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METRONIDAZOLE 500MG/100ML SOLUTION FOR INFUSION

Active substance(s): METRONIDAZOLE

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131/429901/0714

PACKAGE LEAFLET: INFORMATION FOR THE USER
B. Braun Melsungen AG, 34209 Melsungen, Germany

(in the following text named with Metronidazole 500 mg/100 ml)
Metronidazole

Read all of this leaflet carefully before you start using this medicine.
• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

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).

1. What Metronidazole 500 mg/100 ml is and what it is used for
2. Before you use Metronidazole 500 mg/100 ml
3. How to use Metronidazole 500 mg/100 ml
4. Possible side effects
5. How to store Metronidazole 500 mg/100 ml
6. Further information

schwarz

Format = 210 x 980 mm
2 Seiten

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

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 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. BEFORE YOU USE METRONIDAZOLE 500 MG/100 ML
Do not use 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.

Take special care with Metronidazole 500 mg/100 ml
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.)
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.

Taking or using other medicines
Please tell your doctor or pharmacist if you are taking or have recently
taken any other medicines, including medicines obtained without a prescription.
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.

Lätus

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.

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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.

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Metronidazole 500mg/100ml
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GIF – EP
Standort Rubi, Melsungen

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.

Font size: 9 pt.

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.

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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.

Using Metronidazole 500 mg/100 ml with food and drink
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 and breast-feeding
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.

Important information about some of the ingredients of Metronidazole 500 mg/100 ml
This medicine contains 14 mmol (or 322 mg) sodium per 100 ml. Your
doctor will bear this in mind if you are on a low sodium diet.

3. HOW TO USE METRONIDAZOLE 500 MG/100 ML
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.
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.

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SUMMARY OF PRODUCT CHARACTERISTICS
B. Braun Melsungen AG, 34209 Melsungen, Germany

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
Excipients:
1 ml solution contains
Sodium chloride
Disodium phosphate dodecahydrate
Electrolyte content (per 100 ml):
Sodium
Chloride

7.4 mg
1.5 mg
14 mmol
13 mmol

For a full list of excipients, see section 6.1

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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.
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 clostridium difficile), see section 4.8. This intestinal ­disease,
­precipitated by the antibiotic treatment, may be life-threatening and ­requires
immediate appropriate treatment. Anti-peristaltic medicinal ­products must
not be given.

The duration of therapy with metronidazole or drugs containing other nitroimidazoles should not exceed 10 days. Only in specific elective cases and
if definitely needed, the treatment period may be extended, accompanied by
appropriate clinical and laboratory monitoring. Repeat therapy should be restricted as much as possible and to specific elective cases only. These restrictions must be observed strictly because the possibility of metronidazole developing mutagenic activity cannot be safely excluded and because in animal
experiments an increase of the incidence of certain tumours has been noted.
Prolonged therapy with metronidazole may be associated with bone marrow depression, leading to an impairment of haematopoiesis. Manifestations
see section 4.8. Blood cell counts should be carefully monitored during prolonged therapy.
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 Interactions 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.
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.

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Metronidazole 500 mg/100 ml Solution for Infusion

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Metronidazole 500 mg/100 ml Solution for Infusion

131/429901/0714

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, Metronidazole 500 mg/100 ml can cause side effects,
although not everybody gets them.
Side effects occur mostly at high doses or with prolonged use.
The following terms are used to describe the frequency of side effects:
‘very common’ affects more than 1 of 10 treated patients
‘common’
affects 1 to 10 of 100 treated patients
‘uncommon’ affects 1 to 10 of 1,000 treated patients
‘rare’
affects 1 to 10 of 10,000 treated patients
‘very rare’
affects less than 1 of 10,000 treated patients
‘not known’ frequency cannot be estimated from the available data

The following side effects may be serious and, therefore, require immediate treatment:
Rare:
• 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:
• White blood cell and platelet counts may decrease during treatment
(granulocytopenia, agranulocytosis, pancytopenia, thrombocytopenia).
• Hepatitis (liver inflammation), jaundice, inflammation of the pancreas
(isolated reports)
• Brain disorders, lack of coordination
• brain fever not caused by bacterials (aseptic meningitis)
• 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:
• 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 (leucopenia), severe anaemia (aplastic
anaemia)
• Seizures, nervous disorders such as numbness, pain, furry sensation or
tingling in the arms or legs

Other side effects include
Common
• Infections with yeasts (e.g. genital infections)
Uncommon
• Darkened urine (due to a metabolite of metronidazole)
Rare
• Changes in ECG
Very rare:
• Psychotic disorders, including states of confusion, hallucination
• Headache, dizziness, drowsiness, fever, disturbance of sight and movement, giddiness, speech defects, convulsions
• V isual disturbances, e.g. double vision, short-sightedness
• Liver function disorders (such as elevated serum levels of certain enzymes and bilirubin)
• Allergic skin reactions like itching, hives
• Joint and muscle pain
Not known:
• 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:
www.mhra.gov.uk/yellowcard.
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 out of the reach and sight of children.
Keep bottles in the carton in order to protect from light.
Do not use Metronidazole 500 mg/100 ml 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. FURTHER 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 100-ml 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
• 100-ml 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-Straße 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-Straße 1
34212 Melsungen, Germany

Braun Medical, S.A.
Carretera de Terrassa 121
08191 Rubí, Barcelona, Spain

This leaflet was last approved in June 2014..

B|BRAUN

B. Braun Melsungen AG
34209 Melsungen, Germany

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.

  Gardnerella vaginalis°
  Giardia lamblia°
  Trichomonas vaginalis°

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)

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

Infections and infestations
Common: Superinfections with candida (e.g. genital infections)
Rare:
Pseudomembranous colitis
Blood and lymphatic system disorders
Very rare: granulocytopenia, agranulocytosis, pancytopenia and thrombocytopenia
Not known: Leucopenia, aplastic anaemia

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Immune system disorders
Rare:
• Severe acute systemic hypersensitivity reactions: anaphylaxis, up to anaphy lactic 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
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, pancreatitis
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 authorisation of the ­medicinal
product is important. It allows continued monitoring of the benefit/risk
­balance of the medicinal product. Healthcare professionals are asked to
­report any suspected adverse reactions via the Yellow Card Scheme at: www.
mhra.gov.uk/yellowcard.
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 12 g 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 (R) 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°
  Clostridium perfringens°∆
  Eubacterium
  Fusobacterium spp.°
  Peptoniphilus spp.°
  Peptostreptococcus spp.°
  Porphyromonas spp.°
  Prevotella spp.
  Veillonella spp.°
Other micro-organisms
  Entamoeba histolytica°

° 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.
Δ 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 x 100 ml, 20 x 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-Straße 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
14 June 1991 / 13 December 2003
10 DATE OF REVISION OF THE TEXT
June 2014

B|BRAUN

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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.

B. Braun Melsungen AG
34209 Melsungen, Germany

11.07.14 08:07

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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