PRODUCT MONOGRAPH

Pr

Piperacillin for Injection, USP

2 g, 3 g, and 4 g Single-Use Vial 40 g Pharmacy Bulk Vial Antibiotic

ACTIONS AND CLINICAL PHARMACOLOGY

Piperacillin is a semi-synthetic b-lactam antibiotic which is bactericidal and exerts its antibacterial action by inhibiting both septum and cell-wall synthesis in the bacterial cell. Piperacillin was shown to have a particularly high affinity for PBP-3 and also a high affinity for PBP-1A, -1B and -2 of Escherichia coli and Pseudomonas. These results indicate that the enzymes involved in septum (PBP-3) and cell wall (PBP-1A, -1B) synthesis and in the maintenance of the shape (PBP-2) of the bacterium are the primary sites of action of piperacillin. Piperacillin is eliminated primarily (60 - 80%) by glomerular filtration and tubular secretion as unchanged drug in the urine. The mean elimination half-life is 54 minutes after the administration of 2 grams and 63 minutes following 6 grams. The elimination half-life is increased twofold in mild to moderate renal impairment and five- to six-fold in severe renal impairment.

CONTRAINDICATIONS

A history of allergic reactions to any of the penicillins and/or cephalosporins. Piperacillin for Injection, USP when reconstituted with Lidocaine for intramuscular use is contraindicated in patients with a known history of hypersensitivity to local anesthetics of the amide type.

WARNINGS

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with penicillins. These reactions are more apt to occur in persons with a history of sensitivity to multiple allergens. Cross-sensitivity of patients to penicillins and cephalosporins has been reported. Before initiating therapy with Piperacillin for Injection, USP, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins and other allergens. If an allergic reaction occurs, the antibiotic should be discontinued. The usual agents (antihistamines, pressor amines and corticosteroids) should be readily available. SERIOUS ANAPHYLACTOID REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS NECESSARY. Antibiotic-associated pseudomembranous colitis has been reported with nearly all antibacterial agents, including piperacillin, and may range in severity from mild to life-threatening. It is important to consider this diagnosis if significant diarrhea or colitis occurs during therapy. Mild cases usually respond to drug discontinuation alone. However, in moderate to severe cases, management with fluids and electrolytes, protein supplementation and treatment with an oral antibacterial drug effective against Clostridium difficile (e.g., oral vancomycin) should be considered.

PRECAUTIONS

While Piperacillin for Injection, USP possesses the characteristic low toxicity of the penicillin group of antibiotics, it is advisable to check periodically for organ dysfunction (including renal, hepatic and hematopoietic) during prolonged therapy. Bleeding manifestations have occurred in some patients receiving b-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 or significant leukopenia occur, Piperacillin for Injection should be discontinued and appropriate therapy instituted. The possibility of the emergence of resistant organisms and the development of 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 of Piperacillin for Injection are given intravenously. Since piperacillin is excreted not only renally but also by the biliary route, it can be used at reduced dosage (see DOSAGE AND ADMINISTRATION) in patients with severely restricted kidney function and in those who have had nephrotoxic reactions to other drugs. Piperacillin for Injection is a monosodium compound containing 1.85 milliequivalents (42.5 mg) of Na+ per gram based on molecular weight (see PHARMACEUTICAL INFORMATION). 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, receiving cytotoxic therapy or diuretics. Electrolyte and cardiac status should also be monitored during prolonged treatment in patients with impaired cardiac function. Antimicrobials used in high doses for short periods to treat gonorrhea may mask or delay the symptoms of incubating syphilis. Therefore, prior to treatment, patients with gonorrhea should also be evaluated for syphilis. Specimens for darkfield examination should be obtained from patients with any suspected primary lesion, and serologic tests should be performed. In all cases where concomitant syphilis is suspected, monthly serological tests should be made for a minimum of 4 months. The use of some penicillins (ampicillin, amoxicillin) has been associated with morbilliform rashes in some cases of infectious mononucleosis. Piperacillin for Injection should be used with caution, therefore, in the treatment of infections caused by susceptible organisms in patients with infectious mononucleosis. As with other semisynthetic penicillins, Piperacillin for Injection therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients. Because of chemical instability, Piperacillin for Injection should not be used for intravenous administration with solutions containing only sodium bicarbonate (see INCOMPATIBILITY section). Piperacillin for Injection should not be added to blood products.

Drug Interactions

The mixing of Piperacillin for Injection with an aminoglycoside in vitro can result in substantial inactivation of the aminoglycoside. Concurrent administration of probenecid results in higher and more prolonged serum levels of piperacillin. Whenever Piperacillin for Injection is administered concurrently with another antibiotic, the drugs should not be mixed in the same solution but must be administered separately. Piperacillin, when used clinically in the early postoperative period, has been implicated in the prolongation of the neuromuscular blockage of vecuronium. In a controlled clinical study, the ureidopenicillins including piperacillin have been reported to prolong the action of vecuronium. Caution is indicated when piperacillin is used perioperatively with vecuronium and similar neuromuscular blocking agents.

Usage During Pregnancy or Lactation

Although reproduction studies in mice and rats performed at doses up to 4 times the human dose have shown no evidence of impaired fertility or harm to the fetus, safety of piperacillin use in pregnant women has not been determined. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. It has been found to cross the placenta in rats. Caution should be exercised when Piperacillin for Injection is administered to nursing mothers. It is excreted in low concentrations in milk.

Pediatric Use

Dosage for children under the age of 12 has not been established.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Other than general supportive treatment, no specific antidote is known. Excessive serum levels of piperacillin may be reduced by hemodialysis. As with other penicillins, neuromuscular excitability or convulsions have occurred following large intravenous doses. General supportive measures, including administration of phenytoin and barbiturates or other anticonvulsant drugs may be considered. Daily doses of piperacillin of at least 24 g have been administered to humans without observation of adverse effects. For treatment of hypersensitivity reactions, see WARNINGS. DOSAGE AND ADMINISTRATION

Dosage

Piperacillin for Injection, USP may be administered intramuscularly or intravenously (either in a 3 to 5 minute injection or by infusion). Dosage and route of administration should be determined by the severity of the infection and condition of the patient. The usual dosage of Piperacillin for Injection for serious infections is 3 to 4 g given every 4 to 6 hours as a 20 to 30 minute infusion. For serious infections the intravenous route should be used. The maximum daily dose usually administered to adults is 24 g/day, although higher doses have been used.

Dosage Recommendations

One gram of probenecid given orally 1/2 hour prior to injection.

N/A * * No adjustment necessary * * * Hemodialysis removes 30 - 50% of the drug in 4 hours; an additional dose of 1 g of Piperacillin for Injection should be administered following each dialysis period. For patients with renal failure, hepatic insufficiency or biliary tract obstruction measurement of serum levels of Piperacillin for Injection will provide additional guidance for adjusting dosage.

Infants and Children

Dosages in infants and children under 12 years of age have not been established.

Duration of Therapy:

The average duration of Piperacillin for Injection treatment is from 7 to 10 days, except in the treatment of gynecologic infections, in which it is from 3 to 10 days; the duration should be guided by the patient's clinical and bacteriological progress. Some infections such as osteomyelitis may require significantly longer periods of therapy. For most acute infections, treatment should be continued for at least 48 to 72 hours after the patient becomes asymptomatic. Antibiotic therapy for Group A b-hemolytic streptococcal infections should be maintained for at least 10 days to reduce the risk of rheumatic fever or glomerulonephritis.

Administration

Intramuscular Injection:

Intramuscular injections should be limited to 2 g per injection site. This route of administration has been used primarily in the treatment of patients with uncomplicated gonorrhea and urinary tract infections. Injection should be given into the upper outer quadrant of the buttock (i.e., gluteus maximus). When indicated by clinical and bacteriological findings, intramuscular administration of 6 to 8 g daily of Piperacillin for Injection, USP, in divided doses, may be utilized for initiation of therapy. In addition, intramuscular administration of the drug may be considered for maintenance therapy after clinical and bacteriological improvement has been obtained with intravenous Piperacillin for Injection treatment. The deltoid area should be used only if well-developed, and then only with caution to avoid radial nerve injury. Intramuscular injections should not be made into the lower or mid-third of the upper arm.

Intravenous Injection (Bolus):

Reconstituted solution should be injected slowly over a 3 to 5 minute period to help avoid vein irritation.

Intravenous Infusion:

Infusion should be carried out over a period of about 20 - 40 minutes or intermittent infusion over a 30 minute to 2 hour period. During infusion it is desirable to discontinue the primary intravenous solution.

PHARMACEUTICAL INFORMATION

Drug Substance

Common Name:

piperacillin sodium

Chemical Name:

6-[[[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino] phenylacetyl]amino]-3,3-dimethly-7-oxo-4-thia-1- azabicyclo[3.2.0]heptane-2-carboxylic acid, monosodium salt.

Structural Formula:

Molecular Formula: C23H26N5NaO7S

Molecular Weight:

539.54

Description:

Piperacillin sodium is a white to off-white hygroscopic, crystalline powder which is readily soluble in water and gives a colourless to pale-yellow solution. The pH of the aqueous solution is 5.5 to 7.5. The melting point is about 185degC to 187degC. It is very soluble in water, slightly soluble in ethanol, very slightly soluble in acetone, and practically insoluble in chloroform and in ether.

Composition: Vials contain piperacillin sodium equivalent to the labelled amount of piperacillin. The sodium content (Na+), based on the molecular weight is 1.85 mEq/g (42.5 mg/g).

Piperacillin for Injection 2 g/vial:

each vial contains piperacillin sodium equivalent to piperacillin 2 g.

Piperacillin for Injection 3 g/vial:

each vial contains piperacillin sodium equivalent to piperacillin 3 g.

Piperacillin for Injection 4 g/vial:

each vial contains piperacillin sodium equivalent to piperacillin 4 g.

Piperacillin for Injection 40 g/vial:

each vial contains piperacillin sodium equivalent to piperacillin 40 g.

STABILITY AND STORAGE RECOMMENDATIONS

Piperacillin for Injection vials should be stored at controlled room temperatures, between 15 and 30degC. Piperacillin for Injection 2 g/vial, 3 g/vial and 4 g/vial are single-use vials; discard unused portion. Piperacillin for Injection 40 g/vial is a Pharmacy Bulk Vial intended for multiple dispensing for Intravenous Use Only, employing a single puncture. Use reconstituted stock solutions within 8 hours.

RECONSTITUTION

For Intramuscular Use

Solutions for Reconstitution:

Sterile Water for Injection, USP

Shake well until dissolved.

Note

: Intramuscular injections should be limited to 2 g per injection site. Injection should be given into the upper outer quadrant of the buttock (i.e., gluteus maximus).

For Intravenous Injection or Infusion

For intravenous injection or infusion, reconstitute Piperacillin for Injection with Sterile Water for Injection, USP.

Shake well until dissolved. The prepared solution may be further diluted to the desired volume (at least 15 mL/g for infusion) with any Intravenous Solutions listed below.

Pharmacy Bulk Vial

THE AVAILABILITY OF THE PHARMACY BULK VIAL IS RESTRICTED TO HOSPITALS WITH A RECOGNIZED INTRAVENOUS ADMIXTURE PROGRAM.

Directions for Dispensing from Pharmacy Bulk Vial:

The Pharmacy Bulk Vial is intended for multiple dispensing for Intravenous use only, employing a single puncture. Following reconstitution, the solution should be further diluted to the desired volume in any appropriate intravenous solution of Intravenous Admixture listed below. Use reconstituted stock solutions within 8 hours and further diluted solutions within 24 hours at room temperature or 72 hours if refrigerated.

Intravenous Solutions

5% Dextrose Injection, USP (D5W) 0.9% Sodium Chloride Injection, USP (NORMAL SALINE) [NS] 5% Dextrose and 0.9% Sodium Chloride Injection, USP (D5NS) Lactated Ringer's Injection, USP Note: Because of chemical instability, Piperacillin for Injection, USP should not be used for intravenous administration with solutions containing only sodium bicarbonate. (See INCOMPATIBILITY section.)

STABILITY OF SOLUTIONS

Stability studies have demonstrated chemical stability (pH, potency and clarity) through 24 hours at room temperature and up to 72 hours refrigerated. Piperacillin for Injection is stable in PVC containers when reconstituted with recommended diluents and further diluted with the indicated intravenous solutions.

INCOMPATIBILITY

Piperacillin for Injection, USP should not be added to blood products. Because of chemical instability, Piperacillin for Injection should not be used for intravenous administration with solutions containing only sodium bicarbonate. As with all parenteral products, intravenous admixtures should be inspected for clarity of solutions, particulate matter, precipitate, discolouration, and leakage prior to administration whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used. Discard unused portion.

AVAILABILITY OF DOSAGE FORMS

Piperacillin for Injection (sterile piperacillin sodium) is available in vials containing amounts of piperacillin sodium equivalent to 2, 3 and 4 grams of piperacillin. Available in boxes of 10 vials. Also available in a pharmacy bulk vial containing piperacillin sodium equivalent to 40 g of piperacillin. Available in boxes of single-use vials. Product Code: 8685 10 x 2 g single-use vials 8690 10 x 3 g single-use vials 8695 10 x 4 g single-use vials 8698 1 x 40 g Pharmacy Bulk Vial Vial stoppers do not contain natural rubber latex.

MICROBIOLOGY

Piperacillin is a bactericidal, semi-synthetic penicillin with a broad spectrum of activity, encompassing both gram-negative and gram-positive anaerobic and aerobic organisms. TABLE 1 lists the minimal inhibitory concentrations (MICs) of Piperacillin for Injection for 47,119 clinical isolates tested in vitro.

TABLE 1

In Vitro

Activity of Piperacillin against 47,119 Clinical Isolates

% of Isolates Inhibited by (Fq/mL)

No. of Isolates Tested

% of Isolates Inhibited by (Fq/mL)

1 * * 8 16 32 64 128

*Includes strains of both b-lactamase positive and negative bacteria

* * Values at 1 mcg/mL given only for those species for which this is the recommended breakpoint.

Several investigators have shown that, for about 80% of clinical isolates of both gram-negative and gram-positive bacteria that were tested, the minimum bactericidal concentration (MBC) of piperacillin was equal to or at most twice the MIC. For the majority of the remaining 20% of isolates, the MBC/MIC ratio is 4/1. Overall, the MBC/MIC ratio of piperacillin is similar to that of the aminoglycosides. Piperacillin kills isolates of Pseudomonas at about the same rate as cefoperazone and is 2- to 4- fold more active than moxalactam. Table 2 lists the susceptibility of 9,725 clinical isolates of gram-negative aerobic and anaerobic isolates to piperacillin. The data were obtained during 1988 from 11 geographically distinct hospital laboratories throughout the United States. Susceptibility studies of gram-positive pathogens to piperacillin were not included in this study.

TABLE 2

In Vitro

Activity of Piperacillin against 9,725 Clinical Isolates

S = Susceptible, I = Intermediate, R = Resistant

In vitro

, piperacillin is active against most strains of clinical isolates of the following microorganisms:

Aerobic and faculatively anerobic organisms

Gram-negative bacteria:

Escherichia coli Proteus mirabilis Proteus vulgaris *

Morganella morganii *

(formerly Proteus morganii)

Providencia rettgeri *

(formerly Proteus rettgeri)

Serratia spp. including S. marcescens * and S. Liquefaciens * Klebsiella pneumoniae *

Klebsiella

spp.

Enterobacter spp. including E. aerogenes * and E. cloacae * Citrobacter spp. including C. freundii * and C. diversus * Salmonella spp. *

Shigella

spp. *

Pseudomonas aeruginosa

Pseudomonas spp. including P. cepacia *, P. maltophilia *, P. fluorescens * Acinetobacter spp. (formerly Mima-Herellea)

Haemophilus influenzae (non-b-lactamase-producing strains)

Neisseria gonorrhoeae Neisseria meningitidis * Moraxella spp. *

Yersinia spp. * (formerly Pasteurella)

Gram-positive bacteria:

Group D Streptococci including Enterococci (streptoceccus faecalis, S. faecium *)

b-hemolytic streptococci including Group A Streptococcus (S. pyogenes *) Group B Streptococcus (S. agalactiae *) Streptococcus pneumoniae Streptococcus viridans *

Staphylococcus aureus (non-penicillinase-producing) * Staphylococcus epidermidis (non-penicillinase-producing) * Anaerobic bacteria:

Bacteroidea spp. including B. fragilis group (B. fragilis, B. vulgatus *) Non-B fragilis group (B. melaninogenicus *)

B asaccharolyticus

Clostridium spp. including C. perfringens * and C. difficile * Eubacterium spp. *

Fusobecterium spp. * including F. necleatum * and F. necrophorum * Peptococcus spp. *

Peptostreptococcus spp. * Veillonelle spp. * Piperacillin has been shown to be active in vitro against these organisms; however, clinical efficacy has not been established. Piperacillin can be inactivated in vitro by (b-lactamases produced by some strains of gram- negative and staphylococcal bacteria, however, it was found to be active against b-lactamase- producing gonococci.

In vitro testing of piperacillin combinations with gentamicin, tobramycin or amikacin shows a high incidence of synergistic action against strains of Pseudomonas, Serratia, Klebsiella, Proteus (indole-positive), Providencia and Staphylococcus species. Against other organisms, including strains of Enterobacter and Acinetobacter, partial synergy or indifference was noted. Overall, the data suggest that such combinations have clinical potential in the treatment of severe infections caused by these organisms. Combinations of piperacillin with cephalosporin antibiotics may result in synergistic, additive, indifferent, or antagonistic effects. The effect appears to depend on the cephalosporin and the type of organism tested. Against strains of Klebsiella, Escherichia coli, Acinetobacter, Proteus mirabilis, Salmonella, enterococci, and Staphylococcus aureus, combinations of piperacillin with cefamandole or cefoxitin had synergistic, additive, or indifferent but no antagonistic effects. However, against Pseudomonas, Enterobacter, Serratia, and indole-positive Proteus strains, combinations of piperacillin with cefoxitin had a high frequency of antagonistic effects; combinations of piperacillin with cefamandole had additive or indifferent effects and a low frequency of antagonism. Tests in mice reflect the in vitro observations. Piperacillin combinations with moxalactam, cefotaxime or cefoperazone have shown some limited in vitro synergy (18 - 25 % of isolates tested) against Pseudomonas aeruginosa and Serratia marcescens. The data indicate that piperacillin-cephalosporin combinations may have clinical advantages but that susceptibility tests should be conducted.

SUSCEPTIBILITY TESTS

The use of a 100 mcg piperacillin disc with susceptibility test methods which measure zone diameter gives an accurate estimation of in vitro susceptibility of organisms to piperacillin. The following standard procedure has been recommended for use with discs for testing antimicrobials. * Piperacillin 100 mcg discs should be used for the determination of the susceptibility of organisms to piperacillin. With this type of procedure, a report of "susceptible" from the laboratory indicates that the infecting organism is likely to respond to therapy. A report of "intermediate susceptibility" suggests that the organism would be susceptible if high dosage is used or if the infection is confined to tissue and fluids (e.g., bile, urine) in which high antibiotic levels are obtained. A report of "resistant" indicates that the infecting organism is not likely to respond to therapy. With the piperacillin disc, a zone of 18 mm or greater indicates susceptibility, zone sizes of 14 mm or less indicate resistance, and zone sizes of 15 to 17 mm indicate intermediate susceptibility. (See TABLE 3.) NCCLS Approved Standard: M2-A3 (Formerly ASM-2) Performance Standards for Antimicrobial Disc Susceptibility Tests, Third Edition.

Haemophilus, Neisseria and Staphylococcus species which give zones of >= 29 mm are susceptible; resistant strains give zones of <= 28 mm. The above interpretive criteria is based on the use of the standardized procedure. Antibiotic susceptibility testing requires carefully prescribed procedures. Susceptibility tests are biased to a considerable degree when different methods are used. The standardized procedure requires the use of control organisms. The 100 mcg piperacillin disc should give zone diameters between 24 and 30 mm for Escherichia coli ATCC No. 25922 and between 25 and 33 mm for Pseudomonas aeruginosa ATCC No. 27853. Dilution methods such as those described in the International Collaboration Study+ and the NCCLS Approved Standard++ have been used to determine susceptibility of the following organisms: Enterobacteriaceae, Pseudomonas species and Acinetobacter species are considered susceptible if the minimal inhibitory concentration of piperacillin (MIC) is no greater than 16 mcg/mL, and are considered resistant if the MIC is greater than 128 mcg/mL.

Haemophilus and Neisseria species are considered susceptible if the MIC of piperacillin is less than or equal to 1 mcg/mL. Staphylococcus species are considered susceptible if the MIC of piperacillin is less than or equal to 0.12 mcg/mL. (See TABLE 4.) When anaerobic organisms are isolated from infection sites, it is recommended that other tests such as the modified Broth-Disk+++ method be used to determine the antibiotic susceptibility of these slowly-growing organisms.

+

Acta Pathologica et Microbiologica Scandinavica, Section B Suppl. 217, 1971.

++

NCCLS Approved Standards: M7-A Methods for Dilution, Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, December, 1985.

+++

Wilkins, T.D., and Thiel, T. Antimicrob. Agents Chemother. 3:350-356 (March) 1973.

TABLE 3

In Vitro

Susceptibility as Measured with 100 mcg Piperacillin Discs

When minimal inhibitory concentrations (MIC) are determined by standard dilution methods+, the guidelines given in TABLE 4 are suggested.

+

Acta Pathologica et Microbiologica Scandinavica, Section B Suppl. 217, 1971.

TABLE 4

In Vitro

Susceptibility as Measured by the Broth or Agar Dilution Method

PHARMACOLOGY

Peak serum concentrations of piperacillin are attained approximately 30 minutes after intramuscular injection and immediately after intravenous injection or infusion. The serum half- life in healthy volunteers ranges from 36 minutes to 1 hour and 12 minutes. Serum levels after intravenous administration (see Table 5) and renal clearance do not show dose proportionality because of saturation of the renal secretory mechanism.

TABLE 5

Piperacillin Serum Levels in Healthy Adults (mcg/mL)

Note

: Following a 30 minute infusion of 6 g every 6 hours, on the fourth day, mean peak serum concentrations were 420 mcg/mL.

Intramuscular Administration

(see Table 5 above)

Piperacillin for Injection is rapidly absorbed after intramuscular injection. In healthy volunteers, the mean peak serum concentration occurs approximately 30 minutes after a single dose of 2 g and is about 36 mcg/mL. The oral administration of 1 g probenecid before injection produces an increase in piperacillin peak serum level of about 30%. The area under the curve (AUC) is increased by approximately 60%. The substitution of 0.5% lidocaine for Sterile Water as a diluent in an intramuscular pharmacokinetic study showed no significant difference in the area under the serum concentration curve, peak serum concentration or cumulative urine excretion of piperacillin. However, the serum half-lives were prolonged from 67 to 70 minutes at 3 g/day, 56 to 68 minutes at 4 g/day and 52 to 59 minutes at 6 g/day.

Intravenous Administration

(see Table 5 above)

In healthy adult volunteers, mean serum levels immediately after a two to three minute intravenous injection of 2, 4 or 6 g were 305, 412, and 775 mcg/mL. Serum levels lack dose proportionality.

Protein Binding

Piperacillin binding to human serum proteins is 16%.

Distribution

Piperacillin is widely distributed in human tissues and body fluids, including bone, prostate, and heart and reaches high concentrations in bile (see TABLE 6). After a 4 gram bolus, maximum biliary concentrations averaged 3,205 mcg/mL. It penetrates into the cerebrospinal fluid in the presence of inflamed meninges. Because Piperacillin for Injection is excreted by the biliary route (10 - 20%) as well as by the renal route, it can be used safely in appropriate dosage (see

DOSAGE AND ADMINISTRATION

) in patients with mild to severe renal impairment and can be used in treatment of hepato-biliary infections.

TABLE 6

Distribution of Piperacillin in

Adult Human Body Tissues and Fluids

NOT GIVEN

Excretion

As with other penicillins, piperacillin is eliminated primarily by glomerular filtration and tubular secretion; it is excreted rapidly as unchanged drug in high concentrations in the urine. Approximately 60% to 80% of the administered dose is excreted in the urine in the first 24 hours. Piperacillin urine concentrations, determined by microbioassay, were as high as 14,100 mcg/mL following a 6 g intravenous dose and 8,500 mcg/mL following a 4 g intravenous dose. These urine drug concentrations remained well above 1,000 mcg/mL throughout the dosing interval. The elimination half-life is increased two-fold in mild to moderate renal impairment and five-to- six-fold in severe impairment. The mean elimination half-life of piperacillin in healthy adult volunteers is 54 minutes following administration of 2 g and 63 minutes following 6 g.

Miscellaneous

Pharmacokinetic characteristics in patients with cystic fibrosis are somewhat different than in normal subjects in that, in the former, piperacillin has a shorter half-life, a decreased volume of distribution and an increase in clearance. These differences suggest the need for either increased dosages or shortened dosage intervals in patients with cystic fibrosis. While piperacillin reduces platelet aggregation, these effects are less than those caused by ticarcillin or carbenicillin at equivalent therapeutic dosage. There was no significant inactivation of amikacin, gentamicin or tobramycin in serum when the aminoglycoside was administered concomitantly with carbenicillin or piperacillin to subjects with normal renal function. In the urine, lowering of the concentration of tobramycin, and gentamicin to a lesser degree, by the presence of carbenicillin or piperacillin was observed. This possible inactivation effect was greater with carbenicillin than with piperacillin. No urinary inactivation of amikacin by either of these penicillins was observed. The clinical significance of these observations is unknown. A follow-up study was conducted in patients with end-stage renal failure stabilized on chronic intermittent hemodialysis. No inactivation of piperacillin or carbenicillin in these patients was observed when gentamicin was administered concomitantly with either of these penicillins. Carbenicillin and piperacillin, however, inactivated gentamicin in these patients. Gentamicin was inactivated 4 times faster by carbenicillin than by piperacillin.

TOXICOLOGY

Acute Toxicity

The acute median lethal dose (LD50) in rats vas 2 - 3 g/kg (i.v. ), 7 - 10 g/kg (i.p. ), > 10 g/kg (s.c.) in 6 and 12 week old rats, and 9 g/kg (s.c.) in 1 week old rats; in mice, the LD50 vas 5 g/kg (i.v. ), > 10 g/kg (s.c.) and 10 g/kg (i.p. ). Single intravenous doses of 2 and 4 g/kg were well tolerated in the dog with no changes in biochemical or hematological parameters. Signs of toxicity at 6 g/kg (i.v.) included emesis, diarrhea, salivation, and lacrimation. Slight to moderate increases in SGOT and SGPT values, white blond tell counts, and neutrophil-to-lymphocyte ratios were noted 1 day after dosing. A single 4 g/kg intravenous dose in the monkey produced similar biochemical and hematological changes and, in addition, moderate increase in lactic dehydrogenase and decreases in red blond cell counts.

Subacute and Chronic Toxicity

Rats given daily intraperitoneal doses of piperacillin (0.5 - 2 g/kg/day for 6 months and 1 - 4 g/kg/day for 1 month) showed no toxic effects except for reduced body weight gain in females at 4 g/kg/day only and in males at all dose levels. Similar findings, plus evidence of renal damage, were seen in rats given ampicillin (2 g/kg/day for 1 month). In rats given 1, 2 or 4 g/kg twice daily intraperitoneally for 6 months, all showed an increase in lymphocytes at 4 and 6 months. At post-mortem all animals had unilateral hydronephrosis and some had urinary bladder urothelial hyperplasia, probably due to local irritation. Dogs were given piperacillin for 1 month (up to 1 g/kg/day) i.m. (compared with ampicillin) and i.v. (alone and with gentamicin) and for 6 months (up to 2 g/kg/day i.v. ). Transient increases in blond serum enzyme values, increases in kidney and liver weights, and mild local irritation at the injection site were seen in the 1-month i.m. study in both piperacillin- and ampicillin-treated dogs. No other toxic effects were seen in the adult dog studies and there was no synergistic toxicity when piperacillin was combined with gentamicin.

Special Toxicitv Studies

Daily intravenous administration of 0.5 - 1 g/kg/day for 1 month in the rat did not cause loss of pinna reflex (as a measurement of ototoxic effect) at any frequency from 200 - 20,000 Hz. In 4 dogs, daily administration of 2 g/kg intravenously for 1 month resulted in no drug-induced changes in liver or kidney on electron microscopic examination. The same animals showed no eye abnormalities observable by gross examination or direct ophthalmoscopy.

Reproduction and Teratology

Subcutaneous or intravenous administration of piperacillin sodium (0.5, 1 or 2 g/kg) to mice prior to mating (and in females extending into early gestation), during the period of organogenesis, or during late gestation and through the lactation period, had no adverse effect on reproductive success or the development of offspring. Survival rates, weaning rates and body weights were higher in offspring of treated dams than controls. In rats, with the possible exception of a slight decrease in the survival rate of pups of high-dose dams, subcutaneous administration of 0.25 - 1 g/kg of piperacillin sodium during the period of organogenesis had no adverse effects on reproductive success or the development of offspring. Intraperitoneal doses of 0.5, 1.0, and 2.0 g/kg/day, given to rats (males for 9 weeks prior to mating and females for 2 weeks prior to mating and until the offsprings were weaned) had no adverse effects except at the 2 g/kg/day dose level where longer precoital time and a lower pregnancy rate were noted; no firm conclusions can be drawn. In the offspring of these animals, no adverse effects regarding early neonatal development, fertility and reproductive performance attributable to treatment of the parents with piperacillin sodium were demonstrated. In rabbit teratology range finding studies, intravenous doses of 0.25 to 1 g/kg/day of piperacillin sodium from day 6 to 18 of gestation produced marked decreases in food intake and body weight. Maternal mortality and intrauterine deaths were high in all treatment groups; however, fetuses which did survive had no external morphologic abnormalities. Similar results were seen in dams dosed with 1 g/kg/day (single dose or 0.5 g/kg b.i.d.) from day 6 to 8 of gestation.

Mutagenicity

Piperacillin was non-mutagenic in in vivo cytogenetics, Ames Test, Host-Mediated (mouse) assay, Induction of Unscheduled DNA Synthesis, and Dominant Lethal test systems.

Local Irritation

An injection of 0.05 mL of 250 - 500 mg/mL piperacillin given intracutaneously in the rat produced local reaction similar to ampicillin and carbenicillin. In the rabbit eye, a single 0.1 in L instillation of 500 mg/mL piperacillin produced no changes at 24 or 72 hours. Single or multiple intramuscular injections of piperacillin 25, 35 or 40% in Sterile Water were similar to or less irritating than carbenicillin in rabbits. Single or multiple injections of piperacillin 25 or 40% solutions in either saline (with and without lidocaine) or Sterile Water (with and without lidocaine) were generally well tolerated, though aqueous solutions were better tolerated than saline solutions. Single injections of piperacillin 40% solution in saline or Sterile Water solution with lidocaine were better tolerated than 2.5% solutions of tetracycline HCl. In another rabbit study 0.05 mL of a 200 mg/mL solution was injected into an occluded auricular vein for 3 minutes, three times daily for three days. Piperacillin was somewhat less irritating than the carbenicillin or ampicillin controls when incidence, onset or length of thrombus were compared.

Effects on Blood

Concentrations up to 500 mg/mL piperacillin sodium did not produce hemolysis of rabbit erythrocytes in vitro; using human erythrocytes hemolysis was produced at concentrations higher than 240 mg/mL. Ampicillin and carbenicillin produced hemolysis at concentrations of 200 mg/mL and higher with human erythrocytes. Bleeding time in mice was unchanged at i.v. doses of 250 mg/kg piperacillin sodium, but increased at doses of 500 and 1,000 mg/kg. Increases were seen with 1,000 mg/kg of ampicillin and carbenicillin. Neither piperacillin sodium, ampicillin nor carbenicillin affected rabbit blood prothrombin and partial thromboplastin time in vitro at 10-5 to 10-3 g/mL; all compounds prolonged PT and PTT at 10-2 g/mL. IV doses of 0.5 or 1.0 g/kg of the same compounds did not affect PT but decreased PTT. Concentrations of piperacillin sodium, ampicillin and carbenicillin from 10-5 to 10-3 g/mL did not affect platelet aggregation induced by adenosine diphosphate or collagen; all compounds inhibited aggregation at a concentration of 10-2 g/mL.

Possible Immune Responses

No skin sensitization occurred with doses of 1, 5, and 10 mg/0.5 mL of piperacillin sodium in guinea pigs. No signs of anaphylaxis were seen in guinea pigs at doses of 3 to 150 mg/kg. Protein conjugates of piperacillin sodium produced only slightly positive Arthus reactions after subcutaneous injection in rabbits. Cross reactivity (passive cutaneous anaphylaxis) of piperacillin sodium with ampicillin or penicillin G was weak, displaying 1/8 and 1/16 of the titers from the homologous antigen-antibody systems.

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