For the use of a Registered Medical Practitioner or a Hospital or a Institution only.
PIPCIN (Piperacillin Sodium) is a sodium salt of semisynthetic penicillin for parenteral use derived from D(-)-Ü-aminobenzyl penicillin, having a broad spectrum bactericidal activity. Chemically, Piperacillin Sodium is 4 - T h i a - 1 - a z a b i c y c l o [ 3 . 2 . 0 ] h e p t a n e - 2 -
carboxylic acid, 6-[[[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]phenylacetyl]amino]-3,3-dimethyl-7-oxo-, monosodium salt, [2 S-[2Ü,5Ü,6â( S*)]]. The molecular formula is C23H26N5NaO7S and molecular weight is 539.54.
STRUCTURAL FORMULA :
Its structural formula is :
PIPCIN is a white to off white, sterile crystalline, odourless hygroscopic powder filled in flint glass vial. Freshly constituted solution will range in colour from colourless to pale yellow.
1. Piperacillin for Injection USP 1 gm
Each vial contains :
Sterile Piperacillin Sodium USP
equivalent to Piperacillin USP ……...1 gm
2. Piperacillin for Injection USP 2 gm
Each vial contains :
Sterile Piperacillin Sodium USP
equivalent to Piperacillin USP ……...2 gm
3. Piperacillin for Injection USP 4 gm
Each vial contains :
Sterile Piperacillin Sodium USP
equivalent to Piperacillin USP ……...4 gm
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., Pseudomonas sp., Pseudomonas aeruginosa, Serratia sp., Acinetobacter sp., Klebsiella pneumoniae, Haemophilus influenzae (non-â-lactamase-producing strains), Enterobacter PIPCIN sp., Citrobacter sp., Neisseria gonorrhoea, Neisseria meningitidis.
Gram-positive bacteria : Enterococci (Streptococcus faecalis, S. faecium), Streptococcus viridans, Staphylococcus aureus (nonâ-lactamase-producing), â-haemolytic streptococci incl. Group A Streptococcus (S. pyogenes) Group B Streptococcus (S. agalactiae), Streptococcus pneumonia, Staphylococcus epidermidis (non-âlactamase-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 â-lactamases produced by staphylococci and by some Gram-negative bacteria. However, it is active against â-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, carbenicillin, cefalothin or aminoglycosides are susceptible to piperacillin.
Piperacillin can be administered either intramuscularly or intravenously. It is not absorbed when given orally. As shown in Table 1, 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 gm 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 2 hours after administration of a 4 gm intravenous injection. Levels in gall bladder bile are considerably lower.
PIPCIN 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. PIPCIN 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 PIPCIN 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 :
PIPCIN 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.
PIPCIN is administered parenterally. It can be used as a slow intravenous injection (3-5 minutes), intravenous infusion (20-40 minutes) or intramuscular injection.
PIPCIN may be administered by the intramuscular route or intravenous injection. The usual dosage of PIPCIN for serious infections is 3 to 4 gm given every 4 to 6 hours as a 20 to 30 minute infusion. For serious infections, the intravenous route of administration should be used. PIPCIN 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 24 gm/day. Intramuscular injections should be limited to 2 gm 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 2.
Table 2. Dosage recommendation for adults
Renal Insufficiency :
In adults with renal impairment, intravenous or intramuscular dosage should be adjusted. Given in Table 3 are the recommended maximum daily doses of piperacillin according to the degree of renal impairment.
Table 3. Dosage recommendation for adults with renal impairment (q= every; h =hours)
* Haemodialysis removes 30 to 50 % of piperacillin in 4 hours, 1 g additional dose 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.
Duration of Therapy :
The average duration of PIPCIN 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 â-haemolytic streptococcal infections, therapy should be maintained for 10 days to reduce the risk of rheumatic fever or glomerulonephritis.
Prophylactic Use :
When possible, PIPCIN 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 6
Table 6. Dosage recommendations for prophylactic use
Reconstitution and Administration :
Intravenous Injection :
Each gram of PIPCIN should be reconstituted with atleast 5 ml of Sterile Water for Injection USP. It may be further diluted with Sterile Water for Injection USP to obtain a larger volume. This solution should be injected slowly into the vein (3-5 minutes).
Intravenous Infusion :
Each gram of PIPCIN should be reconstituted with at least 5 ml of Sterile Water for Injection USP. The resultant reconstituted solution (of 2 or 4 gm) should then be further diluted to the desired volume (at least 50 ml). 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 PIPCIN is further diluted with Lactated Ringer’s Injection, the diluted solution must be administered within 2 hours.
NOTE : Because of chemical instability, PIPCIN should not be used for intravenous administration with solutions containing only sodium bicarbonate.
Intramuscular Injection :
Each gram of PIPCIN should be reconstituted with at least 2 ml of 0.5-1.0 % lignocaine (without adrenaline) in Sterile Water for Injection USP. (Lignocaine is contraindicated in patients with a hypersensitivity to local anaesthetics of the amide type). A minimum of 2 ml
Sterile Water for Injection USP may also be employed for reconstitution. NOTE : No more than 2 gm of PIPCIN 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).
The use of this medicine is contraindicated in individuals with a history of hypersensitivity to any of the penicillins or cephalosporins. PIPCIN is also contraindicated in patients with infectious mononucleosis. Lignocaine hydrochloride should not be used as a diluent for I.M. injection in patients who are sensitive to lignocaine.
SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC/ ANAPHYLACTOID) REACTIONS HAVE BEEN REPORTED IN PATIENTS ON PENICILLIN THERAPY. THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY AND/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 PIPERACILLIN, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, PIPERACILLIN SHOULD BE DISCONTINUED AND APPROPRIATE THERAPY INSTITUTED. SERIOUS ANAPHYLACTIC/ ANAPHYLACTOID REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including piperacillin and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of antibacterial agents.
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 gm. 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 PIPCIN :
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 PIPCIN administered by intravenous injection (i.e. over 3-5 minutes) should not exceed 4 gm. 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 gonorrhoea 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 4 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 (e.g. 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, PIPCIN 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 PIPCIN should preferably not be administered to nursing mothers unless alternative arrangements for feeding the infant can be made.
Combined Therapy with Other Antibiotics :
Aminoglycosides : Based on in-vitro synergism and clinical results, combined therapy with piperacillin and aminoglycoside antibiotics (e.g. 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 patients with severe renal dysfunction (i.e. chronic haemodialysis patients) has been reported to reduce the elimination half-life and significantly increase the total body clearance of tobramycin and gentamicin in patients with terminal renal insufficiency has been described.
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 probenecid 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.
SIDE EFFECTS :
Piperacillin is generally well tolerated. The type and incidence of adverse reactions reported so far are listed below.
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
Thrombophlebitis was reported in 3.8 % of patients and less frequent reactions included ecchymosis, deep vein thrombosis and haematomas.
Rarely an anaphylactoid reaction 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.
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.
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.
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.
There is no specific information on overdose with piperacillin. Other penicillin-class drugs in overdosage, however, have the potential to cause neuromuscular hyperirritability or convulsive seizures.
TREATMENT OF OVERDOSAGES :
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 gm have been administered in man without observation of adverse effects.
PHARMACEUTICAL PRECAUTIONS :
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Store below 25°C (77°F), protected from moisture & light.
Do not refrigerate.The reconstituted solution should be used immediately after preparation.
SHELF LIFE :
24 months from the date of manufacture.
1. PIPCIN contains Sterile Piperacillin Sodium USP equivalent to Piperacillin USP 1 gm 50 vials in a Box.
2. PIPCIN contains Sterile Piperacillin Sodium USP equivalent to Piperacillin USP 2 gm 25 vials in a Box.
3. PIPCIN contains Sterile Piperacillin Sodium USP equivalent to Piperacillin USP 4 gm 10 vials in a Box.
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