Consumer medicine information

Fluorouracil Accord

Fluorouracil

BRAND INFORMATION

Brand name

Fluorouracil Accord

Active ingredient

Fluorouracil

Schedule

SUMMARY CMI

FLUOROURACIL ACCORD

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I being given Fluorouracil Accord?

Fluorouracil Accord contains the active ingredient Fluorouracil. Fluorouracil Accord belongs to a group of medicines known as antineoplastic or cytotoxic agents. It is used to treat some types of cancer. Fluorouracil Accord is classified as an 'antimetabolite' type of cytotoxic agent. It works by interfering with the growth of cancer cells which are eventually destroyed.

For more information, see Section 1. Why am I using Fluorouracil Accord? in the full CMI.

2. What should I know before I am given Fluorouracil Accord?

Do not use if you have ever had an allergic reaction to any medicine containing Fluorouracil or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I am given Fluorouracil Accord? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Fluorouracil Accord and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How will I be given Fluorouracil Accord?

Fluorouracil Accord will be given to you by a doctor or a nurse.

More instructions can be found in Section 4. How will I be given Fluorouracil Accord? in the full CMI.

5. What should I know while being given Fluorouracil Accord?

Things you should do	Tell your doctor immediately if you have a fever or infection before, during or after being given Fluorouracil Accord. If you become pregnant during or soon after being given Fluorouracil Accord, tell your doctor. Tell the surgeon or anaesthetist that you are being given Fluorouracil Accord if you are going to have surgery.
Driving or using machines	Be careful driving or operating machinery until you know how Fluorouracil Accord affects you. Be careful when drinking alcohol while you are taking this medicine. If you drink alcohol, dizziness or confusion may be worse.

For more information, see Section 5. What should I know while being given Fluorouracil Accord? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

Some of the serious side effects are:

Any signs of an allergic reaction (shortness of breath, wheezing, difficulty breathing or a tight feeling in your chest; swelling of the face, lips, tongue or other parts of the body; rash, itching, hives or flushed, red skin; dizziness or light-headedness); soreness, redness or ulceration of the mouth, rectum or anus; unsteady walking, muscle weakness or muscle cramps; changes in vision, jerky eye movements, excess tears, or uncomfortable sensitivity to light; tingling of the hands and feet followed by pain, redness and swelling; slurred speech; memory loss, disorientation or confusion; an increased sensitivity of the skin to sunlight. (such as redness, itching, swelling, blistering) which may occur more quickly than normal. You should avoid being in the sunlight for too long; fever; pain, stiffness or swelling in joints; swelling, redness, or pain near the injection site; chest pain; loss of fingernails or toenails; irregular and/or rapid heart beat; loss of consciousness; signs of an infection (e.g. fever, chills, sore throat, cough, pain with urination, swollen or red skin); unusual bleeding or bruising (such as bloody or black stools, blood in urine); yellowing of the skin or eyes; severe diarrhoea; severe abdominal pain; severe mouth ulceration; difficulty swallowing; seizures, coma.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

FLUOROURACIL ACCORD

Active ingredient(s): Fluorouracil

Consumer Medicine Information (CMI)

This leaflet provides important information about using Fluorouracil Accord. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Fluorouracil Accord.

Where to find information in this leaflet:

1. Why am I being given Fluorouracil Accord?
2. What should I know before I am given Fluorouracil Accord?
3. What if I am taking other medicines?
4. How will I be given Fluorouracil Accord?
5. What should I know while being given Fluorouracil Accord?
6. Are there any side effects?
7. Product details

1. Why am I being given Fluorouracil Accord?

Fluorouracil Accord contains the active ingredient Fluorouracil. Fluorouracil Accord belongs to a group of medicines known as antineoplastic or cytotoxic agents. You may also hear of these being called chemotherapy medicines.

It is used to treat some types of cancer.

Fluorouracil Accord is classified as an 'antimetabolite' type of cytotoxic agent. It works by interfering with the growth of cancer cells which are eventually destroyed.

Your doctor, however, may prescribe Fluorouracil Accord for another purpose.

2. What should I know before I am given Fluorouracil Accord?

Warnings

You must not be given Fluorouracil Accord if:

you have an allergy to Fluorouracil or to any of the other ingredients listed at the end of this leaflet.
You have, or have had any of the following medical conditions: problems with blood clotting; any blood disorder with a reduced number of red blood cells, white blood cells or platelets; lowered immunity due to diseases including HIV/AIDS or cancer; lowered immunity due to treatment with medicines such as corticosteroids, ciclosporin or other medicines used to treat cancer (including radiation therapy); you have a poor diet or are debilitated, complete dihydropyrimidine dehydrogenase (DPD) deficiency.

Tell your doctor if you:

are allergic to any other medicines, foods, dyes or preservatives
have an infection or high temperature (your doctor may decide to delay your treatment until the infection has gone. A mild illness, such as a cold is not usually a reason to delay treatment)
plan to have surgery
are within four weeks of treatment with brivudine, sorivudine or their chemically related analogues

Tell your doctor if you have or have had:

heart disease
kidney disease
liver disease
problems with stomach or intestinal ulcers
haemorrhoids/piles or other bleeding in or from the bowels
problems with blood clotting
if you have had previous radiation treatment or other cancer treatment
if you have any known enzyme deficiencies.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Tell your doctor if you:

are pregnant, or intend to become pregnant
are breastfeeding or plan to breastfeed.

Like most medicines, Fluorouracil Accord is not recommended for use during pregnancy. Your doctor will discuss with you the risks and benefits of having Fluorouracil Accord during pregnancy.

Fluorouracil Accord may cause birth defects if either the male or female is receiving it at the time of conception or if it is used during pregnancy. You should use some kind of birth control while you are being treated with Fluorouracil Accord and for at least 3 months (for male patients) and 6 months (for female patients) after you stop using it.

It is not known whether Fluorouracil Accord affects fertility.

You should not breast-feed your child during your treatment with Fluorouracil Accord. Fluorouracil Accord may pass into breast milk and therefore there is a possibility that the breast-fed baby may be affected.

3. What if I am taking other medicines?

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

Some medicines and Fluorouracil Accord may interfere with each other.

Tell your doctor if you are taking:

medicines used to treat grout (e.g. allopurinol)
medicines used to treat some types of cancer (e.g. methotrexate)
medicines used to treat some types of infections (e.g. metronidazole)
phenytoin (used to treat epilepsy)
warfarin (used to prevent blood clots)
folinic acid (used as an antidote to some cancer therapy)
cimetidine (used to treat stomach ulcers)
brivudine, sorivudine or their chemically related analogues.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Fluorouracil Accord.

4. How will I be given Fluorouracil Accord?

Fluorouracil Accord will be given to you by a doctor or a nurse. It may be given in three (3) ways:

as a single injection into a vein
as a continuous slow injection via a 'drip' into a vein
as a slow injection via a 'drip' into an artery.

How much will be given

Your doctor will decide on what dose you will receive. This depends on your condition and other factors, such as your weight and height.

When will Fluorouracil Accord be given

Fluorouracil Accord Injection may be given alone or in combination with other drugs. Several courses of Fluorouracil Accord therapy may be needed depending on your response to treatment. Additional treatment may not be repeated until your blood cell numbers return to acceptable levels and any unwanted effects have been controlled.

If you receive too much Fluorouracil Accord

Since Fluorouracil Accord is usually given to you in hospital under the supervision of your doctor, it is very unlikely that you will be given too much of the medicine. If you think that you have been given too much Fluorouracil Accord.

You should immediately:

phone the Poisons Information Centre (by calling 13 11 26), or
contact your doctor, nurse or pharmacist.

5. What should I know while being given Fluorouracil Accord?

Things you should do

Be sure to keep all your doctor's appointments.

It is important to have your follow-up doses/cycles of Fluorouracil Accord at the appropriate times to get the best effects from your treatments.

Your doctor may also want to check your blood pressure and do some blood and other tests from time to time to check on your progress and detect any unwanted side effects

Tell your doctor immediately if you have a fever or infection before, during or after being given Fluorouracil Accord. Fluorouracil Accord can lower the number of white blood cells and platelets in your blood. This means that you have an increased chance of getting an infection or bleeding. The following precautions should be taken to reduce your risk of infection or bleeding:

Avoid people who have infections. Check with your doctor or nurse immediately if you think you may be getting an infection, or if you get a fever, chills, cough, hoarse throat, pain in the lower back or side or you find it painful or difficult to urinate.
Be careful when using a toothbrush, toothpick or dental floss. Your doctor, dentist, nurse or pharmacist may recommend other ways to clean your teeth and gums. Check with your doctor before having any dental work.
Be careful not to cut yourself when you are using sharp objects such as a razor or nail cutters.
Avoid contact sports or other situations where you may bruise or get injured.

Fluorouracil and its breakdown products may be excreted in body fluids and waste, including blood, urine, faeces, vomitus and semen. Precautions to protect other people should be taken while you are receiving chemotherapy and for one week after the treatment period:

Flush the toilet twice to dispose of any body fluids and waste.
Wear gloves to clean any spill of body fluid or waste. Use paper towels or old rags, a strong solution of non-bleaching detergent and large amounts of water to mop up the spill. Discard the towels or rags into a separate waste bag, seal the bag, and dispose into the garbage. Dispose of the fluids in the toilet
Wash linen or clothing that is heavily contaminated by body fluids or waste separately from other items. Use a strong solution of non-bleaching detergent and large amounts of water
Place soiled disposable nappies and other pads in a plastic bag, seal the bag and dispose into the garbage
For sexual intercourse, use a barrier method such as a condom.

If you become pregnant while you are being given Fluorouracil Accord, tell your doctor immediately.

If you are going to have surgery, tell the surgeon or anaesthetist that you are being given Fluorouracil Accord.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are being given Fluorouracil Accord.

Tell any other doctors, dentists, and pharmacists who treat you that you are being given Fluorouracil Accord.

Driving or using machines

Be careful driving or operating machinery until you know how Fluorouracil Accord affects you.

This medicine may cause dizziness or confusion in some people. If you have any of these symptoms, do not drive, operate machinery, or do anything else that could be dangerous.

Be careful when drinking alcohol while you are taking this medicine. If you drink alcohol, dizziness or confusion may be worse.

Looking after your medicine

The hospital will store Fluorouracil Accord under the correct conditions.

Getting rid of any unwanted medicine

Your doctor or pharmacist will dispose of any Fluorouracil Accord that may be left over.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Common side effects

Less serious side effects	What to do
nausea vomiting diarrhoea loss of appetite hair loss skin rash changes in skin or nail appearance euphoria tiredness headache dizziness fatigue irritability restlessness	Speak to your doctor if you have any of these common side effects and they worry you

Serious side effects

Serious side effects

What to do

any signs of an allergic reaction (shortness of breath, wheezing, difficulty breathing or a tight feeling in your chest; swelling of the face, lips, tongue or other parts of the body; rash, itching, hives or flushed, red skin; dizziness or light-headedness)
soreness, redness or ulceration of the mouth, rectum or anus
unsteady walking, muscle weakness or muscle cramps
changes in vision, jerky eye movements, excess tears, or uncomfortable sensitivity to light
tingling of the hands and feet followed by pain, redness and swelling
slurred speech
memory loss, disorientation or confusion
an increased sensitivity of theskin to sunlight. (such as redness, itching, swelling, blistering) which may occur more quickly than normal. You should avoid being in the sunlight for too long
fever
pain, stiffness or swelling in joints
swelling, redness, or pain near the injection site
chest pain
loss of fingernails or toenails
irregular and/or rapid heart beat
loss of consciousness
signs of an infection (e.g. fever, chills, sore throat, cough, pain with urination, swollen or red skin)
unusual bleeding or bruising (such as bloody or black stools, blood in urine)
yellowing of the skin or eyes
severe diarrhoea
severe abdominal pain
severe mouth ulceration
difficulty swallowing
seizures, coma

Call your doctor straight away or go straight to the Emergency Department at your nearest hospital

Treatment with Fluorouracil Accord may cause changes in your blood cells which may be serious. Fluorouracil Accord may also affect how your kidneys and liver work. Your doctor will arrange regular blood tests to detect any changes.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

Fluorouracil Accord is not addictive.

Fluorouracil Accord does not contain gluten, sucrose, lactose, tartrazine or any other azo dyes.

What Fluorouracil Accord contains

Active ingredient (main ingredient)	fluorouracil
Other ingredients (inactive ingredients)	sodium hydroxide hydrochloric acid water for injections

Do not take this medicine if you are allergic to any of these ingredients.

What Fluorouracil Accord looks like

Fluorouracil Accord is a clear colourless solution supplied in single packs. (250 mg/5 mL: AUST R 285799, 500 mg/10 mL: AUST R 285801, 1 g/20 mL: AUST R 285800, 2.5 g/50 mL; AUST R 285803, 5 g/100 mL: AUST R 285802)

Who distributes Fluorouracil Accord

Accord Healthcare Pty Ltd
Level 24, 570 Bourke Street
Melbourne, VIC, 3000
Australia

This leaflet was prepared in September 2023.

Published by MIMS October 2023

BRAND INFORMATION

Brand name

Fluorouracil Accord

Active ingredient

Fluorouracil

Schedule

1 Name of Medicine

Fluorouracil.

2 Qualitative and Quantitative Composition

Fluorouracil Accord injection solution contains fluorouracil as the active ingredient. Five strengths are available as follows: 250 mg/5 mL, 500 mg/10 mL, 1 g/20 mL, 2.5 g/50 mL and 5 g/100 mL. The 2.5 g/50 mL and 5 g/100 mL vials are Pharmacy Bulk Packs.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Fluorouracil Accord Solution for Injection is a clear, colourless to slightly pale yellow solution containing fluorouracil. The pH of the fluorouracil injection solution is approximately 8.9.

4 Clinical Particulars

4.1 Therapeutic Indications

Alone or in combination, for the palliative treatment of malignant tumours, particularly of the breast, colon or rectum; and in the treatment of gastric, primary hepatic, pancreatic, uterine (cervical particularly), ovarian and bladder carcinomas.
Fluorouracil should only be used when other proven measures have failed or are considered impractical.

4.2 Dose and Method of Administration

General directions.

Fluorouracil Accord contains no antimicrobial agent. The product is for single use in one patient only. Discard any residue.
The use of the Pharmacy Bulk Pack should be restricted to suitably qualified pharmacists operating in suitably equipped hospital pharmacies or compounding centres. The Pharmacy Bulk Pack is intended for multiple dispensing but should be spiked only once.
To reduce microbiological hazard, use as soon as practicable after preparation. If storage is necessary, hold at 2°C to 8°C for not more than 24 hours after preparation. Administration should be completed within 24 hours of preparation of the infusion and any residue discarded according to the guidelines for the disposal of cytotoxic drugs (see Handling precautions and Spills and disposal).
Fluorouracil injection may be administered by intravenous infusion or intravenous injection, the dosage being based on the patient's actual weight. Ideal weight is used only if the patient is obese or if there has been a spurious weight gain due to oedema, ascites or other forms of abnormal fluid retention. Prior to treatment, each patient is to be carefully evaluated in order to estimate the optimum initial dosage of fluorouracil. The total daily dose of fluorouracil should not exceed 1 g. The initial recommended doses should be reduced by one-third to one-half if any of the following conditions are present: poor nutritional state; within 30 days after major surgery; inadequate bone marrow function (white blood cell count less than 5,000/mm³, platelet count less than 100,000/mm³); impaired hepatic and/or renal function.
The following regimens have been recommended for use of fluorouracil as a single agent in adults.

Intravenous infusion.

15 mg/kg bodyweight (to a maximum of 1 g) daily diluted in 300 to 500 mL of 5% glucose given over a period of four hours. Infusions may be continued daily until the first gastrointestinal side effects occur, i.e. stomatitis, diarrhoea, leucopenia, thrombocytopenia; treatment should then be discontinued. After the side effects have subsided and the WBC count has risen to 3,000 to 4,000/mm³ or the platelet count to 80,000 to 100,000/mm³ the patient may then be placed on a maintenance therapy program.

Intravenous injection.

12 mg/kg bodyweight daily for three consecutive days. If toxic effects do not appear, the patient may then be given 6 mg/kg intravenously on the 5th, 7th and 9th days. If there are still no signs of toxicity, the patients may be placed on maintenance therapy, otherwise regression of toxic side effects must be awaited before continuing therapy.

Maintenance therapy.

5 to 10 mg/kg bodyweight by intravenous injection once a week. Toxic effects seldom occur during maintenance therapy. If, however, they do appear, therapy must be discontinued until the symptoms regress, otherwise regression of toxic side effects must be awaited before continuing therapy.

Other methods of administration.

Fluorouracil Accord may be used in combination with other cytostatic agents or with radiotherapy; in such cases, doses should be reduced accordingly. Administration of 5 to 7 mg/kg bodyweight daily may also be performed as a 24 hour intra-arterial continuous drip infusion.

Compatibilities.

Fluorouracil Accord is compatible with the following infusion media: 0.9% sodium chloride, 5% glucose, 0.9% sodium chloride with 5% glucose.
Fluorouracil Accord can be used in combination with other antitumour agents, but it is not recommended that it be mixed with these drugs in the same container.

Handling precautions.

As with all antineoplastic agents, trained personnel should prepare Fluorouracil Accord. This should be performed in a designated area (preferably a cytotoxic laminar flow cabinet). Protective gown, mask, gloves and appropriate eye protection should be worn when handling fluorouracil. Where solution accidentally contacts skin or mucosa, the affected area should be immediately washed, thoroughly with soap and water. It is recommended that pregnant personnel not handle cytotoxic agents such as fluorouracil.
Luer-Lok fitting syringes are recommended. Large bore needles are recommended to minimise pressure and possible formation of aerosols. Aerosols may also be reduced by using a venting needle during preparation.
Items used to prepare Fluorouracil Accord, or articles associated with body waste should be disposed of by placing in a double sealed polythene bag and incinerated at 1,100°C.

Spills and disposal.

If spill occurs, restrict access to the affected area. Wear two pairs of latex rubber gloves, a suitable mask, a protective gown and safety glasses. Limit the spread of the spill by covering with a suitable material such as absorbent towels or adsorbent granules. Spills may also be treated with sodium hypochlorite 5%. Collect the absorbent/adsorbent and other debris from the spill and place in a leakproof plastic container and label accordingly. Cytotoxic waste should be regarded as toxic and hazardous and clearly labelled 'Cytotoxic Waste for Incineration at 1,100°C'. Waste material should be incinerated at 1,100°C for at least one second. Clean the remaining spill area with copious amounts of water.

4.3 Contraindications

Fluorouracil is contraindicated in patients:
who have any known hypersensitivity to fluorouracil or its excipients;
who are debilitated;
who are suffering a poor nutritional state;
who are suffering from bone marrow depression following radiotherapy or therapy with other antineoplastic agents (leucocyte count less than 5,000/mm³, platelet count less than 100,000/mm³);
who are suffering from a potentially serious infection;
who are pregnant;
with known complete dihydropyrimidine dehydrogenase (DPD) deficiency (see Section 4.4 Special Warnings and Precautions for Use).
Fluorouracil must not be taken within 4 weeks of treatment with brivudine, sorivudine or their chemically related analogues. Brivudine, sorivudine and their analogues are potent inhibitors of the enzyme dihydropyrimidine dehydrogenase (DPD), which degrades fluorouracil (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Fluorouracil should be administered only by or under strict supervision of a qualified physician experienced in therapy with potent metabolites and only when the potential benefits of fluorouracil outweigh the possible risks. Because of the possibility of severe toxic reactions, all patients should be hospitalised, at least during the initial course of therapy and appropriate facilities should be available for adequate management of complications should they arise.
Fluorouracil should not be re-administered after a documented cardiovascular reaction (arrhythmia, angina, ST segment changes) as there is a risk of sudden death.
Fluorouracil should be used with caution in patients with reduced renal or liver function, jaundice or heart disease.

Toxicity.

Fluorouracil has a narrow margin of safety and is a highly toxic drug. The most pronounced and dose-limiting toxic effects of fluorouracil are on the normal, rapidly proliferating tissues of the bone marrow and the lining of the gastrointestinal tract. Fluorouracil therapy should be discontinued promptly whenever one of the following signs of toxicity appears: leucopenia, thrombocytopenia, stomatitis, oesophagopharyngitis, intractable vomiting, diarrhoea, melaena, haemorrhage, oral ulceration, evidence of gastrointestinal ulceration or bleeding. Rarely, severe and unexpected toxic reactions (including stomatitis, diarrhoea, neutropenia and neurotoxicity) have been reported in association with fluorouracil. These reactions have been attributed to deficiency of dipyrimidine dehydrogenase activity, which appears to cause prolonged clearance of fluorouracil.
Any form of therapy that adds to the stress of the patient, interferes with nutritional uptake or depresses bone marrow function will increase the toxicity of fluorouracil.
The ratio between effective and toxic dose is small and therapeutic response is unlikely without some degree of toxicity. Care must be taken, therefore, in the selection of patients and adjustment of dosage.

Cardiotoxicity.

Fluorouracil administration has been associated with myocardial ischaemia, cardiomyopathy and, very rarely, sudden death. Angina, tachycardia, breathlessness, arrhythmia.
ECG abnormalities, myocardial infarction and stress cardiomyopathy (Takotsubo syndrome) have been reported after administration of fluorouracil. Attention should therefore be paid to patients who experience chest pain during treatment, and patients with a history of heart disease. There is an increased risk of death associated with re-administration of fluorouracil in patients with a documented cardiovascular reaction to fluorouracil (see Section 4.8 Adverse Effects (Undesirable Effects)).

Myelosuppression.

Cytotoxic agents, including fluorouracil, may produce myelosuppression (including, but not limited to leucopenia, granulocytopenia, pancytopenia, and thrombocytopenia). Leucopenia and thrombocytopenia commonly follow treatment with fluorouracil.
The initial dose should be reduced, or treatment should not be started in the presence of diminished leucocytes and/or platelets (see Sections 4.3 Contraindications; Section 4.2 Dose and Method of Administration).
Leucopenia occurs after nearly every treatment period with an effective dose. The nadir for white blood cell count usually occurs from the 9th to the 14th day after initiation of therapy, but may occur as late as the 25th day. The count usually returns to normal by the 30th day. Thrombocytopenia may also occur, with the lowest platelet counts occurring from the 7th to the 17th day of therapy.
Daily monitoring of platelet and white blood cell counts is recommended. Treatment with fluorouracil should be discontinued if the leucocyte count falls rapidly or if it falls below 3,500/mm³, or if there is a fall in the platelet count below 100,000/mm³. If the leucocyte count falls below 2,000/mm³, the patient should be placed in an isolation unit and given an appropriate preventative treatment for systemic infection.
Clinical consequences of severe myelosuppression include infections. Viral, bacterial, fungal and/or parasitic infections, either localized or systemic, may be associated with the use of fluorouracil alone or in combination with other immunosuppressive agents. These infections may be mild, but can be severe and at times fatal.

Combination chemotherapy/radiotherapy.

May depress bone marrow function and increase the toxicity of fluorouracil. Extreme caution is necessary when administering fluorouracil to patients who have had high dose pelvic irradiation or have been previously treated with alkylating agents, and in those who have a widespread involvement of bone marrow by metastatic tumours. Radiation therapy on the bone marrow, especially to the area of the chest and mediastinum, may potentiate the bone marrow effects of fluorouracil. Fluorouracil treatment may potentiate necrosis caused by radiation. Concomitant use of other chemotherapeutic agents may depress bone marrow function and increase the toxicity of fluorouracil.

Dihydropyrimidine dehydrogenase deficiency.

Rarely, severe toxicity (e.g. stomatitis, diarrhoea, neutropenia, and neurotoxicity) associated with fluorouracil has been attributed to deficiency of dihydropyrimidine dehydrogenase (DPD) activity. DPD-deficiency related toxicity usually occurs during the first cycle of treatment or after dose increase. Fatal outcome has been reported in some cases. Absence of this catabolic enzyme appears to result in prolonged clearance of fluorouracil. Special attention should be given to DPD status before therapy through laboratory testing for the detection of total or partial DPD-deficiency, or when evaluating patients experiencing fluorouracil-related toxicities.
Patients with complete DPD deficiency are at high risk of life-threatening or fatal toxicity and must not be treated with fluorouracil injection (see Section 4.3 Contraindications). Patients with partial DPD deficiency are at increased risk of severe and potentially life-threatening toxicity. A reduced starting dose should be considered to limit this toxicity. DPD deficiency should be considered as a parameter to be taken into account in conjunction with other routine measures for dose reduction. Initial dose reduction may impact the efficacy of treatment. Consideration should be given to applicable clinical guidelines.

Gastrointestinal effects.

Loss of appetite, nausea and vomiting are common adverse effects, which generally occur during the first week of therapy. These adverse effects may be treated symptomatically and can often be alleviated by antiemetics. Stomatitis is usually an early sign of impending severe toxicity which may become evident as early as the fourth day, but more commonly appears after 5-8 days of therapy. Symptoms include soreness, erythema or ulceration of the oral cavity or dysphagia. Other reported gastrointestinal symptoms are diarrhoea, proctitis and oesophagitis, therefore, the dose may require adjustment or therapy may need to be discontinued. Diarrhoea is usually mild and occurs later in treatment. Severe diarrhoea may also be accompanied by dehydration and melaena. Gastrointestinal side effects may be exacerbated if fluorouracil is given with folinic acid.

Compatibilities.

See Section 4.2 Dose and Method of Administration, Compatibilities.

Immunosuppressant effects/increased susceptibility to infections.

Administration of live or live attenuated vaccines in patients immunocompromised by chemotherapeutic agents including fluorouracil, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving fluorouracil. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Photosensitivity reactions.

Some patients may experience photosensitivity reactions following administration of fluorouracil, it is recommended that patients are warned to avoid prolonged exposure to sunlight (see Section 4.8 Adverse Effects (Undesirable Effects)).

Monitoring phenytoin levels.

Patients taking phenytoin concomitantly with fluorouracil should undergo regular testing because of the possibility of an elevated plasma level of phenytoin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Hand-foot syndrome.

The administration of fluorouracil has been associated with the occurrence of palmar-plantar erythrodysesthesia syndrome, also known as hand-foot syndrome. Continuous-infusion fluorouracil may increase the incidence and severity of palmar-plantar erythrodysesthesia. This syndrome has been characterised as a tingling sensation of hands and feet, which may progress over the next few days to pain when holding objects or walking. The palms and soles become symmetrically swollen and erythematous with tenderness of the distal phalanges, possibly accompanied by desquamation. Interruption of therapy is followed by gradual resolution over 5 to 7 days. Supplementation of chemotherapy with oral pyridoxine has been reported to prevent or resolve such symptoms.

Multifocal inflammatory leucoencephalopathy (MILE).

Combination therapy with fluorouracil and levamisole has been associated with multifocal inflammatory leucoencephalopathy (MILE). Symptoms may include memory loss, confusion, paraesthesia, lethargy, muscle weakness, speech disturbances, coma and seizures. The cerebrospinal fluid may show mild pleiocytosis, and computed tomography and magnetic resonance scans may show lesions in the white matter suggestive of demyelination. If this syndrome occurs, treatment should be discontinued immediately. The condition is at least partially reversible if fluorouracil and levamisole are discontinued and corticosteroids given.

Embryo-fetal toxicity.

Fluorouracil showed evidence of genotoxicity. An effective method of contraception is required for both male and female patients during and for a period after treatment with fluorouracil. Patients desiring to have children after completion of therapy should be advised to obtain genetic counselling if appropriate and available (see Section 4.6 Fertility, Pregnancy and Lactation).

Tumour lysis syndrome.

Cases of tumour lysis syndrome associated with fluorouracil treatment have been reported from postmarketing sources. Patients at increased risk of tumour lysis syndrome (e.g. with renal impairment, hyperuricemia, high tumour burden, rapid progression) should be closely monitored. Preventive measures (e.g. hydration, correction of high uric acid levels) should be considered.

Use in hepatic impairment.

Fluorouracil should be used with caution in patients with reduced liver function or jaundice.

Use in renal impairment.

Fluorouracil should be used with caution in patients with reduced renal function or heart disease.

Use in the elderly.

Fluorouracil should be used with caution in elderly patients. An age of 70 years or older and the female gender are statistically significant risk factors for severe toxicity from fluorouracil based chemotherapy. These effects may be additive in older women. While advanced age does not contraindicate the use of this type of chemotherapy, close monitoring for multiple organ toxicities and vigorous supportive care of those with toxicity are required.

Paediatric use.

No data available.

Effects on laboratory tests.

Fluorouracil could interfere with diagnostic tests of thyroid function by causing rises in total thyroxine and liothyronine due to increased globulin binding. Plasma albumin may be decreased because of drug-induced protein malabsorption.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Cytotoxic agents.

All myelosuppressive drugs (e.g. cytotoxic agents used in combination chemotherapy) can increase haematotoxicity of fluorouracil.
Folinic acid (leucovorin) enhances the DNA-directed toxicity of fluorouracil. This combination should be used with caution as the toxicity of fluorouracil, especially GI and haematologic, may be increased. Careful monitoring should be observed and the dose of fluorouracil may be decreased based on current guidelines.
Allopurinol may decrease the degree of bone marrow depression produced by fluorouracil. Studies of this possibility have reported conflicting results.
Various agents have been reported to biochemically modulate the antitumour efficacy or toxicity of fluorouracil. Common medicines include methotrexate, metronidazole and folinic acid (leucovorin).

Metronidazole.

Metronidazole may enhance the toxicity of fluorouracil. The mechanism of interaction is presumed to be reduced clearance of fluorouracil by metronidazole. Concurrent administration should be avoided.
Combination therapy with fluorouracil and levamisole has been associated with multifocal inflammatory leukoencephalopathy (MILE). Symptoms may include memory loss, confusion, paraesthesia, lethargy, muscle weakness, speech disturbances, coma and seizures. The cerebrospinal fluid may show mild pleiocytosis, and computed tomography and magnetic resonance scans may show lesions in the white matter suggestive of demyelination. If this syndrome occurs, treatment should be discontinued immediately. The condition is at least partially reversible if fluorouracil and levamisole are discontinued and corticosteroids given. The use of levamisol and fluorouracil is no longer recommended by NH and MRC 'Clinical Practice guidelines: The prevention, early detection and management of colorectal cancer'. This combination regimen has been superceded by fluorouracil and folinic acid.
Pretreatment with cimetidine prior to intravenous fluorouracil increased the area under the concentration time curve (AUC) by 27%. The total body clearance was reduced by 28%. This may lead to increased plasma concentrations of fluorouracil. This effect is probably due to both inhibition of hepatic enzymes and reduction of hepatic blood flow. Caution should be taken if the patient receives fluorouracil and cimetidine concurrently.
Increased phenytoin plasma concentrations have been reported during concomitant use of phenytoin with capecitabine or its metabolite fluorouracil. Formal interaction studies between phenytoin and capecitabine have not been conducted, but the mechanism of interaction is presumed to be inhibition of CYP2C9 isoenzyme system by capecitabine. Serum levels of phenytoin sustained above the optimal range may produce encephalopathy or confusional states (delirium psychosis) or rarely irreversible cerebellar dysfunction. Therefore, patients taking phenytoin concomitantly with capecitabine or fluorouracil should be regularly monitored for increased phenytoin plasma levels, and the phenytoin dosage may need to be reduced (see Section 4.4 Special Warnings and Precautions for Use).

Brivudine and sorivudine.

Brivudine, sorivudine or their chemically related analogues irreversibly inhibit DPD, resulting in a significant increase in fluorouracil exposure. This may lead to increased fluoropyrimidine-related toxicities with potentially fatal outcome. Therefore, either a different antiviral therapy may be used or there should be an interval of at least 4 weeks between the administration of brivudine, sorivudine, or the analogues and the start of fluorouracil treatment (see Section 4.3 Contraindications). In the case of accidental administration of nucleoside analogues that inhibit DPD activity to patients treated with fluorouracil, effective measures should be taken to reduce fluorouracil toxicity. Immediate hospitalisation is recommended.

Radiation therapy.

Radiation therapy on the bone marrow, especially to the area of the chest and mediastinum, may potentiate the bone marrow effects of fluorouracil.

Warfarin.

Elevated INR levels and occasional episodes of bleeding have been reported during concomitant use of warfarin and fluorouracil or its analogues. In these cases, fluorouracil has usually been administered as one component of an antineoplastic combination regimen. Adequate anticoagulant response to warfarin and other coumarin-derivative therapy should be monitored regularly in patients taking fluorouracil.

Live or live-attenuated vaccines.

Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including fluorouracil, may result in serious or fatal infections (see Section 4.4 Special Warnings and Precautions for Use).

Laboratory values.

Fluorouracil treatment may interfere with some laboratory tests. Increases in total serum thyroxine concentration (due to increased binding to globulin) have been reported.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fluorouracil has not been adequately studied in animals to permit an evaluation of its effects on fertility and general reproductive performance. No specific studies to evaluate the effects of fluorouracil on male fertility have been conducted; however, fluorouracil was toxic to male reproductive organs, indicating that fluorouracil has the potential to impact reproductive function and fertility. Adverse effects of fluorouracil were evident in testes in male rats following repeat oral dosing at 30 mg/kg/day for 1 month. Doses of 125 or 250 mg/kg, administered intraperitoneally, have been shown to induce chromosomal aberrations and changes in chromosomal organisation of spermatogonia in rats. Spermatogonial differentiation was also inhibited by fluorouracil, resulting in transient infertility. However, in studies with a strain of mouse which is sensitive to the induction of sperm head abnormalities after exposure to a range of chemical mutagens and carcinogens, fluorouracil did not produce any abnormalities at oral doses of up to 80 mg/kg/day. In female rats, fluorouracil, administered intraperitoneally at weekly doses of 25 or 50 mg/kg for three weeks during the pre-ovulatory phase of oogenesis, significantly reduced the incidence of fertile matings, delayed the development of pre- and post-implantation embryos, increased the incidence of pre-implantation lethality and induced chromosomal anomalies in these embryos. In a limited study in rabbits, a single 25 mg/kg dose of fluorouracil or 5 daily doses of 5 mg/kg had no effect on ovulation, appeared not to affect implantation and had only limited effect in producing zygote destruction.
Effects of fluorouracil on the gonads and reproduction capacity of humans are not fully known. However, based on animal studies, male and female fertility may be compromised. Also, compounds such as fluorouracil which interfere with DNA, RNA and protein synthesis might be expected to have adverse effects on gametogenesis. In general, use of a contraceptive is recommended during cytotoxic therapy.
(Category D)
Category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human foetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
Fluorouracil may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women, however, fetal defects and miscarriages have been reported. Fluorouracil administered parenterally has been shown to be teratogenic in mice, rats and hamsters, and embryolethal in monkeys. Fetal malformations included cleft palate, skeletal defects, and deformed appendages and tails. Potential effects of fluorouracil on peri and postnatal development have not been studied in animals. However, in rats fluorouracil has been found to cross the placental barrier and to cause fetal mortality. Fluorouracil is strictly contraindicated in pregnancy (see Section 4.3 Contraindications).
Safety for use in pregnancy has not been established. Women of childbearing age should be advised to avoid pregnancy and to use a highly effective method of contraception during fluorouracil therapy and for at least 6 months after last dose. Fluorouracil should only be used in women of child bearing potential if the expected benefits outweigh the risks of therapy, and adequate contraception is used. If the patient becomes pregnant whilst receiving the drug she should be advised of the potential hazards to the fetus. It is also recommended to advise the patient to seek genetic counselling prior to treatment with fluorouracil, if appropriate and available.
Men treated with fluorouracil should be advised not to father a child during and for at least 3 months following cessation of treatment. Advise on fertility preservation should be sought prior to treatment by both male and female patients because of the possibility of irreversible infertility due to therapy with fluorouracil. Men undergoing fluorouracil treatment should also ensure they use effective contraception measures.
It is not known whether fluorouracil is excreted in breast milk. To avoid possible harmful effects in the infant, breastfeeding is not advised during fluorouracil therapy.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

The ratio between effective and toxic dose is small and therapy with fluorouracil is usually accompanied by some degree of adverse effects. Adverse effects of fluorouracil mainly result from its effects on rapidly dividing cells of normal tissue and its effects on the gastrointestinal tract and haematopoietic systems (see Section 4.4 Special Warnings and Precautions for Use). Patients should be very carefully observed and dosage adjustment may have to be made. Deaths have been reported.

Gastrointestinal.

The most pronounced and dose limiting toxic effects of fluorouracil are on the normal, rapidly proliferating cells of the bone marrow and the lining of the gastrointestinal tract.
Nausea and vomiting occur and may be treated symptomatically.
Stomatitis is usually an early sign of impending severe toxicity which may be evident after five to eight days of therapy. Symptoms include soreness, erythema or ulceration of the oral cavity or dysphagia. Other reported gastrointestinal symptoms are diarrhoea, proctitis, melaena, gastrointestinal haemorrhage, gastrointestinal ulcer and oesophagitis, therefore, the dose may require adjustment or therapy may need to be discontinued. Gastrointestinal side effects may be exacerbated if fluorouracil is given with folinic acid (leucovorin).

Dermatological.

Alopecia^a may be seen in a substantial number of cases, but it is reversible. Nail disorders^b, dermatitis^c, cutaneous lupus erythematosus and hyperpigmentation of the nail beds and other body areas^d have been reported. Skin rashes and fissures have been associated with fluorouracil therapy. Palmar-plantar erythrodysaesthesia syndrome^e, thrombophlebitis and asymptomatic hyperpigmentation over vascular channels have also been reported. Continuous-infusion fluorouracil may increase incidence and severity of palmar-plantar erythrodysaesthesia, photosensitivity reactions.

Haematological.

Leucopenia, primarily granulocytopenia, commonly occurs. The nadir for white blood cell count usually occurs from the 9th to the 14th day after initiation of therapy, but may occur as late as the 25th day. The count usually returns to normal by the 30th day. Thrombocytopenia may also occur, with the lowest platelet counts occurring from the 7th to the 17th day of therapy. Bone marrow failure and pancytopenia may also occur.

Cardiovascular.

Fluorouracil administration has been associated with angina pectoris^f,g, myocardial ischaemia^f, myocardial infarction^f, cardiac shock^f, cardiac failure^f, myocarditis^f, cardiomyopathy^f, pericarditis^f, stress cardiomyopathy, thrombophlebitis and haemorrhage. There have been reports of chest pain, tachycardia^f, breathlessness, arrhythmia^f, and ECG changes (ST segment changes) after administration of fluorouracil. There have been reports of sudden death in patients readministered fluorouracil after a documented cardiovascular reaction.

Ocular.

Systemic fluorouracil treatment has been associated with various types of ocular toxicity. Additionally, several other reports have been noted including excessive lacrimation, dacryostenosis, visual changes and photophobia.

Neurological.

Combination therapy with fluorouracil and levamisole has been associated with leukoencephalopathy^h and multifocal inflammatory leucoencephalopathy (MILE). Symptoms may include memory loss, confusion, paraesthesia, lethargy, muscle weakness, speech disturbances, coma and seizures. The cerebrospinal fluid may show mild pleiocytosis and computed tomography and magnetic resonance scans may show lesions in the white matter suggestive of demyelination. If this syndrome occurs, treatment should be discontinued immediately. The condition is at least partially reversible if fluorouracil and levamisole are discontinued and corticosteroids given.
Neurotoxicity^h: disorientation, confusion, euphoria, ataxia, nystagmus, headache, slurred speech, dizziness, unsteadiness, muscular weakness, acute cerebellar syndrome and occasionally oculomotor disturbances have occurred in patients receiving fluorouracil. These symptoms may persist after therapy is discontinued.

Infections and infestations.

Septic shock, sepsis, neutropenic sepsis, progressive multifocal leukoencephalopathy, pneumonia, superinfection, urinary tract infection, catheter related infection, cellulitis, pharyngitis, and other infections.

Hepatobiliary disorders.

Hepatocellular injury.

Metabolism and nutrition disorders.

Dehydration, decreased appetite, tumour lysis syndrome.

Immune system disorders.

Anaphylactic reaction, hypersensitivity.

Other.

Local injection site reaction. Fever has also been reported. Rarely, anaphylaxis or generalised allergic reactions have occurred in patients receiving fluorouracil. Pyrexia and chest pain.
^a Reversible.
^b Such as partial or complete detachment of nails.
^c Manifests often as itchy maculopapular rash on the extremities.
^d Skin hyperpigmentation also refers to asymptomatic hyperpigmentation over vascular channels.
^e Observed in patients who received fluorouracil and leucovorin bolus administration.
^f Listed cardiac disorders associated with fluorouracil may lead to cardiac arrest.
^g Observed in patients receiving high dose leucovorin and fluorouracil bolus and continuous infusion.
^h Symptoms may persist after therapy is discontinued.

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 http://www.tga.gov.au/reporting-problems (Australia) or https://nzphvc.otago.ac.nz/reporting/ (New Zealand).

4.9 Overdose

Signs and symptoms.

The possibility of overdosage with fluorouracil is unlikely in view of the mode of administration. High dosages or prolonged treatment with fluorouracil can result in life-threatening intoxication symptoms; the anticipated manifestations include nausea, vomiting, diarrhoea, gastrointestinal ulceration, haemorrhage and bleeding, myelosuppression and bone marrow depression (including thrombocytopenia, leucopenia and agranulocytosis).

Treatment.

Uridine triacetate is a specific antidote for the treatment of fluorouracil overdose or the treatment of severe early-onset toxicities. It should be administered within 96 hours after end of fluorouracil infusion. In the event uridine triacetate is not available, treatment is symptomatic and supportive. Patients who have been exposed to an overdose of fluorouracil should be monitored haematologically for at least four weeks. Should abnormalities appear, appropriate therapy should be utilised.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia) or the national Poisons Centre, 0800 POISON or 0800 764 766 (New Zealand).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Fluorouracil is an analogue of uracil, a component of ribonucleic acid. The drug is believed to function as an antimetabolite. Fluorouracil itself is inactive and is converted intracellularly to active metabolites. After conversion to the active deoxynucleotide, it interferes with the synthesis of DNA by blocking the conversion of deoxyuridylic acid to thymidylic acid by the cellular enzyme thymidylate synthetase. Fluorouracil may also interfere with RNA synthesis.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Distribution.

After intravenous administration, fluorouracil is distributed throughout body tissues and fluids. The plasma half-life is 8 to 22 minutes and is dose dependent. Fluorouracil disappears from the blood within four hours. It is preferentially taken up by actively dividing tissues and tumours after conversion to its nucleotide. Fluorouracil readily enters the cerebrospinal fluid (CSF).

Metabolism and excretion.

About 20% is excreted unchanged in the urine and the remainder is mostly metabolised in the liver by the usual body mechanisms for uracil.

5.3 Preclinical Safety Data

Genotoxicity.

Fluorouracil was genotoxic in the majority of the in vitro studies in bacteria (Salmonella typhimurium and Saccharomyces cerevisiae) or in vivo studies performed. Fluorouracil has been shown to be mutagenic and clastogenic in a number of studies. Oncogenic transformation of fibroblasts from mouse embryo has been induced in vitro by fluorouracil, but the relationship between oncogenicity and mutagenicity is not clear. A positive effect was observed in the micronucleus test on bone marrow cells of the mouse, and fluorouracil at very high concentrations produced chromosomal breaks in hamster fibroblasts in vitro.

Carcinogenicity.

Insufficient evidence of carcinogenicity was found in long-term studies in rats and mice. Conventional long-term studies in animals to determine the carcinogenic potential of fluorouracil have not been performed. Insufficient evidence of carcinogenicity was found in long-term studies following oral or IV administration in rats and mice for up to 1 year. Nevertheless, the risk of carcinogenicity cannot be totally excluded.

6 Pharmaceutical Particulars

6.1 List of Excipients

Water for injections, hydrochloric acid, sodium hydroxide.

6.2 Incompatibilities

Admixtures with acidic medicines or medicines that decompose in an alkaline environment should be avoided. Fluorouracil is reported to be incompatible with cytarabine, diazepam, methotrexate, platinum compounds, doxorubicin (and presumably other anthracyclines that are unstable at alkaline pH), and calcium folinate (leucovorin) or levoleucovorin calcium.

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. Do not refrigerate. Do not freeze. Protect from light.
If a precipitate has formed as a result of exposure to low temperature, redissolve by heating to 60°C accompanied by vigorous shaking. Allow to cool to body temperature prior to use.

6.5 Nature and Contents of Container

Five strengths are available as follows: 250 mg/5 mL, 500 mg/10 mL, 1 g/20 mL, 2.5 g/50 mL and 5 g/100 mL in glass vials in packs of 1. The 2.5 g/50 mL and 5 g/100 mL vials are Pharmacy Bulk Packs.
Not all presentations may be marketed in Australia.

6.6 Special Precautions for Disposal

See Section 4.2 Dose and Method of Administration, Spills and disposal.

6.7 Physicochemical Properties

Fluorouracil is a white to almost white, practically odourless, crystalline powder. It is sparingly soluble in water, slightly soluble in alcohol and practically insoluble in chloroform and ether.
Chemical name: 5-fluoro-1H, 3H-pyrimidine-2, 4-dione.
Molecular formula: C₄H₃FN₂O₂.
Molecular weight: 130.1.

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