Consumer medicine information

DBL Metronidazole Intravenous Infusion

Metronidazole

BRAND INFORMATION

Brand name

DBL Metronidazole Intravenous Infusion

Active ingredient

Metronidazole

Schedule

What is in this leaflet

This leaflet answers some common questions about DBL Metronidazole Intravenous Infusion. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you receiving Metronidazole against the benefits this medicine is expected to have for you.

If you have any concerns about receiving this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What DBL Metronidazole Intravenous Infusion is used for

Metronidazole is used to treat

serious infections caused by bacteria and other organisms when metronidazole cannot be given orally
prevent certain infections that may occur during surgery.

Metronidazole is an antibiotic.

Metronidazole works by killing or stopping the growth of bacteria and other organisms causing these infections.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed metronidazole for another reason.

This medicine is not addictive.

This medicine is available only with a doctor's prescription.

Before you are given DBL Metronidazole Intravenous Infusion

When you must not be given it

You must not be given DBL Metronidazole Intravenous Infusion if:

you have an allergy to:

Metronidazole or any other medicines used to treat infections
any of the ingredients listed at the end of this leaflet

Symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

You must not be given this medicine if:

you have or have had a blood disorder
you have a disease or disorder of the brain, spinal cord or nerves

If you are not sure whether you should be given DBL Metronidazole Intravenous Infusion, contact your doctor.

Before you are given it

Tell your doctor if:

you have any allergies to any other medicines or any other substances such as foods, preservatives or dyes, or you have or have ever had any other health problems/ medical conditions including:

blood disease or history of blood disease
disease or disorder of the brain, spinal cord or nerves
any heart problems
any kidney problems
any liver problems
Crohn’s disease, an inflammatory disease of the intestines

Tell your doctor if:

you drink alcohol.

Do not drink alcohol during (and for one day after stopping) treatment with metronidazole.

you are on a low sodium diet.

you plan to become pregnant or breastfeed.

Metronidazole may affect your developing baby if you are given it during pregnancy.

You should discuss with your doctor the need for metronidazole treatment during pregnancy, and the possible risks and benefits of using metronidazole during pregnancy.

you are breast-feeding or intend to breast-feed.

Metronidazole passes into breast milk and may affect your baby. The use of metronidazole is not recommended while breast- feeding. Your doctor will discuss the risks and benefits of using it when breast-feeding.

If you have not told your doctor about any of the above, tell them before you start receiving metronidazole.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines may interfere with metronidazole. These include:

warfarin, a medicine used to prevent blood clots
disulfiram, a medicine used to treat chronic alcohol dependence
some anticancer medicines such as BiCNU (carmustine), cyclophosphamide, fluorouracil and 5-fluorouracil
azathioprine, a medicine used to suppress the immune system
lithium, a medicine used to treat some types of depression
corticosteroids such as prednisone or cortisone
cimetidine, a medicine used to treat ulcers
phenytoin, a medicine used to treat convulsions
phenobarbitone, a medicine to treat convulsions or for sedation
cyclosporin, a medicine used to help prevent organ transplant rejection or to treat certain problems with the immune system

These medicines may be affected by metronidazole or may affect how well it works. You may need different amounts of your medicine or you may need to take different medicines. Your doctor will advise you.

Do not drink alcohol while you are being given Metronidazole Intravenous Infusion. Metronidazole and alcohol together can cause abdominal cramps, nausea, vomiting, headaches and flushing.

Talk to your doctor about the need for an additional method of contraception while receiving DBL Metronidazole Intravenous Infusion. Some antibiotics may decrease the effectiveness of some birth control pills, although this has not been shown with metronidazole.

Your doctor and pharmacist may have more information on medicines to be careful with or avoid while using metronidazole.

How DBL Metronidazole Intravenous Infusion is given

Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand these instructions, ask your doctor or pharmacist for help.

How it is given

DBL Metronidazole Intravenous Infusion is given by injection into a vein.

It must only be given by a doctor or nurse.

Your doctor will decide what dose of metronidazole to give you and how long you will need to be given this medicine for.

The dose will vary from patient to patient. This will depend on your age, weight, type of infection and how well your kidneys and liver are working. However, the usual adult dose of Metronidazole Intravenous Infusion is 500mg every eight hours for the course of treatment, as decided by your doctor.

Your doctor will decide the right dose for you. However, depending on your condition and how you react to the medicine, your doctor may give you a different dose.

If you are given too much (overdose)

As DBL Metronidazole Intravenous Infusion will most likely be given to you in hospital or clinic, it is very unlikely that you will receive an overdose. However if you experience severe side effects tell your doctor immediately.

Symptoms of an overdose may include the side effects listed below in the 'Side Effects' section but are usually of a more severe nature.

Please contact the Poisons Information Centre in Australia on 131 126 for advice on overdose management.

Ask your doctor or pharmacist if you have any concerns.

While you are being given DBL Metronidazole Intravenous Infusion

Things you must do

If you become pregnant while you are being given DBL Metronidazole Intravenous Infusion, tell your doctor immediately.

If the symptoms of your infection do not improve, or if they become worse, tell your doctor.

If you are using DBL Metronidazole Intravenous Infusion for 10 days or longer, make sure you have any tests of your blood and nervous system that your doctor may request.

If you need to have any other blood tests, tell your doctor you are receiving DBL Metronidazole Intravenous Infusion. Metronidazole may affect the results of some laboratory tests.

If you get a sore, white mouth or tongue while receiving or soon after stopping DBL Metronidazole Intravenous Infusion, tell your doctor. Also tell your doctor if you get vaginal itching or discharge. This may mean you have a fungal / yeast infection called thrush. Sometimes the use of metronidazole allows fungi / yeast to grow and the above symptoms to occur. Metronidazole does not work against fungi / yeast.

If you get severe diarrhoea tell your doctor, pharmacist or nurse immediately. Do this even if it occurs several weeks after Metronidazole Intravenous Infusion has been stopped. Diarrhoea may mean that you have a serious condition affecting your bowel. You may need urgent medical care. Do not take any diarrhoea medicine without first checking with your doctor.

If you are about to start using any new medicine, tell your doctor and pharmacist that you are being treated with Metronidazole Intravenous Infusion.

Tell all doctors, dentists and pharmacists that you are being treated with Metronidazole.

Things you must not do

Do not drink any alcohol or any alcoholic drinks while being treated with (and for one day after stopping) DBL Metronidazole Intravenous Infusion. The use of alcohol with metronidazole may make you feel sick, vomit or have stomach cramps, headaches or flushing.

Things to be careful of

Be careful driving or operating machinery until you know how DBL Metronidazole Intravenous Infusion affects you. This medicine may cause dizziness, confusion, hallucination (hearing or seeing strange or unusual things), convulsions (“fits”) or affect how you see things.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using DBL Metronidazole Intravenous Infusion.

Metronidazole helps most people with infections, but it may have unwanted side effects in a few people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Tell your doctor if you notice any of the following and they worry you:

nausea, vomiting, loss of appetite
abdominal pain, indigestion or discomfort
constipation/diarrhoea
metallic or unpleasant taste in the mouth
sore red mouth
ulcers or cold sores
oral thrush - white, furry, sore tongue and/or mouth
swollen red or sore tongue
vaginal thrush - sore and itchy vagina and/or discharge
dryness of the mouth, vagina or genitals
loss of sex drive or painful sex
joint pains
nasal congestion

Tell your doctor immediately if you notice any of the following:

confusion, irritability, depression, disorientation
clumsiness, lack of co-ordination, problems with moving or balancing
difficulty in speaking
headache, stiff neck and extreme sensitivity to bright light
dizziness or spinning sensation
problems with sleeping
fits or seizures
ringing/ persistent noise in the ears (tinnitus) or other hearing problems
blurred vision/double vision or other eye problems
yellowing of the eyes/skin or flushing
swelling or redness along the vein which is extremely tender when touched.
frequent or painful urination
blood or pus in the urine
more or darker urine than normal
loss of control of your bladder or bowels
feeling of pressure around the pelvis
sore back passage, sometimes with bleeding or discharge

These may be serious side effects. You may need urgent medical attention.

If any of the following happen, tell your doctor immediately or go to casualty at your nearest hospital:

rash, itchiness, hives
swelling of the face, lips, mouth, throat or neck which may cause difficulty swallowing or breathing
tingling or numbness of the hands or feet, pins and needles or muscle weakness
severe blisters and bleeding in the lips, eyes, mouth, nose and genitals
signs of frequent infections such as fever, severe chills, sore throat or mouth ulcers
severe abdominal cramps or stomach cramps
watery and severe diarrhoea, which may also be bloody

These are very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some patients.

Some of these side effects (changes in the liver, levels of blood cells or changes in heart rhythm) can only be found when your doctor does tests from time to time to check your progress.

After receiving DBL Metronidazole Intravenous Infusion

Storage

DBL Metronidazole Intravenous Infusion will be stored in the pharmacy or on the ward. The infusion is kept in a cool dry place, protected from light, where the temperature stays below 25°C.

Product description

What it looks like

DBL Metronidazole Intravenous Infusion is an almost colourless to pale yellow solution in plastic minibags.

Ingredients

DBL Metronidazole Intravenous Infusion contains metronidazole as the active ingredient. It also contains:

citric acid
dibasic sodium phosphate
sodium chloride
water for injections

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier

DBL Metronidazole Intravenous Infusion is supplied in Australia by:

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizer.com.au

Australian Registration Numbers

DBL Metronidazole Intravenous Infusion is available as 10 infusion bags per pack:

500mg in 100mL infusion bags
AUST R 129476

Date of Preparation

This leaflet was prepared in October 2019.

™=Trademark

Published by MIMS December 2019

BRAND INFORMATION

Brand name

DBL Metronidazole Intravenous Infusion

Active ingredient

Metronidazole

Schedule

1 Name of Medicine

Metronidazole.

6.7 Physicochemical Properties

Chemical Name: 2-(5-nitro-2-methylimidazol-1-yl)ethanol.
Molecular Formula: C₆H₉N₃O₃.
Molecular Weight: 171.2.

Chemical structure.

CAS number.

443-48-1.

2 Qualitative and Quantitative Composition

DBL Metronidazole Intravenous Infusion contains Metronidazole EP 5 mg/mL, citric acid 0.36 mg/mL, dibasic sodium phosphate 0.6 mg/mL equivalent to dibasic sodium phosphate dodecahydrate 1.5 mg/mL, and sodium chloride 7.4 mg/mL in water for injections. Each mL contains 0.135 mmol sodium.
Metronidazole is a white or yellowish, crystalline powder, slightly soluble in water, in acetone, in alcohol and in methylene chloride.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

DBL Metronidazole Intravenous Infusion is an almost colourless to pale yellow, sterile, isotonic, preservative-free, ready to use solution.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Metronidazole is active in vitro against anaerobic bacteria and as an antiprotozoal agent. It does not appear to possess any clinically relevant activity against facultative anaerobes or obligate aerobes. Against susceptible organisms, metronidazole is generally bactericidal at concentrations equal to or slightly higher than the minimal inhibitory concentrations (MIC).
Metronidazole has been shown to have in vitro activity against many anaerobic Gram negative bacilli including Bacteroides fragilis and other Bacteroides sp., Fusobacterium, Eubacterium, Clostridium and anaerobic Streptococci. Metronidazole is also active against a wide range of pathogenic protozoa including Trichomonas vaginalis and other trichomonads, Entamoeba histolytica, Giardia lamblia, Balantidium coli and the causative organisms of active ulcerative gingivitis.

Susceptibility tests.

Dilution or diffusion techniques, either quantitative (MIC) or breakpoint, should be used following a regularly updated, recognised and standardised method (e.g. National Committee for Clinical Laboratory Standards). Standardised susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.
A report of 'susceptible' indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of 'intermediate' indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of 'resistant' indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Note.

The prevalence of resistance may vary geographically for selected species and local information on resistance is desirable, particularly when treating severe infections.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Note.

Polarographic estimation of metronidazole in serum or urine tends to give higher values than microbiological assay because the former measures both unchanged drug and metabolites. Erroneously high serum values may be obtained in the presence of severe renal failure because of the retention of metabolites in the blood.

Absorption.

Following intravenous infusion, peak plasma levels of metronidazole occur at the end of the infusion.

Distribution.

Metronidazole is distributed widely throughout body tissues both intracellularly and extracellularly. It is found in saliva and breast milk in concentrations equivalent to those in plasma. It also crosses the placenta and is found in the CSF. Therapeutic levels have been found in abscesses, bile, CSF, seminal fluid and in synovial fluid.

Protein binding.

There is no significant plasma protein binding of metronidazole.

Metabolism.

Metronidazole is partly metabolised in the liver by both acid oxidation and glucuronide conjugation. The principal metabolites are the hydroxy metabolite (1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole) and the acid metabolite (1-acetic acid-2-methyl-5-nitroimidazole). The hydroxy metabolite has approximately 30% of the bioactivity of metronidazole against anaerobic bacteria whereas the acid metabolite has only 5% of the activity of unchanged metronidazole.

Excretion.

About 15 to 20% of an administered dose is excreted in the urine as unchanged metronidazole. Overall, about 50-80% of an administered dose is excreted as nitro containing compounds, of which unchanged metronidazole and the hydroxymethyl homologue each account for about one-third. The fate of the remainder of an administered dose is unknown. Metronidazole is also excreted into saliva and breast milk reaching concentrations equivalent to those in plasma.

Half-life.

The half-life of metronidazole after single, intravenous infusion has been reported as 7.3 ± 1.0 hours.

5.3 Preclinical Safety Data

Genotoxicity.

Metronidazole has been found to be mutagenic in bacteria and some animal species. In studies on the mutagenic potential of metronidazole, the Ames mutagenicity test was positive while several nonbacterial tests in animals were negative. In patients suffering from Crohn's disease, metronidazole increased chromosome abnormalities. In addition, the drug has been shown to be tumorigenic in rodents. The benefit/ risk ratio should, therefore, be carefully assessed in each case, particularly in relation to the severity of the disease and the age of the patient.

Carcinogenicity.

Metronidazole has shown evidence of tumorigenic activity in a number of studies involving chronic oral administration in mice and rats. Most prominent among the effects in the mouse was the promotion of pulmonary tumorigenesis. This has been observed in multiple studies in that species, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). The published results of one of the mouse studies indicated an increase in the incidence of malignant lymphomas as well as pulmonary neoplasms associated with lifetime feeding of the drug. All these effects were statistically significant.
In the rat, there was a statistically significant increase in the incidence of various neoplasms, particularly mammary tumours, among female rats administered metronidazole over that noted in the concurrent female control groups. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative.
Results of a retrospective epidemiological study of 771 women treated with metronidazole for T. vaginalis have not revealed any statistically significant increase in cancer incidence over that expected in the normal population. The apparent increase in cervical carcinoma in situ in the metronidazole treated group was no different from the incidence in women documented to have had trichomoniasis not treated by metronidazole. Because of the limitations of a relatively small retrospective study, these results do not provide definite answers and the risk of carcinogenicity emphasises the need to avoid indiscriminate use of the drug.

4 Clinical Particulars

4.1 Therapeutic Indications

DBL Metronidazole Intravenous Infusion is indicated for:
treatment of severe anaerobic infection when oral medication is not possible or is contraindicated, when immediate antianaerobic therapy is required;
metronidazole may be used prophylactically to prevent infection of the surgical site which may have been contaminated or potentially contaminated with anaerobic organisms. Procedures in which this may be assumed to have happened include appendectomy, colonic surgery, vaginal hysterectomy, abdominal surgery in the presence of anaerobes in the peritoneal cavity and surgery performed in the presence of anaerobic septicaemia.

4.3 Contraindications

In patients with evidence of a history of blood dyscrasias (Occasionally a mild leucopenia has been observed during administration. however, no persistent haematological abnormalities have been observed in animals or clinical studies).
In the presence of active organic disease of the central nervous system.
In patients who are hypersensitive to metronidazole, other nitro-imidazoles or any of the excipients.

4.4 Special Warnings and Precautions for Use

Long-term therapy.

If metronidazole is to be administered for more than 10 days, it is recommended that haematological tests, especially total and differential leukocyte counts, be carried out regularly and that patients be monitored for adverse reactions such as peripheral neuropathy. If leucopenia or abnormal neurological signs occur, the drug should be discontinued immediately.

Cardiac function impairment.

Care should be taken because of the sodium content (0.135 mmol/mL) in this dosage form.

Sodium retention.

Administration of solutions containing sodium ions may result in sodium retention. Care should be taken when administering DBL Metronidazole Intravenous Infusion to patients receiving corticosteroids or patients predisposed to oedema (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Central and peripheral nervous system.

Metronidazole should be used with caution in patients with active or chronic severe peripheral or central nervous system diseases due to the risk of neurological damage. Patients should be warned about the potential for confusion, dizziness, hallucinations, convulsions or transient visual disorders.
Cases of encephalopathy and peripheral neuropathy (including optic neuropathy) have been reported with metronidazole. Encephalopathy has been reported in association with cerebellar toxicity characterised by ataxia, dizziness and dysarthria. CNS lesions seen on MRI have been described in reports of encephalopathy. CNS symptoms are generally reversible within days to weeks upon discontinuation of metronidazole. CNS lesions seen on MRI have also been described as reversible.
Peripheral neuropathy mainly of sensory type has been reported and is characterised by numbness or paraesthesia of the extremities.
Convulsive seizures have been reported in patients treated with metronidazole.
Cases of aseptic meningitis have been reported with metronidazole. Symptoms can occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued.
The appearance of abnormal neurological signs demands the prompt evaluation of the benefit/ risk ratio of the continuation of therapy.

Candidiasis.

Candida overgrowth in the gastrointestinal or genital tract may occur during metronidazole therapy and may require treatment with a candicidal drug.

Surgical drainage.

Use of metronidazole does not obviate the need for aspiration of pus whenever indicated, such as in amoebic hepatic abscess or abscesses in other inaccessible positions.

Pseudomembranous colitis.

Pseudomembranous colitis associated with the administration of metronidazole has been reported.

Ototoxicity.

A number of cases of deafness associated with the use of metronidazole have been reported.

History of blood dyscrasia.

Metronidazole is a nitroimidazole and should be used with care in patients with evidence of or a history of blood dyscrasia. A mild leucopenia has been observed during its administration however no persistent haematological abnormalities attributable to metronidazole have been observed in clinical studies. Total and differential leukocytes counts are recommended before and after therapy.

Use in hepatic impairment.

Since metronidazole is mainly metabolised by hepatic oxidation, accumulation of metronidazole and its metabolites in plasma is likely in patients with severely impaired hepatic function. Metronidazole should therefore be administered with cautions and at reduced doses to patients with severe hepatic impairment.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration.

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

No data available.

Effects on laboratory tests.

Metronidazole may interfere with AST (SGOT), ALT (SGPT), LDH, triglycerides or glucose determinations when these are based on the decrease in ultraviolet absorbance which occurs when NADH is oxidised to NAD. Metronidazole interferes with these assays because the drug has an absorbance peak of 322 nanometres at pH 7, which is close to the 340 nanometre absorbance peak of NADH; this causes an increase in absorbance at 340 nanometres resulting in falsely decreased values.

Instructions to be given to patients.

Patients should be warned to refrain from consumption of alcohol whilst taking metronidazole.
Patients should be advised to report any signs of toxicity, especially neurological disturbances, to the doctor.
Patients should be warned about the possibility of their urine darkening in colour.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Alcohol.

Metronidazole appears to inhibit alcohol dehydrogenase and other alcohol oxidising enzymes. Mild disulfiram-like reactions including flushing, headache, nausea, vomiting, abdominal cramps and sweating have occurred in patients ingesting alcohol while being treated with metronidazole. Patients should be advised not to take alcohol during therapy or for at least one day afterwards because of the possibility of a disulfiram-like reaction.

Disulfiram.

Administration of disulfiram with metronidazole has been associated with acute psychoses and confusion in some patients; therefore, the two drugs should not be administered concurrently. Metronidazole should not be given to patients who have taken disulfiram within the last two weeks.

Warfarin and other coumarin anticoagulants.

Oral or IV metronidazole potentiates the effects of oral anticoagulants resulting in prolongation of the prothrombin time, concurrent administration should be avoided if possible. If metronidazole is used in patients receiving an oral anticoagulant, prothrombin time should be monitored and the dosage of the anticoagulant adjusted accordingly.

Cyclosporin.

There is a risk of cyclosporin serum levels increasing when it is used in combination with metronidazole. Serum cyclosporin and serum creatinine should be closely monitored when coadministration is necessary.

Phenobarbitone and phenytoin.

The simultaneous administration of drugs that induce microsomal hepatic enzyme activity, such as phenobarbitone, pentobarbitone or phenytoin, may accelerate the elimination of metronidazole, resulting in reduced plasma concentrations and increased concentrations of its 2-hydroxymethyl metabolite. Impaired clearance of phenytoin has also been reported.

Lithium.

Initiation of short-term metronidazole therapy in patients stabilised on relatively high dosages of lithium has been reported to increase serum lithium concentrations, resulting in signs of lithium toxicity in several patients. Serum lithium and serum creatinine levels should be obtained several days after beginning metronidazole therapy to detect any increase that may precede clinical symptoms of lithium intoxication.

Cimetidine.

The simultaneous administration of drugs that decrease microsomal hepatic enzyme activity, such as cimetidine, may prolong the half-life and decrease the plasma clearance of metronidazole. It is not clear if ranitidine exerts a similar effect.

Corticosteroids.

Care should be taken when administering metronidazole infusion to patients receiving corticosteroid therapy or to patients predisposed to oedema since administration of solutions containing sodium ions may result in sodium retention.

Cyclophosphamide and BiCNU (carmustine).

Metronidazole should be used with caution in patients who are receiving BiCNU or cyclophosphamide as a drug interaction shown in mice leads to increased toxicity.

Fluorouracil and azathioprine.

Transient neutropenia has been reported in twelve patients who received oral and intravenous metronidazole in conjunction with intravenous fluorouracil and in at least one patient who received oral metronidazole in conjunction with azathioprine.

5-Fluorouracil.

Metronidazole used in combination with 5-fluorouracil may lead to reduced clearance resulting in increased toxicity.
See Section 4.2, Compatibility with intravenous infusions and other medicines.
See Section 6.2 Incompatibilities.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category B2)
Metronidazole should not be given in the first trimester of pregnancy as it crosses the placenta and rapidly enters foetal circulation. Although it has not been shown to be teratogenic in either human or animal studies, such a possibility cannot be excluded.
Use of metronidazole for trichomoniasis in the second and third trimesters of pregnancy be restricted to those in whom local palliative treatment has been inadequate to control symptoms.
Metronidazole is secreted in breast milk. In view of the tumorigenic and mutagenic potential of metronidazole, breastfeeding is not recommended.

4.8 Adverse Effects (Undesirable Effects)

When administered intravenously, metronidazole is well tolerated.

Gastrointestinal.

The most common adverse reactions have involved the gastrointestinal tract and include vomiting, diarrhoea, epigastric distress and abdominal cramping; constipation and oral mucositis.
A metallic, sharp unpleasant taste is not unusual. Furry tongue, glossitis and stomatitis have occurred; these may be associated with Candida overgrowth. Proliferation of Candida may also occur in the vagina.
Rare cases of pancreatitis, abating on withdrawal of the drug, have been reported.
There have been a number of reports both in Australia and in overseas literature of cases of pseudomembranous colitis whilst on metronidazole therapy.

Haematological.

A moderate and transient leukopenia may occasionally be observed. If this occurs, the total leukocyte count may be expected to return to normal after the course of medication is completed. Reversible thrombocytopenia and thrombophlebitis has been reported rarely.
Very rare cases of bone marrow aplasia, agranulocytosis and neutropenia have been reported.

Neurological.

The most serious adverse reactions in patients treated with metronidazole injection have been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy. Lack of coordination and ataxia have been reported. Confusion, irritability, depression, weakness, and insomnia have been experienced as has peripheral neuropathy, characterised mainly by numbness or paresthesia of an extremity. Since persistent peripheral neuropathy has been reported in some patients receiving prolonged metronidazole therapy, such subjects should be specifically warned about these reports and told to stop the drug and report immediately if any neurological symptoms occur. Headache, dizziness, syncope and dysarthria have also been reported. Transient vision disorders such as diplopia and myopia have been reported.

Psychiatric disorders.

Psychotic reactions have been reported in alcoholic patients receiving metronidazole and disulfiram concurrently. Metronidazole should not be given to patients who have taken disulfiram in the previous two weeks.

Hepatic disorders.

Very rare cases of reversible abnormal liver function tests and cholestatic hepatitis have been reported.

Auditory and vestibular.

Dizziness, vertigo, and tinnitus have been reported.

Dermatological.

Erythematous rash and pruritus.

Hypersensitivity.

Urticaria, erythematous rash, Stevens-Johnson Syndrome, flushing, nasal congestion, dryness of mouth (or vagina or vulva), fever, angioedema and rare anaphylactic shock have been reported.

Musculo-skeletal.

Fleeting joint pains sometimes resembling "serum sickness" have been reported.

Urogenital.

Dysuria, cystitis and a sense of pelvic pressure have been reported. Very rarely, dyspareunia, fever, polyuria, incontinence, decrease in libido, proctitis and pyuria have occurred in patients receiving the drug. Instances of darkened urine have been reported and this manifestation has been the subject of investigation. Although the pigment which is probably responsible for this phenomenon has not been positively identified, it almost certainly is a metabolite of metronidazole. It seems certain that it is of no clinical significance and may be encountered only when metronidazole is administered in higher than recommended doses.

Cardiac.

Flattening of the T-wave and prolongation of the QT interval may be seen in ECG tracings.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

DBL Metronidazole Intravenous Infusion contains no microbial agent. It should be used in one patient on one occasion only and any residue discarded.
A maximum of 4 g should not be exceeded during a 24 hour period.

Dosage.

Adult.

The adult dose is 500 mg metronidazole (i.e. 100 mL) by infusion eight hourly.

Children over 12 years.

Same dosage as adults.

Children under 12 years.

Eight hourly as for adults but the single intravenous dose is based on 7.5 mg (1.5 mL) metronidazole/kg bodyweight.

Geriatric.

Use adult dosage with care as some degree of impaired hepatic or renal function may be present in elderly patients. In elderly patients, the pharmacokinetics of metronidazole may be altered, therefore, monitoring of serum levels may be necessary to adjust the metronidazole dosage accordingly.

Method of administration.

Adult.

Metronidazole should be infused intravenously at the rate of 5 mL (25 mg) per minute. Metronidazole infusion may be administered alone or concurrently (but separately) with other appropriate antibacterial agents in parenteral dosage forms (see Compatibility with intravenous infusions and other medicines). Other intravenous drugs or infusions should, if possible, be discontinued during its administration.
For prophylactic use, the appropriate dose should be infused shortly before surgery and repeated 8 hourly for the next 24 hours.
Dosages should be decreased in patients with severe hepatic disease; plasma metronidazole levels should be monitored. In elderly patients, the pharmacokinetics of metronidazole may be altered, therefore, monitoring of serum levels may be necessary to adjust metronidazole dosage accordingly.
Parenteral drugs should be inspected visually for particulate matter and discolouration prior to administration, wherever solution or container permit. Do not use if the solution is cloudy or precipitated or if the seal is not intact. While the solution should be protected from direct sunlight during administration, exposure to fluorescent light for short periods will not result in its degradation.
Do not use plastic infusion bags in series connections. This practice could result in air embolism due to air being drawn from the primary container before administration of the fluid from the secondary container is complete.

Duration of therapy.

Treatment for seven days should be satisfactory for most patients but depending on clinical and bacteriological assessment, the clinician 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 female genital tract. Oral medication should be substituted as soon as possible.

Instructions to be given to the patient.

1. Patients, especially pregnant women, should be warned to refrain from alcohol whilst taking metronidazole.
2. Patients should be advised to report any signs of toxicity, especially neurological disturbances, to their doctor.
3. Patients should be warned about the possibility of their urine darkening in colour.

Note.

Prevention of infection at the surgical site requires that adequate tissue concentrations of the drug should have been achieved at the time of surgery. The dose and route of administration should be selected in each case to achieve this objective.
Although metronidazole has been used for some years in children, recent evidence concerning mutagenicity and tumorigenicity suggests that caution should be exercised when using metronidazole in this age group.
In infants and other patients maintained on intravenous infusions, metronidazole may be diluted 1 in 5 or greater with isotonic intravenous infusions (sodium chloride 0.9%, glucose/ saline combinations, glucose 5%) but not sodium lactate compound (Hartman's) infusion or sodium chloride compound (Ringer's) infusion (see Compatibility with intravenous infusions and other medicines).

Dosage adjustments.

Renal impairment.

In patients on twice weekly haemodialysis, metronidazole and its major active metabolite are rapidly removed during an 8 hour period of dialysis so the plasma concentration quickly falls below the therapeutic range. Hence, a further dose of metronidazole would be needed after dialysis to restore an adequate plasma concentration. In patients with renal failure, the half-life of metronidazole is unchanged but those of its major metabolites are prolonged 4-fold or greater. The accumulation of the hydroxy metabolite could be associated with side effects and measurement of its plasma concentrations by high pressure liquid chromatography (HPLC) has been recommended.
In the absence of haemodialysis, the plasma clearance and elimination half-life of metronidazole are equivalent to those in patients with normal renal clearance so dosage adjustment is not necessary.
While the pharmacokinetics of metronidazole are little changed in the presence of anuria, there is retention of the metabolites, the clinical significance of which is unknown.

Hepatic impairment.

As metronidazole is partly metabolised in the liver, caution should be exercised in patients with impaired liver function. Empirical dosage reduction and serum level monitoring may be necessary.

Compatibility with intravenous infusions and other medicines.

DBL Metronidazole Intravenous Infusion may be diluted to 1 in 5 or greater with appropriate volumes of sodium chloride 0.9%, glucose/ saline combinations, glucose 5% or potassium chloride injections 20 and 40 mmol/L. While physically compatible with compound sodium lactate infusion (Hartman's solution) and compound sodium chloride infusion (Ringer's solution), metronidazole is not chemically compatible with them over extended periods of time. Therefore, addition of DBL Metronidazole Intravenous Infusion to these solutions is not recommended. However, it may be delivered through the administration set Y site of fast running infusions of Hartman's or Ringer's solutions. While glucose 10% is compatible, its use as a diluent and vehicle is not recommended because of the high osmolarity of the resulting solution.

4.7 Effects on Ability to Drive and Use Machines

Patients should be warned about the potential for confusion, dizziness, hallucinations, convulsions or transient visual disorders and advised not to drive or use machinery if these symptoms occur.

4.9 Overdose

Overdosage with metronidazole appears to be associated with very few abnormal signs or symptoms. Disorientation and vomiting may occur, especially after ingestion of large amounts. In the event of accidental overdosage, treatment consists of supportive and symptomatic measures.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Citric acid, dibasic sodium phosphate, sodium chloride, water for injections.

6.2 Incompatibilities

DBL Metronidazole Intravenous Infusion is incompatible with aluminium; do not use equipment containing aluminium components (e.g. needle or cannula hubs). Other drugs should not be added directly to DBL Metronidazole Intravenous Infusion.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

DBL Metronidazole Intravenous Infusion 500 mg in 100 mL (sterile) is available in 10 infusion bags per pack.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

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