Nildin 2 G/3 G/4 G Solution

NILDIN is indicated for the treatment of the following systemic and/or local bacterial infections in which susceptible organisms have been detected or are suspected:

Adults:

• Community acquired pneumonia due to Haemophilus influenzae.
• Intra-abdominal infections caused by piperacillin-resistant beta-lactamase-producing strains of Escherichia coli and Bacteroides fragilis.
• Skin and skin structure infections caused by piperacilllin-resistant beta-lactamase-producing strains of Staphylococcus aureus.
• In neutropenic patients, NILDIN plus an aminoglycoside is indicated for bacterial infections.
• Gynaecological infections including endometritis caused by piperacillin-resistant beta-lactamase-producing strains of E.coli.

Children:

CHILDREN UNDER THE AGE OF 12 YEARS: In neutropenic patients, NILDIN plus an aminoglycoside is indicated for bacterial infections.

CHILDREN 2-12 YEARS: NILDIN is indicated for the treatment of serious intra-abdominal infections, caused by E.coli or Bacteroides species, in hospitalised children aged 2 to 12 years. For paediatric patients below the age of 2 years, NILDIN has not been evaluated in this indication.

NILDIN may be given by slow intravenous infusion over a 30 minute period.

Adults and Children 12 Years and Older:

The usual dosage for adults and juveniles with normal renal function is 4/0,5 g piperacillin/tazobactam given every eight hours. The dosage in immunocompromised and neutropenic patients with infection is 4/0,5 g piperacillin/tazobactam every 6 hours in combination with an aminoglycoside.

Children under the Age of 12 Years:

NILDIN is only recommended for the treatment of children with neutropenia. For children weighing over 50 kg, follow the adult dosing guidance, including the aminoglycoside. For children with normal renal function and weighing less than 50 kg, the dose should be adjusted to 90 mg/kg (80 mg piperacillin/10 mg tazobactam) administered every 6 hours, in combination with an aminoglycoside.

Renal Insufficiency:

In patients with renal insufficiency, the intravenous dose should be adjusted to the degree of actual renal function impairment. The suggested daily doses are as follows:

IN INTRAVENOUS DOSAGE SCHEDULE FOR ADULTS WITH IMPAIRED RENAL FUNCTION

For patients on haemodialysis, the maximum daily dose is 2 g/0,25 g every 8 hours piperacillin/tazobactam. In addition, because haemodialysis removes 30 % - 40 % of piperacillin in 4 hours, one additional dose of 0,75 g piperacillin/tazobactam should be administered following each dialysis period. For patients with renal failure and hepatic insufficiency, measurement of serum levels of piperacillin/tazobactam will provide additional guidance for adjusting dosage.

Neutropenic Patients:

In treating neutropenic patients, full therapeutic doses of NILDIN and an aminoglycoside should be used. The possibility of hypokalaemia should be kept in mind in patients who have low potassium reserves, and periodic electrolyte determinations should be made in these patients.

Duration of Therapy:

In acute infections, treatment with NILDIN should be for a minimum of five days and continued for forty-eight hours beyond resolution of clinical symptoms or the fever. The usual duration of treatment is 7 - 10 days.

Hospitalised Children with intra-abdominal infection:

For children aged 2 to 12 years, weighing up to 40 kg, and with normal renal function, the recommended dosage is 112,5 mg/kg (100 mg piperacillin / 12,5 mg tazobactam) every 8 hours. For children aged 2 to 12 years, weighing over 40 kg, and with normal renal function, follow the adult dose guidance, i.e. 4,5 g (4 g piperacillin / 0,5 g tazobactam) every 8 hours. The duration of therapy should be guided by the severity of the infection and the patientu2019s clinical and bacteriological progress. Therapy is recommended to be a minimum of 5 days and a maximum of 14 days, considering the dose administration should continue at least 48 hours after the resolution of clinical signs and symptoms.

Children Aged 2 u2013 12 Years with Renal Insufficiency:

The pharmacokinetics of NILDIN have not been studied in paediatric patients with renal impairment. The following dosage adjustment for paediatric patients aged 2 to 12 years with renal impairment is recommended.

IN INTRAVENOUS DOSAGE SCHEDULE FOR CHILDREN AGED 2 u2013 12 YEARS WITH IMPAIRED RENAL FUNCTION

The dosage modification is only an approximation. Each patient must be monitored closely for signs of medicine toxicity. Medicine dose and interval should be adjusted accordingly.

NILDIN is contra-indicated in patients with a history of allergic reactions to any of the penicillins and/or cephalosporins or u03b2-lactamase inhibitors or any of the constituents of NILDIN. Safety in pregnancy and lactation has not been established (see PREGNANCY AND LACTATION).

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 NILDIN. If an allergic reaction occurs during therapy with NILDIN, 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 NILDIN 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 C.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 u03b2-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. NILDIN 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 patientu2019s 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.

No interaction is found between NILDIN and vancomycin. Concurrent administration of probenecid and NILDIN 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 NILDIN 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-depolarizsing 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.

Safety in pregnancy and lactation has not been established. Adequate studies on the use of NILDIN during pregnancy and the period of breast feeding are not available. NILDIN 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 NILDIN affects the ability to drive a car or operate machinery.

Adverse reactions are listed according to CIOMS frequency categories:

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.

See u201cSIDE - EFFECTSu201d. The majority of events experienced during overdosage including nausea, vomiting and diarrhoea have also been reported with the usual recommended dosages. If higher than recommended doses are given intravenously, particularly in the presence of renal failure, patients may experience neuromuscular excitability or convulsions. Treatment should be supportive and symptomatic according to the patientu2019s clinical presentation. There is no known specific antidote. Excessive serum concentrations of either piperacillin or tazobactam may be reduced by haemodialysis. In the event or an emergency, all required intensive medical measures are indicated as in the case of piperacillin. In case of motor excitability or convulsions, anticonvulsive agents (e.g. diazepam or barbiturates) may be indicated. In case of severe, hyperallergic (anaphylactic) reactions, the usual countermeasures are to be initiated (antihistamines, corticosteroids, sympathicomimetic medicines and, if required, oxygen and airway management). The possibility of antibiotic-induced life-threatening pseudomembranous colitis must be taken into consideration in case of severe, persistent diarrhoea. Therefore, NILDIN must be discontinued immediately in such cases and suitable therapy be initiated (e.g. oral teicoplanin or oral vancomycin). Preparations, which inhibit peristalsis, are contraindicated.