Treatment and prophylaxis of infections caused by metronidazole
susceptible microorganisms (mainly anaerobic bacteria). See section
5.1 for further information.
Metronidazole Intravenous Infusion 5 mg/ml is indicated in adults
and children for the following indications:
• infections of the central nervous system (e. g. brain abscess,
meningitis)
• infections of lung and pleura (e. g. necrotising pneumonia, aspiration
pneumonia, lung abscess)
• endocarditis
• infections in the gastrointestinal tract and the abdominal area
(e.g. peritonitis, liver abscess, postoperative infections after colonic
and rectal surgery, purulent diseases in the abdominal and pelvic
cavities)
• gynaecologic infections (e. g. endometritis, after hysterectomy or
caesarean section, childbed fever, septic abortion)
• infections in the ear-nose-throat and tooth-mouth-jaw regions
(e. g. PLAUT-VINCENT-angina)
• bone and joint infections (e. g. osteomyelitis)
• gas gangrene
• septicaemia with thrombophlebitis.
In a mixed aerobic and anaerobic infection, antibiotics appropriate for
the treatment of the aerobic infection should be used in addition to
Metronidazole Intravenous Infusion 5 mg/ml.
A prophylactic use is always indicated prior to operations with a
high risk of anaerobic infections (gynaecologic and intra-abdominal
operations).
Consideration should be given to official guidance on the appropriate
use of antibacterial agents.

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
Usually a single dose of 1500 mg (300 ml) is given on the first day of
treatment followed by 1000 mg (200 ml) given as single doses on the
subsequent days.
Alternatively, 500 mg (100 ml) may be given every 8 hours. If medically
indicated a loading dose of 15 mg/kg body weight (BW) may be given
at the beginning of treatment
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 e.g. for the
eradication of infection from sites which cannot be drained or are
liable to endogenous recontamination by anaerobic pathogens from
the gut,oropharynx or genital tract. (See also section 4.4.)

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

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

Giardiasis:
> 10 years: 2000mg once daily for 3 days, or 400mg three times daily
for 5 days, or 500mg twice daily for 7 to 10 days
Alternatively, as expressed in mg per kg of body weight: 15-40mg/kg/
day divided in 2-3 doses.

Amoebiasis:
> 10 years: 400 to 800mg 3 times daily for 5-10 days
Alternatively, doses may be expressed by body weight: 35 to 50mg/kg
daily in 3 divided doses for 5 to 10 days, not to exceed 2400mg/day

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. Oral doses
of 200 mg or 400 mg 8 hourly to be started as soon as feasible.

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.
• Children < 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 gestation age < 40 weeks,
accumulation of metronidazole can occur during the first week of
life; therefore the concentrations of metronidazole in serum should
preferably be monitored after a few days 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

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

Giardiasis:
Children 7 to 10 years: 1000 mg once daily for 3 days
Chi ldren 3 to 7 years: 600 to 800mg once daily for 3 days
Chi ldren 1 to 3 years: 500mg once daily for 3 days
Alternatively, as expressed in mg per kg of body weight: 15-40mg/kg/
day divided in 2-3 doses.

Amoebiasis:
Children 7 to 10 years: 200 to 400mg 3 times daily for 5-10 days
Children 3 to 7 years: 100 to 200mg 4 times daily for 5-10 days
Children 1 to 3 years: 100 to 200mg 3 times daily for 5-10 days
Alternatively, doses may be expressed by body weight: 35 to 50mg/kg
daily in 3 divided doses for 5 to 10 days, not to exceed 2400mg/day

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

Patients with renal insufficiency
No dose reduction is required, see section 5.2.
In patients undergoing haemodialysis the conventional dose of
metronidazole should be scheduled after haemodialysis on dialysis
days to compensate the escape of metronidazole during the procedure.

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).
 

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 Intravenous Infusion 5 mg/ml 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.

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

In patients with severe liver damage or impaired haematopoiesis (e. g.
granulocytopenia), metronidazole should only be used if its expected
benefits clearly outweigh potential hazards.
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.
In the case of severe hypersensitivity reactions (e.g. anaphylactic shock),
treatment with Metronidazole Intravenous Infusion 5 mg/ml 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. Antiperistaltic
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.
Special warnings/precautions regarding excipients
This medicinal product contains 3.22 mg sodium per ml, equivalent
to 0.16 % of the WHO recommended maximum daily intake of 2 g
sodium for an adult.

Interference with laboratory tests
Metronidazole interferes with the enzymatic-spectrophotometric
determination of aspartate aminotransferase (AST), alanine
aminotransferase (ALT), lactate dehydrogenase (LDH), triglycerides
and glucose hexokinase resulting in decreased values (possibly down
to zero).
Metronidazole has a high absorbance at the wavelength at
which nicotinamide-adenine dinucleotide (NADH) is determined.
Therefore elevated liver enzyme concentrations may be masked by
metronidazole when measured by continuous-flow methods based
on endpoint decrease in reduced NADH. Unusually low liver enzyme
concentrations, including zero values, have been reported.

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 reabsorption
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.
Vitamin K antagonists
Concomitant treatment with metronidazole may potentiate the
anticoagulant effect of vitamin K antagonists, e.g. coumarin
derivatives, 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.
Mycophenolate mofetil
Substances that alter the gastrointestinal flora (e.g., antibiotics)
may reduce the oral bioavailability of mycophenolic acid products.
Close clinical and laboratory monitoring for evidence of diminished
immunosuppressive effect of mycophenolic acid is recommended
during concomitant therapy with anti-infective agents.
Phenytoin
Metronidazole inhibits the metabolism of concurrently administered
phenytoin, i.e. the plasma concentration of phenytoin is increased.
On the other hand, the efficacy of metronidazole is reduced when
phenytoin is administered concurrently.
Tacrolimus
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
Intake of alcoholic beverages must be avoided during metronidazole
therapy since adverse reactions such as dizziness and vomiting may
occur (disulfiram-like effect).

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 experiments metronidazole
did not show teratogenic effects (see section 5.3).
During the first trimester, Metronidazole Intravenous Infusion 5 mg/ml
should only be used to treat severe life-threatening infections, if there is
no safer alternative. During the second and third trimester, Metronidazole
Intravenous Infusion 5 mg/ml may also be used to treat other infections
if its expected benefits clearly outweigh any possible risk.
Pregnancy Category B
Breast-feeding
Since metronidazole is secreted into breastmilk, nursing is to be
interrupted during therapy. Also after the end of the therapy with
metronidazole, nursing should not be resumed before another 2 – 3
days because of the prolonged half-life period of metronidazole.
Fertility
Animal studies only indicate a potential negative influence of
metronidazole on the male reproductive system if high doses lying
well above the maximum recommended dose for humans were
administered.

Even when used as directed, metronidazole may alter reactivity so far
that the ability to drive or to use machinery is impaired. This holds
true to still a higher degree in combination with alcohol intake.

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, which may occur during or
after therapy, manifesting as severe persistent diarrhoea.
Details regarding emergency treatment see section 4.4.

Blood and lymphatic system disorders
Very rare: During therapy with metronidazole, decreases of
leukocyte and platelet counts (granulocytopenia,
agranulocytosis, pancytopenia and thrombocytopenia)
Not known: Leucopenia, aplastic anaemia.
During prolonged administration regular monitoring of blood cell
counts is mandatory.

Immune system disorders
Rare: Severe acute systemic hypersensitivity reactions:
anaphylaxis, up to anaphylactic shock.
Severe skin reactions, see “Skin and subcutaneous
disorders” below.
These severe reactions demand immediate therapeutic
intervention.
Not known: Mild to moderate hypersensitivity reactions, e. g. skin
reactions (see “Skin and subcutaneous disorders” below)
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, myoclonus, seizures, peripheral
neuropathy manifesting as paraesthesia, pain, furry
sensation, and tingling in the extremities
Aseptic meningitis

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

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), pancreatitis.

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
(isolated reports)

The two latter reactions demand immediate
therapeutic intervention
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 to
The National Pharmacovigilance and Drug Safety Centre (NPC)
Fax: +966-11-205-7662
Call NPC at +966-11-2038222,
Exts: 2317-2356-2353-2354-2334-2340.
Toll free phone: 8002490000
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc

Symptoms
As signs and symptoms of overdose the undesirable effects described
under section 4.8 may appear.
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.

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
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)
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.
Source: Zentralstelle für die Auswertung von Resistenzdaten (Z.A.R.S.)
bei systemisch wirkenden Antibiotika, Germany, January 2011

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
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)
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.
Source: Zentralstelle für die Auswertung von Resistenzdaten (Z.A.R.S.)
bei systemisch wirkenden Antibiotika, Germany, January 2011

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
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)
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.
Source: Zentralstelle für die Auswertung von Resistenzdaten (Z.A.R.S.)
bei systemisch wirkenden Antibiotika, Germany, January 2011

Commonly susceptible species

Anaerobes

Bacteroides fragilis=

Clostridium difficile

Clostridium perfringens

Fusobacterium spp.

Peptoniphilus spp.

Peptostreptococcus spp.

Porphyromonas spp.

Prevotella spp.

Veillonella spp.

Other micro-organismsp.

Entamoeba histolytica

Gardnerella vaginalis.

Giardia lamblia.

Trichomonas vaginalis.

 

Species for which acquired resistance may be a problem

Gram-negative aerobes

Helicobacter pylori

 

Inherently resistant organisms

All obligate aerobes

Gram-positive micro-organismss

Enterococcus spp.

Staphylococcus spp.

Streptococcus spp.

Gram-negative micro-organismss

Enterobacteriaceae

Haemophilus spp.

 

- 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.
- 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.
In H.pylori resistance to metronidazole is caused by mutations of a
gene that encodes NADPH nitroreductase. These mutations lead to
an exchange of amino acids, rendering the enzyme inactive. Thus the
step of activation of metronidazole to the active nitroso radical does
not take place.
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

Absorption:
Since Metronidazole Intravenous Infusion 5 mg/ml is infused
intravenously the bioavailability is 100%.
Distribution:
Metronidazole is widely distributed in body tissues after injection.
Metronidazole appears in most body tissues and fluids including
bile, bone, cerebral abscess, cerebro-spinal fluid, liver, saliva, seminal
fluid, and vaginal secretions, and achieves concentrations similar to
those in plasma. 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.
Paediatric population
See section 4.2.
Characteristics in special patient groups:
Renal insufficiency delays excretion only to an unimportant degree.
Delayed plasma clearance and prolonged serum half-life (up to 30 h)
is to be expected in severe liver disease

Single-dose toxicity
The lowest published toxic dose for intravenously administered
Metronidazole has been referred to as 30 mg/kg BW.

Repeated dose toxicity
In dogs, toxic effects after repeated administration appeared in the
form of ataxia and tremor. In investigations in monkeys a dosedependent
increase of hepatocellular degeneration was demonstrated
after administration over one year.

Mutagenic and tumorigenic potential
Metronidazole has been shown to be carcinogenic in the mouse
and in the rat following chronic oral administration however similar
studies in the hamster have given negative results. Epidemiological
studies have provided no clear evidence of an increased carcinogenic
risk in humans.
Metronidazole has been shown to be mutagenic in bacteria in vitro. In
studies conducted in mammalian cells in vitro. as well as in rodent or
humans in vivo, there was inadequate evidence of a mutagenic effect
of metronidazole, with some studies reporting mutagenic effects,
while others studies were negative.

Reproduction toxicity
No teratogenic or other embryotoxic effects have been observed in
investigations with rats and rabbits.
After repeated administration of metronidazole over 26 – 80 weeks to
rats, testicular and prostatic dystrophy has only been observed with
high doses.

Sodium chloride,
Disodium phosphate dodecahydrate,
Citric acid monohydrate,
Water for injections

This medicinal product must not be mixed with other medicinal
products except mentioned in section 6.6

Unopened 3 years. after first opening the container Unused contents must be discarded and not be stored for later use. after dilution according to directions From a microbiological point of view, dilutions should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 °C, unless dilution has taken place in controlled and validated aseptic conditions.

Keep the container in the outer carton in order to protect from light.
Storage conditions for diluted medicinal product see section 6.3.

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.

No special requirements

Other handling instructions:
For single use only. Discard container and any unused contents after
use.

The product can be diluted in sodium chloride 0.9 % w/v or glucose
5 % w/v solutions for infusion. For dilution procedures the usual
precautions of asepsis must be adhered to.

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