RAZOBIN Powder for solution for injection/infusion Ref.[115313] Active ingredients: Piperacillin Tazobactam

Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid including shocks) reactions have been reported in patients receiving therapy with penicillins. These reactions are more apt to occur in persons with a history of penicillin hypersensitivity or a sensitivity to multiple allergens. There have been reports of patients with a history of penicillin hypersensitivity who have experienced severe hypersensitivity reactions when treated with a cephalosporin. Careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, and other allergens, before initiating therapy with RAZOBIN.

If an allergic reaction occurs during therapy with RAZOBIN, the antibiotic should be discontinued. Serious hypersensitivity reactions require immediate emergency measures, with epinephrine (adrenaline), corticosteroids and antihistamines. An open airway must be maintained.

Pseudomembranous colitis has been reported. Antibiotic-induced pseudomembranous colitis may occur manifesting in symptoms of severe, persistent diarrhoea which may be life-threatening. The onset of pseudomembranous colitis may occur during or after antibacterial treatment. Therefore, in patients who present with diarrhoea subsequent to the administration of antibacterial agents, it is important to consider this diagnosis. After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to RAZOBIN discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes; protein supplementation and treatment with an oral antibacterial medicine effective against Clostridium difficile.

Periodic assessment of organ system functions including renal and hepatic during prolonged therapy is advisable. Leukopenia and neutropenia may occur, especially during prolonged therapy. Therefore, periodic assessment of haematopoietic function should be performed. In some patients receiving β-lactam antibiotics, bleeding manifestations have occurred. 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. RAZOBIN should be discontinued and appropriate therapy instituted if bleeding manifestations occur.

The possibility of the emergence of resistant organisms, which may cause superinfections, should be kept in mind, particularly during prolonged treatment. If this occurs, appropriate measures should be taken. As with other penicillins, if higher than recommended doses are given intravenously, patients may experience convulsions or neuromuscular excitability. This product contains 2, 35 mEq (54 mg) of sodium per gram of piperacillin which may increase a patient's overall sodium intake. In patients with low potassium reserves, periodic electrolyte determinations should be made and the possibility of hypokalaemia should be kept in mind with patients who have potentially low potassium reserves and who are receiving diuretics or cytotoxic therapy. Modest elevation of indices of liver function may be observed. In patients with renal insufficiency or haemodialysis patients, the intravenous dose should be adjusted to the degree of renal function impairment. Patients over 65 years are not at an increased risk of developing adverse effects solely because of age. However, dosage should be adjusted in the presence of renal insufficiency.

Haemophagocytic lymphohistiocytosis (haemophagocytic syndrome)

Haemophagocytic lymphohistiocytosis may occur. Patients should be carefully monitored, and if any abnormalities such as pyrexia, rash, neurological symptoms, splenomegaly, swollen lymph nodes, cytopenia, increased LDH, hyperferritinaemia, hypertriglyceridaemia, hepatic impairment, or coagulation abnormalities are observed, administration of RAZOBIN should be discontinued, and appropriate measures should be taken.

Interactions with Other Medicines

No interaction is found between RAZOBIN and vancomycin.

Concurrent administration of probenecid and RAZOBIN produced a lower renal clearance and a longer half-life for both piperacillin and tazobactam; however, peak plasma concentrations of either medicine are unaffected.

The pharmacokinetics of tobramycin in subjects with normal renal function and with mild or moderate renal impairment was not significantly altered by piperacillin either alone or with tazobactam. The pharmacokinetics of piperacillin, tazobactam, and the M1 metabolite were also not significantly altered by tobramycin administration.

Whenever RAZOBIN 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.

During simultaneous administration of high doses of heparin, oral anticoagulants and other medicines that may affect the blood coagulation system and/or the thrombocyte function, the coagulation parameters should be monitored regularly and tested more frequently. Piperacillin has been implicated in the prolongation of the neuromuscular blockage of vecuronium, when given concomitantly with 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.

Since piperacillin may reduce the excretion of methotrexate; the serum levels of methotrexate should be monitored in patients to avoid medicine toxicity.

Pharmaceutical Incompatibilities

RAZOBIN should not be mixed with other medicines in a infusion bottle or syringe since compatibility has not been established. Whenever RAZOBIN is used concurrently with another antibiotic (e.g. aminoglycosides), the medicines must be administered separately. The mixing of RAZOBIN with an aminoglycoside in vitro can result in the aminoglycoside being substantially inactivated.

RAZOBIN should not be used with solutions containing only sodium bicarbonate, because of chemical instability.

Lactated Ringer's solution is not compatible with RAZOBIN.

RAZOBIN should not be added to albumin hydrolysates or blood products.

Laboratory Tests

There have been reports of positive test results using the Bio-Rad Laboratories Platella Aspergillus EIA test in patients receiving RAZOBIN injection who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platella Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving RAZOBIN should be interpreted cautiously and confirmed by other diagnostic methods. The administration of RAZOBIN may result in a false-positive reaction for glucose in the urine using a copper-reduction method. Therefore, it is recommended that glucose tests based on enzymatic glucose oxidase reactions should be used.

Safety in pregnancy and lactation has not been established.

Adequate studies on the use of RAZOBIN during pregnancy and the period of breast feeding are not available. RAZOBIN did not affect fertility in rats and was not teratogenic in rats or mice. Piperacillin and tazobactam cross the placenta. Piperacillin is excreted in low concentrations in human milk.

Tazobactam concentrations in human milk have not been studied.

There is no information to show that RAZOBIN affects the ability to drive a car or operate machinery.

Infections and infestations

Less frequent: Candidal superinfections

Blood and the 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 nutrition disorders

Less frequent: Hypoalbuminaemia, hypoglycaemia, hypoproteinaemia, hypokalaemia

Psychiatric disorders

Less frequent: Hallucinations, confusion, depression

Nervous system disorders

Less frequent: Headache, insomnia, muscular weakness, convulsion, dry mouth

Cardiac disorders

Less frequent: Tachycardia, including supraventricular and ventricular; bradycardia; dysrhythmia, including atrial fibrillation, ventricular fibrillation, cardiac arrest, cardiac failure, circulatory failure, myocardial infarction

Vascular disorders

Less frequent: Hypotension, phlebitis, thrombophlebitis, flushing

Gastrointestinal disorders

Frequent: Diarrhoea, nausea, vomiting

Less frequent: Constipation, dyspepsia, jaundice, stomatitis, abdominal pain, pseudomembranous colitis

Hepato-biliary disorders

Less frequent: increased alanine aminotransferase, increased aspartate aminotransferase, increased bilirubin, increased blood alkaline phosphatise, increased gamma-glutamyltransferase, hepatitis

Skin and subcutaneous tissue disorders

Frequent: Rash

Less frequent: Pruritus, urticaria, erythema, bullous dermatitis, erythema multiforme, increased sweating, eczema, exanthema, Stevens-Johnson Syndrome, toxic epidermal necrolysis

Musculoskeletal, connective tissue and bone disorders

Less frequent: Arthralgia, myalgia

Renal and urinary disorders

Less frequent: increased blood creatinine, dysuria, urinary retention, interstitial nephritis, renal failure increased blood urea

General disorders and administrative site conditions

Less frequent: Fever, injection site reaction, rigors, tiredness, oedema.

Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.