Name of the medicinal product Metronidazole 500 mg / 100 ml Intravenous Infusion 2. Qualitative and quantitative composition Metronidazole 5 mg/ml 100 ml of solution for infusion containing 500 mg of Metronidazole.       For excipients see 6.1 Osmolarity: 308 mOsm/l pH: 4.5 to 6.0            3. Pharmaceutical form Solution for infusion A clear, almost colourless to pale yellow solution.                                      4. Clinical particulars 4.1 Therapeutic indications Metronidazole 500mg/100ml Intravenous Infusion is indicated in adults and children when oral medication is not possible for the following indications: - The prophylaxis of postoperative infections due to sensitive anaerobic bacteria particularly species of Bacteroides and anaerobic Streptococci, during abdominal, gynaecological gastrointestinal or colorectal surgery which carries a high risk of occurrence of this type of infection. The solution may also be used in combination with an antibiotic active against aerobic bacteria. - The treatment of severe intraabdominal and gynaecological infections in which sensitive anaerobic bacteria particularly Bacteriodes and anaerobic Streptococci have been identified or are suspected to be the cause.

Consideration should be given to official guidance on the appropriate use of antibacterial agents. 4.2 Posology and method of administration Method of Administration Metronidazole 500mg/100ml Intravenous Infusion should be infused intravenously at an approximate rate of 5 ml/minute (or one bag infused over 20 to 60 minutes). Oral medication should be substituted as soon as feasible. Prophylaxis against postoperative infections caused by anaerobic bacteria: Primarily in the context of abdominal, (especially colorectal) and gynaecological surgery. Antibiotic prophylaxis duration should be short, mostly limited to the post operative period (24 hours but never more than 48 hours). Various schedules are possible. Adults: Intra-venous injection of single dose of 1000mg-1500mg, 30-60 minutes preoperatively or alternatively 500mg immediately before, during or after operation, then 500mg 8 hourly.Metronidazole is mainly metabolised by hepatic oxidation.

Substantial impairment of Metronidazole clearance may occur in the presence of advanced hepatic insufficiency. The risk/benefit ratio of using Metronidazole to treat trichomoniasis in such patients should be carefully considered (for dosage adjustment see section 4.2). Plasma levels of Metronidazole should be closely monitored. Cases of severe hepatotoxicity/acute hepatic failure, including cases with a fatal outcome with very rapid onset after treatment initiation in patients with Cockayne syndrome have been reported with products containing metronidazole for systemic use. In this population, metronidazole should therefore be used after careful benefit-risk assessment and only if no alternative treatment is available. Liver function tests must be performed just prior to the start of therapy, throughout and after end of treatment until liver function is within normal ranges, or until the baseline values are reached. If the liver function tests become markedly elevated during treatment, the drug should be discontinued. Patients with Cockayne syndrome should be advised to immediately report any symptoms of potential liver injury to their physician and stop taking metronidazole. Active Central Nervous System disease: Metronidazole should be used with caution in patients with active disease of the Central Nervous System. The treatment should be withdrawn in case of ataxia, dizziness, or confusion. The risk of aggravation of the neurological state should be considered in patients suffering from severe central and peripheral neurological diseases, fixed or progressive paraesthesia and epilepsy. Caution is required in patients with active disease of the central nervous system except for brain abscess.

Renal Disease: Metronidazole is removed during haemodialysis and should be administered after the procedure is finished. Sodium restricted patients: May be harmful to patients on a low sodium diet. Alcohol: Patients should be advised not to take alcohol during Metronidazole therapy and at least 48 hours afterwards because of a disulfram-like effect (flushing, vomiting, tachycardia). See Section 4.5. Intensive or prolonged Metronidazole therapy: As a rule, the usual duration of therapy with i.v Metronidazole or other imidazole derivatives is usually less than 10 days. This period may only be exceeded in individual cases after a very strict benefit-risk assessment. Only in the rarest possible case should the treatment be repeated. Limiting the duration of treatment is necessary because damage to human germ cells cannot be excluded. Intensive or prolonged Metronidazole therapy should be conducted only under conditions of close surveillance for clinical and biological effects and under specialist direction. If prolonged therapy is required, the physician should bear in mind the possibility of peripheral neuropathy or leucopenia. Both effects are usually reversible. In case of prolonged treatment, occurrence of undesirable effects such as paraesthesia, ataxia, dizziness and convulsive crises should be checked. High dose regimes have been associated with transient epileptiform seizures. Monitoring: Regular clinical and laboratory monitoring (including leukocyte formula) are advised in cases of high-dose or prolonged treatment, in case of antecedents of blood dyscrasia, in case of severe infection and in severe hepatic insufficiency. General: Patients should be warned that Metronidazole may darken urine (due to Metronidazole metabolite). 4.5 Interaction with other medicinal products and other forms of interaction Not recommended concomitant therapy: Alcohol: Disulfram-like effect (warmth, redness, vomiting, tachycardia). Alcohol beverage and drugs containing alcohol should be avoided. Patients should be advised not to take alcohol during Metronidazole therapy and at least 48 hours afterwards because of a disulfram-like (antabuse effect) reaction (flushing, vomiting, tachycardia). Concomitant therapy requiring special precautions: Oral anticoagulants : increase of the effects of oral anticoagulants and the risk of haemorrhage (decrease in its liver catabolism). Prothrombin time should be monitored more frequently. The dose of oral anticoagulants should be adjusted during the treatment with Metronidazole and 8 days after withdrawal. A large number of patients have been reported showing an increase in oral anticoagulant activity whilst receiving concomitant antibiotic therapy. The infectious and inflammatory status of the patient, together with their age and general well-being are all risk factors in this context. However, in these circumstances it is not clear as to the part played by the disease itself or its treatment in the occurrence of prothrombin time disorders. Some classes of antibiotics are more likely to result in this interaction, notably

fluoroquinolones, macrolides, cyclines, cotrimoxazole and some cephalosporins. Vecuronium (non depolarising curaremimetic): Metronidazole can potentialise the effects of vecuronium. Combinations to be considered: 5 Fluoro-uracile: increase in the toxicity of 5 fluoro-uracile due to a decrease of its clearance. Lithium: lithium retention accompanied by evidence of possible renal damage has been reported in patients treated simultaneously with lithium and Metronidazole. Lithium treatment should be tapered or withdrawn before administering Metronidazole. Plasma concentrations of lithium, creatinine and electrolytes should be monitored in patients under treatment with lithium while they receive Metronidazole. Barbiturates - Phenobarbital might induce the metabolism of Metronidazole, which could lead to decreased efficacy of Metronidazole. Cholestyramine may delay or reduce the absorption of Metronidazole. Concomitant administration of phenytoin and following intravenous treatment with Metronidazole on the ability to drive and use machines