4.1. Therapeutic indications

Metronidazole 500 mg/100 ml Solution for infusion is indicated in adults and children when oral medication is not possible for the following indications:

• Prevention of post-operative infections due to anaerobic bacteria, particularly species of bacteroids and anaerobic streptococci.

• The treatment of septicaemia, bacteraemia, peritonitis, brain abscess, necrotising pneumonia, osteomyelitis, puerperal sepsis, pelvic abscess, pelvic cellulitis and post-operative wound infections from which pathogenic anaerobes have been isolated.

(see also section 4.4 and 5.1)

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 500 mg/100 ml Solution for infusion should be infused intravenously at an approximate rate of 5 ml/minute (or one bottle 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 1000 mg - 1500 mg, 30-60 minutes preoperatively or alternatively 500 mg immediately before, during or after operation, then 500 mg 8 hourly.

Children < 12 years: 20-30 mg/kg as a single dose given 1-2 hours before surgery.

Newborns with a gestation age <40 weeks: 10 mg/kg body weight as a single dose before operation.

The Elderly: Caution is advised in the elderly, particularly at high doses, although there is limited information available on modification of dosage.

Anaerobic infections:

Intravenous route is to be used initially if patient symptoms preclude oral therapy. Various schedules are possible.

Adults: 1000 mg – 1500 mg daily as a single dose or alternatively 500 mg every 8 hours.

Children > 8 weeks to 12 years of age: The usual daily dose is 20-30mg/kg/day as a single dose or divided into 7.5 mg/kg every 8 hours. The daily dose may be increased to 40 mg/kg, depending on the severity of the infection. Duration of treatment is usually 7 days.

Children < 8 weeks of age: 15 mg/kg as a single dose daily or divided into 7.5 mg/kg every 12 hours.

In newborns with a gestation age < 40 weeks: accumulation of metronidazole can occur during the first week of life, therefore the concentrations of metronidazole in serum should preferably be monitored after a few days of therapy.

Oral medication could be given, at the same dose regimen. Oral medication should be substituted as soon as feasible.

Duration of treatment:

Treatment for seven to ten days should be satisfactory for most patients but, depending upon clinical and bacteriological assessments, the physician might decide to prolong treatment e.g.; for the eradication of infection from sites which cannot be drained or are liable to endogenous recontamination by anaerobic pathogens from the gut, oropharynx or genital tract.

Bacterial vaginosis:

Adolescents: 400 mg twice daily for 5-7 days or 2000 mg as a single dose.

Urogenital trichomoniasis:

Adults and adolescents: 2000 mg as a single dose or 200 mg 3 times daily for 7 days or 400 mg twice daily for 5-7 days.

Children < 10 years: 40 mg/kg orally as a single dose or 15 – 30 mg/kg/day divided in 2-3 doses for 7 days; not to exceed 2000 mg/dose.

Giardiasis:

> 10 years: 2000 mg once daily for 3 days, or 400 mg three times daily for 5 days, or 500 mg twice daily for 7 to 10 days.

Children 7 to 10 years: 1000 mg once daily for 3 days.

Children 3 to 7 years: 600 to 800 mg once daily for 3 days.

Children 1 to 3 years: 500 mg once daily for 3 days

Alternatively, as expressed in mg per kg of body weight:

15-40 mg/kg/day divided in 2-3 doses.

Amoebiasis:

> 10 years: 400 to 800 mg 3 times daily for 5-10 days.

Children 7 to 10 years: 200 to 400 mg 3 times daily for 5-10 days.

Children 3 to 7 years: 100 to 200 mg 4 times daily for 5-10 days

Children 1 to 3 years: 100 to 200 mg 3 times daily for 5-10 days.

Alternatively, doses may be expressed by body weight 35 to 50 mg/kg daily in 3 divided doses for 5 to 10 days, not to exceed 2400 mg/day.

Eradication of Helicobacter pylori in paediatric patients:

As a part of a combination therapy, 20 mg/kg/day not to exceed 500 mg twice daily for 7-14 days. Official guidelines should be consulted before initiating therapy.

Elderly Population

Caution is advised in the elderly, particularly at high doses, although there is limited information available on modification of dosage.

Patients with renal failure

Routine adjustments of the dosage of Metronidazole are not considered necessary in the presence of renal failure.

No routine adjustment in the dosage of Metronidazole needs to be made in patients with renal failure undergoing intermittent peritoneal dialysis (IDP) or continuous ambulatory peritoneal dialysis (CAPD). However dosage reduction may be necessary when excessive concentrations of metabolites are found.

In patients undergoing haemodialysis, Metronidazole should be re-administered immediately after haemodialysis.

Patients with advanced hepatic insufficiency

In patients with advanced hepatic insufficiency a dosage reduction with serum level monitoring is necessary.

4.3. Contraindications

• Hypersensitivity to the active substance metronidazole or other nitroimidazole derivatives or to any of the excipients listed in section 6.1.

• Pregnancy - metronidazole should not be used in the first trimester in patients with trichomoniasis or bacterial vaginosis (see section 4.6).

• Breast feeding should be discontinued for 12-24 hours when single high dose (e.g. 2g) therapy is used (see section 4.6).

4.4. Special warnings and precautions for use

Regular clinical and laboratory monitoring (including full blood count) 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.

In patients with severe liver damage or impaired haematopoiesis (e.g. granulocytopenia) metronidazole should only be used if its expected benefits clearly outweigh potential hazards.

Metronidazole is mainly metabolised by hepatic oxidation. Substantial impairment of metronidazole clearance may occur in the presence of advanced hepatic insufficiency.

Significant cumulation may occur in patients with hepatic encephalopathy and the resulting high plasma concentrations of metronidazole may contribute to symptoms of the encephalopathy. Therefore, metronidazole should be administered with caution to patients with hepatic encephalopathy. The daily dosage should be reduced to one third and may be administered once daily.

Due to the risk of aggravation, metronidazole should also be used in patients with active or chronic severe peripheral and central nervous system diseases only if its expected benefits clearly outweigh potential hazards.

Convulsive seizures, myoclonus and peripheral neuropathy, the latter mainly characterized by numbness or paresthesia of an extremity, have been reported in patients treated with metronidazole. The appearance of abnormal neurological signs demands the prompt evaluation of the benefit/risk ratio of the continuation of therapy (see section 4.8).

In the case of severe hypersensitivity reactions (e.g. anaphylactic shock; see also section 4.8), treatment with Metronidazole must be discontinued immediately and established emergency treatment must be initiated by qualified healthcare professionals.

Severe persistent diarrhoea occurring during treatment or during the subsequent weeks may be due to pseudomembranous colitis (in most cases caused by Clostridium difficile), see section 4.8. This intestinal disease, precipitated by the antibiotic treatment, may be life-threatening and requires immediate appropriate treatment.

Anti-peristaltic medicinal products must not be given.

The duration of therapy with metronidazole or drugs containing other nitroimidazoles should not exceed 10 days. Only in specific elective cases and if definitely needed, the treatment period may be extended, accompanied by appropriate clinical and laboratory monitoring. Repeat therapy should be restricted as much as possible and to specific elective cases only. These restrictions must be observed strictly because the possibility of metronidazole developing mutagenic activity cannot be safely excluded and because in animal experiments an increase of the incidence of certain tumours has been noted.

Prolonged therapy with metronidazole may be associated with bone marrow depression, leading to an impairment of haematopoiesis. Manifestations see section 4.8. Blood cell counts should be carefully monitored during prolonged therapy.

Interference with laboratory tests

Metronidazole interferes with the enzymatic-spectrophotometric determination of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), triglycerides and glucose hexokinase resulting in decreased values (possibly down to zero).

Metronidazole has a high absorbance at the wavelength at which nicotinamideadenine dinucleotide (NADH) is determined. Therefore elevated liver enzyme concentrations may be masked by metronidazole when measured by continuous-flow methods based on endpoint decrease in reduced NADH. Unusually low liver enzyme concentrations, including zero values, have been reported.

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.

Patients should be warned that metronidazole may darken urine.

Due to inadequate evidence on the mutagenicity risk in humans (see section 5.3), the use of metronidazole for longer treatment than usually required should be carefully considered.

This medicinal product contains 310 mg (13.5 mmol) of sodium per dose, equivalent to 16% of the WHO recommended maximum daily intake for sodium.

Metronidazole 500 mg/100 ml Solution for infusion is considered high in sodium. This should be particularly taken into account for those on a low salt diet.

4.5. Interaction with other medicinal products and other forms of interaction

Interactions to be used with caution:

Amiodarone:

QT interval prolongation and torsade de pointes have been reported with the co administration of metronidazole and amiodarone. It may be appropriate to monitor QT interval on the ECG if amiodarone is used in combination with metronidazole.

Patients treated on an outpatient basis should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.

Barbiturates:

Phenobarbital may increase the hepatic metabolism of metronidazole, reducing its plasma half-life to 3 hours.

Busulfan:

Co administration with metronidazole may significantly increase the plasma concentrations of busulfan. The mechanism of interaction has not been described.

Due to the potential for severe toxicity and mortality associated with elevated busulfan plasma levels, concomitant use with metronidazole should be avoided.

Carbamazepine:

Metronidazole may inhibit the metabolism of carbamazepine and raise the plasma concentrations as a consequence.

Cimetidine:

Concurrently administered cimetidine may reduce the elimination of metronidazole in isolated cases and subsequently lead to increased metronidazole concentrations in serum.

Contraceptive drugs:

Some antibiotics can, in some exceptional cases, decrease the effect of contraceptive pills by interfering with the bacterial hydrolysis of steroid conjugates in the intestine and hereby reduce the re-absorption of unconjugated steroid. Therefore the plasma levels of the active steroid decrease. This unusual interaction can occur in women with a high excretion of steroid conjugates through the bile. There are case reports of oral contraceptive failure in association with different antibiotics, e.g. ampicillin, amoxicillin, tetracyclines and also metronidazole.

Coumarin derivatives:

Concomitant treatment with metronidazole may potentiate the anticoagulant effect of these and increase the risk for bleeding as a consequence of decreased hepatic degradation. Dose adjustment of the anticoagulant can be necessary.

Cyclosporine:

During simultaneous therapy with cyclosporine and metronidazole there is a risk for increased serum concentrations of cyclosporine. Frequent monitoring of cyclosporine and creatinine is required.

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 concentration of lithium, creatinine, and electrolytes should be monitored in patients under treatment with lithium while they receive metronidazole.

Disulfiram:

Simultaneous administration of disulfiram may cause states of confusion or even psychotic reactions. Combination of both agents must be avoided.

Fluorouracil:

Metronidazole inhibits the metabolism of concurrently administered fluorouracil, i.e. the plasma concentration of fluorouracil is increased.

Mycophenolate mofetil:

Substances that alter the gastrointestinal flora (e.g., antibiotics) may reduce the oral bioavailability of mycophenolic acid products. Close clinical and laboratory monitoring for evidence of diminished immunosuppressive effect of mycophenolic acid is recommended during concomitant therapy with anti-infective agents.

Phenytoin:

Metronidazole inhibits the metabolism of concurrently administered phenytoin, i.e. the plasma concentration of phenytoin is increased. On the other hand, the efficacy of metronidazole is reduced when phenytoin is administered concurrently.

Tacrolimus:

Co administration with metronidazole may increase the blood concentrations of tacrolimus. The proposed mechanism is inhibition of hepatic tacrolimus metabolism via CYP 3A4. Tacrolimus blood levels and renal function should be checked frequently and the dosage adjusted accordingly, particularly following initiation or discontinuation of metronidazole therapy in patients who are stabilized on their tacrolimus regimen.

Other forms of interaction

Alcohol:

Intake of alcoholic beverages must be avoided during metronidazole therapy since adverse reactions such as dizziness and vomiting may occur (disulfiram-like effect).

4.6. Fertility, pregnancy and lactation

Contraception in males and females: See section 4.5 'contraceptive drugs'.

Pregnancy

The safety of the use of metronidazole during pregnancy has not sufficiently been demonstrated. In particular, reports on the use during early pregnancy are contradictory. Some studies indicated an increased rate of malformations. In animal studies with metronidazole no teratogenicity was observed (see section 5.3).

During the first trimester, Metronidazole should only be used to treat severe life-threatening infections, if there is no safer alternative. During second and third trimester, Metronidazole may also be used to treat other infections if its expected benefits clearly outweigh any possible risk.

Breast-feeding

Since metronidazole is secreted into breast milk, nursing should be stopped during therapy. Also after the end of the therapy with metronidazole, nursing should not be resumed before another 2 – 3 days because of the prolonged half-life period of metronidazole.

Fertility

Animal studies only indicate a potential negative influence of metronidazole on the male reproductive system if high doses lying well above the maximum recommended dose for humans were administered.

4.7. Effects on ability to drive and use machines

Patients should be warned about the potential for drowsiness, dizziness, confusion, hallucinations, convulsions or transient visual disorders, and advised not to drive or operate machinery if these symptoms occur.

4.8. Undesirable effects

Undesirable effects are mainly associated with prolonged use or high doses.

The most commonly observed effects include nausea, abnormal taste sensations and the risk of neuropathy in case of long term treatment.

Frequency, type and severity of adverse reactions in children are the same as in adults.

The frequency of adverse events listed below is defined using the following convention: very common (≥1/10); common (≥1/100 to < 1/10); uncommon (≥1/1,000 to < 1/100); rare (≥1/10,000 to < 1/1,000); very rare (< 1/10,000),

Not known (frequency cannot be estimated from the available data).

System Organ Class

(MedDRA)

Common

Rare

Very Rare

Not Known

Infections and infestations

Superinfections with candida (e.g. genital infections)

Pseudomembranous colitis, which may occur during or after therapy, manifesting as severe persistent diarrhea. For details regarding emergency treatment (see section 4.4)

Blood and lymphatic system disorders

Granulocytopenia, Agranulocytosis, thrombocytopenia, pancytopenia. See section 4.4

Leucopenia, aplastic anaemia

Immune system disorders

Severe acute systemic hypersensitivity reactions: anaphylaxis, up to anaphylactic shock (see section 4.4).

Mild to moderate hypersensitivity reactions, e. g. skin reactions (see “Skin and subcutaneous disorders” below)

Angiodema

Metabolism and nutrition disorders

Anorexia

Psychiatric disorders

Psychotic disorders,

including states confusion,

hallucination

Depression

Nervous system disorders

Encephalopathy, fever, headache, disturbances in sight and movement, ataxia, dysathria, vertigo drowsiness, dizziness, convulsions

Somnolence or insomnia, myoclonus, seizures, peripheral neuropathy manifesting as paraesthesia, pain, furry sensation, and tingling in the extremities, aseptic meningitis

If seizures or signs of peripheral neuropathy or encephalopathy appear, the attending doctor should be informed immediately. See section 4.4

Eye disorders

Disturbance of vision, e.g. diplopia, myopia

Oculogyric crisis,

Optic neuropathy/neuritis (isolated cases)

Cardiac disorders

ECG changes like flattening of the T-wave

Gastrointestinal disorders

Vomiting, nausea, diarrhoea, glossitis and stomatitis, eructation with taste, epigastric pressure, metallic taste,furred tongue

Dysphagia (caused by central nervous effects of metronidazole)

Hepatobiliary disorders

Abnormal values of hepatic enzymes and bilirubin

Hepatitis,

jaundice,

pancreatitis

Skin and subcutaneous tissue disorders

Allergic skin reactions, e. g. pruritus, urticaria

Stevens-Johnson syndrome

Toxic epidermal necrolysis

Erythema multiforme

Musculoskeletal and connective tissue disorders

Myalgia, arthralgia

Renal and urinary disorders

Dark coloured urine (due to metronidazole metabolite)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

As signs and symptoms of overdose the undesirable effects described under section 4.8 may appear. Single oral doses of metronidazole, up to 12g have been reported in suicide attempts and accidental overdoses. Symptoms were limited to vomiting, ataxia and slight disorientation.

Treatment

There is no specific treatment or antidote that can be applied in the case of gross overdose of metronidazole. If required, metronidazole can be effectively eliminated by haemodialysis.