INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo LITHA PIPERACILLIN CO 2/0,250
LITHA PIPERACILLIN CO 3/0,375
LITHA PIPERACILLIN CO 4/0,5

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

LITHA PIPERACILLIN CO 2/0,250
LITHA PIPERACILLIN CO 3/0,375
LITHA PIPERACILLIN CO 4/0,5
powder for injection

COMPOSITION:
Each vial of LITHA PIPERACILLIN CO 2/0,250 contains 2 g
piperacillin and 0,250 g tazobactam as sodium salts.
Each vial of LITHA PIPERACILLIN CO 3/0,375 contains 3 g piperacillin and 0,375 g tazobactam as sodium salts.
Each vial of LITHA PIPERACILLIN CO 4/0,5 contains 4 g piperacillin and 0,5 g tazobactam as sodium salts.
Contains 2,35 mEq (54 mg) of sodium per gram of piperacillin.

PHARMACOLOGICAL CLASSIFICATION
A 20.1.1. Broad and medium spectrum antibiotics

PHARMACOLOGICAL ACTION:
Pharmacodynamics

Piperacillin is a broad spectrum, semi synthetic penicillin, with bactericidal activity. Penicillins bind to enzymes that are vital for the development of the bacterial cell wall during growth and division, inactivating them and thereby exerting bactericidal activity through inhibition of both septum and cell wall synthesis
Tazobactam, is a penicillanic acid sulphone beta-lactamase inhibitor. The beta-lactamase inhibitors bind irreversibly to beta-lactamases, thereby protecting the penicillin from hydrolysis. Tazobactam combined with piperacillin enhances and extends the spectrum of the antibacterial activity of piperacillin against beta-lactamase-producing bacteria.
Microbiology
Piperacillin/tazobactam is highly active against piperacillin-sensitive micro-organisms as well as beta-lactamase producing, piperacillin-resistant micro-organisms.
Mechanism of resistance
The two main mechanisms of resistance to piperacillin / tazobactam are:
- Inactivation of the piperacillin component by those beta-lactamases that are not inhibited by tazobactam: beta-lactamases in the Molecular class B, C and D. In addition, tazobactam does not provide protection against extended-spectrum beta-lactamases (ESBLs) in the Molecular class A and D enzyme groups.
- Alteration of penicillin-binding proteins (PBPs), which results in the reduction of the affinity of piperacillin for the molecular target in bacteria.
Additionally, alterations in bacterial membrane permeability, as well as expression of multi-medicine efflux pumps, may cause or contribute to bacterial resistance to piperacillin/tazobactam, especially in Gram-negative bacteria.
In vitro efficacy does not necessarily imply in vivo efficacy.
Pharmacokinetics
Peak piperacillin and tazobactam plasma concentrations are attained after completion of an intravenous infusion or injection. Piperacillin and tazobactam are widely distributed in tissue and body fluids including intestinal mucosa, gallbladder, lung, bile and bone.
Both piperacillin and tazobactam are 20 to 30% bound to plasma proteins. Piperacillin is hepatically metabolised to the microbiologically active desethyl metabolite. Tazobactam is metabolised to a single metabolite which has been found to be microbiologically inactive.
The plasma half-life of piperacillin and tazobactam ranges from 0.7 to 1.2 hours. Approximately 68% to 80% of an administered dose of piperacillin and tazobactam respectively are excreted unchanged in the urine.
Piperacillin and tazobactam are eliminated by the kidney via glomerular filtration and tubular secretion.
Piperacillin is excreted rapidly unchanged with 68% of the administered dose appearing in the urine. Tazobactam and its metabolite are eliminated primarily by renal excretion with 80% of the administered dose appearing as unchanged substance and the remainder as the single metabolite. Piperacillin, tazobactam, and desethyl piperacillin are also secreted into the bile.

INDICATIONS:
LITHA PIPERACILLIN CO is indicated for treatment of the following systemic and/or local bacterial infections in which susceptible organisms have been detected or are suspected:
Adults
Bacterial infections in neutropenic patients, in combination with an aminoglycoside.
Community acquired pneumonia caused by Haemophilus influenzae.
Intra-abdominal infections caused by piperacillin-resistant beta-lactamase producing strains of Escherichia coli and Bacteroides fragilis.
Gynaecological infections, including endometritis caused by piperacillin-resistant beta-lactamase producing strains of Escherichia coli.
Skin and soft tissue infections caused by piperacillin-resistant beta-lactamase producing strains of Staphylococcus aureus.
Children
Bacterial infections in neutropenic patients, in combination with an aminoglycoside.
Serious intra-abdominal infections, caused by E.coli or Bacteriodes species, in hospitalised children aged 2-12 years. LITHA PIPERACILLIN CO has not been evaluated for this condition in younger children.
Because of its broad spectrum of activity, LITHA PIPERACILLIN CO is useful in the treatment of mixed infections and in presumptive therapy before the results of sensitivity tests are known.
There is no need to add an additional antibiotic to the treatment of mixed infections caused by piperacillin-sensitive beta-lactamase producing organisms

CONTRA-INDICATIONS:
Hypersensitivity to any of the beta-lactams (including penicillins and cephalosporins) or to beta-lactamase inhibitors. (see WARNINGS)

WARNINGS:
Use with caution in patients with:
A history of sensitivity to multiple allergens. Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid, including shock) reactions have been reported in patients receiving therapy with penicillins. There have been reports of patients with a history of penicillin hypersensitivity that have experienced severe reactions when treated with a cephalosporin. If an allergic reaction occurs during therapy with LITHA PIPERACILLIN CO, discontinue treatment immediately. Serious hypersensitivity reactions may require adrenaline (epinephrine) or other emergency measures. Before initiating therapy with LITHA PIPERACILLIN CO careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins and other allergens.
Renal insufficiency or patients on haemodialysis. The dosage of LITHA PIPERACILLIN CO must be adjusted (see DOSAGE AND DIRECTIONS FOR USE).
A history of bleeding disorders, as penicillins, especially piperacillin, may cause platelet dysfunction and bleeding. This is more likely in patients with renal failure. If bleeding manifestations occur, LITHA PIPERACILLIN CO should be discontinued and appropriate therapy instituted.
  Cystic fibrosis, as treatment with LITHA PIPERACILLIN CO may pose an increased risk of fever and skin rash.
LITHA PIPERACILLIN CO has been associated with pseudomembranous colitis which can be fatal.
It presents as severe abdominal pain with cramps, fever and severe watery stools which may become bloody. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment. (see SIDE EFFECTS). Discontinue therapy with LITHA PIPERACILLIN CO immediately and initiate suitable therapy (e.g. fluid and electrolyte management, protein supplementation and administration of an oral antibacterial agent effective against Clostridium difficile). Preparations which inhibit peristalsis are contraindicated.
Leukopenia and neutropenia may occur, especially during prolonged therapy. Therefore periodic assessment of haematopoietic function should be performed. Periodic assessment of organ system functions including renal and hepatic, is advisable during prolonged therapy.
The possibility of the emergence of resistant organisms which might cause super infections should be kept in mind, particularly during prolonged treatment.
Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously.
Pregnant women and women breastfeeding their infants should not be treated with LITHA PIPERACILLIN CO (see PREGNANCY AND LACTATION).
The product contains 2,35 mEq (54 mg) of sodium per gram of piperacillin which may increase the patients overall sodium intake. This may be harmful to people on a low sodium diet, such as those with renal impairment.
Serum potassium levels should be periodically determined in patients with low potassium reserves who are receiving concomitant medications that may lower potassium levels, as hypokalaemia may occur.

INTERACTIONS:
Concurrent administration of probenecid and piperacillin/tazobactam produced a longer half-life and lower renal clearance for both piperacillin and tazobactam. However, peak plasma concentrations of either substance are unaffected.
Piperacillin either alone or with tazobactam did not cause clinically important alterations to the pharmacokinetics of tobramycin in subjects with normal renal function and with mild or moderate renal impairment. The pharmacokinetics of piperacillin, tazobactam, and the M1 metabolite were not significantly altered by tobramycin administration. No clinically important pharmacokinetic interactions have been noted between LITHA PIPERACILLIN CO and vancomycin in healthy adults with normal renal function.
Whenever LITHA PIPERACILLIN CO is used concurrently with another antibiotic, especially an aminoglycoside, the medicines must not be mixed in intravenous solutions or administered concurrently due to physical incompatibility. The mixing of LITHA PIPERACILLIN CO with an aminoglycoside in vitro can result in substantial inactivation of the aminoglycoside.
During simultaneous administration of heparin, oral anticoagulants and other medicines which may affect the blood coagulation system including thrombocyte function, appropriate coagulation tests should be performed more frequently and monitored regularly.
Anticoagulants, heparin, thrombolytic agents or other medicines affecting the blood coagulation system: may increase the risk of haemorrhage as LITHA PIPERACILLIN CO inhibits platelet aggregation. Patients should be monitored carefully for signs of bleeding.
Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. Due to their similar mechanism of action, it is expected that the neuromuscular blockade produced by any of the non-depolarising muscle relaxants could be prolonged in the presence of piperacillin.
Methotrexate used concomitantly with piperacillin may result in a reduction of methotrexate excretion. Serum levels should be monitored to avoid methotrexate toxicity.
The administration of LITHA PIPERACILLIN CO 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 reaction be used.
There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving piperacillin-tazobactam injection who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving piperacillin-tazobactam should be interpreted cautiously and confirmed by other diagnostic methods. Because of chemical instability, piperacillin/tazobactam should not be used with solutions containing only sodium bicarbonate. Lactated Ringer’s injection is not compatible as an initial diluent with piperacillin and tazobactam combination.
Piperacillin/tazobactam should not be mixed with blood or albumin products.

PREGNANCY AND LACTATION
Use in pregnancy:
Piperacillin tazobactam cross the placenta. The safety has not been established.
Use during the lactation period:
Piperacillin is excreted in low concentrations in human milk. The safety has not been established.

DOSAGE AND DIRECTIONS FOR USE:
LITHA PIPERACILLIN CO may be given by slow intravenous infusion (over 30 minutes).
Duration of therapy
The usual duration of treatment is 7-10 days. It however should be guided by the severity of the infection and the patient’s clinical progress. Treatment with LITHA PIPERACILLIN CO is recommended for a minimum of 5 days and a maximum of 14 days. In acute infections, the treatment should be continued for 48 hours beyond the resolution of clinical symptoms or the fever.
Neutropenic patients
Neutropenic patients should be treated with full therapeutic doses of LITHA PIPERACILLIN CO plus an aminoglycoside.
Adults and children over 12 years with normal renal function
The usual dosage for adults and children over 12 years is 4 g piperacillin/0,5 g tazobactam given every 8 hours.
In immunocompromised and neutropenic patients the recommended dose is 4 g piperacillin/0,5 g tazobactam given every 6 hours in combination with an aminoglycoside.
For nosocomial pneumonia and bacterial infections in neutropenic patients, the recommended dose is 4 g piperacillin/0,5 g tazobactam administered every 6 hours. This regimen may also be applicable to treat patients with other indicated infections when particularly severe.

The following table summarises the treatment frequency and the recommended dose for adult and adolescent patients by indication or condition:
Treatment frequency LITHA PIPERACILLIN CO 4/0,5
Every 6 hours Severe pneumonia Neutropenic adults with fever suspected to be due to a bacterial infection.
Every 8 hours Complicated urinary tract infections (including pyelonephritis)

Complicated intra-abdominal infections

Skin and soft tissue infections (including diabetic foot infections)

Children aged 2 to 12 years and under with normal renal function
For children weighing over 50 kg follow the adult dosage guide, including the aminoglycoside.

The following table summarises the treatment frequency and the dose per kg body weight for paediatric patients 2-12 years of age by indication or condition:
Dose per kg body weight and treatment frequency Indication / condition  
80 mg piperacillin/10 mg tazobactam/kg body weight every 6 hours Neutropenic children with fever suspected to be due to bacterial infections*  
100 mg piperacillin/12,5 mg tazobactam/kg body weight every 8 hours Complicated intra-abdominal infections*  
* Not to exceed the maximum 4 g piperacillin/0,5 g tazobactam per dose over 30 minutes.

Elderly with normal renal function
LITHA PIPERACILLIN CO may be used at the same dose levels as adults except in cases of renal impairment (see below).

Renal insufficiency in adults, the elderly and children over the age of 12 years
In patients with renal insufficiency, the intravenous dose should be adjusted to the degree of actual renal impairment.
The suggested daily doses are as follows:
Creatinine clearance (mL/min) Recommended piperacillin tazobactam dosage  
90 to 40 12 g piperacillin/1,5 g tazobactam/day in divided doses of 4 g/0,5 g every 8 hours or 3 g/0,375 g every 6 hours.  
20 to 40 8 g piperacillin/1,0 g tazobactam/day in divided doses of 2 g/0,250 g every 6 hours.  
< 20 6 g piperacillin/0,75 g tazobactam/day in divided doses of 2 g/0,250 g every 8 hours.  

For patients on haemodialysis, one additional dose of 2 g piperacillin/0,25 g tazobactam should be administered following each dialysis period, because haemodialysis removes 30-50 % of piperacillin in 4 hours.

Renal insufficiency in children aged 2-12 years
The pharmacokinetics of LITHA PIPERACILLIN CO has not been studied in children with renal insufficiency. The following dosage adjustment is recommended according to the degree of renal impairment as follows:
Creatinine clearance
(mL/min)
Recommended piperacillin tazobactam dosage
>50 100 mg piperacillin/12,5 mg tazobactam/kg every 8 hours.
<50 70 mg piperacillin/8,75 mg tazobactam/kg every 8 hours
The above dosage modifications are only an approximation. Each patient must be monitored closely for signs of drug toxicity. Dosage and intervals should be adjusted accordingly.
For children on haemodialysis, one additional dose of 40 mg piperacillin/5 mg tazobactam/kg should be administered following each dialysis period.
Use in children aged below 2 years
The safety and efficacy of LITHA PIPERACILLIN CO in children 0 - 2 years of age has not been established.
Reconstitution directions
Each vial of LITHA PIPERACILLIN CO 2/0,250 should be reconstituted with 10 ml of the suggested diluents below.
Each vial of LITHA PIPERACILLIN CO 3/0,375 should be reconstituted with 15 ml of the suggested diluents below.
Each vial of LITHA PIPERACILLIN CO 4/0,5 should be reconstituted with 20 ml of the suggested diluents below.
Suggested diluents
0,9 % Sodium chloride for injection.
Swirl until dissolved. Intravenous injection should be given over at least 3-5 minutes.
Preparation of IV infusion
The reconstituted solution may be further diluted to the desired volume e.g. 50 ml or 100 ml with one of the suggested diluents, or with dextrose 5 % in water.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side effects
Infections and infestations
Less frequent: Candida super-infections.
Blood and lymphatic system disorders
Less frequent: Leukopenia, neutropenia, thrombocytopenia, anaemia, bleeding manifestations (including purpura, epistaxis, bleeding time prolonged); eosinophilia, haemolytic anaemia, agranulocytosis, Coombs direct test positive, pancytopenia, prolonged partial thromboplastin time, prothrombin time prolonged, thrombocytosis.
Immune system disorders
Less frequent: hypersensitivity reaction, anaphylactic/anaphylactoid reaction (including shock).
Metabolism and nutritional disorders
Less frequent: Blood albumin decreased, blood glucose decreased, blood total protein decreased, hypokalaemia.
Nervous system disorders
Less frequent: headache, insomnia, convulsions (if high doses are given to patients with renal failure).
Vascular disorders
Less frequent: hypotension, phlebitis, thrombophlebitis, flushing.
Gastro-intestinal disorders
Frequent: diarrhoea, nausea, vomiting.
Less frequent: Constipation, dyspepsia, jaundice, stomatitis, abdominal pain, pseudomembranous colitis (see WARNINGS and Special precautions).
Hepatobiliary disorders
Less frequent: Alanine aminotransferase increased, aspartate aminotransferase increased, bilirubin increased, blood alkaline phosphatase increased, gamma-glutamyl transferase increased.
Skin and subcutaneous tissue disorders
Frequent: Rash
Less frequent: Pruritus, urticaria, bulbous dermatitis, erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis.
Musculoskeletal, connective tissue and bone disorders
Less frequent: Arthralgia.
Renal and urinary disorders
Less frequent: Blood creatinine increased, interstitial nephritis, renal failure, blood urea increased.
General disorders and administration site conditions
Less frequent: Fever, injection site reaction, rigor. Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.

Special precautions
While LITHA PIPERACILLIN CO possesses the characteristic low toxicity of the penicillin group of antibiotics, periodic assessment of organ system functions including renal and hepatic is advisable during prolonged therapy.
Leukopenia and neutropenia may occur, especially during prolonged therapy. Therefore, periodic assessment of haematopoietic function should be performed.
Bleeding manifestations have occurred in some patients receiving beta-lactams antibiotics. These reactions have sometimes been associated with abnormalities of coagulation tests such as clotting time, platelet aggregation and prothrombin time (INR), and are more likely to occur in patients with renal failure. If bleeding manifestations occur, the antibiotic should be discontinued and appropriate therapy instituted.
The possibility of the emergence of resistant organisms which might cause superinfections should be kept in mind, particularly during prolonged treatment. Microbiological follow-up may be required to detect any important superinfection. If this occurs, appropriate measures should be taken.
Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously.
This product contains 2,35 mEq (54 mg) of sodium per gram of piperacillin which may increase a patient's overall sodium intake. This may be harmful to people on a low sodium diet.
Hypokalaemia may occur in patients with low potassium reserves or who are receiving concomitant medications that may lower potassium levels; periodic electrolyte determinations should be performed in such patients. Modest elevation of indices of liver function may be observed.
Effects on ability to drive and use machines
LITHA PIPERACILLIN CO is not known to affect the ability to drive or operate machines.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
(See SIDE EFFECTS).
Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure).
Treatment is symptomatic and supportive. No specific antidote is known. Excessive serum concentrations of LITHA PIPERACILLIN CO may be reduced by haemodialysis. In case of motor excitability or convulsions, anticonvulsive agents (e.g. diazepam or barbiturates) may be indicated. Emergency measures should be carried out in case of severe, anaphylactic reactions, including oxygen, airway management, antihistamines, corticosteroids and sympathomimetics.
Consider the possibility of antibiotic-induced life-threatening pseudomembranous colitis in the case of severe persistent diarrhoea and discontinue LITHA PIPERACILLIN CO immediately. Start treatment with appropriate therapy such as oral teicoplanin or oral vancomycin and avoid agents that inhibit peristalsis.

IDENTIFICATION
Clear colourless glass vials fitted with a grey rubber stopper and aluminium tear-off cap contain white to off-white powder.
The reconstituted solution is clear and colourless to pale yellow and free from visible particulate matter.

PRESENTATION
All presentations are either individually packed in a carton or in 5’s or 10’s or 12’s per carton.
Each 20 ml single dose clear Type I glass vial of LITHA PIPERACILLIN CO 2/0,250 contains sterile piperacillin 2 g and tazobactam 0,250 g as sodium salts and is fitted with a grey bromobutyl rubber stopper and silver aluminium cap with a polypropylene flip-off system.
Each 20 ml single dose clear Type I glass vial of LITHA PIPERACILLIN CO 3/0,375 contains sterile piperacillin 3 g and tazobactam 0,375 g as sodium salts and is fitted with a grey bromobutyl rubber stopper and silver aluminium cap with a polypropylene flip-off system.
Each 50 ml single dose clear Type I glass vial of LITHA PIPERACILLIN CO 4/0,5 contains sterile piperacillin 4 g and tazobactam 0,5 g as sodium salts and is fitted with a grey bromobutyl rubber stopper and silver aluminium cap with a polypropylene flip-off system.

STORAGE INSTRUCTIONS
Dry powder
Store at or below 25ºC, in the original carton and protect from light.
Reconstituted solutions and infusions
Each vial contains a single dose. From a microbiological risk point of view, reconstituted solutions should be used immediately and any unused portion should be discarded. Physical and chemical stability have been demonstrated for 24 hours when stored in a refrigerator at 2 –8ºC. Aseptic preparation is implied for such storage.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS
LITHA PIPERACILLIN CO 2/0,250 Powder for injection: 42/20.1.1/0251
LITHA PIPERACILLIN CO 3/0,375 Powder for injection: 42/20.1.1/0252
LITHA PIPERACILLIN CO 4/0,500 Powder for injection: 42/20.1.1/0253

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
LITHA PHARMA (PTY) LTD
106 16
TH ROAD
MIDRAND

DATE OF PUBLICATION
26 October 2012

New addition to this site: May 2014
Source: Pharmaceutical Industry

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