Data Sheet

PIPERACILLIN

Piperacillin as 1g, 2g and 4g injections.

Presentation

Piperacillin sodium as equivalent to piperacillin 1g, 2g and 4g injections: white to off-white hygroscopic , lyophilised, crystalline powder packed in white, transparent glass vials. It is readily soluble in water and gives a colourless to pale- yellow solution.

Uses

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PIPERACILLIN is a broad spectrum semisynthetic penicillin bactericidal against Gram-positive and Gram-negative aerobic and anaerobic organisms. PIPERACILLIN exerts its bactericidal action by inhibiting cell septum and wall synthesis.

PIPERACILLIN is active in-vitro against most strains of the following clinically important organisms:

Gram-negative bacteria:

Escherichia coli, Proteus mirabilis, Proteus (indole positive) , Salmonella sp ., Pseudonmonas sp., Pseudomonas aeruginosa, Serratia sp., Acinetobacter sp., Klebsiella pneumoniae, Haemophilus influenzae ( non-β-lactamase-producing strains), Enterobacter sp., Citrobacter sp., Neisseria gonorrhoea, Neisseria meningitidis.

Gram-positive bacteria:

Enterococci (Streptococcus faecalis, S. faecium), Streptococcus viridans, Staphylococcus aureus ( non-β-lactamase-producing), β-haemolytic streptococci incl. Group A Streptococcus (S. pyogenes) Group B Streptococcus (S. agalactiae), Streptococcus pneumonia, Staphylococcus epidermidis ( non-β-lactamase-producing).

Anaerobes:

Bacteroides species including the B. fragilis group, Fusobacterium sp., Peptococcus sp., Peptostreptococcus sp., Clostridium sp., Veillonella sp., Eubacterium sp.

Bacterial in-vitro susceptibilities cannot be reliably translated into clinical efficacy.

In-vitro, piperacillin is inactivated by β-lactamases produced by staphylococci and by some Gram-negative bacteria. However, it is active against β-lactamase producing gonococci. Methicillin resistant strains of Staphylococcus aureus are resistant to piperacillin.

Many strains of Gram-negative microorganisms, including Pseudomonas species resistant to ampicillin, carbenilcillin, cefalothin or aminoglycosides, are susceptible to piperacillin.

Susceptibility Tests:

The use of antibiotic disc susceptibility test methods that measure zone diameter gives an accurate estimation of susceptibility of organisms to PIPERACILLIN.

The following standard procedure is recommended for use with 100mcg piperacillin discs:

*NCCLS M2-A2 (Formerly ASM-2): Approved Performance Standard for Antimicrobial Disk Susceptibility Tests, Second Edition. (Available from NCCLS, Lancaster Avenue, Villanova, Pa. 19085 USA).

The guidelines shown in Table 1 are recommended when this method* is employed.

A report of 'susceptible' indicates that the infecting organism is likely to respond to therapy. A report of 'intermediate' suggests that the organism would be susceptible if high dosage is used or if the infection is confined to tissue and fluids (eg. Urine) in which high antibiotic levels are obtained. A report of 'resistant' indicates that the infecting organism is not likely to respond to therapy.

The NCCLS standardised procedure requires the use of control organisms. The 100mcg piperacillin disc should give zone diameters between 24 and 30mm for Escherichia coli ATCC No. 25922 and between 25 and 33mm for Pseudomonas aeruginosa ATCC No. 27853.

Dilution methods such as those used described in the international Collaborative Study** have been used to determine susceptibility of organisms to PIPERACILLIN.

** Acta Pathalogica et Microbiologica Scandinavia,Section B. Suppl. 217 (1971).

When minimal inhibitory concentrations (MIC) are determined by these procedures, the guidelines in Table 2 are suggested.

When anaerobic organisms are isolated from infection sites, it is recommended that other tests such as the modified Broth-Disc Method*** be used to determine the antibiotic susceptibility of these slowly-growing organisms.

*** Wilkins, T.D., Thiel , T. Antimicrob Agents Chemother 3.350-356 (1973).

Pharmacokinetics

PIPERACILLIN can be administered either intramuscularly or intravenously. It is not absorbed when given orally. As shown in Table 3, peak human serum levels are attained about 30 minutes after intramuscular injection and immediately upon completion of intravenous injection or infusion.

The serum half-life of piperacillin in healthy adults ranges between 36 and 72 minutes. The mean elimination half-life of piperacillin in healthy adults is approximately 60 minutes and is increased 2-fold in mild to moderate renal impairment and 5- to 6- fold in severe impairment.

The half-life of PIPERACILLIN in neonates (ca. 220 minutes) is much longer than that for adults (ca. 60 minutes). The half-life of children between 2 months and 2 years of age (ca. 42 minutes) is somewhat less than that seen in normal adults. The half-life in children between 2-6 months is approximately 50 minutes. The half-life in children 2-12 years of age (ca. 35 minutes) is approximately half the adult value.

As with other penicillins, PIPERACILLIN is eliminated primarily by glomerular filtration and tubular secretion. Approximately 60-80% appears in the urine in 24 hours. Except in cases with urinary tract infection, piperacillin is excreted unchanged, reaching mean concentrations in excess of 3000 mg/ml after a single 2 gram intramuscular dose (0-2 hour collection period); urinary levels still remain in the range of 66-920 mg/ml during the 6-12 hour collection period. In the presence of urinary tract infection, piperacillin appears to undergo some bacterial degradation.

Piperacillin binding to human serum protein is low (16%). It is widely distributed in human tissues and body fluids including bone, heart, prostate, bronchial secretions and bile. In bile, taken from the common bile duct, maximal levels ranging from 980 to 4987 mcg/ml were achieved within the first two hours after administration of a 4 gram intravenous injection. Levels in gall bladder bile are considerably lower.

*Value at 5.5 hours.

** In the case of infusion, time after completion of 30 minutes infusion.

Patients with either liver or renal disease require reduced doses of piperacillin to achieve therapeutic plasma concentrations.

However dose dependent piperacillin elimination is due to capacity limited renal excretion rather than saturable hepatic biotransformation or biliary excretion.

Data to support dosage adjustment in hepatically impaired patients are unsubstantiated. Due to the broad spectrum activity and wide distribution in tissues and fluids, piperacillin can be used safely and effectively in the treatment of patients with hepatobiliary infections.

Indications

PIPERACILLIN is indicated for the treatment of systemic and local infections due to susceptible Gram-negative and Gram-positive aerobic and anaerobic bacteria.

Its efficacy has also been demonstrated in infections caused by some carbenicillin resistant organisms. Appropriate cultures should be made before initiating treatment. Therapy may be started while awaiting results of susceptibility testing. Treatment should be adjusted, if necessary, when results of testing become available.

PIPERACILLIN is indicated for prophylactic use in surgery including intra-abdominal (gastrointestinal and biliary) procedures, vaginal hysterectomy, abdominal hysterectomy and caesarean section. Effective prophylactic use depends on the time of administration and PIPERACILLIN should be given ½ to 1 hour before the operation so that effective levels can be achieved in the wound prior to the procedure .

Types of Infection:

PIPERACILLIN is recommended for the treatment of the following types of infection caused by one or more susceptible pathogens.

• Severe systemic infections, including bacterial septicaemia, endocarditis.
• Genitourinary tract infections (complicated and uncomplicated, including urethritis, cystitis and pyelonephritis. It is also effective in acute, uncomplicated infections caused by Neisseria gonorrhoeae.
• Respiratory tract infections (acute and chronic), including bronchitis, pneumonia, empyema and lung abscess. In patients with chronic respiratory infections or cystic fibrosis, clinical improvement has been achieved but bacterial eradication may not occur.
• Ear, nose, throat and oral cavity infections.
• Intra-abdominal infections , including those of the biliary tract and intra-abdominal abscess.
• Gynaecological and obstetric infections, including endometritis, pelvic abscess and inflammation, salpingitis and puerperal infections.
• Skin and soft tissue infections, including those following infected wounds and burns, surgery and trauma.
• Bone and joint infections.

Dosage and Administration

PIPERACILLIN may be administered by the intramuscular route or intravenous injection. The usual dosage of PIPERACILLIN for serious infections is 3 to 4 grams given every 4 to 6 hours as a 20- to 30- minute infusion. For serious infections, the intravenous route of administration should be used.

PIPERACILLIN should not be mixed with an aminoglycoside in a syringe or infusion bottle since this can result in inactivation of the aminoglycoside.

The maximum daily dose for adults is 24g/day.

Intramuscular injections should be limited to 2 grams per injection site.

This route of administration has been used primarily in the treatment of patients with uncomplicated gonorrhoea and urinary tract infections.

Adults

- see Table 4.

* One gram of probenecid given orally ½ hour prior to injection

Renal Insufficiency:

In adults with renal impairment, intravenous or intramuscular dosage should be adjusted. Given in Table 5 are the recommended maximum daily doses of piperacillin according to the degree of renal impairment.

* Haemodialysis removes 30 to 50% of PIPERACILLIN should be administered following each dialysis period. For patients with renal failure and hepatic insufficiency, measurement of serum levels of piperacillin will provide additional guidelines for adjusting dosage.

Infants and Children (to 14 Years of Age )

- see Table 6. For infants and children intravenous administration of PIPERACILLIN is recommended.

Renal Insufficiency:

Dosages for children over one month of age with renal impairment are shown in Table 7.

* Adjusted to body surface, 1.73m²

Neonates:

Dosage for this age group has not yet been established.

Duration of Therapy:

The average duration of PIPERACILLIN treatment is from 7 to 10 days. The duration of therapy should be guided by the clinical and bacteriological course of the infection. In most acute infections, treatment should be continued for at least 48 to 72 hours after the patient becomes asymptomatic. For Group A β-haemolytic streptococcal infections, therapy should be maintained for 10 days to reduce the risk of rheumatic fever or glomerulonephritis.

Prophylatic Use:

When possible, PIPERACILLIN should be administered as a 20-30 minute infusion just prior to anaesthesia. Administration while the patient is awake will facilitate identification of possible adverse reactions.

In prophylactic use the following dosage regimens are recommended - Table 8.

Directions for Use:

PIPERACILLIN is administered parenterally. It can be used as a slow intravenous injection (3-5 minutes), intravenous infusion (20-40 minutes) or intramuscular injection.

Reconstitution and Administration

Intravenous injection:

Each gram of PIPERACILLIN should be reconstituted with at least 5ml of Sterile Water for Injection. It may be further diluted with Sterile Water for Injection to obtain a larger volume. This solution should be injected slowly into the vein (3-5 minutes).

Intravenous Infusion:

Each gram of PIPERACILLIN should be reconstituted with at least 5ml of Sterile Water for Injection. The resultant reconstituted solution (of 2 or 4 grams) should then be further diluted to the desired volume (at least 50ml). Infusion should be carried out over a period of about 20-40 minutes or intermittent infusion over a 30-minute to 2-hour period. The following preparations are suitable as diluents:

Intravenous Injections

• Dextrose 5% in Water,
• Sodium Chloride 0.9% Injection,
• Dextrose 5% in Sodium Chloride 0.9% Injection,
• Dextran 6% in Sodium Chloride 0.9% Injection,
• Lactated Ringer's Injection,
• Intravenous Admixtures,
• Normal Saline (plus Potassium Chloride 40 mEq),
• 5% Dextrose/Water (plus Potassium Chloride 40 mEq),
• 5% Dextrose/Normal saline (plus Potassium Chloride 40 mEq) , Ringer's Injection (plus Potassium Chloride 40 mEq),
• Lactated Ringer's Injection (plus Potassium Chloride 40 mEq). When PIPERACILLIN is further diluted with Lactated Ringer's Injection, the diluted solution must be administered within 2 hours.

NOTE: Because of chemical instability, PIPERACILLIN should not be used for intravenous administration with solutions containing only sodium bicarbonate.

Intramuscular Injection

Each gram of PIPERACILLIN should be reconstituted with at least 2ml of 0.5-1.0% lignocaine (without adrenaline) in Sterile Water for Injection. (Lignocaine is contraindicated in patients with a hypersensitivity to local anaesthetics of the amide type). A minimum of 2ml Sterile Water for Injection may also be employed for reconstitution.

NOTE: No more than 2 grams of PIPERACILLIN should be administered intramuscularly at a single injection site in adults. Injection should be given into the upper quadrant of the gluteal muscle mass (buttocks).

Contraindications

The use of this medicine is contraindicated in individuals with a history of hypersensitivity to any of the penicillins or cephalosporins. PIPERACILLIN is also contraindicated in patients with infectious mononucleosis.

Lignocaine hydrochloride should not be used as a diluent for IM injection in patients who are sensitive to lignocaine.

Warnings and Precautions

Before initiating therapy with a penicillin such as PIPERACILLIN, careful inquiry should be made to determine whether a patient has had previous hypersensitivity reactions to penicillins, cephalosporins or other allergens. Cross-allergenicity between the penicillins and cephalosporins has been reported in patients.

Piperacillin should always be administered with caution to patients who have demonstrated any form of hypersensitivity. If an allergic reaction occurs, PIPERACILLIN should be discontinued.

The usual agents (antihistamines, pressor amines and corticosteroids) should be readily available to initiate appropriate treatment. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been seen with the penicillins. These are more apt to occur in persons with a history of sensitivity to multiple allergens.

Serious anaphylactoid reactions require, in addition to discontinuation of PIPERACILLIN, immediate emergency treatment with adrenaline, oxygen and intravenous corticosteroids. Airway management, including intubation, should be administered as indicated.

While PIPERACILLIN shows the characteristic low toxicity of the penicillin group of antibiotics, it is advisable to check periodically for organ system dysfunction (including haematopoietic, hepatic and renal) during prolonged therapy. Piperacillin levels should be monitored in renal or hepatic impairment.

PIPERACILLIN is a monosodium compound containing 1.85 milliequivalents of Na⁺ per gram. 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 hypokalaemia should be kept in mind with patients who have potentially low potassium reserves and who are receiving cytotoxic therapy or diuretics.

The following reactions may occur, especially in patients receiving high doses of PIPERACILLIN:

Bleeding manifestations, sometimes associated with abnormalities in coagulation tests, such as clotting and prothrombin time and platelet aggregation; these are more likely to occur in patients with renal failure. If bleeding manifestations occur, piperacillin should be discontinued and appropriate therapy instituted.

Neuromuscular excitability or convulsions when higher than recommended doses are given intravenously.

The dose of PIPERACILLIN administered by intravenous injection ( ie over 3-5 minutes) should not exceed 4 grams. For patients with renal impairment and/or hepatic insufficiency, measurement of serum levels of piperacillin will provide guidance for adjusting dosage.

Antimicrobials used in high doses for short periods to treat gonorrhea may mask or delay symptoms of incubating syphilis. Therefore, prior to treatment, patients with gonorrhoea should also be evaluated for syphilis. Specimens for darkfield examination should be obtained from patients with any suspected primary lesions and serological tests should be performed. In all cases where concomitant syphilis is suspected, monthly serological tests should be made for a minimum of four months.

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.

Because of its poor penetration into the CSF, piperacillin is not advised in the treatment of meningitis and brain abscess.

Repeated use of lignocaine as diluent should be avoided in patients with severe liver disease or decreased hepatic blood flow due to the possibility of lignocaine toxicity (resulting from decreased metabolism and accumulation).

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 diarrhoea 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 (eg oral teicoplanin or oral vancomycin) should be considered.

Use in Pregnancy:

Safety for use in pregnant women has not been established. However, limited studies in mice and rats revealed no impaired fertility or teratogenic effects; piperacillin has been found to cross the placenta in rats. Because animal reproduction studies are not always predictive of human response , PIPERACILLIN should not be used during pregnancy unless, in the judgement of the treating clinician, such use is judged essential for patient welfare and potential benefits outweigh any risks.

Use in Lactation:

PIPERACILLIN is excreted in low concentrations in milk. Therefore PIPERACILLIN should preferably not be administered to nursing mothers unless alternative arrangements for feeding the infant can be made.

Adverse Effects

PIPERACILLIN is generally well tolerated. The type and incidence of adverse reactions reported so far are listed below.

Local

Intramuscular Administration: Pain and erythema (and/or induration) at the injection site occurred in 1.9% of patients. (Pain after intramuscular injection can be minimised by reconstituting PIPERACILLIN with 0.5-1.0% lignocaine(without adrenaline).

Intravenous Administration: Thrombophlebitis was reported in 3.8% of patients and less frequent reactions included ecchymosis, deep vein thrombosis and haematomas.

Systemic

Hypersensitivity: Rarely an anaphylactoid reaction ( see Warnings and Precautions ) has been reported. Rash was noted in 1.9% of patients. Drug fever in 2.2%.

NOTE: Incidence of rash and fever is higher in cystic fibrosis patients. Other less frequent findings included pruritus and vesicular eruptions and positive Coombs' tests occurred rarely. Other dermatological manifestations such as erythema multiforme and Stevens-Johnson syndrome have been reported rarely.

Gastrointestinal: Diarrhoea and loose stools were noted in 2.8% of patients. Other less frequent reactions included nausea, vomiting and bloody diarrhoea; rarely pseudomembranous colitis has been reported.

Hepatic: Transient increases in liver enzymes were noted in the following percentages of patients: Alkaline phosphatase 2.7%, LDH 2.2%, AST 3.0%, ALT 3.0%. Transient hyperbilirubinaemia was observed in 2.9% of patients. Cholestatic jaundice was reported only rarely.

Renal: Elevations of creatinine or BUN were observed infrequently. Rarely interstitial nephritis may occur.

Haematological and Lymphatic: Transient leucopenia, neutropenia, thrombocytopenia (and/or eosinophilia) have been reported. Reversible leucopenia (neutropenia) is more likely to occur during prolonged therapy at high dosages or in association with substances known to cause this reaction.

Haemorrhagic manifestations have been observed only rarely.

Hypokalaemia: This was reported rarely in patients with liver disease and those receiving cytotoxic therapy or diuretics when given high doses of PIPERACILLIN.

Central Nervous System: Headache, dizziness and fatigue may occur. Convulsions with high doses.

Skeletal: Rarely, prolonged muscle relaxation has been noted.

Superinfection: Superinfection, including candidiasis, was observed rarely, usually associated with prolonged treatment.

Interactions

Combined Therapy with Other Antibiotics

Aminoglycosides. Based on in-vitro synergism and clinical results, combined therapy with piperacillin and aminoglycoside antibiotics (eg amikacin) may be used in the treatment of serious infections caused by such organisms as Klebsiella, indole-positive Proteus, Pseudomonas and Serratia. Both Piperacillin and the respective aminoglycoside should be given at the full therapeutic dose.

It is known that certain aminoglycosides in the presence of various penicillin class drugs are inactivated. Concurrent administration of piperacillin and tobramycin in pateints with severe renal dysfunction (ie chronic haemodialysis patients) has been reported to reduce the elimination half-life and significantly increase the total body clearance of tobramycin and gentimicin in patients with terminal renal insufficiency has been described.

Cephalosporins. If PIPERACILLIN is proposed to be administered concomitantly with a cephalosporin, an additive, synergistic or antagonistic antibacterial action of the two antibiotics should first be ascertained through in-vitro tests. Based on in-vitro data, cefoxitin should not be given with piperacillin.

PIPERACILLIN has not been shown to be physically compatible with cephalosporins when mixed in the same infusion fluid.

NOTE: Whenever PIPERACILLIN is administered concurrently with another antibiotic, they 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 vercuronium.

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.

Concurrent administration of probenicid and penicillins produces a longer half-life and lower renal clearance of penicillin, however, peak plasma concentrations are unaffected.

During simultaneous administration of penicillin and high doses of heparin, warfarin, oral anticoagulants and other drugs which may affect the blood coagulation system and/or thrombocyte function, the coagulation parameters should be tested more frequently and monitored regularly.

Laboratory Test Interactions

As with other penicillins, the administration of PIPERACILLIN may result in a false-positive reaction for glucose in the urine using a copper reduction method. It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.

Overdosage

Other than general supportive treatment, no specific antidote is known. Excessive serum levels of piperacillin may be reduced by dialysis. Neuromuscular excitability or convulsions have been known to occur following large intravenous doses of penicillins.

General supportive measures, including administration of appropriate anticonvulsant agents such as diazepam or barbiturates, may be indicated. Daily doses of piperacillin of 24 grams have been administered in man without observation of adverse effects. For treatment of hypersensitivity reactions, see Warnings and Precautions.

Pharmaceutical Precautions

When the diluents listed under Reconstitution and Administration are used, PIPERACILLIN solutions lose less than 5% of their activity if the following storage periods and temperatures are not exceeded:

• 24 hours at 23°C.
• 48 hours at 4°C.

Any unused portions must be discarded after the storage period. PIPERACILLIN should not be employed after the expiration date indicated on the package.

PIPERACILLIN should be stored below 25°C.

Medicine Classification

Prescription Medicine.

Package Quantities

PIPERACILLIN 1g and 2g vials are available in quantities of 5.

PIPERACILLIN 4g vials are available in quantities of 1

Further Information

PIPERACILLIN (piperacillin sodium) is a semisynthetic penicillin derived from D(-)-α-aminobenzyl-penicillin. Chemically, it is sodium [2S-[2α,5α,6β,(S*)]]-6[[[[(4- ethyl-2,3-dioxo-1-piperazinyl) carbonyl] amino] phenylacetyl]amino]-3,3-dimethyl-7-oxo-thia-1-azabicyclo[3,2,0] heptane -2-carboxylate.

Name and Address

Douglas Pharmaceuticals Ltd
P.O. Box 45-027
AUCKLAND 8

Ph: (09) 835-0660
Fax: (09) 835-0690

Date of Preparation

21 September 1999