivation of the aminoglycoside by beta-lactam antibiotics, TRIBACT-PZ and the aminoglycoside are recommended for separate administration. TRIBACT-PZ and the aminoglycoside should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated. In circumstances where co-administration via Y-site is necessary, reformulated TRIBACT-PZ containing EDTA supplied in vials or bulk pharmacy containers is compatible for simultaneous coadministration via Y-site infusion only with the following aminoglycosides under the following conditions:

Directions for Reconstitution and Dilution for Use

Intravenous Administration

For conventional vials, reconstitute TRIBACT-PZ per gram of piperacillin with 5 mL of a compatible reconstitution diluent from the list provided below. 4.5 g TRIBACT-PZ should be reconstituted with 20 mL, . Swirl until dissolved. Pharmacy vials should be used immediately after reconstitution. Discard any unused portion after 24 hours if stored at room temperature (20°C to 25°C [68°F to 77°F]), or after 48 hours if stored at refrigerated temperature (2°C to 8°C [36°F to 46°F]).

Compatible Reconstitution Diluents

0.9% Sodium Chloride for Injection Sterile Water for Injection‡ Dextrose 5% Bacteriostatic Saline/Parabens Bacteriostatic Water/Parabens Bacteriostatic Saline/Benzyl Alcohol Bacteriostatic Water/Benzyl Alcohol Reconstituted TRIBACT-PZ solution should be further diluted (recommended volume per dose of 50 mL to 150 mL) in a compatible intravenous solution listed below. Administer by infusion over a period of at least 30 minutes. During the infusion it is desirable to discontinue the primary infusion solution.

Compatible Intravenous Solutions

0.9% Sodium Chloride for Injection Sterile Water for Injection‡ Dextrose 5% Dextran 6% in Saline Lactated Ringer's Solution (Compatible only with reformulated TRIBACT-PZ containing EDTA) ‡Maximum recommended volume per dose of Sterile Water for Injection is 50 mL. TRIBACT-PZ should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established. TRIBACT-PZ is not chemically stable in solutions that contain only sodium bicarbonate and solutions that significantly alter the pH. TRIBACT-PZ should not be added to blood products or albumin hydrolysates. TRIBACT-PZ can be used in ambulatory intravenous infusion pumps.

Stability of TRIBACT-PZ Following Reconstitution

TRIBACT-PZ is stable in glass and plastic containers (plastic syringes, I.V. bags, and tubing) when used with compatible diluents. Pharmacy vials should be used immediately after reconstitution. Discard any unused portion after 24 hours if stored at room temperature (20°C to 25°C [68°F to 77°F]), or after 48 hours if stored at refrigerated temperature (2°C to 8°C [36°F to 46°F]). Vials should not be frozen after reconstitution. Stability studies in the I.V. bags have demonstrated chemical stability (potency, pH of reconstituted solution, and clarity of solution) for up to 24 hours at room temperature and up to one week at refrigerated temperature. TRIBACT-PZ contains no preservatives. Appropriate consideration of aseptic technique should be used. Stability of TRIBACT-PZ in an ambulatory intravenous infusion pump has been demonstrated for a period of 12 hours at room temperature. Each dose was reconstituted and diluted to a volume of 37.5 mL or 25 mL. One-day supplies of dosing solution were aseptically transferred into the medication reservoir (I.V. bags or cartridge). The reservoir was fitted to a preprogrammed ambulatory intravenous infusion pump per the manufacturer's instructions. Stability of TRIBACT-PZ is not affected when administered using an ambulatory intravenous infusion pump. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.