Package leaflet: Information for the user Agicil 50 mg/ml solution for injection/infusion

Fluorouracil

Read all of this leaflet carefully before you start using this medicine because it contains important information for you

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

-    If you have any further questions, ask your doctor, pharmacist or nurse.

-    This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.

-    If you get any side effects, talk to your doctor or pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See Section 4.

What is in this leaflet

1.    What Agicil is and what it is used for

2.    What you need to know before you use Agicil

3.    How to use Agicil

4.    Possible side effects

5.    How to store Agicil

6.    Contents of the pack and other information

1.    What Agicil is and what it is used for

Agicil contains the active ingredient fluorouracil. It is an anti-cancer medicine..

This medicine is used to treat many common cancers, particularly cancers of the large bowel, oesophagus, pancreas, stomach, head and neck and breast. It may be used in combination with other anti-cancer medicines and radiotherapy.

2.    What you need to know before you use Agicil

Do not use Agicil

•    if you are allergic to fluorouracil or any of the other ingredients of this medicine (listed in section 6.1).

•    if you have serious infections (e.g. Herpes zoster, chickenpox)

•    if your tumour is non-malignant.

•    if you have been very much weakened by long illness.

•    if your bone marrow has been damaged by other treatments (including radiotherapy).

•    if you are taking brivudin, sorivudin and analogues (an antiviral medicine)

•    if you are pregnant or breast feeding women

•    if you have serious impaired liver function

•    if you are homozygotic for dihydropyrimidine dehydrogenase (DPD) enzyme Warnings and precautions

Talk to your doctor or pharmacist or nurse before using Agicil. Take special care with Agicil:

•    if the number of cells in your blood become too low (you will have blood tests to check this)

•    if you have oral ulceration, fever or hemorrhage at any site or weakness (these symptoms may be the consequence of the very low number of cells in your blood),

•    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 problems with your heart. Tell your doctor if you experience any chest pain during treatment

•    if you have reduced activity/deficiency of the enzyme DPD (dihydropyrimidine dehydrogenase)

•    if you have had high-dose pelvic radiation.

•    if you have gastrointestinal side effects (stomatitis, diarrhoea, bleeding from the G.I. tract) or hemorrhage at any site.

Other medicines and Agicil:

Tell your doctor or nurse if you are using, have recently used or might use any other medicines.

In particular tell your doctor if you are taking any of the following medicines because they affect how Agicil works:

•    Methotrexate (an anti-cancer medicine)

•    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, brivudin, sorivudine and analogues (an antiviral)

•    Cisplatin (an anti-cancer medicine)

•    Phenytoin (used to control epilepsy/fits and irregular heart rhythm)

•    Vaccines

•    Vinorelbine (an anti-cancer medicine)

•    Cyclophosphamide (an anti-cancer medicine)

•    Levamisol (medicine used to treat worm infection)

•    Tamoxifen (an anti-cancer medicine)

The above medicines affect the effect of Fluorouracil.

Pregnancy, breast-feeding and fertility

You must not take this medicine if you are pregnant or planning to become pregnant.

If you are a woman of childbearing potential you must use an effective method of contraception while taking this medicine and atleast for 6 months afterwards. If pregnancy occurs during your treatment you must inform your doctor and should use genetic counselling..

Since it is not known whether fluorouracil passes into breast milk, breast-feeding must be discontinued if the mother is treated with Agicil.

If you are a man you should avoid fathering a child during and for up to 6 months following cessation of treatment with Agicil. You are advised to sought conservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with flurouracil.

Ask your doctor for advice before taking any medicine.

Driving and using machines

Do not drive or use machines because fluorouracil may produce side effects like nausea and vomiting. It can also produce adverse events on your nervous system and visual changes. If you experience any of these effects, do not drive or use any tools or machines, because they may impair your ability to drive or use machines.

Agicil contains sodium

This product contains sodium approximately from 0.34 to 0.39mmol / ml (or 7.9-9.0 mg/ ml) of solution in the form of Sodium Hydroxide. This information should be taken into consideration in patients with controlled intake of sodium.

3.    How to use Agicil

The dose of medicine given to you will depend on your medical condition, your body weight, if you have had recent surgery and how well your liver and kidneys are working. It will also depend on the results of your blood tests.

Your first course of treatment may be given daily or at weekly intervals. Further courses may be given according to your response to treatment. You may also receive treatment in combination with radiotherapy.

The medicine may be diluted with glucose solution, sodium chloride solution or Water for injections before it is given to you. It will be given into a vein either as a normal injection or a slow injection via a drip (infusion).

If you are given more Agicil than you should

As this medicine will be given to you whilst you are in hospital is unlikely that you will be given too little or too much, however, tell your doctor or nurse if you have any concerns. You will need to have blood tests during and after treatment with Agicil to check the levels of cells in your blood. Treatment may have to be stopped if the level of white blood cells drops too low.

Nausea, vomiting, diarrhoea, severe mucositis and gastrointestinal ulceration and bleeding may occur if you have too much fluorouracil.

If you have any further question on the use of this medicine ask your doctor.

4.    Possible side effects

Like all medicines, this medicine can have 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

your bowel motions are bloodstained or black your mouth becomes sore or develops ulcers numbness, tingling or tremor in the hands or feet

quickening of your heart rate and breathlessness

feeling confused or feeling unsteady on your feet, coordination problems in arms and

legs, thinking/speech difficulties, vision/memory problems These are serious side effects. You may need urgent medical attention. Very common (may affect more than 1 in 10 patients)

Ischemic ECG abnormalities (an insufficient supply of blood to an organ, usually due to a blocked artery)

Anemia (decrease in number of red blood cells that can cause tiredness and lack of energy)

•    High fever and a sharp drop in circulating granular white blood cells

•    Inflammation of the rectum or anus

•    Nausea

•    Delayed wound healing

•    General weakness

•    Inflammation of the mucous lining of the mouth

The following information is intended for medical or healthcare professionals only:

INSTRUCTIONS FOR USE/HANDLING, PREPARATION AND DISPOSAL GUIDE FOR USE WITH FLUOROURACIL INJECTION

Neutropenia (an abnormally low level of neutrophils in the blood)

Pancytopenia (a disorder in which the bone marrow greatly decreases or stops production of blood cells)

•    The inflammation of the lining of the mouth and digestive tract

•    Loss of appetite

•    Vomiting

•    Bleeding from the nose

•    Tiredness

•    Inflammation of the esophagus(the tube that connects your mouth to your stomach)

•    Increase in uric acid in the blood

Common (may affect up to 1 in 10 patients)

•    Angina pectoris (severe chest pain)

Leucopoenia (an abnormally low number of white blood cells in the circulating blood)

Decrease in the production of blood cells

Pharyngitis (inflammation of the mucous membranes lining the throat)

Watery diarrhoea

Hair loss Hand-foot syndrome (a toxic skin reaction That may cause redness, tenderness, and possibly peeling of the palms and soles) Fatigue Lack of energy

Uncommon (may affect up to 1 in 100 patients)

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Cytotoxic Handling Guidelines

Fluorouracil should be administered only by or under the supervision of a qualified physician who is experienced in the use of cancer chemotherapeutic drugs.

Preparation guidelines:

Contamination

In the event of contact with the skin or eyes, the affected area should be washed with copious amounts of water or normal saline. Hydrocortisone cream 1% 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.

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.

First Aid

Eye contact: Irrigate immediately with water and seek medical advice.

Skin contact: Wash thoroughly with soap and water and remove-contaminated clothing.

Inhalation, Ingestion: Seek medical advice.

Disposal

Syringes, containers, absorbent materials, solution and any other contaminated material should be placed in a thick plastic bag or other impervious container, marked as cytotoxic waste and incinerated at a minimum of 700°C.

Chemical inactivation can be achieved by 5% sodium Hypochlorite over 24 hours.

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 in the designated area.

c)    The personnel carrying out these procedures should be adequately protected with special clothing, two pairs of gloves one latex, one PVC, (the latex being worn beneath the PVC), this covers differences in permeabilities to the various antineoplastics, and eye shields. Luerlock syringes and fittings should always be used both in the preparation of cytotoxic products and for their administration.

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

(e) Refer to local guidelines before commencing.

Instructions for use

Fluorouracil injection can be given by intravenous injection or infusion.

Incompatibilities

Fluorouracil is incompatible with calcium folinate, carboplatin, cisplatin, cytarabine, diazepam, doxorubicin, droperidol, filgrastim, gallium nitrate, methotrexate, metoclopramide, morphine, ondansetrone, parenteral nutrition, vinorelbin, other anthracyclines.

Formulated solutions are alkaline and it is recommended that admixture with acidic drugs or preparations should be avoided. In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. Preparation Instructions

Fluorouracil injection may be diluted with glucose 5% injection or sodium chloride 0.9% injection or water for injections immediately before parenteral use.

Dosage and Administration

Selection of an appropriate dose and treatment regime depend upon the condition of the patient, the type of carcinoma being treated and whether fluorouracil is to be administered alone or in combination with other therapy. Initial treatment should be given in hospital and the total daily dose should not exceed 1gram. It is customary to calculate the dose in accordance with patient’s actual weight unless there is obesity, oedema or some other form of abnormal fluid retention such as ascites. In this case, ideal weight is used as the basis for calculation.

Reduction of the dose is advisable in patients with any of the following:

1.    Cachexia

2.    Major surgery within preceding 30 days

3.    Reduced bone marrow function

4.    Impaired hepatic or renal function

Fluorouracil injection can be given by intravenous injection.

ADULT DOSE

The following regimen have been recommended for use as a single agent.

Initial Treatment:

This may be in the form of an infusion or an injection, the former usually being preferred because of lesser toxicity. Intravenous Infusion:

15 mg/kg bodyweight or 600 mg/m² but not more than 1 g per infusion, diluted in 500 ml of 5% glucose or 0.9% NaCl

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injection and given by intravenous infusion at a rate of 40 drops per minute over 4 hours. Alternatively the daily dose may be infused over 30-60 minutes or may be given as a continuous infusion over 24 hours. The infusion may be repeated daily until there is evidence of toxicity (stomatitis, diarrhea, leucopenia or thrombocytopenia) or a total dose of 12-15 g has been reached.

Intravenous Injection:

12 mg/kg bodyweight or 480 mg/m² may be given daily for 3 days and then, if there is no evidence of toxicity (stomatitis, diarrhea, leucopenia or thrombocytopenia), 6 mg/kg or 240 mg/m² on alternate days for 3 further doses (day 5-7-9). An alternative regime is 15 mg/kg as a single intravenous injection once a week throughout the course.

Maintenance Therapy:

An initial intensive course may be followed by maintenance therapy providing there are no significant toxic effects. In all instances, toxic side effects must disappear before maintenance therapy is started.

Treatment can be continued with intravenous injections of 5 - 10 mg/kg bodyweight or 200-400 mg /m² at weekly intervals. In combination with Irradiation:

Irradiation combined with 5-FU has been found to be useful in the treatment of certain types of metastatic lesions in the lungs and for the relief of pain caused by recurrent, inoperable growth. The standard dose of 5-FU should be used.

Combination with other cytostatic agents:

Fluorouracil can be used with other cytostatic agents. In this case the standard dose is reduced.

Special populations Renal or hepatic impairment.

Caution is advised and the dose might need to be reduced in patients with renal or hepatic impairment.

CHILDREN

Fluorouracil is not recommended for use in children due to insufficient data on safety and efficacy.

ELDERLY

No dosage adjustment necessary.

Shelf Life and storage Shelf-life of unopened vial

10 months. Single use only. Discard any unused portion.

Do not store above 25°C. Do not refrigerate or freeze,

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

Shelf Life after dilution

Chemical and physical in-use stability with the selected physiological solutions (0.9 % sodium chloride, 5 % dextrose and water for injections) at concentration 2.0 mg/ml has been demonstrated for 120 hours at 20-21°C and for 24 hours at 2°C to 8°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 normally not be longer than 24 hours at 2-8°C, unless dilution has taken place in controlled and validated aseptic conditions

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Appearance of itchy, red marks on the skin

Streaky darkening (hyperpigmentation) or lightenng (depigmentation) near the veins.

An inflammation of the matrix of the nail with formation of pus and shedding of the nail Secretion of tears

Rare (may affect up to 1 in 1,000 patients)

•    Insufficient blood flow in brain, intestine and peripheral organs

•    swelling (inflammation) of a vein caused by a blood clot

systemic vasodilation (widening of blood vessels) which results in low blood pressure

l^ery rare (may affect up to 1

Cardiac arrest (sudden cessation of heartbeat and cardiac function)

Acute cerebellar syndrome

Mental confusion or impaired awareness especially regarding to time, place or identity Convulsion or coma in patients receiving high doses of fluorouracil and in patients with dihydropyrimidine dehydrogenase deficiency inflammation of the gall bladder

Eye movement disturbance

decrease in visual sharpness

lower eyelid turns outwards

possible side effects not listed in this leaflet.

You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov. uk/yellowcard.By reporting side effects you can help provide more information on the safety of this medicine.

5.    How to store Agicil

Keepthis medicine out of the sight and reach of children.

Do not use this medicine after the expiry date, which is stated on the label and carton after EXP. Single use only. Discard any unused portion.

Storage of the unopened vial: Do not store above 25°C. Do not refrigerate or freeze.

Shelf life after dilution: Chemical and physical in-use stability has been demonstrated for 5 days at 20-21°C and for 24 hours at 2°C to 8°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 normally not be longer than 24 hours at 2-8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Do not use this medicine if it appears brown or dark yellow in solution.

Do not use if you notice that the container is damaged or particles/crystals are visible. Since this product will be administered by a healthcare professional, the medical staff are responsible for the correct storage of the product both before and during its use, as well as for the correct disposal

6.    Contents of the pack and other information

What Agicil contains

-    The active substance is fluorouracil. One (1) ml of solution contains 50mg of fluoro-uracil.

-    The other ingredients are water for injections and sodium hydroxide.

What Agicil looks like and content of the pack

Agicil is clear colourless to yellow solution available in Type I flint moulded vials with a grey rubber closure and grey flip-off aluminium seal.

Each 10 ml vial contains 500 mg of fluorouracil.

Each 20 ml vial contains 1 g of fluorouracil.

Each 50 ml vial contains 2.5g of fluorouracil.

Each 100 ml vial contains 5 g of fluorouracil.

Agicil is available in packs of 1, 5 or 10 vials.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder:

Strides Arcolab International Limited

Unit 4, Metro Centre, Dwight Road,

Watford, Hertfordshire WD 189SS United Kingdom Manufacturer:

Pharmadox Healthcare Ltd.

KW20A Kordin Industrial park, Paola PLA 3000, Malta

The leaflet was last revised in 06/2014.

slow progressive destruction of the small bile ducts

Not known (frequency can not be estimated from the available data):

•    fever

•    numbness or weakness of the arms and legs Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist or nurse. This includes any

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