Consumer medicine information

Metronidazole Intravenous Infusion

Metronidazole

BRAND INFORMATION

Brand name

Metronidazole Intravenous Infusion (Pfizer)

Active ingredient

Metronidazole

Schedule

What is in this leaflet

This leaflet answers some common questions about 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 benefits and risks. Your doctor has weighed the risks of you taking Metronidazole Intravenous Infusion against the benefits this medicine is expected to have for you.

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

Keep this leaflet. You may need to read it again.

What METRONIDAZOLE INTRAVENOUS INFUSION is used for

This medicine 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

This medicine is an antibiotic.

This medicine 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 it for another reason.

This medicine is not addictive.

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

Before you are given METRONIDAZOLE INTRAVENOUS INFUSION

When you must not be given it

Do not use Metronidazole Intravenous Infusion if:

you have an allergy to any medicine containing metronidazole, any other medicines used to treat infections or 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.

you have or have had a blood disorder
you have a disease or disorder involving the brain, spinal cord or nerves
you have taken disulfiram (a medicine used to treat chronic alcohol dependence) within the last two weeks
you have ingested alcohol or products containing propylene glycol

If you are not sure whether you should be given this medicine, talk to your doctor.

Before you are given it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

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

Tell your doctor if you drink alcohol or ingest products containing propylene glycol. Do not drink alcohol or ingest products containing propylene glycol during (and for three days after stopping) treatment with metronidazole.

Tell your doctor if you are on a low sodium diet.

Tell your doctor if you are pregnant or intend to become pregnant. Metronidazole may affect your developing baby if you use it during pregnancy. Your doctor will discuss the risks and benefits of using metronidazole during pregnancy.

Tell your doctor if 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 your doctor before you are given Metronidazole Intravenous Infusion.

Taking other medicines

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

Some medicines and Metronidazole Intravenous Infusion may interfere with each other. These include:

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

These medicines may be affected by Metronidazole Intravenous Infusion or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

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

Talk to your doctor about the need for an additional method of contraception while you are being given metronidazole. Some antibiotics may decrease the effectiveness of some birth control pills, although this has not been shown with metronidazole.

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

How METRONIDAZOLE INTRAVENOUS INFUSION is given

Metronidazole Intravenous Infusion is given by injection into a vein. Metronidazole Intravenous Infusion must only be given by a doctor or nurse.

Your doctor will decide what dose and how long you will receive Metronidazole Intravenous Infusion. 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.

If you are given too much (overdose)

As Metronidazole Intravenous Infusion is usually given to you in hospital or clinic, it is very unlikely that you will receive an overdose. However, if you are given too much metronidazole, you may experience some of the effects listed under "Side Effects" below.

Contact Poisons Information Centre (telephone 13 11 26) for advice or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have been given too much Metronidazole Intravenous Infusion.

While you are given METRONIDAZOLE INTRAVENOUS INFUSION

Things you must do

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

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

If you become pregnant while you are being treated with Metronidazole Intravenous Infusion tell your doctor immediately.

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

If you need to have any blood tests tell your doctor you are being given Metronidazole Intravenous Infusion. Metronidazole Intravenous Infusion may affect the results of some blood tests.

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

Things you must not do

Do not drink any alcohol or any alcoholic drinks while being treated with (and for at least one day after stopping) Metronidazole Intravenous Infusion. The use of alcohol with Metronidazole Intravenous Infusion 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 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, nurse or pharmacist as soon as possible if you do not feel well while you are using metronidazole.

Like other medicines, metronidazole can cause some side effects. If they occur, most are likely to be minor or temporary. However, some may be serious and need medical attention.

Ask your doctor or pharmacist to answer any questions that you may have.

Do not be alarmed by this list of possible 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
constipation/diarrhoea
abdominal pain, indigestion or discomfort
metallic or unpleasant taste in the mouth
swollen red or sore tongue
sore, red mouth
ulcers or cold sores
oral thrush - white, furry, sore tongue and/or mouth
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 or nurse as soon as possible 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
problems with sleeping
fits or seizures
dizziness or spinning sensation
ringing/ persistent noise in the ears (tinnitus) or other hearing problems
blurred/ 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
pain when passing urine or passing more urine than normal
blood or pus in the urine, darker urine
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 medical attention.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency 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 or pharmacist if you notice anything 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.

Storage

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

Metronidazole Intravenous Infusion is a clear, almost colourless to pale yellow solution in a glass vial.

Ingredients

Metronidazole Intravenous Infusion contains 500 mg of metronidazole as the active ingredient.

The intravenous infusion also contains:

citric acid
dibasic sodium phosphate
sodium chloride
water for Injections

It does not contain preservatives.

Supplier

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

Australian Registration Numbers

Metronidazole intravenous infusion 500 mg in 100 mL (sterile) glass vial, available as 10 vials per pack.

AUST R 12728

Date of Preparation

This leaflet was prepared in December 2020.

Published by MIMS January 2021

BRAND INFORMATION

Brand name

Metronidazole Intravenous Infusion (Pfizer)

Active ingredient

Metronidazole

Schedule

1 Name of Medicine

Metronidazole.

2 Qualitative and Quantitative Composition

Metronidazole Intravenous Infusion contains Metronidazole 5 mg/mL.
It is a white or yellowish, crystalline powder, slightly soluble in water, in acetone, in alcohol and in methylene chloride.
Metronidazole Intravenous Infusion is a clear, almost colourless to pale yellow, sterile, isotonic, preservative-free, ready to use solution. Each mL contains 0.135 mmoles sodium.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Intravenous Infusion.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of severe anaerobic infection when oral medication is not possible or is contraindicated, when immediate anti-anaerobic 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.

4.2 Dose and Method of Administration

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.

Single use only.
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 Section 6.2 Incompatibilities). 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 permits. 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.

Additional information.

Metronidazole Intravenous Infusion is an isotonic (280 mOsm per kg), ready to use solution, requiring no dilution or buffering prior to administration.
The total sodium content (derived from sodium phosphate buffer and sodium chloride) is approximately 13.5 mmol (13.5 mEq, 310 mg) per 100 mL of solution. This must be considered in patients on a restricted sodium intake when calculating total daily sodium intake.

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.
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.

4.3 Contraindications

1. Patients with evidence of or a history of blood dyscrasias should not receive the drug since upon occasion a moderate leucopenia has been observed during its administration. However, no persistent haematological abnormalities have been observed in animals or clinical studies (see Section 4.4 Special Warnings and Precautions for Use).
2. Active organic disease of the central nervous system.
3. Hypersensitivity to metronidazole and other nitroimidazoles.
4. Patients who have taken disulfiram within the last two weeks should not be administered metronidazole. Use of oral metronidazole is associated with psychotic reactions in alcoholic patients who were using disulfiram concurrently (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
5. Consumption of alcohol or products containing propylene glycol. Use of oral metronidazole is associated with a disulfiram-like reaction to alcohol, including abdominal cramps, nausea, vomiting, headaches, and flushing. Discontinue consumption of alcohol or products containing propylene glycol during and for at least three days after therapy with metronidazole (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Alcohol.

Alcoholic beverages, drugs containing alcohol or products containing propylene glycol should not be consumed by patients being treated with metronidazole and for at least three days after treatment as nausea, vomiting, abdominal cramps, headaches, tachycardia and flushing may occur. There is the possibility of a disulfiram-like (Antabuse) effect reaction (see Section 4.3 Contraindications).

Treatment of bacterial infections.

Patients should be counselled that antibacterial drugs including Metronidazole Intravenous Infusion should only be used to treat bacterial infections. They do not treat viral infections (e.g. the common cold). When Metronidazole Intravenous Infusion is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be completed for the full course of therapy. Otherwise this may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Metronidazole Intravenous Infusion or other antibacterial drugs in the future.

Candidiasis.

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

Cockayne syndrome.

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, such as abdominal pain, nausea, change in stool colour or jaundice to their physician and stop taking metronidazole.

Use in patients with blood dyscrasias.

Metronidazole is a nitroimidazole and should be used with care in patients with evidence of or history of blood dyscrasia. A moderate leucopenia has been observed during its administration; however, no persistent hematologic abnormalities attributable to metronidazole have been observed in clinical studies. (see Section 4.3 Contraindications).

Long term therapy.

If metronidazole is to be administered for more than 10 days, it is recommended that haematological tests, especially total and differential leucocyte counts, be carried out regularly and that patients be monitored for adverse reactions such as peripheral or central neuropathy (such as paresthesia, ataxia, dizziness, convulsive seizures). 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 Metronidazole Intravenous Infusion to patients receiving corticosteroids or patients predisposed to oedema.

Surgical drainage.

Use of metronidazole does not obviate the need for aspirations of pus whenever indicated.

Nervous system.

Metronidazole should be used with caution in patients with active or chronic severe peripheral and 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 and advised not to drive or use machinery if these symptoms occur.
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 paresthesia of an extremity.
Convulsive seizures have been reported in patients treated with metronidazole.

Aseptic meningitis.

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 neurologic signs demands prompt discontinuation of metronidazole therapy and, when severe, immediate medical attention. See Section 4.8 Adverse Effects (Undesirable Effects).

Carcinogenicity/mutagenicity.

In studies on the mutagenic potential of metronidazole, the Ames test was positive while several nonbacterial tests in animals were negative. In the patients with Crohn's disease, metronidazole increased the chromosome abnormalities in circulating lymphocytes. In addition, the drug has been shown to be tumorigenic and carcinogenic in rodents. The use of metronidazole for longer treatment than usually required should be carefully weighed (see Section 4.4 Special Warnings and Precautions for Use) and the benefit/risks should, therefore, be carefully assessed in each case particularly in relation to the severity of the disease and the age of the patient.

Drug resistant bacteria.

Prescribing metronidazole in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Use in 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 that 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 concentration by high pressure liquid chromatography (HPLC) has been recommended (see Section 4.2 Dose and Method of Administration).

Use in hepatic impairment.

No information available. As metronidazole is partly metabolised in the liver, caution should be exercised in patients with impaired liver function or hepatic encephalopathy.
For patients with severe hepatic impairment (Child-Pugh C), a reduced dose of metronidazole is recommended. For patients with mild to moderate hepatic impairment, no dosage adjustment is needed but these patients should be monitored for metronidazole associated adverse events (see Section 4.2 Dose and Method of Administration).
Metronidazole may interfere with certain chemical analysis of serum aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), triglycerides and hexokinase glucose to give abnormally low values.

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

See Section 4.2 Dose and Method of Administration.

Effects on laboratory tests.

Metronidazole may show negative interference with continuous flow spectrophotometry of aspartate aminotransferase (previously GOT), so that hepatocellular damage which is detectable by raised serum AST may be missed. 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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

1. Metronidazole enhances the activity of warfarin, and if metronidazole is to be given to patients receiving this or other anticoagulants, the dosages of the latter should be recalibrated. There is an increased haemorrhagic risk caused by decreased hepatic metabolism. Prothrombin times should be monitored as should anticoagulant activity.
2. The simultaneous administration of drugs that induce microsomal liver enzymes, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma levels; impaired clearance of phenytoin has also been reported.
3. The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may prolong the half-life and decrease plasma clearance of metronidazole.
4. In patients stabilised on relatively high doses of lithium, short-term metronidazole therapy has been associated with elevation of serum lithium and, in a few cases, signs of lithium toxicity. Serum lithium and serum creatinine levels and electrolytes should be obtained several days after beginning metronidazole to detect any increase that may precede clinical symptoms of lithium intoxication.
5. Disulfiram: In a clinical trial of combined therapy with disulfiram and metronidazole in the treatment of chronic alcoholics, severe acute psychotic reactions occurred in 6 out of 29 patients. Psychotic reactions have been reported in patients who were using metronidazole and disulfiram concurrently. Metronidazole should not be given to patients who have taken disulfiram within the last two weeks (see Section 4.3 Contraindications).
6. Carmustine, cyclophosphamide: Metronidazole should be used with caution in patients receiving these drugs.
7. 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.
8. 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.
9. Metronidazole used in combination with 5-fluorouracil may lead to reduced clearance of 5-fluorouracil, resulting in increased toxicity.
10. Alcoholic beverages, drugs containing alcohol or products containing propylene glycol should not be consumed during metronidazole therapy and for at least three days afterwards because of the possibility of a disulfiram-like (antabuse effect) reaction (flushing, vomiting, tachycardia). See Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use.
11. Plasma levels of busulfan may be increased by metronidazole, which may lead to severe busulfan toxicity. Metronidazole should not be administered concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to metronidazole are available, and concomitant administration with busulfan is medically needed, frequent monitoring of busulfan plasma concentration should be performed and the busulfan dose should be adjusted accordingly.
12. 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.

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 enters fetal circulation rapidly. As its effects on human fetal organogenesis are not known, its use in pregnancy should be carefully evaluated. 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 should be restricted to those in whom local palliative treatment has been inadequate to control symptoms.
Metronidazole is secreted in breast milk (see Section 5.2 Pharmacokinetic Properties). In view of its tumorigenic and mutagenic potential (see Section 4.4 Special Warnings and Precautions for Use, Carcinogenicity/mutagenicity), breastfeeding is not recommended.

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. See Section 4.4 Special Warnings and Precautions for Use.

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.
Patients with Crohn's disease are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers. There have been some reports in the medical literature of breast and colon cancer in Crohn's disease patients who have been treated with metronidazole at high doses for extended periods of time. A cause and effect relationship has not been established.
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.

Body as a whole.

Hypersensitivity reactions include rash, pruritus, flushing, urticaria, fever, angioedema and anaphylactic shock. Nasal congestion and dryness of the mouth have been reported. Mild erythematous eruptions have been experienced, as have fleeting joint pains sometimes resembling serum sickness. Pustular eruptions and acute generalised exanthematous pustulosis have been reported. Fixed drug eruption has been reported. Stevens-Johnson syndrome and toxic epidermal necrolysis have also been reported.

Liver.

Increase in liver enzymes (AST, ALT, alkaline phosphatase), cholestatic or mixed hepatitis and hepatocellular liver injury, sometimes with jaundice, have been reported.
Cases of liver failure requiring liver transplant have been reported in patients treated with metronidazole in combination with other antibiotic drugs; all spiramycin except one case of tetracycline.

Haematology.

A moderate leucopenia may be observed occasionally. If this occurs, the total leucocyte count may be expected to return to normal after the course of medication is completed. One case of bone marrow depression has been reported. If profound bone marrow suppression occurs, use of metronidazole should be ceased and appropriate supportive therapy instituted. Cases of agranulocytosis, neutropenia or thrombocytopenia have been reported.
Thrombophlebitis has been reported after intravenous infusion. This reaction can be minimised or avoided by limiting the duration of infusion and frequent resting of the indwelling IV cannula.

Psychiatric/CNS disorders.

Dizziness, vertigo, incoordination, headache and convulsive seizures have been reported. Psychotic disorders such as confusion and hallucinations have been reported. Depression, depressed mood, insomnia, irritability, weakness have been experienced, as has peripheral neuropathy, characterised mainly by numbness or paraesthesia of an extremity. There have been reports of encephalopathy (e.g. confusion) and subacute cerebellar syndrome (e.g. ataxia, dysarthria, gait impairment, nystagmus and tremor), which may resolve with the discontinuation of the drug. Since persistent peripheral neuropathy has been reported in some patients receiving prolonged administration of metronidazole, such subjects should be specifically warned about these reports and should be told to stop the drug and report immediately if any neurological symptoms occur. Aseptic meningitis has been reported.

Eye disorders.

Optic neuropathy/neuritis and transient vision disorders such as diplopia, myopia, blurred vision, decreased visual acuity and changes in colour vision have been reported.

Ear and labyrinth disorders.

Impaired hearing/hearing loss (including sensorineural) and tinnitus have been reported.

Genito-urinary tract.

Proliferation of Candida also may occur in the vagina. Dryness of the vagina or vulva, pruritus, dysuria, cystitis and a sense of pelvic pressure have been reported. Very rarely dyspareunia, fever, polyuria, incontinence, decrease of 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 special investigation. Although the pigment which is probably responsible for this phenomenon has not been positively identified, it is almost certainly 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.

Cardiovascular.

Flattening of the T wave may be seen in ECG tracings.

Reporting suspected adverse reactions.

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Signs and symptoms.

Overdosage with metronidazole appears to be associated with very few abnormal signs or symptoms. Disorientation, ataxia and vomiting may occur, especially after ingestion of large amounts. In case of suspected massive overdosages, a symptomatic and supportive treatment should be instituted.

Recommended treatment.

There is no specific antidote for metronidazole overdosage. In cases of suspected overdosage, a symptomatic and supportive treatment should be instituted.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antibacterials for systemic use, ATC code J01X D01.

Mechanism of action.

Specific bactericidal activity against important obligate anaerobes.
Metronidazole is effective in vitro against several species of anaerobic bacteria, particularly Bacteroides fragilis and other species of bacteroides, and other species such as fusobacteria, eubacteria, clostridia, and anaerobic streptococci. The MIC for most susceptible anaerobes is < 6.2 micrograms/mL.

Note.

Metronidazole is inactive against aerobic and facultative anaerobic bacteria.
Metronidazole is active against a wide range of pathogenic microorganisms notably Trichomonas vaginalis and other trichomonads, Entamoeba histolytica, Giardia lamblia, Balantidium coli and the causative organisms of acute ulcerative gingivitis.

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.

See Section 4.4 Special Warnings and Precautions for Use, Carcinogenicity/mutagenicity.

Carcinogenicity.

See Section 4.4 Special Warnings and Precautions for Use, Carcinogenicity/mutagenicity.

6 Pharmaceutical Particulars

6.1 List of Excipients

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

6.2 Incompatibilities

Additives should not be introduced into intravenous metronidazole solutions. If used with a primary intravenous fluid system, the primary solution should be discontinued during metronidazole 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

AUST R 12728 Metronidazole Intravenous Infusion 500 mg in 100 mL (sterile) plastic* or glass vial.
Pack sizes of 1* and 10 vials.

Note.

* Not marketed.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.

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

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