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

The prophylaxis of postoperative infections due to sensitive anaerobic bacteria particularly species of Bacteroides and anaerobic Streptococci, during abdominal, gynaecological gastrointestinal or colorectal surgery which carries a high risk of occurrence of this type of infection. The solution may also be used in combination with an antibiotic active against aerobic  bacteria

The treatment of severe intra-abdominal and gynaecological infections in which sensitive anaerobic bacteria particularly

Bacteriodes and anaerobic Streptococci have been identified or are suspected to be the cause
 

Metronidazole 500mg/100ml Intravenous Infusion should be infused intravenously at an approximate rate of 5 ml/minute (or one bag infused over 20 to 60 minutes). Oral medication should be substituted as soon as feasible
 

:Prophylaxis against postoperative infections caused by anaerobic bacteria

Primarily in the context of abdominal, (especially colorectal) and gynaecological surgery.
Antibiotic prophylaxis duration should be short, mostly limited to the post-operative period (24 hours but never more than 48 hours). Various schedules are possible.Adults: Intra-venous injection of single dose of 1000mg-1500mg, 30-60 minutes preoperatively or alternatively 500mg immediately before, during or after operation, then 500mg 8 hourly

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

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

:Anaerobic infections

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

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

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

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

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

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

Duration of Treatment

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

:Bacterial vaginosis

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

:Urogenital trichomoniasis

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

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

:Giardiasis

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

Children 7 to 10 years: 1000 mg once daily for 3 days
Children 3 to 7 years: 600 to 800 mg once daily for 3 days
Children 1 to 3 years: 500 mg once daily for 3 days

Alternatively, as expressed in mg per kg of body weight: 15-40 mg/kg/day divided in 2-3 doses

Amoebiasis
more than 10  years: 400 to 800 mg 3 times daily for 5-10 days

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

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

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

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

Eradication of helicobacter pylori in paediatric patients

As a part of a combination therapy, 20 mg/kg/day not to exceed 500 mg twice daily for 7- 14 days

Official guidelines should be consulted before initiating therapy

Elderly population

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

Patients with renal failure

.Routine adjustments of the dosage of Metronidazole are not considered necessary in the presence of renal failure No routine adjustment in the dosage of Metronidazole needs to be made in patients with renal failure undergoing intermittent peritoneal dialysis (IDP) or continuous ambulatory peritoneal dialysis (CAPD). However dosage reduction may be necessary when excessive concentrations of metabolites are found

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

Patients with advanced hepatic insufficiency
 

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

Caution is needed in patients with severe hepatic impairment. The dose of metronidazole should be reduced as necessary. Metronidazole is mainly metabolized by hepatic oxidation. Substantial impairment of Metronidazole clearance may occur in the presence of advanced hepatic insufficiency. The risk/benefit ratio of using Metronidazole to treat trichomoniasis in such  patients should be carefully considered (for dosage adjustment see section 4.2). Plasma levels of Metronidazole should be closely monitored

Caution is needed in patients with hepatic encephalopathy. Patients with severe hepatic encephalopathy metabolize metronidazole slowly, with resultant accumulation of metronidazole. This  may cause exacerbation of CNS adverse effects. The dose of metronidazole should be reduced as necessary

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- 

:Active central nervous system disease

 .Metronidazole should be used with caution in patients with active disease of the Peripheral and Central Nervous System Severe neurological disturbances (including seizures and peripheral and optic neuropathies) have been reported in patients treated with metronidazole. Stop metronidazole treatment if any abnormal neurologic symptoms occur such as ataxia, dizziness, confusion or any other CNS adverse reaction. The risk of aggravation of the neurological state should be considered in patients with fixed or progressive paraesthesia, epilepsy and active disease of the central nervous system except for brain abscess

Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia, dizziness, dysarthria, and accompanied by CNS lesions seen on magnetic resonance imaging

(MRI). CNS symptoms and CNS lesions, are generally reversible within days to weeks upon discontinuation of metronidazole

Aseptic meningitis can occur with metronidazole. Symptoms can start within hours of dose administration and generally resolve after metronidazole therapy is discontinued
 

Blood dyscrasis

Metronidazole should be used with caution in patients with evidence or history of blood dyscrasia as agranulocytosis, leukopenia and neutropenia have been observed following metronidazole administration

:Renal disease

.Metronidazole is removed during haemodialysis and should be administered after the procedure is finished

.Patients with renal impairment, including patients receiving peritoneal dialysis, should be monitored for signs of toxicity due to the potential accumulation of toxic metronidazole metabolites

:Sodium restricted patients

This medicinal product contains 13.5 mmol (310 mg) sodium per 100 mL. To be taken into consideration by patients on a controlled sodium die

Alcohol
Patients should be advised to discontinue consumption of alcoholic beverages or alcoholcontaining products before, during, and up to 72 hours after taking metronidazole because of a  disulfram-like effect (abdominal cramps, nausea, headaches, flushing, vomiting and tachycardia)

Intensive or prolonged metronidazole therapy

As a rule, the usual duration of therapy with i.v Metronidazole or other imidazole derivatives is usually less than 10 days

.As a rule, the usual duration of therapy with i.v Metronidazole or other imidazole derivatives is usually less than 10 days

Intensive or prolonged Metronidazole therapy should be conducted only under conditions of close surveillance for clinical and biological effects and under specialist direction. If prolonged therapy is required, the physician should bear in mind the possibility of peripheral neuropathy or leucopenia. Both effects are usually reversible

In case of prolonged treatment, occurrence of undesirable effects such as paraesthesia, ataxia, dizziness and convulsive crises should be checked. High dose regimes have been associated with transient epileptiform seizures.

Monitoring

Due to increased risk for adverse reactions, regular clinical and laboratory monitoring (including blood count) are advised in cases of high-dose, prolonged or repeatedtreatment, in case of antecedents of blood dyscrasia, in case of severe infection and insevere hepatic insufficiency

General
(Patients should be warned that Metronidazole may darken urine (due to Metronidazole metabolite

Not recommended concomitant therapy
Disulfiram: Concurrent use of metronidazole and disulfiram may result in psychotic reactions and confusion.
Metronidazole should not be given to patients who have taken disulfiram within the last two weeks

(Alcohol: Disulfiram-like effect (warmth, redness, vomiting, tachycardia

Alcohol beverage and drugs containing alcohol should be avoided. Patients should be advised not to take alcohol during

Alcohol beverage and drugs containing alcohol should be avoided. Patients should be advised not to take alcohol during

Concomitant therapy requiring special precautions
Oral anticoagulants (warfarin): metronidazole may increase the anticoagulant effects of warfarin and other oral anticoagulants, resulting in a prolongation of the prothrombin time and increased risk of haemorrhage (decrease in its liver catabolism). Patients taking metronidazole and warfarin or other oral coumarins concomitantly should have their prothrombin time and international normalized ratio (INR) monitored more frequently. Patients should be monitored for signs and symptoms of bleeding

A large number of patients have been reported showing an increase in oral anticoagulant activity whilst receiving concomitant antibiotic therapy. The infectious and inflammatory status of the patient, together with their age and general well-being are all risk factors in this context. However, in these circumstances it is not clear as to the part played by the disease itself or its treatment in the occurrence of prothrombin time disorders. Some classes of antibiotics are more likely to result in this interaction, notably fluoroquinolones, macrolides, cyclines, cotrimoxazole and some cephalosporins

Vecuronium (non depolarising curaremimetic): Metronidazole can potentialise the effects of vecuronium

Combination to be considered

5 Fluoro-uracile: increase in the toxicity of 5 fluoro-uracile due to a decrease of its clearance Lithium: lithium retention accompanied by evidence of possible renal damage has been reported in patients treated simultaneously with lithium and Metronidazole. Lithium treatment should be tapered or withdrawn before administering

Lithium: lithium retention accompanied by evidence of possible renal damage has been reported in patients treated simultaneously with lithium and Metronidazole. Lithium treatment should be tapered or withdrawn before administering

Cholestyramine may delay or reduce the absorption of Metronidazole

Phenytoin, barbiturates (phenobarbital): concomitant administration of drugs that induce microsomal liver enzyme activity, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole and therefore decrease its efficacy. Cimetidine: concomitant administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may cause decreased metabolism and reduced plasma clearance of metronidazole which may result in metronidazole toxicity

Phenytoin, barbiturates (phenobarbital): concomitant administration of drugs that induce microsomal liver enzyme activity, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole and therefore decrease its efficacy. Cimetidine: concomitant administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may cause decreased metabolism and reduced plasma clearance of metronidazole which may result in metronidazole toxicity

Busulfan: Plasma concentrations of busulfan may increase during concomitant treatment with metronidazole, which can result in serious busulfan toxicity such as sinusoidal obstruction syndrome, gastrointestinal mucositis, and hepatic Veno-occlusive disease

Laboratory tests

Metronidazole may immobilise Treponema and thus may lead to falsely positive Nelson's test

Metronidazole may interfere with serum aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), triglycerides, and glucose hexokinase determinations. Metronidazole causes an increase in ultraviolet absorbance at 340 nm resulting in falsely decreased values

Pregnancy

Metronidazole crosses the placental barrier

Clinical data on a large number of exposed pregnancies and animal data did not show a teratogenic or foetotoxic effect

However unrestricted administration of nitroimidazolene to the mother may be associated with a carcinogenic or mutagenic risk for the unborn or newborn child

Therefore Metronidazole should not be given during pregnancy unless clearly necessary
 

Lactation

Metronidazole is excreted in breast milk. During lactation either breast-feeding or Metronidazole should be discontinued

Fertility

There are no clinical data relating to the effect of metronidazole on fertility
Animal studies demonstrated adverse effects on the male reproductive system that are wholly or partially reversible after treatment withdrawal


 

No studies have been performed following intravenous treatment with Metronidazole on the ability to drive and use machines. Some adverse reactions to metronidazole such as seizure, dizziness, optic neuropathy, may impair the ability to drive or operate machines
 

Therefore it is recommended that patients should not drive or use machines.

 

There are no data available on adverse reactions from Baxter-sponsored clinical trials conducted with Metronidazole.

(The following adverse reactions have been reported with Metronidazole, listed by MedDRA System Organ Class (SOC

Preferred Term and frequency. The following frequency groupings are used: very common (≥1/10); common (≥1/100 and <1/10); uncommon (≥1/1,000 and <1/100); rare (≥1/10,000 and <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from the available data

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

Symptoms
In cases of overdose in adults, the clinical symptoms are usually limited to nausea,
vomiting and neurotoxic effects, including ataxia, slight disorientation, confusion,
seizures and peripheral neuropathy

Treatment
There is no specific treatment for Metronidazole overdose, Metronidazole infusion should be discontinued. Patients should be treated symptomatically

Metronidazole is an anti-infectious drug belonging to the pharmacotherapeutic group of
nitroimidazole derivatives, which have effect mainly on strict anaerobes. This effect is
probably caused by interaction with DNS and different metabolites.
Pharmacotherapeutic group: Antibacterials for systemic use: imidazole derivatives
ATC Code: J01XD01 and
Pharmacotherapeutic group: Antiprotozoals: nitroimidazole derivatives
ATC Code: P01AB01.
Metronidazole has antibacterial and antiprotozoal actions and is effective against
anaerobic bacteria and against Trichomonas vaginalis and other protozoa including
Entamoeba histolytica and Giardia lamblia.
Anti-microbial spectrum
The MIC breakpoints separating susceptible from intermediately susceptible and
intermediately susceptible from resistant organisms are as following:
S ≤ 4 mg/l and R > 4 mg/l
The prevalence of acquired resistance may vary geographically and with time for selected
species and local information is desirable, particularly when treating severe infections.
This information gives only approximate guidance on probabilities whether
microorganisms will be susceptible to Metronidazole or not
 

Distribution: After administration of a single 500 mg dose, mean Metronidazole peak
plasma concentrations of ca. 14 – 18 μg/ml are reached at the end of a 20 minute
infusion. 2-hydroxy-metabolite peak plasma concentrations of ca. 3μg/ml are obtained
after a 1 g single i.v. dose. Steady state Metronidazole plasma concentrations of about 17
and 13μg/ml are reached after administration of Metronidazole every 8 or 12 hours,
respectively.
Plasma protein binding is less than 10%, and the volume of distribution 1.1 ± 0.4 l/kg.
Metabolism: Metronidazole is metabolized in the liver by hydroxylation, oxidation and
glucuronidation. The major metabolites are a 2-hydroxy- and an acetic acid metabolite.
Elimination: More than 50% of the administered dose is excreted in the urine, as
unchanged Metronidazole (ca. 20% of the dose) and its metabolites. About 20% of the
dose is excreted with faeces. Clearance is 1.3 ± 0.3 ml/min/kg, while renal clearance is
about 0.15 ml/min/kg. The plasma elimination half-life of Metronidazole is ca. 8 hours,
and of the 2-hydroxy-metabolite ca. 10 hours.
Special patient groups: The plasma elimination half-life of Metronidazole is not
influenced by renal impairment, however this may be increased for 2-hydroxy- and an
acetic acid metabolite. In the case of haemodialysis, Metronidazole is rapidly excreted
and the plasma elimination half-life is decreased to ca. 2.5 h. Peritoneal dialysis does not
appear to affect the elimination of Metronidazole or its metabolites compared to patients
with renal impairment
In patients with impaired liver function, the metabolism of Metronidazole is expected to
decrease, leading to an increase in the plasma elimination half-life. In patients with
severe liver impairment, clearance may be decreased up to ca. 65%, resulting in an
accumulation of Metronidazole in the body
 

Metronidazole has been shown to be non-mutagenic in mammalian cells in vitro and in
vivo.
Metronidazole and a metabolite have been shown to be mutagenic is some tests with nonmammalian cells
Although Metronidazole has been shown to be carcinogenic in certain species of mice, it
was not carcinogenic in either rats or guinea pigs. There is no suspicion of
carcinogenicity in man.
Daily per oral metronidazole at 5-times the maximum human daily dose for greater than 4
weeks caused testicular toxicity and infertility in male rats. Fertility was restored in most
subjects by 8 weeks after cessation of treatment, whereas the lower testicular and
epididymal weights and sperm counts had improved but were still observed
 

Daily per oral metronidazole at approximately 6-times the maximum human daily dose
for ≥2 weeks caused testicular toxicity in male mice. Most indices of testicular toxicity
were restored within 2 months after cessation of treatment, whereas the lower testicular
and epididymal weights had improved but were still observed.
These studies demonstrate that the adverse effects of metronidazole on the male
reproductive system are wholly or partially reversible after treatment withdrawal
 

Sodium phosphate dibasic anhydrous
Citric acid
Sodium chloride
Water for injection
 

Do not use equipment containing aluminum (e.g., needles, cannulae) that would come in
contact with the drug solution as precipitates may form.
Metronidazole is incompatible with (includes but is not limited to):
- Aztreonam
- Cefamandole nafate
- Cefoxitin
- Penicillin G
In the absence of compatibility studies, this medicinal product must not be mixed with
other medicinal product
 

Store below 30°C, protect from light
 

Carton box containing transparent colorless (type II) glass vial containing 100 ml solution
sealed with bromobutyl rubber bungs with AL over-caps covered with polypropylene
plastic flip off seal disc + inner leaflet.
 

Use only if the solution is clear, without visible particles and if the container is
undamaged. Administer immediately following the insertion of infusion set.
Do not remove unit from overpouch until ready for use.
The inner bag maintains the sterility of the product.
Do not use plastic containers in series connections. Such use could result in air embolism
due to residual air being drawn from the primary container before the administration of
the fluid from the secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase
flow rates can result in air embolism if the residual air in the container is not fully
evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could
result in air embolism. Vented intravenous administration sets with the vent in the open
position should not be used with flexible plastic containers.
The solution should be administered with sterile equipment using an aseptic technique.
The equipment should be primed with the solution in order to prevent air entering the
system.
In patients maintained on intravenous fluids, Metronidazole 500mg/100ml Intravenous
Infusion may be diluted with appropriate volumes of 0.9% sodium chloride solution,
dextrose 5% - 0.9% sodium chloride solution, dextrose 5% w/v or potassium chloride
infusions (20 and 40 mmol/litre).
Using an incorrect administration technique might cause the appearance of fever
reactions due to the possible introduction of pyrogens. In the case of adverse reaction,
infusion must be stopped immediately.
Additives:
Additives known or determined to be incompatible should not be used.
Before adding a substance or medication, verify that it is soluble and stable in
metronidazole, and that the pH range of metronidazole is appropriate. Additives may be
incompatible. When introducing additives, the instructions for use of the medication to be
added and other relevant literature must be consulted (see Section 6.2).
Mix the solution thoroughly when additives have been introduced
Use only if the solution is clear, without visible particles and if the container is
undamaged. Administer immediately following the insertion of infusion set.
Do not remove unit from overpouch until ready for use.
The inner bag maintains the sterility of the product.
Do not use plastic containers in series connections. Such use could result in air embolism
due to residual air being drawn from the primary container before the administration of
the fluid from the secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase
flow rates can result in air embolism if the residual air in the container is not fully
evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could
result in air embolism. Vented intravenous administration sets with the vent in the open
position should not be used with flexible plastic containers.
The solution should be administered with sterile equipment using an aseptic technique.
The equipment should be primed with the solution in order to prevent air entering the
system.
In patients maintained on intravenous fluids, Metronidazole 500mg/100ml Intravenous
Infusion may be diluted with appropriate volumes of 0.9% sodium chloride solution,
dextrose 5% - 0.9% sodium chloride solution, dextrose 5% w/v or potassium chloride
infusions (20 and 40 mmol/litre).
Using an incorrect administration technique might cause the appearance of fever
reactions due to the possible introduction of pyrogens. In the case of adverse reaction,
infusion must be stopped immediately.
Additives:
Additives known or determined to be incompatible should not be used.
Before adding a substance or medication, verify that it is soluble and stable in
metronidazole, and that the pH range of metronidazole is appropriate. Additives may be
incompatible. When introducing additives, the instructions for use of the medication to be
added and other relevant literature must be consulted (see Section 6.2).
Mix the solution thoroughly when additives have been introduced