4.1. Therapeutic indications

Metronidazole 500 mg/100 ml Solution for Infusion is indicated in adults and children for the prophylaxis and treatment of infections in which susceptible anaerobic micro-organisms have been identified or are suspected to be the cause (see sections 4.4 and 5.1).

1. The prevention of post-operative infections where anaerobic bacteria are expected to be causative pathogens

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

Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2. Posology and method of administration

The dosage is adjusted according to the patient's individual response to therapy, her/his age and body weight and according to nature and severity of the disease.

The following dosage guidelines should be followed:

Adults and adolescents:

Treatment of anaerobic infections

500 mg (100 ml) every 8 hours. Alternatively 1000 mg – 1500 mg may be given daily as a single dose.

The duration of therapy is dependent on the effect of the treatment. In most cases a treatment course of 7 days will be sufficient. If clinically indicated, treatment may be continued beyond this time although a duration of 10 days should not normally be exceeded. (See also section 4.4.)

Prophylaxis against post-operative infection caused by anaerobic bacteria:

500 mg, with administration completed approximately one hour before surgery. The dose is repeated after 8 and 16 hours.

The Elderly:

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

Paediatric population

Treatment of anaerobic infections

● Children > 8 weeks to 12 years of age:

The usual daily dose is 20 – 30 mg per kg BW per day as a single dose or divided into 7.5 mg per kg BW every 8 hours. The daily dose may be increased to 40 mg per kg BW, depending on the severity of the infection.

● Neonates and infants < 8 weeks of age:

15 mg per kg BW as a single dose daily or divided into 7.5 mg per kg BW every 12 hours.

● In newborns with a gestational 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 therapy.

Duration of treatment is usually 7 days.

Prophylaxis against postoperative infections caused by anaerobic bacteria:

● Children < 12 years:

20 – 30 mg/kg BW as a single dose given 1 – 2 hours before surgery

● Newborns with a gestation age <40 weeks:

10 mg/kg BW as a single dose before surgery

Patients with renal insufficiency

Limited data are available in this population. These data do not indicate the need for dose reduction (see section 5.2.)

In patients undergoing haemodialysis the conventional dose of metronidazole should be scheduled after haemodialysis on dialysis days to compensate the removal of metronidazole during the procedure.

No routine dose adjustment is necessary in patients with renal failure undergoing intermittent peritoneal dialysis (IDP) or continuous ambulatory peritoneal dialysis (CAPD).

Patients with hepatic insufficiency

As serum half-life is prolonged and plasma clearance is delayed in severe hepatic insufficiency, patients with severe liver disease will require lower doses (see section 5.2).

In patients with hepatic encephalopathy, the daily dosage should be reduced to one third and may be administered once daily (see section 4.4).

Method of administration

Intravenous use.

The contents of one bottle are to be infused slowly i.v., i.e. 100 ml max. over not less than 20 minutes, but normally over one hour.

Metronidazole 500mg/100ml Solution for Infusion can also be diluted before administration, adding the medicinal product to an i.v. vehicle solution such as 0.9 % sodium chloride or 5 % glucose infusion solution.

Concurrently prescribed antibiotics are to be administered separately.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Patients with hepatic impairment

In patients with severe liver damage 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 the symptoms of the encephalopathy. Metronidazole should therefore be administered with caution to patients with hepatic encephalopathy. (see section 4.2).

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.

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).

In the case of severe hypersensitivity reactions (e.g. anaphylactic shock), treatment with Metronidazole 500 mg/100 ml Solution for Infusion 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 Clostridioides 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.

Imbalances of the normal flora (fungal/bacterial overgrowth) and possible superinfections may occur, especially with prolonged metronidazole treatment or in immunocompromised patients.

Severe Cutaneous Adverse Reactions-Severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the use of metronidazole. Symptoms can be serious and potentially life threatening. If symptoms or signs of SCARs develop, discontinue Metronidazole injection immediately and institute appropriate therapy.

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.

Hepatotoxicity in patients with Cockayne Syndrome

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 not be used unless the benefit is considered to outweigh the risk and 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 (see section 4.8).

Special warnings / precautions regarding excipients

This medicinal product contains 322 mg sodium per 100 ml, equivalent to 16% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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 nicotinamide-adenine 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.

Patients should be warned that Metronidazole may darken urine.

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

Interactions with other medicinal products

Drugs that prolong the QT interval

Prolongation of the QT interval has been reported, especially when metronidazole is administered to-gether with drugs that have the potential to prolong the QT interval. QT interval prolongation and tor-sade de pointes have been reported with the coadministration of metronidazole and amiodarone or ciprofloxacin, respectively. It may be appropriate to monitor QT interval on the ECG if amiodarone or ciprofloxacin 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

Coadministration 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.

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.

Ciclosporine

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.

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.

Lithium

Caution is to be exercised when metronidazole is administered simultaneously with lithium salts, because under metronidazole therapy raised serum concentrations of lithium have been observed. 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.

Mycophenolat 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

Coadministration 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

Disulfiram-like effect. Alcoholic beverages and drugs containing alcohol should be avoided.

4.6. Fertility, pregnancy and lactation

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.

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 500 mg/100 ml Solution for Infusion should only be used to treat severe life-threatening infections, if there is no safer alternative. During the second and third trimester, Metronidazole 500 mg/100 ml Solution for Infusion 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.

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 are 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.

In the following listing, for the description of the frequencies of undesirable effects the following terms are used:

Very common

Common

Uncommon

Rare

Very rare

Not known

: ≥ 1/10

: ≥ 1/100 to < 1/10

: ≥ 1/1,000 to < 1/100

: ≥ 1/10,000 to < 1/1,000

: < 1/10,000

:(Frequency cannot be estimated from the available data)

Infections and infestations

Common:

Fungal and bacterial superinfections

Rare:

Pseudomembranous colitis

Details regarding emergency treatment see section 4.4.

Blood and lymphatic system disorders

Very rare:

granulocytopenia, agranulocytosis, pancytopenia and thrombocytopenia

Not known:

Leucopenia, aplastic anaemia

Immune system disorders

Rare:

Severe acute systemic hypersensitivity reactions: anaphylaxis, up to anaphylactic shock.

Not known:

Angioedema.

Metabolism and nutrition disorders

Not known:

Anorexia

Psychiatric disorders

Very rare:

Psychotic disorders, including states of confusion, hallucination

Not known:

Depression

Nervous system disorders

Very rare:

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

Not known:

Somnolence or insomnia, myoclonuis, seizures, peripheral neuropathy manifesting as paraesthesia, tinnitus, hearing impairment, hearing loss (including sensorineural hearing loss), pain, furry sensation, and tingling in the extremities.

Aseptic meningitis.

Eye disorders

Very rare:

Disturbance of vision, e.g. diplopia, myopia.

Not known:

Oculogyric crisis, optic neuropathy/neuritis (isolated cases)

Cardiac disorders

Rare:

ECG changes like flattening of T‑wave

Gastro-intestinal disorders

Very rare:

Pancreatitis

Not Known:

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

Dysphagia (caused by central nervous effects of metronidazole)

Hepatobiliary disorders

Very rare:

Abnormal values of hepatic enzymes and bilirubin

Hepatitis, jaundice

Cases of severe irreversible hepatotoxicity/acute liver failure, including cases with fatal outcomes with very rapid onset after initiation of systemic use of metronidazole, have been reported in patients with Cockayne Syndrome (see section 4.4).

Skin and subcutaneous tissue disorders

Very rare:

Allergic skin reactions, e. g. pruritus, urticaria,

Not known:

Erythema multiforme, Toxic epidermal necrolysis (TEN), Stevens-Johnson Syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) (see section 4.4)

Musculoskeletal and connective tissue disorders

Very rare:

Arthralgia, myalgia

Renal and urinary disorders

Uncommon:

Dark coloured urine (due to a metabolite of metronidazole)

General disorders and administration site conditions

Not known:

Vein irritations (up to thrombophlebitis) after intravenous administration.

States of weakness, fever

Paediatric population

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.