1. what fluorouracil injection is and what it is used for

Fluorouracil Injection is an anti-cancer medicine. Treatment with an anti-cancer medicine is sometimes called cancer chemotherapy.

Fluorouracil Injection is used to treat many common cancers, particularly cancers of the large bowel and breast. It may be used in combination with other anti-cancer medicines or radiotherapy.

2. what you need to know before you use fluorouracil injection

Do not use Fluorouracil Injection

• if you have shown signs of severe allergy to fluorouracil in the past
• if you are in a seriously weakened state due to long illness
• if your bone marrow has been damaged by other cancer treatments (including radiotherapy)
• if you know that you do not have any activity of the enzyme dihydropyrimidine dehydrogenase (DPD) (complete dPd deficiency)
• if you have a potentially serious infection
• if your cancer is non-malignant
• if you are pregnant or you are breast-feeding
• if you are taking or have taken in the past 4 weeks brivudine, sorivudine and similar drugs (antivirals)

Tell your doctor if any of the above applies to you before this medicine is used.

Talk to your doctor or pharmacist before using Fluorouracil Injection

• if your bone marrow is not producing blood cells normally (your doctor will do a blood test to check this)
• if you have any problems with your kidneys
• if you have any problems with your liver including jaundice (yellowing of the skin)
• if you have suffered from angina (chest pain) or have a history of heart disease
• if you have problems with your heart. Tell your doctor if you experience any chest pain during treatment
• if you are in generally poor health and have lost a lot of weight
• if you have had surgery within the last 30 days
• if you are elderly
• if you know that you have a partial deficiency in the activity of the enzyme dihydropyrimidine dehydrogenase (DPD)
• if you have a family member who has partial or complete deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD)

DPD deficiency: DPD deficiency is a genetic condition that is not usually associated with health problems unless you receive certain medicines. If you have DPD deficiency and take Fluorouracil injection, you are at an increased risk of severe side effects (listed under section 4 Possible side effects). It is recommended to test you for DPD deficiency before start of treatment. If you have no activity of the enzyme you should not take Fluorouracil injection. If you have a reduced enzyme activity (partial deficiency) your doctor might prescribe a reduced dose. If you have negative test results for dPd deficiency, severe and life-threatening side effects may still occur.

Contact your doctor immediately if you are concerned about any of the side effects or if you notice any additional side effects not listed in the leaflet (see section 4 Possible side effects).

Contact your healthcare provider immediately, if you experience the following signs or symptoms: new onset of confusion, disorientation, or otherwise altered mental status, difficulty with balance or coordination, visual disturbances. These could be signs of encephalopathy which can lead to coma and death, if left untreated.

Tell your doctor if any of the above applies to you before this medicine is used.

Taking/using other medicines

Special care is needed if you are taking/using other medicines as some could interact with Fluorouracil Injection, for example:

• methotrexate, cisplatin, cytarabine, mitomycin-C, tamoxifen (anti-cancer medicines)
• metronidazole (an antibiotic)
• calcium leucovorin (also called calcium folinate – used to reduce the harmful effects of anti-cancer medicines)
• allopurinol (used to treat gout)
• cimetidine (used to treat stomach ulcers)
• warfarin (used to treat blood clots)
• interferon alpha 2a; brivudine, sorivudine and similar drugs (antivirals)
• phenytoin (an anti-epilepsy medicine)
• vaccines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Pregnancy and breast-feeding

Tell your doctor if you are pregnant, trying to become pregnant or breast-feeding.

This medicine must not be used during pregnancy and breast-feeding.

Both women of childbearing potential and men must use an effective method of contraception while taking fluorouracil and for at least 6 months afterwards.

Men are advised to seek advice on the conservation of sperm due to the possibility of irreversible infertility due to using fluorouracil.

If a pregnancy does occur during your treatment, you must inform your doctor who will advise you of the potential hazards and may recommend genetic counselling for you. Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Do not drive or use machines if you experience any side effect from Fluorouracil, such as nausea and vomiting. Fluorouracil can also produce adverse events on your nervous system and cause visual changes. If you experience any of these effects, do not drive or use any tools or machines, as they may impair your ability to do so.

Important information about one of the ingredients of Fluorouracil Injection

This medicinal product contains 7 mmol (160 mg) sodium per 1 gram dose. To be taken into consideration by patients on a controlled sodium diet.

3. how to use fluorouracil injection

This medicine is given into a vein or an artery. If it is given into a vein, it can either be injected (using a syringe) or infused (using a drip). If it is given into an artery, it will be given as an infusion.

If it is to be given as an infusion the medicine will be diluted before use.

Dose

Your doctor will work out the correct dose of Fluorouracil Injection for you and how often it must be given.

The dose of medicine given to you will depend on your medical condition, your size, if you have had recent surgery and how well your bone marrow, liver and kidneys are working.

Your doctor will tell how well your bone marrow, liver and kidneys are working using blood tests.

The total daily dose should not exceed 1 gram.

If you are given too much or too little Fluorouracil Injection

This medicine will be given to you by a doctor or nurse. It is unlikely that you will be given too much or too little, however, tell your doctor or nurse if you have any concerns. If you have taken too much, your doctor will monitor you closely for at least 4 weeks.

Fluorouracil 50 mg/ml Injection

The following information is intended for medical or healthcare professionals only

Further to the information included in section 3, practical information on the preparation/han­dling of the medicinal product is provided here.

Incompatibilities

Fluorouracil Injection is incompatible with carboplatin, cisplatin, cytarabine, diazepam, doxorubicin, epirubicin, levamisole, other anthracyclines and possibly methotrexate.

Formulated solutions are alkaline and it is recommended that admixture with acidic drugs or preparations should be avoided.

Use and handling, and disposal

The pH of Fluorouracil Injection is 8.9 and the drug has maximal stability over the pH range 8.6 to 9.0.

If a precipitate has formed as a result of exposure to low temperatures, re-dissolve by heating to 60°C accompanied by vigorous shaking. Allow to cool to body temperature prior to use.

The product should be discarded if it appears brown or dark yellow in colour.

Fluorouracil Injection may be diluted with Glucose 5% Injection or Sodium Chloride 0.9% Injection or Water for Injections immediately before use.

Fluorouracil injection should not be mixed directly, in the same container, with other chemotherapeutic agents or intravenous additives.

Chemical and physical in-use stability has been demonstrated for 5 days at 20–21°C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would not normally be longer than 24 hours at 2–8 °C, unless dilution has taken place in controlled and validated aseptic conditions.

Cytotoxic Handling Guidelines

Should be administered only by, or under the direct supervision of, a qualified physician who is experienced in the use of cancer chemotherapeutic agents.

4. possible side effects

Like all medicines, fluorouracil can cause side effects, although not everybody gets them.

If any of the following happen, tell your doctor immediately:

• severe allergic reaction – you may experience a sudden itchy rash (hives), swelling of the hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty in swallowing or breathing), and you may feel you are going to faint
• chest pains (which may be due to heart problems, including having a heart attack) shortness of breath
• your bowel motions are bloodstained or black
• your mouth becomes sore or develops ulcers
• symptoms of leucoencephalopathy (disease of brain) – extreme weakness and fatigue, staggering while walking, thinking or speech difficulties, seizures, coma.

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

The frequency of possible side effects listed below is defined using the following convention:

Very common: may affect more than 1 in 10 people

Common: may affect up to 1 in 10 people

Uncommon: may affect up to 1 in 100 people

Rare: may affect up to 1 in 1,000 people

Very rare: may affect up to 1 in 10,000 people

Not known (frequency cannot be estimated from the available data)

If you experience any of the following tell your doctor as soon as possible:

Very common side effects

• abnormality in the heart’s rhythm
• anaemia
• diarrhoea
• infections
• feeling or being sick
• anorexia
• tiredness
• reddening of the palms of the hands and/or the soles of the feet
• hair loss (especially in women)
• increased chance of picking up infections and/or delayed wound healing due to low white blood cells
• inflammation of the lining of the mouth, throat, gut, rectum or anus

Common side effects

• low white blood cells accompanied by fever

Uncommon side effects

• low blood pressure (you may feel faint)
• watering eyes, changes in vision, sensitivity to light, side-to-side movements of the eyes
• numbness, tingling or tremor in the hands or feet
• feeling euphoric
• symptoms of Parkinson’s disease (e.g. shaking hands)
• headache
• skin problems, (including dry skin, itchy weals, rash, redness, inflammation)
• skin may appear lighter or darker
• changes in your nails, such as changes in colour or thickening of the nails

Rare side effects

• feeling confused
• discolouration in your fingers and toes (Raynaud’s syn­drome)
• reduced circulation to the brain, intestines and extremities (ischaemia)
• blood clots (pain, redness or swelling of the part affected)

Very rare side effects

• muscle weakness
• cardiac arrest
• sudden cardiac death

Frequency unknown

• quickening of your heart rate
• fever
• the vein where fluorouracil is administered may become painful or discoloured, which may be the sign of a blood clot
• hyperammonaemic encephalopathy (brain dysfunction caused by elevated ammonia)

Fluorouracil may lead to changes in your blood cells. Your doctor will take blood samples to check for abnormalities (e.g. bone marrow depression which may result in low white cells, low red cells, low platelets, low gamma globulins).

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at: or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

5. how to store fluorouracil injection

Keep out of the sight and reach of children

Expiry

This medicine must not be used after the expiry date which is stated on the vial label and carton after ‘EXP’. Where only a month and year is stated, the expiry date refers to the last day of that month.

Storage

Keep the vials in the outer carton, in order to protect from light and store at or below 25°C. They should not be refrigerated or frozen.

Prepared infusions should be used immediately, however, if this is not possible they can be stored for up to 5 days provided they have been prepared in a way to exclude microbial contamination.

Visible signs of deterioration

The product should be discarded if it appears brown or dark yellow in colour.

Disposal

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

• 6. FURTHER INFORMATION

What Fluorouracil Injection contains

The active substance is fluorouracil. Each millilitre (ml) of solution contains 50 mg of fluorouracil.

The other ingredients are sodium hydroxide and Water for Injections.

What Fluorouracil Injection looks like and contents of the pack

1. what fluorouracil injection is and what it is used for

Fluorouracil Injection is an anti-cancer medicine. Treatment with an anti-cancer medicine is sometimes called cancer chemotherapy.

Fluorouracil Injection is used to treat many common cancers, particularly cancers of the large bowel and breast. It may be used in combination with other anti-cancer medicines or radiotherapy.

2. what you need to know before you use fluorouracil injection

Do not use Fluorouracil Injection

• if you have shown signs of severe allergy to fluorouracil in the past
• if you are in a seriously weakened state due to long illness
• if your bone marrow has been damaged by other cancer treatments (including radiotherapy)
• if you know that you do not have any activity of the enzyme dihydropyrimidine dehydrogenase (DPD) (complete DPD deficiency)
• if you have a potentially serious infection
• if your cancer is non-malignant
• if you are pregnant or you are breast-feeding
• if you are taking or have taken in the past 4 weeks brivudine, sorivudine and similar drugs (antivirals)

Tell your doctor if any of the above applies to you before this medicine is used.

Talk to your doctor or pharmacist before using Fluorouracil Injection

• if your bone marrow is not producing blood cells normally (your doctor will do a blood test to check this)
• if you have any problems with your kidneys
• if you have any problems with your liver including jaundice (yellowing of the skin)
• if you have suffered from angina (chest pain) or have a history of heart disease
• if you have problems with your heart. Tell your doctor if you experience any chesHt paoin dsuringira

treatment p

• if you are in generally poor health and have lost a lot of weight Review freque
• if you have had surgery within the last 30 days Tree years rom
• if you are elderly
• if you know that you have a partial deficiency in the activity of the enzyme dihydropyrimidine dehydrogenase (DPD) Version 2
• if you have a family member who has partial or complete deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD) Prepared by

DPD deficiency: DPD deficiency is a genetic condition that is not usually associated with health problems unless you receive certain medicines. If you have DPD deficiency and takDeaFtleuorou­racil injection, you are at an increased risk of severe side effects (listed under section 4 Possible side effects). It is recommended to test you for DPD deficiency before start of treatment.TIit­fleyou have no activity of the enzyme you should not take Fluorouracil injection. If you have a reduced enzyme activity (partial deficiency) your doctor might prescribe a reduced dose. If you have negative test results for DPD deficiency, severe and life-threatening side effects may still occur.

Contact your doctor immediately if you are concerned about any of the side effects or if you notice any additional side effects not listed in the leaflet (see section 4 Possible side effects).

Contact your healthcare provider immediately, if you experience the following signs or symptoms: new onset of confusion, disorientation, or otherwise altered mental status, difficulty with balance or coordination, visual disturbances. These could be signs of encephalopathy which can lead to coma and death, if left untreated.

Tell your doctor if any of the above applies to you before this medicine is used.

Taking/using other medicines

Special care is needed if you are taking/using other medicines as some could interact with Fluorouracil Injection, for example:

• methotrexate, cisplatin, cytarabine, mitomycin-C, tamoxifen (anti-cancer medicines)
• metronidazole (an antibiotic)
• calcium leucovorin (also called calcium folinate – used to reduce the harmful effects of anti-cancer medicines)
• allopurinol (used to treat gout)
• cimetidine (used to treat stomach ulcers)
• warfarin (used to treat blood clots)
• interferon alpha 2a; brivudine, sorivudine and similar drugs (antivirals)
• phenytoin (an anti-epilepsy medicine)Leaflet specification
• vaccines

Pregnancy and breast-feedin 13g 7 × 47 mm 12 panel (3 × 4)

Both women of childbearing potential and men must use an effective method of contraception while taking fluorouracil and fV ore ari tfi le ad sb t y 6 months afterwards. Authorised by

Men are advised to seek advice on the conservation of sperm due to the possibility of irreversible infertility due to using fluDoartoeura­cil. Date

If a pregnancy does occur during your treatment, you must inform your doctor who will advise you of the potential hazards anTditlemay recommend genetic counselling for you. Title

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Do not drive or use machines if you experience any side effect from Fluorouracil, such as nausea and vomiting. Fluorouracil can also produce adverse events on your nervous system and cause visual changes. If you experience any of these effects, do not drive or use any tools or machines, as they may impair your ability to do so.

Important information about one of the ingredients of Fiuorouracii Injection

This medicinal product contains 7 mmol (160 mg) sodium per 1 gram dose. To be taken into consideration by patients on a controlled sodium diet.

3. how to use fluorouracil injection

This medicine is given into a vein or an artery. If it is given into a vein, it can either be injected (using a syringe) or infused (using a drip). If it is given into an artery, it will be given as an infusion.

If it is to be given as an infusion the medicine will be diluted before use.

Dose

Your doctor will work out the correct dose of Fluorouracil Injection for you and how often it must be given.

The dose of medicine given to you will depend on your medical condition, your size, if you have had recent surgery and how well your bone marrow, liver and kidneys are working.Your doctor will tell how well your bone marrow, liver and kidneys are working using blood tests.

The total daily dose should not exceed 1 gram.

If you are given too much or too little Fluorouracil Injection

This medicine will be given to you by a doctor or nurse. It is unlikely that you will be given too much or too little,however, tell your doctor or nurse if you have any concerns. If you have taken too much, your doctor will monitor you closely for at least 4 weeks.

m

. POSSIBLE SIDE EFFECTS

Like all medicines, fluorouracil can cause side effects, although not everybody gets them.

If any of the following happen, tell your doctor immediately:

• severe allergic reaction – you may experience a sudden itchy rash (hives), swelling of the hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty in swallowing or breathing), and you may feel you are going to faint
• chest pains (which may be due to heart problems, including having a heart attack)
• shortness of breath
• your bowel motions are bloodstained or black
• your mouth becomes sore or develops ulcers
• symptoms of leucoencephalopathy (disease of brain) – extreme weakness and fatigue, staggering while walking, thinking or speech difficulties, seizures, coma.

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

The frequency of possible side effects listed below is defined using the following convention:

Very common: may affect more than 1 in 10 people

Common: may affect up to 1 in 10 people

I Fluorouracil 50 mg/ml Injection

The following information is intended for medical or healthcare professionals only

Further to the information included in section 3, practical information on the preparation/han­dling of the medicinal product is provided here.

^Incompatibili­ties

Fluorouracil Injection is incompatible with carboplatin, cisplatin, cytarabine, diazepam, doxorubicin, epirubicin, levamisole, other anthracyclines and possibly methotrexate.

Formulated solutions are alkaline and it is recommended that admixture with acidic drugs or preparations

I should be avoided.

| Use and handling, and disposal

| The pH of Fluorouracil Injection is 8.9 and the drug has maximal stability over the pH range 8.6 to 9.0.

I If a precipitate has formed as a result of exposure to low temperatures, re-dissolve by heating to 60°C accompanied by vigorous shaking. Allow to cool to body temperature prior to use.

The product should be discarded if it appears brown or dark yellow in colour.

I Fluorouracil Injection may be diluted with Glucose 5% Injection or Sodium Chloride 0.9% Injection or Water

| for Injections immediately before use.

I Fluorouracil injection should not be mixed directly, in the same container, with other chemotherapeutic agents or intravenous additives.

• 1 Chemical and physical in-use stability has been demonstrated for 5 days at 20–21°C. From a

| microbiological point of view, the product should be used immediately. If not used immediately, in-use

। storage times and conditions prior to use are the responsibility of the user and would not normally be longer I than 24 hours at 2–8°C, unless dilution has taken place in controlled and validated aseptic conditions.

I Cytotoxic Handling Guidelines

I Should be administered only by, or under the direct supervision of, a qualified physician who is experienced

| in the use of cancer chemotherapeutic agents.

। Fluorouracil Injection should only be prepared for administration by professionals who have been trained

I in the safe use of the preparation. Preparation should only be carried out in an aseptic cabinet or suite

I dedicated for the assembly of cytotoxics.

। In the event of spillage, operators should put on gloves, face mask, eye protection and disposable apron and I mop up the spilled material with an absorbent material kept in the area for that purpose. The area should then be I cleaned and all contaminated material transferred to a cytotoxic spillage bag or bin and sealed for incineration.

Contamination

Fluorouracil is an irritant, contact with skin and mucous membranes should be avoided.

In the event of contact with the skin or eyes, the affected area should be washed with copious amounts of water or normal saline. A bland cream may be used to treat the transient stinging of the skin. Medical advice should be sought if the eyes are affected or if the preparation is inhaled or ingested.

Please refer to the marketing authorisation holder for COSHH hazard datasheets.

Preparation Guidelines

• a) Chemotherapeutic agents should be prepared for administration only by professionals who have been trained in the safe use of the preparation.

• b) Operations such as reconstitution of powder and transfer to syringes should be carried out only under aseptic conditions in a suite or cabinet dedicated for the assembly of cytotoxics.

• c) The personnel carrying out these procedures should be adequately protected with clothing, gloves and eye shield.

• d) Pregnant personnel are advised not to handle chemotherapeutic agents.

Disposal

Syringes, ONCO-VIAL™s and adaptors containing remaining solution, absorbent materials, and any other contaminated material should be placed in a thick plastic bag or other impervious container and incinerated at 700°C.

Directions for use of the ONCO-VIAL ™

ONCO-VIAL™should be used with an appropriate Hospira administration device.

Uncommon: may affect up to 1 in 100 people

Rare: may affect up to 1 in 1,000 people

Very rare: may affect up to 1 in 10,000 people

Not known (frequency cannot be estimated from the available data)

If you experience any of the following tell your doctor as soon as possible:

Very common side effects

• abnormality in the heart’s rhythm
• anaemia
• diarrhoea
• infections
• feeling or being sick
• anorexia Hospira

• tiredness Review freque

• reddening of the palms of the hands and/or the soles of the feet Three years from
• hair loss (especially in women)
• increased chance of picking up infections and/or delayed wound healing due to low white blood cells
• inflammation of the lining of the mouth, throat, gut, rectum or anus Version 2

Common side effects

• low white blood cells accompanied by fever Prepared by

Uncommon side effects

• low blood pressure (you may feel faint) Date
• watering eyes, changes in vision, sensitivity to light, side-to-side movements of the eyes
• numbness, tingling or tremor in the hands or feet Title
• feeling euphoric
• symptoms of Parkinson’s disease (e.g. shaking hands)
• headache
• skin problems, (including dry skin, itchy weals, rash, redness, inflammation)
• skin may appear lighter or darker
• changes in your nails, such as changes in colour or thickening of the nails

Rare side effects

• feeling confused
• discolouration in your fingers and toes (Raynaud’s syn­drome)
• reduced circulation to the brain, intestines and extremities (ischaemia)
• blood clots (pain, redness or swelling of the part affected)

Very rare side effects

• muscle weakness
• cardiac arrest
• sudden cardiac death

Frequency unknown

• quickening of your heart rate
• fever
• the vein where fluorouracil is administered may become painful or discoloured, which may be the sign of a blood clot
• hyperammonaemic encephalopathy (brain dysfunction caused by elevated ammonia) Fluorouracil may lead to changes in your LVbeilaoaolfldec­teslplse. cYiofiucradti­oocntor will take8b8loSod2sa0m7pleL­setaoflcehteT­cykpe sfor rabanormaalities (e.gy. bone marrow depression which may result in low white cells, low red cells,ylpow platelets, low gamma globulins). S

sR se up eo /rr eti vn ieg wof side effects 1F 3o 7ld xe 4d 7d mim mensions 1P 2an pe al ns ei lz (e 3/ xs 4) TP

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can alsU on rf eo pl od re t d sidd eim efe fen cs ti so dn irs ectly viaP tha ene Yl elw loi wdt Ch ard Scheme at: or search for MHRAYellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

5. how to store fluorouracil injection

Keep out of the sight anDdarteach of children Date

Expiry Title Title

This medicine must not be used after the expiry date which is stated on the vial label and carton after ‘EXP’. Where only a month and year is stated, the expiry date refers to the last day of that month.

Storage

Keep the vials in the outer carton, in order to protect from light and store at or below 25°C. They should not be refrigerated or frozen.

Prepared infusions should be used immediately, however, if this is not possible they can be stored for up to 5 days provided they have been prepared in a way to exclude microbial contamination.

Visible signs of deterioration

The product should be discarded if it appears brown or dark yellow in colour.

Disposal

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

• 6. FURTHER INFORMATION

What Fluorouracil Injection contains

The active substance is fluorouracil. Each millilitre (ml) of solution contains 50 mg of fluorouracil.

The other ingredients are sodium hydroxide and Water for Injections.

What Fluorouracil Injection looks like and contents of the pack

Fluorouracil Injection is a clear, colourless or slightly yellow solution for injection which comes in glass containers called vials.

It may be supplied in packs containing:

• 5 × 250 mg/5 ml vials
• 5 × 500 mg/10 ml vials
• 5 × 1 g/20 ml vials
• 1 or 10 × 2.5 g/50 ml vial
• 1 × 5 g/100 ml vial
• 1 × 500 mg/10 ml ONCO-VIAL®
• 1 × 1 g/20 ml ONCO-VIAL®
• 1 × 2.5 g/50 ml ONCO-VIAL®

Not all packs may be marketed.

Marketing Authorisation Holder and Manufacturer

Hospira UK Limited, Horizon, Honey Lane, Hurley, Maidenhead, SL6 6RJ, UK

This leaflet was last revised in 11/2020

Ref: gxFU 7_0

Fluorouracil Injection should only be prepared for administration by professionals who have been trained in the safe use of the preparation. Preparation should only be carried out in an aseptic cabinet or suite dedicated for the assembly of cytotoxics.

In the event of spillage, operators should put on gloves, face mask, eye protection and disposable apron and mop up the spilled material with an absorbent material kept in the area for that purpose. The area should then be cleaned and all contaminated material transferred to a cytotoxic spillage bag or bin and sealed for incineration.

Contamination

Fluorouracil is an irritant, contact with skin and mucous membranes should be avoided.

In the event of contact with the skin or eyes, the affected area should be washed with copious amounts of water or normal saline. A bland cream may be used to treat the transient stinging of the skin. Medical advice should be sought if the eyes are affected or if the preparation is inhaled or ingested.

Please refer to the marketing authorisation holder for COSHH hazard datasheets.

Preparation Guidelines

• a) Chemotherapeutic agents should be prepared for administration only by professionals who have been trained in the safe use of the preparation.

• b) Operations such as reconstitution of powder and transfer to syringes should be carried out only under aseptic conditions in a suite or cabinet dedicated for the assembly of cytotoxics.

• c) The personnel carrying out these procedures should be adequately protected with clothing, gloves and eye shield.

• d) Pregnant personnel are advised not to handle chemotherapeutic agents.

Disposal

Syringes, ONCO-VIAL®s and adaptors containing remaining solution, absorbent materials, and any other contaminated material should be placed in a thick plastic bag or other impervious container and incinerated at 700°C.

Directions for use of the ONCO-VIAL ®

ONCO-VIAL® should be used with an appropriate Hospira administration device.

PACKAGE LEAFLET:

INFORMATION FOR THE USER Fluorouracil 50 mg/ml Injection

Read all of this leaflet carefully before you start taking this medicine.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

What is in this leaflet:

• 1. What Fluorouracil Injection is and what it is used for

• 2. What you need to know before you use Fluorouracil Injection

• 3. How to use Fluorouracil Injection

• 4. Possible side effects

• 5. How to store Fluorouracil Injection

• 6. Further information

1. what fluorouracil injection is and what it is used for

Fluorouracil Injection is an anti-cancer medicine. Treatment with an anti-cancer medicine is sometimes called cancer chemotherapy.

Fluorouracil Injection is used to treat many common cancers, particularly cancers of the large bowel and breast. It may be used in combination with other anti-cancer medicines or radiotherapy.

2. what you need to know before you use fluorouracil injection

Do not use Fluorouracil Injection

• if you have shown signs of severe allergy to fluorouracil in the past
• if you are in a seriously weakened state due to long illness
• if your bone marrow has been damaged by other cancer treatments (including radiotherapy)
• if you know that you do not have any activity of the enzyme dihydropyrimidine dehydrogenase (DPD) (complete DPD deficiency)
• if you have a potentially serious infection
• if your cancer is non-malignant
• if you are pregnant or you are breast-feeding
• if you are taking or have taken in the past 4 weeks brivudine, sorivudine and similar drugs (antivirals)

Tell your doctor if any of the above applies to you before this medicine is used.

Talk to your doctor or pharmacist before using Fluorouracil Injection

• if your bone marrow is not producing blood cells normally (your doctor will do a blood test to check this)
• if you have any problems with your kidneys
• if you have any problems with your liver including jaundice (yellowing of the skin)
• if you have suffered from angina (chest pain) or have a history of heart disease
• if you have problems with your heart. Tell your doctor if you experience any chesHt paoin dsuringira

treatment p

• if you are in generally poor health and have lost a lot of weight Review freque
• if you have had surgery within the last 30 days Tree years rom
• if you are elderly
• if you know that you have a partial deficiency in the activity of the enzyme dihydropyrimidine dehydrogenase (DPD) Version 2
• if you have a family member who has partial or complete deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD) Prepared by

DPD deficiency: DPD deficiency is a genetic condition that is not usually associated with health problems unless you receive certain medicines. If you have DPD deficiency and takDeaFtleuorou­racil injection, you are at an increased risk of severe side effects (listed under section 4 Possible side effects). It is recommended to test you for DPD deficiency before start of treatment.TIit­fleyou have no activity of the enzyme you should not take Fluorouracil injection. If you have a reduced enzyme activity (partial deficiency) your doctor might prescribe a reduced dose. If you have negative test results for DPD deficiency, severe and life-threatening side effects may still occur.

Contact your doctor immediately if you are concerned about any of the side effects or if you notice any additional side effects not listed in the leaflet (see section 4 Possible side effects).

Contact your healthcare provider immediately, if you experience the following signs or symptoms: new onset of confusion, disorientation, or otherwise altered mental status, difficulty with balance or coordination, visual disturbances. These could be signs of encephalopathy which can lead to coma and death, if left untreated.

Tell your doctor if any of the above applies to you before this medicine is used.

Taking/using other medicines

Special care is needed if you are taking/using other medicines as some could interact with Fluorouracil Injection, for example:

• methotrexate, cisplatin, cytarabine, mitomycin-C, tamoxifen (anti-cancer medicines)
• metronidazole (an antibiotic)
• calcium leucovorin (also called calcium folinate – used to reduce the harmful effects of anti-cancer medicines)
• allopurinol (used to treat gout)
• cimetidine (used to treat stomach ulcers)
• warfarin (used to treat blood clots)
• interferon alpha 2a; brivudine, sorivudine and similar drugs (antivirals)
• phenytoin (an anti-epilepsy medicine)Leaflet specification
• vaccines

Pregnancy and breast-feedin 13g 7 × 47 mm 12 panel (3 × 4)

Both women of childbearing potential and men must use an effective method of contraception while taking fluorouracil and fV ore ari tfi le ad sb t y 6 months afterwards. Authorised by

Men are advised to seek advice on the conservation of sperm due to the possibility of irreversible infertility due to using fluDoartoeura­cil. Date

If a pregnancy does occur during your treatment, you must inform your doctor who will advise you of the potential hazards anTditlemay recommend genetic counselling for you. Title

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Do not drive or use machines if you experience any side effect from Fluorouracil, such as nausea and vomiting. Fluorouracil can also produce adverse events on your nervous system and cause visual changes. If you experience any of these effects, do not drive or use any tools or machines, as they may impair your ability to do so.

Important information about one of the ingredients of Fiuorouracii Injection

This medicinal product contains 7 mmol (160 mg) sodium per 1 gram dose. To be taken into consideration by patients on a controlled sodium diet.

3. how to use fluorouracil injection

This medicine is given into a vein or an artery. If it is given into a vein, it can either be injected (using a syringe) or infused (using a drip). If it is given into an artery, it will be given as an infusion.

If it is to be given as an infusion the medicine will be diluted before use.

Dose

Your doctor will work out the correct dose of Fluorouracil Injection for you and how often it must be given.

The dose of medicine given to you will depend on your medical condition, your size, if you have had recent surgery and how well your bone marrow, liver and kidneys are working.Your doctor will tell how well your bone marrow, liver and kidneys are working using blood tests.

The total daily dose should not exceed 1 gram.

If you are given too much or too little Fluorouracil Injection

This medicine will be given to you by a doctor or nurse. It is unlikely that you will be given too much or too little,however, tell your doctor or nurse if you have any concerns. If you have taken too much, your doctor will monitor you closely for at least 4 weeks.

m

. POSSIBLE SIDE EFFECTS

Like all medicines, fluorouracil can cause side effects, although not everybody gets them.

If any of the following happen, tell your doctor immediately:

• severe allergic reaction – you may experience a sudden itchy rash (hives), swelling of the hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty in swallowing or breathing), and you may feel you are going to faint
• chest pains (which may be due to heart problems, including having a heart attack)
• shortness of breath
• your bowel motions are bloodstained or black
• your mouth becomes sore or develops ulcers
• symptoms of leucoencephalopathy (disease of brain) – extreme weakness and fatigue, staggering while walking, thinking or speech difficulties, seizures, coma.

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

The frequency of possible side effects listed below is defined using the following convention:

Very common: may affect more than 1 in 10 people

Common: may affect up to 1 in 10 people

I Fluorouracil 50 mg/ml Injection

The following information is intended for medical or healthcare professionals only

Further to the information included in section 3, practical information on the preparation/han­dling of the medicinal product is provided here.

^Incompatibili­ties

Fluorouracil Injection is incompatible with carboplatin, cisplatin, cytarabine, diazepam, doxorubicin, epirubicin, levamisole, other anthracyclines and possibly methotrexate.

Formulated solutions are alkaline and it is recommended that admixture with acidic drugs or preparations

I should be avoided.

| Use and handling, and disposal

| The pH of Fluorouracil Injection is 8.9 and the drug has maximal stability over the pH range 8.6 to 9.0.

I If a precipitate has formed as a result of exposure to low temperatures, re-dissolve by heating to 60°C accompanied by vigorous shaking. Allow to cool to body temperature prior to use.

The product should be discarded if it appears brown or dark yellow in colour.

I Fluorouracil Injection may be diluted with Glucose 5% Injection or Sodium Chloride 0.9% Injection or Water

| for Injections immediately before use.

I Fluorouracil injection should not be mixed directly, in the same container, with other chemotherapeutic agents or intravenous additives.

• 1 Chemical and physical in-use stability has been demonstrated for 5 days at 20–21°C. From a

| microbiological point of view, the product should be used immediately. If not used immediately, in-use

। storage times and conditions prior to use are the responsibility of the user and would not normally be longer I than 24 hours at 2–8°C, unless dilution has taken place in controlled and validated aseptic conditions.

I Cytotoxic Handling Guidelines

I Should be administered only by, or under the direct supervision of, a qualified physician who is experienced

| in the use of cancer chemotherapeutic agents.

। Fluorouracil Injection should only be prepared for administration by professionals who have been trained

I in the safe use of the preparation. Preparation should only be carried out in an aseptic cabinet or suite

I dedicated for the assembly of cytotoxics.

। In the event of spillage, operators should put on gloves, face mask, eye protection and disposable apron and I mop up the spilled material with an absorbent material kept in the area for that purpose. The area should then be I cleaned and all contaminated material transferred to a cytotoxic spillage bag or bin and sealed for incineration.

Contamination

Fluorouracil is an irritant, contact with skin and mucous membranes should be avoided.

In the event of contact with the skin or eyes, the affected area should be washed with copious amounts of water or normal saline. A bland cream may be used to treat the transient stinging of the skin. Medical advice should be sought if the eyes are affected or if the preparation is inhaled or ingested.

Please refer to the marketing authorisation holder for COSHH hazard datasheets.

Preparation Guidelines

• a) Chemotherapeutic agents should be prepared for administration only by professionals who have been trained in the safe use of the preparation.

• b) Operations such as reconstitution of powder and transfer to syringes should be carried out only under aseptic conditions in a suite or cabinet dedicated for the assembly of cytotoxics.

• c) The personnel carrying out these procedures should be adequately protected with clothing, gloves and eye shield.

• d) Pregnant personnel are advised not to handle chemotherapeutic agents.

Disposal

Syringes, ONCO-VIAL™s and adaptors containing remaining solution, absorbent materials, and any other contaminated material should be placed in a thick plastic bag or other impervious container and incinerated at 700°C.

Directions for use of the ONCO-VIAL ™

ONCO-VIAL™should be used with an appropriate Hospira administration device.

Uncommon: may affect up to 1 in 100 people

Rare: may affect up to 1 in 1,000 people

Very rare: may affect up to 1 in 10,000 people

Not known (frequency cannot be estimated from the available data)

If you experience any of the following tell your doctor as soon as possible:

Very common side effects

• abnormality in the heart’s rhythm
• anaemia
• diarrhoea
• infections
• feeling or being sick
• anorexia Hospira

• tiredness Review freque

• reddening of the palms of the hands and/or the soles of the feet Three years from
• hair loss (especially in women)
• increased chance of picking up infections and/or delayed wound healing due to low white blood cells
• inflammation of the lining of the mouth, throat, gut, rectum or anus Version 2

Common side effects

• low white blood cells accompanied by fever Prepared by

Uncommon side effects

• low blood pressure (you may feel faint) Date
• watering eyes, changes in vision, sensitivity to light, side-to-side movements of the eyes
• numbness, tingling or tremor in the hands or feet Title
• feeling euphoric
• symptoms of Parkinson’s disease (e.g. shaking hands)
• headache
• skin problems, (including dry skin, itchy weals, rash, redness, inflammation)
• skin may appear lighter or darker
• changes in your nails, such as changes in colour or thickening of the nails

Rare side effects

• feeling confused
• discolouration in your fingers and toes (Raynaud’s syn­drome)
• reduced circulation to the brain, intestines and extremities (ischaemia)
• blood clots (pain, redness or swelling of the part affected)

Very rare side effects

• muscle weakness
• cardiac arrest
• sudden cardiac death

Frequency unknown

• quickening of your heart rate
• fever
• the vein where fluorouracil is administered may become painful or discoloured, which may be the sign of a blood clot
• hyperammonaemic encephalopathy (brain dysfunction caused by elevated ammonia) Fluorouracil may lead to changes in your LVbeilaoaolfldec­teslplse. cYiofiucradti­oocntor will take8b8loSod2sa0m7pleL­setaoflcehteT­cykpe sfor rabanormaalities (e.gy. bone marrow depression which may result in low white cells, low red cells,ylpow platelets, low gamma globulins). S

sR se up eo /rr eti vn ieg wof side effects 1F 3o 7ld xe 4d 7d mim mensions 1P 2an pe al ns ei lz (e 3/ xs 4) TP

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can alsU on rf eo pl od re t d sidd eim efe fen cs ti so dn irs ectly viaP tha ene Yl elw loi wdt Ch ard Scheme at: or search for MHRAYellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

5. how to store fluorouracil injection

Keep out of the sight anDdarteach of children Date

Expiry Title Title

This medicine must not be used after the expiry date which is stated on the vial label and carton after ‘EXP’. Where only a month and year is stated, the expiry date refers to the last day of that month.

Storage

Keep the vials in the outer carton, in order to protect from light and store at or below 25°C. They should not be refrigerated or frozen.

Prepared infusions should be used immediately, however, if this is not possible they can be stored for up to 5 days provided they have been prepared in a way to exclude microbial contamination.

Visible signs of deterioration

The product should be discarded if it appears brown or dark yellow in colour.

Disposal

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

• 6. FURTHER INFORMATION

What Fluorouracil Injection contains

The active substance is fluorouracil. Each millilitre (ml) of solution contains 50 mg of fluorouracil.

The other ingredients are sodium hydroxide and Water for Injections.

What Fluorouracil Injection looks like and contents of the pack

Fluorouracil Injection is a clear, colourless or slightly yellow solution for injection which comes in glass containers called vials.

It may be supplied in packs containing:

• 5 × 250 mg/5 ml vials
• 5×500 mg/10 ml vials
• 5 × 1 g/20 ml vials
• 1 or 10 × 2.5 g/50 ml.a EOT
• 1 × 5 g/100 ml vial
• 1 × 500 mg/10 ml ONCO-VIAL™
• 1 × 1 g/20 ml ONCO-VIAL™
• 1 × 2.5 g/50 ml ONCO-VIAL™