Consumer medicine information

Metronidazole Kabi

Metronidazole

BRAND INFORMATION

Brand name

Metronidazole Kabi

Active ingredient

Metronidazole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Metronidazole Kabi.

What is in this leaflet

This leaflet answers some common questions about Metronidazole Kabi.

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 taking Metronidazole Kabi 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 Kabi 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 your infection.

Your doctor may have prescribed Metronidazole Kabi for another reason. Ask your doctor if you have any questions about why Metronidazole Kabi has been prescribed for you.

Metronidazole Kabi is available only with a doctor's prescription.

Metronidazole Kabi is not addictive.

Before you are given Metronidazole Kabi

When you must not be given it

Do not use Metronidazole Kabi if:

  1. 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 wheezing or difficulty breathing, shortness of breath, swelling of the face, lips, tongue or other parts of the body, rash, itching or hives.

You must not be given this medicine if:

  • you have or have ever 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
  • you have Cockayne syndrome

If you are not sure whether you should be given Metronidazole Kabi, talk to 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.

Tell your doctor if you have ever had any other health problems/medical conditions including:

  • 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
  • liver disease or any liver problems
  • Crohn’s disease, an inflammatory disease of the intestines.

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 breastfeeding. 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 Kabi.

Taking other medicines

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

Some medicines may interfere with Metronidazole Kabi.

These include:

  • disulfiram, a medicine used to treat chronic alcohol dependence
  • some anticancer medicines 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
  • ciclosporin, a medicine used to prevent organ transplant rejection or to treat immune responses.
  • Medicines that affect the heart rate or heart rhythm.

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

Do not drink alcohol or ingest products containing propylene glycol while you are being given Metronidazole Kabi. 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 being given Metronidazole Kabi. Some antibiotics may decrease the effectiveness of some birth control pills, although this hasn't been shown with metronidazole.

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

How Metronidazole Kabi is given

Metronidazole Kabi is given as a slow injection into a vein. Metronidazole Kabi must only be given by a doctor or nurse.

Your doctor will decide what dose and how long you will receive Metronidazole Kabi. 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 Kabi is 500 mg every eight hours for the course of the treatment, as decided by your doctor.

If you are given too much (overdose)

As Metronidazole Kabi 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.

If you are given too much Metronidazole Kabi you may experience symptoms such as vomiting or disorientation.

Contact Poisons Information Centre (phone 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 Kabi.

While you are given Metronidazole Kabi

Things you must do

If the symptoms of your infection do not improve within a few days, 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 Kabi 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 Kabi, 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 Kabi allows fungi to grow and the above symptoms to occur. Metronidazole Kabi does not work against fungi.

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

If you are using Metronidazole Kabi 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 Kabi.

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

Tell all the doctors, dentists and pharmacists who are treating you that you are being treated with Metronidazole Kabi.

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 Kabi. The use of alcohol with Metronidazole Kabi 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 Kabi affects you.

Metronidazole Kabi may cause dizziness, confusion, hallucination (hearing or seeing strange orunusual things), convulsions ("fits") or transient visual disorders in some people.

Make sure you know how you react to Metronidazole Kabi before you drive a car, operate machinery or do anything else that may be dangerous if you are affected.

Side Effects

Tell your doctor, nurse or pharmacist as soon as possible if you do not feel well while you are being given Metronidazole Kabi.

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.

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

Do not be alarmed by this list of possible side effects. You may not experience any of them.

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

  • nausea (feeling sick), vomiting or 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.

These side effects are usually mild.

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:

  • sudden signs of allergy such as rash, itching or hives, swelling of the face, lips, mouth, throat or neck which may cause difficulty swallowing or breathing
  • skin rash that can be widespread with blisters, swelling, pain, burning, itching or peeling, often with fever
  • 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
  • fast, erratic heartbeats and/or fainting

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 Kabi will be stored in the pharmacy or on the ward.

Metronidazole Kabi in glass infusion bottles is kept in a cool dry place, protected from light where the temperature stays below 25°C.

Metronidazole Kabi in Kabipac® (Polyethylene) bags is kept in a cool dry place, protected from light where the temperature stays below 25°C.

Product Description

What it looks like

Metronidazole Kabi is a clear and slightly yellowish, isotonic infusion solution.

Ingredients

Active ingredient

Each Metronidazole Kabi glass bottle or Kabipac® (Polyethylene) bag contains 500 mg of metronidazole as the active ingredient.

Inactive ingredients

Metronidazole Kabi also contains the following inactive ingredients:

  • citric acid monohydrate
  • dibasic sodium phosphate dodecahydrate
  • sodium chloride
  • water for injections.

Supplier

Metronidazole Kabi is supplied in Australia by:

Fresenius Kabi Australia Pty Limited
Level 2, 2 Woodland Way
Mount Kuring-gai NSW 2080
Australia
Telephone: 1300 732 001

Australian Registration Number

AUST R 310261

® = Registered Trademark

This leaflet was prepared in October 2023.

Published by MIMS December 2023

BRAND INFORMATION

Brand name

Metronidazole Kabi

Active ingredient

Metronidazole

Schedule

S4

 

1 Name of Medicine

Metronidazole.

2 Qualitative and Quantitative Composition

Metronidazole Kabi contains the active substance metronidazole, which belongs to the substance group of nitroimidazole derivatives.
Active: metronidazole, concentration: 500 mg/100 mL.
Metronidazole is a white or yellowish crystalline powder with melting point 159-162°C. Solubility in water at 20°C is 1 g/100 mL; in ethyl alcohol, 0.5 g/100 mL; and soluble in dilute acids. When reconstituted as Metronidazole Kabi, it has a pH of between 4.5 and 6.0. Each mL contains 0.135 mmol sodium.
Metronidazole Kabi is a clear and slightly yellowish, sterile, isotonic infusion solution for intravenous use only. Solution is practically free from visible particles. Solutions that are hazy or contain visible particulate matter should be discarded.
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

Metronidazole intravenous infusion is indicated:
(a) For treatment of anaerobic infections in patients for whom oral administration is not possible.
(b) Where immediate anti-anaerobic chemotherapy is required.
(c) Where prophylactic cover is required at lower abdominal surgical sites presumed contaminated or potentially contaminated by anaerobic micro-organisms. Procedures of this type 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.

Note.

Metronidazole is inactive against aerobic or facultative anaerobic bacteria.

4.2 Dose and Method of Administration

A maximum of 4 g should not be exceeded in a 24 hour period. For prophylactic use, the appropriate dose should be infused shortly before surgery and repeated every eight hours for the next 24 hours. Dosages should be decreased in patients with severe hepatic disease; plasma metronidazole levels should be monitored.
Metronidazole should be infused intravenously at a rate of 5 mL (25 mg) per minute. Metronidazole infusion may be administered alone or concurrently (but separately) with other bacteriologically appropriate parenteral antibacterial agents. Other IV drugs or infusions should, if possible, be discontinued during its administration. While the solution should be protected from direct sunlight during administration, exposure to fluorescent light for short periods will not result in its degradation.

Adults and children over 12 years.

100 mL containing 500 mg metronidazole by intravenous infusion every eight hours.

Children under 12 years.

As for adults, but a single intravenous dose is based on 1.5 mL (7.5 mg metronidazole)/kg body weight.

Elderly.

Use the adult dose with care as some degree of hepatic or renal impairment may be present. In elderly patients, the pharmacokinetics of metronidazole may be altered; therefore, monitoring of serum levels may be necessary to adjust metronidazole dosage accordingly.
If dilution is necessary, hold at 2° to 8°C for not more than 24 hours to reduce microbiological hazard.
Contains no antimicrobial preservative. Product is for single use in one patient only. Discard any residue.

Duration of therapy.

Treatment for seven days should be satisfactory for most patients but, depending upon clinical and bacteriological assessment, the clinician may decide to prolong treatment, e.g. for the eradication of infection from sites which cannot be drained or are prone to endogenous recontamination by anaerobic pathogens from the gut, nasopharynx or the female genital tract. Oral metronidazole should be substituted as soon as possible.

Administration.

One dose in one patient only. Discard any remaining contents.

Notes.

Prevention of infection at the surgical site requires adequate tissue concentration of the drug being attained 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 in children for some years, recent evidence concerning mutagenicity and tumorigenicity suggests caution 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 (Hartmann's) infusion or sodium chloride compound (Ringer's) infusion (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Compatibility with intravenous infusions and other drugs).

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 hydroxymetabolite 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. 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 or any of the excipients.
(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).
(6) Metronidazole intravenous infusion is contraindicated in patients with Cockayne syndrome. Severe irreversible hepatotoxicity/acute liver failure with fatal outcomes have been reported after initiation of metronidazole in patients with Cockayne syndrome (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.4 Special Warnings and Precautions for Use

Hypersensitivity reactions.

Hypersensitivity reactions including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalised exanthematous pustulosis (AGEP) have been reported with the use of metronidazole. Symptoms can be serious and potentially life threatening [see Section 4.8 Adverse Effects (Undesirable Effects)].

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

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 ten 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 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 Kabi to patients receiving corticosteroids or patients predisposed to oedema. (See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.)

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 in patients being treated 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 the sensory type has been reported and is characterised by numbness or paraesthesia 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 and symptoms 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 ciclosporin serum levels increasing when it is used in combination with metronidazole. Serum ciclosporin 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.
13. Drugs that prolong the QT interval: QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval.

Compatibility with intravenous infusions and other drugs.

Metronidazole 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 mmol/L and 40 mmol/L. While physically compatible with compound sodium lactate infusion (Hartmann'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 metronidazole infusion to these solutions is not recommended.
However, it may be delivered through the administration set Y-site of fast-running infusions of Hartmann's or Ringer's solutions. While Glucose 10% is compatible with metronidazole infusion, its use as a diluent and vehicle is not recommended because of the high osmolarity of the resulting solution.
If dilution is necessary, the resultant solution should be held at 2°C to 8°C for no longer than 24 hours.
See Section 6.2 Incompatibilities for product 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 since it crosses the placenta and rapidly enters the fetal circulation rapidly. As it 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). There are reports of diarrhoea and Candida infection in breastfed infants of mothers receiving treatment with metronidazole. In view of the drug's 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, drowsiness, dizziness, hallucinations, convulsions, or transient visual disorders and advised not to drive or operate 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 erythematous 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. Dermatitis bullous and fixed drug eruption has been reported. Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP) 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.
Cases of severe irreversible hepatoxicity/acute liver failure, including cases with fatal outcomes with very rapid onset after initiation of systemic use of metronidazole, have been reported in patients with Cockayne syndrome (latency from drug start to signs of liver failure as short as 2 days) (see Section 4.3 Contraindications).

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.

QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval. Flattening of the T wave 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.

4.9 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, 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 Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Specific bactericidal activity against important obligate anaerobes and protozoa.

Mode of action.

Metronidazole is bactericidal, amoebicidal and trichomonicidal. The exact mode of action has not been fully elucidated. Metronidazole is reduced by low-redox-potential electron transfer proteins (e.g. nitro-reductases such as ferredoxin) to unidentified polar product(s) which lack the nitro group. The reduction product(s) appears to be responsible for the cytotoxic and antimicrobial effects of the drug which include disruption of DNA and inhibition of nucleic acid synthesis.

Microbiology.

Metronidazole is bactericidal in vitro against many anaerobic Gram negative bacilli including Bacteroides fragilis, and other Bacteroides species, also other species including Fusobacterium. The drug is effective against many anaerobic Gram-positive bacilli including Clostridium species, Eubacterium, and anaerobic Streptococcus.
The MIC for most susceptible anaerobes is < 6.2 microgram/mL. Serum levels higher than this are achieved at the recommended doses.
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 acute ulcerative gingivitis.
Metronidazole is ineffective against both aerobic and facultative anaerobic bacteria.

Susceptibility tests.

Dilution or diffusion techniques, either quantitative (MIC) or breakpoint, should be used following a regularly updated, recognised and standardised method (e.g. NCCLS). 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 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.

Bioavailability.

For both oral and intravenous administration, the area under the plasma clearance curve is equivalent.

Absorption.

Following intravenous infusion, peak plasma levels of metronidazole occur at the end of the infusion. Traces are detected after 24 hours.

Distribution.

Metronidazole is distributed widely throughout body tissues both intracellularly and extracellularly. It diffuses across the blood-brain barrier, crosses the placenta and appears in the saliva and breast milk of nursing mothers in concentrations equivalent to those found in the plasma. It attains therapeutic concentrations in the bile and the CSF.

Plasma protein binding.

There is no significant plasma protein binding of metronidazole.

Metabolism.

An oral or intravenous dose of metronidazole is partially metabolised in the liver by hydroxylation, acid side-chain oxidation and glucuronide conjugation. The major metabolite, 2-hydroxymethylmetronidazole, has some antiprotozoal activity in vitro.

Excretion.

Approximately three-fourths of a single 750 mg oral dose is excreted as nitro-containing compounds (unchanged drug and its metabolites) in the urine within 5 days. Most of the remainder is excreted in the faeces. Urine may be dark or reddish brown in colour following oral and IV administration of the drug due to the presence of water-soluble pigments which result from its metabolism.

Half life.

The biological half-life of a single intravenously administered dose of metronidazole has been determined as 7.3 hours ± 1.0 hours.

5.3 Preclinical Safety Data

Genotoxicity.

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

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, including one in which the animals were dosed on an intermittent schedule (every fourth week only). The results of one of the mouse studies indicates a statistically significant increase in the incidence of malignant lymphomas as well as pulmonary neoplasms associated with lifetime feeding.
In the rat, there was a statistically significant increase in the incidence of various neoplasms, particularly mammary tumours, among females fed metronidazole on a lifetime basis, over that observed in concurrent female control groups.
Two lifetime tumorigenicity studies have been performed in hamsters; in both cases the results were negative.
A retrospective study of 771 women treated with metronidazole for Trichomonas vaginalis has revealed no statistically significant increase in cancer incidence over that expected in the normal population. An apparent increase in the incidence of cervical carcinoma observed in the metronidazole-treated group was no different from the incidence observed in women documented to have had trichomoniasis not treated by metronidazole.

6 Pharmaceutical Particulars

6.1 List of Excipients

Water for injections, sodium chloride, dibasic sodium phosphate dodecahydrate and citric acid monohydrate.

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.
If dilution is necessary, the resultant solution should be held at 2°C to 8°C for no longer than 24 hours.

6.4 Special Precautions for Storage

Store below 25°C. Do not freeze. Protect from light.

6.5 Nature and Contents of Container

Metronidazole Kabi 500 mg/100 mL is a colourless to pale yellow, ready to use solution.
Metronidazole Kabi 500 mg/100 mL (AUST R 310261) is supplied in 100 mL colourless glass bottle (type II glass) with halobutyl rubber stopper and cap or polyethylene bottle (KabiPac) available in packs of 5, 10 or 12.
* Not all pack types and sizes may be 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-(2-Methyl-5-nitro-1H-imidazol-1-yl)ethanol.
Molecular Formula: C6H9N3O3.
Molecular weight: 171.2.

CAS number.

443-48-1.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only.

Summary Table of Changes