1. what metronidazole 500 mg/100 ml is and what it is used for

Metronidazole 500 mg/100 ml belongs to a group of medicines known as antibiotics and is used to treat severe infections caused by bacteria that can be killed by the active substance metronidazole.

You may be given Metronidazole 500 mg/100 ml for the treatment and prevention of any of the following diseases:

• Infections of the blood, brain, lung, bones, genital tract, pelvic area and stomach

If required, your treatment may be supplemented by other antibiotics. Metronidazole 500 mg/100 ml may be given as a preventive measure prior to operations.

2. what you need to know before you receive metronidazole 500 mg/100 ml

You must not be given Metronidazole 500 mg/100 ml

• if you are allergic (hypersensitive) to metronidazole, other similar substances or any of the other ingredients of Metronidazole 500 mg/100 ml (listed in section 6).

Warnings and precautions

Talk to your doctor before receiving Metronidazole 500 mg/100 ml. Please tell your doctor if you have:

• severe liver damage or occurrence of confusion, altered level of consciousness and coma as a result of severe liver damage (hepatic encephalopathy)
• a disease of brain, spinal cord or nerves.

Therefore, your doctor will very carefully determine whether you should be treated with Metronidazole 500 mg/100 ml.

If convulsive fits or any other nerve affections (e.g. numbness in limbs) become apparent during therapy, your treatment will promptly be revised. Treatment must be stopped or revised immediately if you get severe diarrhoea which may be due to a severe large bowel disease called “pseudomembranous colitis” (see also section 4.)

Cases of severe liver toxicity/acute liver failure, including cases with a fatal outcome, in patients with Cockayne syndrome have been reported with product containing metronidazole.

If you are affected by Cockayne syndrome, your doctor should also monitor your liver function frequently while you are being treated with metronidazole and afterwards.

Tell your doctor immediately and stop taking metronidazole if you develop:

• Stomach pain, anorexia, nausea, vomiting, fever, malaise, fatigue, jaundice, dark urine, putty or mastic coloured stools or itching.

As prolonged use of metronidazole may impair blood formation (see section “Possible side effects”), your blood counts will be monitored during treatment.

If you received this medicine your urine may be darkened.

Other medicines and Metronidazole 500 mg/100 ml

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Amiodarone (used to treat irregular heartbeat)

When you receive this medicine, your heart function should be monitored. You should see your doctor if you notice any heart function abnormalities, dizziness or fainting.

Barbiturates (the active substance in sleeping pills)

The duration of action of metronidazole is reduced by phenobarbital; your metronidazole dose may therefore have to be increased.

Birth control pills

Your birth control pill may be less reliable while you are being given metronidazole.

Busulfan

Metronidazole should not be given to patients receiving busulfan because in that case toxic effects are more likely to occur.

Carbamazepine (a drug for the treatment of epilepsy)

This combination also warrants caution because metronidazole may increase the duration of action of carbamazepine.

Cimetidine (a drug for the treatment of stomach disorders)

Cimetidine may reduce the elimination of metronidazole in isolated cases and subsequently leads to increased serum metronidazole concentrations.

Coumarin derivatives (drugs that inhibit blood clotting)

Metronidazole may enhance the blood clotting inhibition brought about by coumarins. So if you are taking a medicine that inhibits blood clotting (for example warfarin), you may need less of it during treatment with metronidazole.

Cyclosporin (a drug used to suppress undesirable immune responses)

When cyclosporin is given together with metronidazole, the blood levels of cyclosporin may increase; your doctor will therefore have to adjust your cyclosporin dose as appropriate.

Disulfiram (used in alcohol withdrawal therapy)

If you are taking disulfiram, you must not be given metronidazole, or disulfiram must be stopped. Combined use of these two drugs may lead to states of confusion up to the point of a serious mental disorder (psychosis).

Drugs containing alcohol

Please refer to section ‘Using Metronidazole 500 mg/100 ml’ with food and drink.

Fluorouracil (an anticancer drug)

The daily dose of Fluorouracil may have to be reduced when giving it together with metronidazole because metronidazole may lead to an increase of the blood level of Fluorouracil.

Lithium (used to treat mental illness)

Treatment with lithium preparations requires particularly careful monitoring during treatment with metronidazole, and the dose of the lithium preparation may need to be re-adjusted. Lithium treatment should be tapered or withdrawn before administration of metronidazole.

Mycophenolate mofetil (used for the prevention of rejection reactions after organ transplant)

Its effect may be weakened by metronidazole, so careful monitoring of the effect of the medicine is recommended.

Phenytoin (a drug for the treatment of epilepsy)

If you are taking phenytoin, your doctor will treat you with metronidazole only with caution because metronidazole may increase the duration of action of phenytoin. On the other hand, phenytoin may reduce the effect of metronidazole.

Tacrolimus (used to suppress unwanted immune reactions)

The blood levels of this agent and your kidney function should be checked when starting and stopping treatment with metronidazole.

Metronidazole 500 mg/100 ml with Alcohol

You must not drink any alcoholic beverages or drugs containing alcohol while you are being given metronidazole and up to 48 hours afterwards because this may cause intolerance reactions such as dizziness and vomiting.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or planning to have a baby, ask your doctor, pharmacist or nurse for advice before taking this medicine.

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.

Contraception in males and females

If you are taking a birth-control pill, please refer to section “Taking or using other medicines”.

Pregnancy

If you are pregnant, your doctor will not treat you with metronidazole unless she/he considers this absolutely necessary.

Breast-feeding

You should not breast-feed during treatment with metronidazole and not resume nursing for another 2–3 days thereafter because metronidazole passes into breast milk.

Driving and using machines

While taking Metronidazole 500 mg/100 ml you may feel sleepy, dizzy, confused, see or hear things, that are not there (hallucinations), have fits (convulsions) or temporary eyesight problems (such as blurred or double vision). If this happens do not drive or use any machinery or tools.

Metronidazole 500 mg/100 ml contains sodium

This medicine contains 3.22 mg sodium (main component of cooking/ table salt) in each ml.

This is equivalent to 0.16% of the recommended maximum daily dietary intake of sodium for an adult.

• 3. How METRONIDAZOLE 500 MG/100 ML will be given to you

Dosage

Dosage depends on the nature and severity of your illness, your age and body weight, and your individual response to treatment.

The following dosages are usually prescribed:

Adults and adolescents

Treatment of infections:

You may be given 100 ml of the medicine (corresponding to 500 mg of metronidazole) every 8 hours.

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SUMMARY OF PRODUCT CHARACTERISTICS

• B. Braun Melsungen AG, 34209 Melsungen, Germany

Metronidazole 500 mg/100 ml Solution for Infusion

• 1 NAME OF THE MEDICINAL PRODUCT

Metronidazole 500mg/100ml Solution for Infusion

• 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 ml of solution contains 5 mg of metronidazole

100 ml of solution contain 500 mg of metronidazole

Excipient with known effect:

1 ml solution contains

Sodium chloride 7.4 mg

Disodium phosphate dodecahydrate 1.5 mg

Electrolyte content (per 100 ml):

Sodium 14 mmol

Chloride 13 mmol

This medicinal product contains 14 mmol (or 322 mg) sodium per 100 ml.

For the full list of excipients, see section 6.1

• 3 PHARMACEUTICAL FORM

Solution for infusion;

Clear, colourless or slightly yellowish aqueous solution

• 4 CLINICAL PARTICULARS

  • 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 500mg/100ml 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 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.

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.

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.

This medicinal product contains 14 mmol (or 322 mg) sodium per 100 ml. This is to be taken into consideration for patients on a controlled sodium diet.

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

Amiodarone

QT interval prolongation and torsade de pointes have been reported with the coadministration 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

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.

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.

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.

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 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.

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As an alternative you may receive 200 – 300 ml (corresponding to 1000 –1500 mg of metronidazole) as a single dose. In most cases treatment will ■ take 7 days. Only exceptionally treatment may be continued beyond this time, although a duration of 10 days should not normally be exceeded.

The dose will be the same for patients with kidney diseases.

For patients with liver diseases, lower doses may be required.

If you were treated by artificial kidney your doctor will schedule your infusion after dialysis has been finished. No routine dose adjustment is necessary.

Prevention of infections that might occur after operations

When used for prevention of infection in surgery, you may be given 500 mg of the medicine before the operation. The dose will be repeated 8 and 16 hours after the operation.

The Elderly:

Your doctor will give you this medicine only with special caution.

Children

Dosing in children is based on body weight (BW).

Treatment of infections:

Age	Dosage
8 weeks to 12 years	20 – 30 mg of metronidazole per kg BW per day as a single dose or divided into 7.5 mg of metronidazole per kg BW every 8 hours. The daily dose may be increased to 40 mg of metronidazole per kg BW if infection is severe.
Under 8 weeks	15 mg of metronidazole per kg BW as a single dose daily or divided into 7.5 mg per kg BW every 12 hours.
Newborns of less than 40 weeks gestational age	As metronidazole may accumulate in these patients during the first week of life, the concentration of metronidazole in the blood will be checked after a few days of treatment

Usually treatment will take 7 days.

Prevention of infections that might occur after operations:

Age	Dosage
Less than 12 years	20 – 30 mg of metronidazole per kg BW as a single dose given 1 – 2 hours before surgery
Newborns of less than 40 weeks gestational age	10 mg of metronidazole per kg BW as a single dose before surgery

Method of administration and duration of treatment

Metronidazole 500 mg/100 ml is administered through a drip directly into a vein (intravenous infusion.

The infusion of one bottle usually takes 60 minutes, but it should not be done within less than 20 minutes.

This medicine may be diluted in a suitable vehicle solution for infusion.

The entire metronidazole treatment period is usually 7 days and must not exceed 10 days unless this is absolutely necessary (see also “Take special care with Metronidazole 500 mg/100 ml”).

If you are concurrently receiving other antibiotics your doctor will give you those medicines separately.

If you receive more Metronidazole 500 mg/100 ml than you should

Undesirable effects, as described in the next section, may occur as signs or symptoms of an overdose. Single oral doses of metronidazole, up to 12 g have been reported in suicide attempts and accidental overdoses. Symptoms were limited to vomiting, ataxia and slight disorientation. There is no known specific antidote or specific treatment of a massive overdose, but metronidazole can be removed by dialysis (that is treatment with artificial kidney) from the body.

4. possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Side effects occur mostly at high doses or with prolonged use.

The following side effects may be serious and, therefore, require immediate treatment:

Rare (may affect up to 1 in 1,000 people):

• Severe persistent diarrhoea (possibly a symptom of a severe bowel infection called pseudomembranous colitis, see below)
• Severe acute hypersensitivity reactions up to allergic shock

Very rare (may affect up to 1 in 10,000 people):

• White blood cell and platelet counts may decrease during treatment (granulocytopaenia, agranulocytosis, pancytopaenia, thrombocyto-paenia).
• Hepatitis (liver inflammation), jaundice, inflammation of the pancreas (isolated reports)
• Brain disorders, lack of coordination
• Severe inflammatory rash on mucous membranes and the skin with fever, redness and blistering, in extremely rare cases up to skin detachment over extended areas (Stevens-Johnson Syndrome, toxic epidermal necrolysis)

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

• Mild to moderate hypersensitivity reactions, swelling of your face, mouth, throat and/or tongue (angioedema).
• Gaze spasm, damage or inflammation of the nerves of your eyes
• Reduced white blood cell, count (leucopaenia), severe anaemia (aplastic anaemia)
• Seizures, nervous disorders such as numbness, pain, furry sensation or tingling in the arms or legs
• Brain fever not caused by bacterials (aseptic meningitis)

Other side effects include

Common (may affect up to 1 in 10 people):

• Infections with yeasts (e.g. genital infections).

Uncommon (may affect up to 1 in 100 people):

• Darkened urine (due to a metabolite of metronidazole)

Rare (may affect up to 1 in 1,000 people):

• Changes in ECG

Very rare (may affect up to 1 in 10,000 people):

• Psychotic disorders, including states of confusion, hallucination
• Headache, dizziness, drowsiness, fever, disturbance of sight and movement, giddiness, speech defects, convulsions
• Visual disturbances, e.g. double vision, short-sightedness
• Liver function disorders (such as elevated serum levels of certain enzymes and bilirubin)
• Joint and muscle pain

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

• Sickness, feeling sick, diarrhoea, inflammation of tongue or mouth, belching and bitter taste, metallic taste, pressure above the stomach, furry tongue
• Difficulty swallowing
• Anorexia
• Sad (depressed) mood
• Sleepiness or sleeplessness, muscle twitching
• Reddening and itching of the skin (erythema multiforme)
• Vein wall irritation (to the point of inflamed veins and thrombosis) after intravenous administration, states of weakness, fever

Emergency management of pseudomembranous enterocolitis

In the event of severe persistent diarrhoea, you must promptly inform your doctor because this may be due to pseudomembranous colitis, a serious condition that must be treated immediately. Your doctor will stop metronidazole and provide appropriate treatment. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in the package leaflet. You can also report side effects directly via the Yellow Card Scheme at: or search for MHRA Yellow Card in the Google Play or Apple App Store.

By reporting side effects, you can help provide more information on the safety of this medicine.

5. how to store metronidazole 500 mg/100 ml

Keep this medicine out of the sight and reach of children.

Keep bottles in the carton in order to protect from light.

Do not use this medicine after the expiry date which is stated on the container and carton. The expiry date refers to the last day of that month.

Use only if the solution is clear and free of visible particles, and the bottle and closure are intact.

This medicinal product is intended for single use only. Discard any unused portions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect environment.

6. contents of the pack and other information

What METRONIDAZOLE 500 MG/100 ML contains:

• – The active substance is metronidazole. 1 ml Metronidazole 500 mg/100 ml solution for infusion contains 5 mg metronidazole. One 100ml polyethylene bottle contains 500 mg metronidazole.

• – The other ingredients are sodium chloride, disodium phosphate dodecahydrate, citric acid monohydrate, water for injections

What Metronidazole 500 mg/100 ml looks like and contents of the pack

Metronidazole 500 mg/ 100ml is a clear, colourless or slightly yellowish aqueous solution. Metronidazole 500 mg/ 100ml is supplied in

• 100ml polyethylene bottles, available in packs of 10 × 100 ml, 20 × 100 ml

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Braun Melsungen AG

Carl-Braun-StraBe 1

34212 Melsungen,

Germany

Postal address:

34209 Melsungen,

Germany

Tel. +49–5661–71–0

Fax +49–5661–71–4567

Manufacturer(s)

Braun Melsungen AG

Carl-Braun-StraBe 1

34212 Melsungen, Germany

Braun Medical, S.A.

Carretera de Terrassa 121

08191 RubL Barcelona, Spain

This leaflet was last revised in 12/2019.

This leaflet was last approved in

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• B. Braun Melsungen AG

34209 Melsungen, Germany

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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 : > 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)

Infections and infestations

Common: Superinfections with candida (e.g. genital infections)

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, 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

Skin and subcutaneous tissue disorders

Very rare: Allergic skin reactions, e. g. pruritus, urticaria, STEVENS-JOHNSON syndrome , toxic epidermal necrolysis

Not known : Erythema multiforme

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: 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.

• 5 PHARMACOLOGICAL PROPERTIES

• 5.1 Pharmacody­namic properties

Pharmaco-therapeutic group: Anti-infectives for systemic use – imidazole derivatives

ATC Code: J01X D01

Mechanism of action

Metronidazole itself is ineffective. It is a stable compound able to penetrate into microorganisms.

Under anaerobic conditions nitroso radicals acting on DNA are formed from metronidazole by the microbial pyruvate-ferredoxin-oxidoreductase, with oxidation of ferredoxin and flavodoxin. Nitroso radicals form adducts with base pairs of the DNA, thus leading to breaking of the DNA chain and consecutively to cell death.

PK/PD relationship

Metronidazole acts in a concentration dependent manner. The efficacy of metronidazole mainly depends on the quotient of the maximum serum concentration (cmax) and the minimum inhibitory concentration (MIC) relevant for the microorganism concerned.

Breakpoints

For the testing of metronidazole usual dilution series are applied. The following minimum inhibitory concentration have been established to distinguish susceptible from resistant microorganisms:

EUCAST (European Committee on Antimicrobial Susceptibility Testing, Version 1.3, January 5, 2011) breakpoints separating susceptible (S) from resistant organisms ® are as follows:

Gram-positive anaerobes (S: < 4 mg/l R > 4 mg/l)

Gram-negative anaerobes (S: < 4 mg/l R > 4 mg/l)

List of susceptible and resistant organisms.

Commonly susceptible species

Anaerobes

Bacteroides fragilis

Clostridium difficile o

Clostridium perfringens!:A

Eubacterium

Fusobacterium spp. o

Peptoniphilus spp. o

Peptostreptococcus spp. o

Porphyromonas spp. o

Prevotella spp.

Veillonella spp. o

Other micro-organisms Entamoeba histolyticao Gardnerella vaginaliso Giardia lamblia° Trichomonas vaginaliso

Inherently resistant organisms All obligate aerobes

Gram-positive micro-organisms Actinomyces spp.

Enterococcus spp. Propionibacterium acnes Staphylococcus spp. Streptococcus spp.

Gram-negative micro-organisms Enterobacteriaceae Haemophilus spp. Mobiluncus

o At the time of publication of these tables, no up-to-date data were available. In primary literature, standard reference books and therapy recommendations susceptibility of the respective strains is assumed.

• 4 Only to be used in patients with allergy to penicillin

Mechanisms of resistance to metronidazole

The mechanisms of metronidazole resistance are still understood only in part. Strains of Bacteroides being resistant to metronidazole possess genes encoding nitroimidazole reductases converting nitroimidazoles to aminoimidazoles. Therefore the formation of the antibacterially effective nitroso radicals is inhibited.

There is full cross resistance between metronidazole and the other nitroimidazole derivatives (tinidazole, ornidazole, nimorazole).

The prevalence of acquired resistance of individual species may vary, depending on region and time. Therefore especially for the adequate treatment of severe infections specific local information regarding resistance should be available. If there is doubt about the efficacy of metronidazole due to the local resistance situation, expert advice should be sought. Especially in the case of severe infections or failure of treatment, microbiological diagnosis including determination of species of the microorganism and its susceptibility to metronidazole is required.

• 5.2 Pharmacoki­netic properties
  
  Absorption:

  Metronidazole is readily absorbed from the gastrointestinal tract and the oral bioavailability is > 90%. Consequently, the same mg dose will result in similar exposure (AUC) when switching between intravenous and oral dosing.

Distribution:

Metronidazole is widely distributed in body tissues after injection. It also diffuses across the placenta, and is found in breast milk of nursing mothers in concentrations equivalent to those in serum. Protein binding is less than 20 %, the apparent volume of distribution is 36 litres.

Biotransforma­tion:

Metronidazole is metabolised in the liver by side-chain oxidation and glucuronide formation. Its metabolites include an acid oxidation product, a hydroxy derivative and glucuronide. The major metabolite in the serum is the hydroxylated metabolite, the major metabolite in the urine is the acid metabolite.

Elimination:

Approximately 80% of the substance is excreted in urine with less than 10% in the form of the unchanged drug substance. Small quantities are excreted via the liver. Elimination half-life is 8 (6–10) hours.

Characteristics in special patient groups:

Renal insufficiency delays excretion only to an unimportant degree. The elimination half-life of metronidazole remains unchanged in the presence of renal failure, however such patients retain the metabolites of metronidazole. The clinical significance of this is not known at present.

Delayed plasma clearance and prolonged serum half-life (up to 30 h) is to be expected in severe liver disease.

• 5.3 Preclinical safety data
  
  Repeated dose toxicity

  Following repeated administration ataxia and tremor were observed in the dog and a dose-dependent increase in hepatocellular degeneration was observed in the monkey during a 12 month study.

Mutagenic and tumorigenic potential

Metronidazole was mutagenic in bacteria after nitroreduction, however it was not mutagenic in mammalian cells in vitro and in vivo. In addition, DNA damage was not observed in the lymphocytes of patients treated with metronidazole.

There is evidence to suggest that metronidazole is tumorigenic in the mouse and rat. There was an increase in the incidence of lung tumours in mice (after the oral administration of 3.1-fold the maximum recommended human dose of metronidazole of 1,500 mg/d), however, this does not seem to be due to a genotoxic mechanism as no changes in the mutation rates were observed in various organs of transgenic mice following high doses of metronidazole.

Reproduction toxicity

No teratogenicity or embryotoxicity was observed in the rat or rabbit.

Following repeated administration for 26–80 weeks to rats, testicular and prostatic dystrophy were observed at high doses (14.2 to 28.5-fold the maximum recommended human dose of metronidazole of 1,500 mg/d).

• 6 PHARMACEUTICAL PARTICULARS

  • 6.1 List of excipients

Sodium chloride,

Disodium phosphate dodecahydrate, Citric acid monohydrate, Water for injections

• 6.2 Incompati­bilities

In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products.

• 6.3 Shelf life
  
  Unopened

  3 years.

After first opening the container

Unused contents must be discarded and not be stored for later use.

• 6.4 Special precautions for storage

Do not store above 25 °C.

Keep the container in the outer carton in order to protect from light.

• 6.5 Nature and contents of container

The product is supplied in:

• – bottles of low-density polyethylene, contents: 100 ml available in packs of 10 × 100 ml, 20 × 100 ml

Not all pack sizes may be marketed.

• 6.6 Special precautions for disposal

No special requirements

Other handling instructions:

For single use only. Discard container and any unused contents after use. Only to be used if solution is clear and colourless or slightly yellowish and the container and its closure do not show visible signs of damage.

• 7 MARKETING AUTHORISATION HOLDER

• B. Braun Melsungen AG

Carl-Braun-StraBe 1

34212 Melsungen, Germany

Postal address:

34209 Melsungen, Germany

Phone: +49/5661/71–0

Fax: +49/5661/71–4567

• 8 MARKETING AUTHORISATION NUMBER(S)

PL 03551/0033

• 9 DATE OF FIRST AUTHORISATION/RE­NEWAL OF THE AUTHORISATION

26/03/2004

• 10 DATE OF REVISION OF THE TEXT

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SUMMARY OF PRODUCT CHARACTERISTICS

• B. Braun Melsungen AG, 34209 Melsungen, Germany

Metronidazole 500 mg/100 ml Solution for Infusion

• 1 NAME OF THE MEDICINAL PRODUCT

Metronidazole 500mg/100ml Solution for Infusion

• 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 ml of solution contains 5 mg of metronidazole

100 ml of solution contain 500 mg of metronidazole

Excipient with known effect:

1 ml solution contains

Sodium chloride 7.4 mg

Disodium phosphate dodecahydrate 1.5 mg

Electrolyte content (per 100 ml):

Sodium 14 mmol

Chloride 13 mmol

This medicinal product contains 14 mmol (or 322 mg) sodium per 100 ml.

For the full list of excipients, see section 6.1

• 3 PHARMACEUTICAL FORM

Solution for infusion;

Clear, colourless or slightly yellowish aqueous solution

• 4 CLINICAL PARTICULARS

  • 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 500mg/100ml 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 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.

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.

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.

This medicinal product contains 14 mmol (or 322 mg) sodium per 100 ml. This is to be taken into consideration for patients on a controlled sodium diet.

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

Amiodarone

QT interval prolongation and torsade de pointes have been reported with the coadministration 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

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.

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.

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.

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 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.

B|BRAUN

131/429901/1219

As an alternative you may receive 200 – 300 ml (corresponding to 1000 –1500 mg of metronidazole) as a single dose. In most cases treatment will ■ take 7 days. Only exceptionally treatment may be continued beyond this time, although a duration of 10 days should not normally be exceeded.

The dose will be the same for patients with kidney diseases.

For patients with liver diseases, lower doses may be required.

If you were treated by artificial kidney your doctor will schedule your infusion after dialysis has been finished. No routine dose adjustment is necessary.

Prevention of infections that might occur after operations

When used for prevention of infection in surgery, you may be given 500 mg of the medicine before the operation. The dose will be repeated 8 and 16 hours after the operation.

The Elderly:

Your doctor will give you this medicine only with special caution.

Children

Dosing in children is based on body weight (BW).

Treatment of infections:

Age	Dosage
8 weeks to 12 years	20 – 30 mg of metronidazole per kg BW per day as a single dose or divided into 7.5 mg of metronidazole per kg BW every 8 hours. The daily dose may be increased to 40 mg of metronidazole per kg BW if infection is severe.
Under 8 weeks	15 mg of metronidazole per kg BW as a single dose daily or divided into 7.5 mg per kg BW every 12 hours.
Newborns of less than 40 weeks gestational age	As metronidazole may accumulate in these patients during the first week of life, the concentration of metronidazole in the blood will be checked after a few days of treatment

Usually treatment will take 7 days.

Prevention of infections that might occur after operations:

Age	Dosage
Less than 12 years	20 – 30 mg of metronidazole per kg BW as a single dose given 1 – 2 hours before surgery
Newborns of less than 40 weeks gestational age	10 mg of metronidazole per kg BW as a single dose before surgery

Method of administration and duration of treatment

Metronidazole 500 mg/100 ml is administered through a drip directly into a vein (intravenous infusion.

The infusion of one bottle usually takes 60 minutes, but it should not be done within less than 20 minutes.

This medicine may be diluted in a suitable vehicle solution for infusion.

The entire metronidazole treatment period is usually 7 days and must not exceed 10 days unless this is absolutely necessary (see also “Take special care with Metronidazole 500 mg/100 ml”).

If you are concurrently receiving other antibiotics your doctor will give you those medicines separately.

If you receive more Metronidazole 500 mg/100 ml than you should

Undesirable effects, as described in the next section, may occur as signs or symptoms of an overdose. Single oral doses of metronidazole, up to 12 g have been reported in suicide attempts and accidental overdoses. Symptoms were limited to vomiting, ataxia and slight disorientation. There is no known specific antidote or specific treatment of a massive overdose, but metronidazole can be removed by dialysis (that is treatment with artificial kidney) from the body.

4. possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Side effects occur mostly at high doses or with prolonged use.

The following side effects may be serious and, therefore, require immediate treatment:

Rare (may affect up to 1 in 1,000 people):

• Severe persistent diarrhoea (possibly a symptom of a severe bowel infection called pseudomembranous colitis, see below)
• Severe acute hypersensitivity reactions up to allergic shock

Very rare (may affect up to 1 in 10,000 people):

• White blood cell and platelet counts may decrease during treatment (granulocytopaenia, agranulocytosis, pancytopaenia, thrombocyto-paenia).
• Hepatitis (liver inflammation), jaundice, inflammation of the pancreas (isolated reports)
• Brain disorders, lack of coordination
• Severe inflammatory rash on mucous membranes and the skin with fever, redness and blistering, in extremely rare cases up to skin detachment over extended areas (Stevens-Johnson Syndrome, toxic epidermal necrolysis)

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

• Mild to moderate hypersensitivity reactions, swelling of your face, mouth, throat and/or tongue (angioedema).
• Gaze spasm, damage or inflammation of the nerves of your eyes
• Reduced white blood cell, count (leucopaenia), severe anaemia (aplastic anaemia)
• Seizures, nervous disorders such as numbness, pain, furry sensation or tingling in the arms or legs
• Brain fever not caused by bacterials (aseptic meningitis)

Other side effects include

Common (may affect up to 1 in 10 people):

• Infections with yeasts (e.g. genital infections).

Uncommon (may affect up to 1 in 100 people):

• Darkened urine (due to a metabolite of metronidazole)

Rare (may affect up to 1 in 1,000 people):

• Changes in ECG

Very rare (may affect up to 1 in 10,000 people):

• Psychotic disorders, including states of confusion, hallucination
• Headache, dizziness, drowsiness, fever, disturbance of sight and movement, giddiness, speech defects, convulsions
• Visual disturbances, e.g. double vision, short-sightedness
• Liver function disorders (such as elevated serum levels of certain enzymes and bilirubin)
• Joint and muscle pain

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

• Sickness, feeling sick, diarrhoea, inflammation of tongue or mouth, belching and bitter taste, metallic taste, pressure above the stomach, furry tongue
• Difficulty swallowing
• Anorexia
• Sad (depressed) mood
• Sleepiness or sleeplessness, muscle twitching
• Reddening and itching of the skin (erythema multiforme)
• Vein wall irritation (to the point of inflamed veins and thrombosis) after intravenous administration, states of weakness, fever

Emergency management of pseudomembranous enterocolitis

In the event of severe persistent diarrhoea, you must promptly inform your doctor because this may be due to pseudomembranous colitis, a serious condition that must be treated immediately. Your doctor will stop metronidazole and provide appropriate treatment. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in the package leaflet. You can also report side effects directly via the Yellow Card Scheme at: or search for MHRA Yellow Card in the Google Play or Apple App Store.

By reporting side effects, you can help provide more information on the safety of this medicine.

5. how to store metronidazole 500 mg/100 ml

Keep this medicine out of the sight and reach of children.

Keep bottles in the carton in order to protect from light.

Do not use this medicine after the expiry date which is stated on the container and carton. The expiry date refers to the last day of that month.

Use only if the solution is clear and free of visible particles, and the bottle and closure are intact.

This medicinal product is intended for single use only. Discard any unused portions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect environment.

6. contents of the pack and other information

What METRONIDAZOLE 500 MG/100 ML contains:

• – The active substance is metronidazole. 1 ml Metronidazole 500 mg/100 ml solution for infusion contains 5 mg metronidazole. One 100ml polyethylene bottle contains 500 mg metronidazole.

• – The other ingredients are sodium chloride, disodium phosphate dodecahydrate, citric acid monohydrate, water for injections

What Metronidazole 500 mg/100 ml looks like and contents of the pack

Metronidazole 500 mg/ 100ml is a clear, colourless or slightly yellowish aqueous solution. Metronidazole 500 mg/ 100ml is supplied in

• 100ml polyethylene bottles, available in packs of 10 × 100 ml, 20 × 100 ml

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Braun Melsungen AG

Carl-Braun-StraBe 1

34212 Melsungen,

Germany

Postal address:

34209 Melsungen,

Germany

Tel. +49–5661–71–0

Fax +49–5661–71–4567

Manufacturer(s)

Braun Melsungen AG

Carl-Braun-StraBe 1

34212 Melsungen, Germany

Braun Medical, S.A.

Carretera de Terrassa 121

08191 RubL Barcelona, Spain

This leaflet was last revised in 12/2019.

This leaflet was last approved in

B|BRAUN

• B. Braun Melsungen AG

34209 Melsungen, Germany

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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 : > 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)

Infections and infestations

Common: Superinfections with candida (e.g. genital infections)

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, 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

Skin and subcutaneous tissue disorders

Very rare: Allergic skin reactions, e. g. pruritus, urticaria, STEVENS-JOHNSON syndrome , toxic epidermal necrolysis

Not known : Erythema multiforme

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: 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.

• 5 PHARMACOLOGICAL PROPERTIES

• 5.1 Pharmacody­namic properties

Pharmaco-therapeutic group: Anti-infectives for systemic use – imidazole derivatives

ATC Code: J01X D01

Mechanism of action

Metronidazole itself is ineffective. It is a stable compound able to penetrate into microorganisms.

Under anaerobic conditions nitroso radicals acting on DNA are formed from metronidazole by the microbial pyruvate-ferredoxin-oxidoreductase, with oxidation of ferredoxin and flavodoxin. Nitroso radicals form adducts with base pairs of the DNA, thus leading to breaking of the DNA chain and consecutively to cell death.

PK/PD relationship

Metronidazole acts in a concentration dependent manner. The efficacy of metronidazole mainly depends on the quotient of the maximum serum concentration (cmax) and the minimum inhibitory concentration (MIC) relevant for the microorganism concerned.

Breakpoints

For the testing of metronidazole usual dilution series are applied. The following minimum inhibitory concentration have been established to distinguish susceptible from resistant microorganisms:

EUCAST (European Committee on Antimicrobial Susceptibility Testing, Version 1.3, January 5, 2011) breakpoints separating susceptible (S) from resistant organisms ® are as follows:

Gram-positive anaerobes (S: < 4 mg/l R > 4 mg/l)

Gram-negative anaerobes (S: < 4 mg/l R > 4 mg/l)

List of susceptible and resistant organisms.

Commonly susceptible species

Anaerobes

Bacteroides fragilis

Clostridium difficile o

Clostridium perfringens!:A

Eubacterium

Fusobacterium spp. o

Peptoniphilus spp. o

Peptostreptococcus spp. o

Porphyromonas spp. o

Prevotella spp.

Veillonella spp. o

Other micro-organisms Entamoeba histolyticao Gardnerella vaginaliso Giardia lamblia° Trichomonas vaginaliso

Inherently resistant organisms All obligate aerobes

Gram-positive micro-organisms Actinomyces spp.

Enterococcus spp. Propionibacterium acnes Staphylococcus spp. Streptococcus spp.

Gram-negative micro-organisms Enterobacteriaceae Haemophilus spp. Mobiluncus

o At the time of publication of these tables, no up-to-date data were available. In primary literature, standard reference books and therapy recommendations susceptibility of the respective strains is assumed.

• 4 Only to be used in patients with allergy to penicillin

Mechanisms of resistance to metronidazole

The mechanisms of metronidazole resistance are still understood only in part. Strains of Bacteroides being resistant to metronidazole possess genes encoding nitroimidazole reductases converting nitroimidazoles to aminoimidazoles. Therefore the formation of the antibacterially effective nitroso radicals is inhibited.

There is full cross resistance between metronidazole and the other nitroimidazole derivatives (tinidazole, ornidazole, nimorazole).

The prevalence of acquired resistance of individual species may vary, depending on region and time. Therefore especially for the adequate treatment of severe infections specific local information regarding resistance should be available. If there is doubt about the efficacy of metronidazole due to the local resistance situation, expert advice should be sought. Especially in the case of severe infections or failure of treatment, microbiological diagnosis including determination of species of the microorganism and its susceptibility to metronidazole is required.

• 5.2 Pharmacoki­netic properties
  
  Absorption:

  Metronidazole is readily absorbed from the gastrointestinal tract and the oral bioavailability is > 90%. Consequently, the same mg dose will result in similar exposure (AUC) when switching between intravenous and oral dosing.

Distribution:

Metronidazole is widely distributed in body tissues after injection. It also diffuses across the placenta, and is found in breast milk of nursing mothers in concentrations equivalent to those in serum. Protein binding is less than 20 %, the apparent volume of distribution is 36 litres.

Biotransforma­tion:

Metronidazole is metabolised in the liver by side-chain oxidation and glucuronide formation. Its metabolites include an acid oxidation product, a hydroxy derivative and glucuronide. The major metabolite in the serum is the hydroxylated metabolite, the major metabolite in the urine is the acid metabolite.

Elimination:

Approximately 80% of the substance is excreted in urine with less than 10% in the form of the unchanged drug substance. Small quantities are excreted via the liver. Elimination half-life is 8 (6–10) hours.

Characteristics in special patient groups:

Renal insufficiency delays excretion only to an unimportant degree. The elimination half-life of metronidazole remains unchanged in the presence of renal failure, however such patients retain the metabolites of metronidazole. The clinical significance of this is not known at present.

Delayed plasma clearance and prolonged serum half-life (up to 30 h) is to be expected in severe liver disease.

• 5.3 Preclinical safety data
  
  Repeated dose toxicity

  Following repeated administration ataxia and tremor were observed in the dog and a dose-dependent increase in hepatocellular degeneration was observed in the monkey during a 12 month study.

Mutagenic and tumorigenic potential

Metronidazole was mutagenic in bacteria after nitroreduction, however it was not mutagenic in mammalian cells in vitro and in vivo. In addition, DNA damage was not observed in the lymphocytes of patients treated with metronidazole.

There is evidence to suggest that metronidazole is tumorigenic in the mouse and rat. There was an increase in the incidence of lung tumours in mice (after the oral administration of 3.1-fold the maximum recommended human dose of metronidazole of 1,500 mg/d), however, this does not seem to be due to a genotoxic mechanism as no changes in the mutation rates were observed in various organs of transgenic mice following high doses of metronidazole.

Reproduction toxicity

No teratogenicity or embryotoxicity was observed in the rat or rabbit.

Following repeated administration for 26–80 weeks to rats, testicular and prostatic dystrophy were observed at high doses (14.2 to 28.5-fold the maximum recommended human dose of metronidazole of 1,500 mg/d).

• 6 PHARMACEUTICAL PARTICULARS

  • 6.1 List of excipients

Sodium chloride,

Disodium phosphate dodecahydrate, Citric acid monohydrate, Water for injections

• 6.2 Incompati­bilities

In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products.

• 6.3 Shelf life
  
  Unopened

  3 years.

After first opening the container

Unused contents must be discarded and not be stored for later use.

• 6.4 Special precautions for storage

Do not store above 25 °C.

Keep the container in the outer carton in order to protect from light.

• 6.5 Nature and contents of container

The product is supplied in:

• – bottles of low-density polyethylene, contents: 100 ml available in packs of 10 × 100 ml, 20 × 100 ml

Not all pack sizes may be marketed.

• 6.6 Special precautions for disposal

No special requirements

Other handling instructions:

For single use only. Discard container and any unused contents after use. Only to be used if solution is clear and colourless or slightly yellowish and the container and its closure do not show visible signs of damage.

• 7 MARKETING AUTHORISATION HOLDER

• B. Braun Melsungen AG

Carl-Braun-StraBe 1

34212 Melsungen, Germany

Postal address:

34209 Melsungen, Germany

Phone: +49/5661/71–0

Fax: +49/5661/71–4567

• 8 MARKETING AUTHORISATION NUMBER(S)

PL 03551/0033

• 9 DATE OF FIRST AUTHORISATION/RE­NEWAL OF THE AUTHORISATION

26/03/2004

• 10 DATE OF REVISION OF THE TEXT