FLUOROURACIL ACCORD 50 mg/ml INJECTABLE SOLUTION OR FOR INFUSION

Introduction

Package Leaflet: Information for the Patient

Fluorouracil Accord 50 mg/ml Solution for Injection or Infusion EFG

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 or 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.

Contents of the pack:

1. What is Fluorouracil Accord and what is it used for
2. What you need to know before you use Fluorouracil Accord
3. How to use Fluorouracil Accord
4. Possible side effects
5. Storage of Fluorouracil Accord
6. Contents of the pack and further information

1. What is Fluorouracil Accord and what is it used for

What is Fluorouracil Accord

Fluorouracil Accord contains the active substance fluorouracil. It is a cancer medicine. It is part of chemotherapy.

What is Fluorouracil Accord used for

Fluorouracil Accord is used to treat many common types of cancer, especially cancers of the colon, oesophagus, pancreas, stomach, head, neck and breast. It may be used in combination with other cancer medicines or radiotherapy.

You should talk to your doctor if you do not feel better or if you feel worse.

2. What you need to know before you use Fluorouracil Accord

Do not use Fluorouracil Accord

• if you are allergic to fluorouracil or any of the other ingredients of this medicine (listed in section 6).
• if you are in a state of severe weakness due to a long illness.
• if you have a severe infection (e.g. chickenpox, shingles or herpes zoster).
• if your cancer is not malignant.
• if your bone marrow has been damaged due to other cancer treatments (including radiotherapy).
• if you are taking brivudine, sorivudine or their chemically related analogues (antiviral medicines). Fluorouracil must not be used in the 4 weeks following treatment with brivudine, sorivudine or their chemically related analogues.
• if you are breast-feeding.
• if you have severe liver disease
• if you are homozygous for the dihydropyrimidine dehydrogenase (DPD) enzyme
• if you have reduced or deficient activity of the dihydropyrimidine dehydrogenase (DPD) enzyme

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

Warnings and precautions

Consult your doctor or pharmacist or nurse before starting treatment with Fluorouracil Accord. Be particularly careful with Fluorouracil Accord:

• if your bone marrow is not producing blood cells normally (your doctor will do a blood test to check this)
• if you have kidney problems.
• if you have any liver problems, including jaundice (yellow skin).
• if you have had angina (chest pain) or have a history of heart disease, as you are more likely to have an angina attack or a heart attack, or show signs of heart problems when you have an ECG test
• if you have received radiation to the pelvis at a high dose.
• if the tumours have spread (metastasised) to your bone marrow
• if you are in poor general health and have lost a lot of weight
• if you have had surgery in the last 30 days
• if you have had gastrointestinal (GI) adverse reactions (oral ulceration (stomatitis), diarrhoea, bleeding from the gastrointestinal tract) or bleeding at any other site.
• if you know you have a partial deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme activity
• if you have heart problems. Tell your doctor if you experience chest pain during treatment.
• if you are a relative of a person with a partial or complete deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme.

DPD deficiency: DPD deficiency is a genetic condition that is not usually associated with health problems unless you are being treated with certain medicines. If you have a DPD deficiency and take Fluorouracil Accord, you will have a higher risk of experiencing severe side effects (indicated in section 4, Possible side effects). It is recommended that you have a test to detect DPD deficiency before starting treatment. If you have no enzyme activity, you must not take Fluorouracil Accord. If you have reduced enzyme activity (partial deficiency), your doctor may prescribe a reduced dose. Even if the test results for DPD deficiency are negative, severe and potentially 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 mentioned in this leaflet (see section 4 Possible side effects).

Contact your doctor immediately if you experience any of the following signs or symptoms: new onset of confusion, disorientation or altered mental status, difficulty with balance or coordination, visual disturbances. These could be signs of encephalopathy that can lead to coma and death if not treated.

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

Fluorouracil may cause sensitivity to sunlight. This can result in an increased risk of skin reactions. To avoid this, you should try to stay away from direct sunlight as much as possible while using it and should not use a sun lamp or a sunbed.

Exposure to ultraviolet radiation (e.g. natural sunlight, sunbed) should be avoided.

Treatment with fluorouracil may increase the likelihood of necrosis (death of tissue or skin) caused by radiation after radiotherapy.

Administration of fluorouracil has been associated with the development of hand-foot syndrome, characterised by a tingling sensation in hands and feet, which can evolve over a few days into pain when holding objects or walking. The palms of the hands and the soles of the feet become swollen and sensitive.

UsingFluorouracil Accord withother medicines

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

• Special care is needed if you are taking/using other medicines, as some may interact with the fluorouracil injection: Methotrexate, cyclophosphamide, cisplatin, vinorelbine (a cancer medicine)
• Metronidazole (an antibiotic)
• Folinic acid (also known as calcium folinate or leucovorin calcium - used to reduce the harmful effects of cancer medicines)
• Allopurinol (used to treat gout)
• Cimetidine (used to treat stomach ulcers)
• Warfarin (used to treat blood clots)
• Interferon alfa (used in the treatment of lymphomas and chronic hepatitis)
• Brivudine, sorivudine or their chemically related analogues (antiviral medicines)
• Phenytoin (used to control epilepsy, seizures and also heart arrhythmias)
• Live vaccines should be avoided, as they can cause serious or life-threatening infections. You should avoid contact with people who have recently been treated with the polio virus vaccine. Inactivated or killed vaccines may be administered; however, the response may be affected
• Levamisole (a medicine used to treat worm infections)
• Tamoxifen (used in some types of breast cancer)
• Clozapine (used in psychiatric disorders)

Tell your doctor or pharmacist if you are taking or have recently taken any of these or other medicines, including those obtained without a prescription.

Pregnancy, breast-feeding and fertility

Pregnancy

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a child, consult your doctor before taking this medicine.

Fluorouracil should only be used during pregnancy if the potential benefit justifies the potential risk to the foetus. If pregnancy occurs during treatment, you should inform your doctor and seek genetic counselling.

Women should avoid becoming pregnant and use a highly effective method of contraception during treatment with Fluorouracil and for at least 6 months after.

Breast-feeding

As it is not known whether fluorouracil passes into breast milk, breast-feeding should be discontinued before treatment with Fluorouracil injectable.

Ask your doctor for advice before taking any medicine.

Fertility

Men treated with Fluorouracil are advised not to father a child during treatment and for up to 3 months after finishing treatment.

Both men and women should seek advice on fertility, such as egg or sperm conservation, before treatment, due to the possibility of irreversible infertility caused by therapy.

Driving and using machines

Do not drive or use machines because fluorouracil can cause side effects such as nausea and vomiting. It can also cause adverse events on the nervous system and changes in vision. If you experience any of these effects, do not drive or use tools or machines, as it may affect your ability to drive or use machines.

Fluorouracil Accord contains sodium

Fluorouracil Accord contains 7.78 mmol (178.2 mg) of sodium per maximum daily dose (600mg/m2). This should be taken into consideration for patients on a controlled sodium diet.

3. How to use Fluorouracil Accord

Recommended dose

Your doctor will decide the correct dose of Fluorouracil solution for injection or infusion for you and how often it should be given.

The dose of the medicine that you will be given will depend on your general health, your body weight, whether you have been operated on recently and the condition of your bone marrow, liver and kidneys. The first treatment cycle can be given daily or at weekly intervals. The following cycles can be given according to your response to treatment. You may also receive treatment in combination with radiotherapy.

Use of fluorouracil in children is not recommended due to insufficient data on safety and efficacy.

Before administration, the medicine can be diluted with a glucose solution, saline solution or water for injection preparations. It will be given to you through a vein as a normal injection or as a slow injection by drip (infusion).

If you use more Fluorouracil Accord than you should

As 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, talk to your doctor or nurse if you have any concerns.

You will have blood tests during and after treatment with Fluorouracil Accord to check the levels of cells in your blood, and you may need to stop treatment if the number of white blood cells is too low.

Nausea, vomiting, diarrhoea, severe mucositis and ulcers and gastrointestinal bleeding may occur if you receive too much fluorouracil. If you have any doubts about the use of this medicine, ask your doctor.

If you forget to use Fluorouracil Accord

Do not take a double dose to make up for forgotten doses.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them.

If you experience any of the following adverse effects, consult your doctor immediately:

• Severe allergic reaction – you may experience itching (urticaria), swelling of the hands, feet, ankles, face, lips, mouth, or throat (which could cause difficulty swallowing or breathing) or feel like you are going to faint.
• Chest pain
• Stools with blood or black stools
• Pain in the mouth or appearance of ulcers
• Numbness, tingling, or tremors in the hands or feet
• Myocardial infarction or other heart problems such as rapid heart rate and shortness of breath
• Symptoms of leukoencephalopathy (brain disease) weakness, coordination problems in arms and legs, difficulty thinking or speaking, vision or memory problems, seizures, headaches
• Difficulty breathing

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

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

Veryfrequent:may affect more than 1 in 10 people:

• Throat irritation
• Insufficient blood supply to the heart shown in the ECG tracing
• Myelosuppression (a disorder in which the bone marrow produces a reduced number of all types of blood cells [pancytopenia])
• Neutropenia and leukopenia (an abnormally low level of types of white blood cells in the blood)
• Thrombocytopenia (reduced platelet count in the blood that reduces the blood's ability to clot)
• A sharp drop in circulating granulocytes (agranulocytosis)
• Anemia (a condition in which red blood cells are reduced)
• Increased risk of infection due to immunosuppression
• Wheezing (bronchospasm)
• Nausea
• Vomiting
• Diarrhea
• Infections
• Delayed wound healing
• Inflammation of the mucous membrane lining any of the structures of the mouth, throat, and digestive tract, e.g., esophagus (throat), rectum, or anus
• Increased uric acid in the blood
• Nosebleeds
• Hair loss
• Hand-foot syndrome (toxic skin reaction with redness and swelling of hands and feet)
• Fatigue, tiredness, and lack of energy
• Malaise

Infrequent:may affect up to 1 in 100 people:

• Cardiac arrhythmia
• Heart attack
• Myocardial ischemia (reduced oxygen supply to the heart)
• Myocarditis (inflammatory disease of the heart muscle)
• Dilated cardiomyopathy (a type of heart disease in which the heart muscle is abnormally large, thick, and/or hardened)
• Cardiac shock
• Hypotension
• Somnolence
• Dehydration
• Hepatocellular damage
• Gastrointestinal ulcer and bleeding
• Skin exfoliation
• Gastrointestinal hemorrhage
• Rhythmic eye movements (nystagmus)
• Headache
• Dizziness
• Feelings of imbalance and instability
• Symptoms of Parkinson's disease (a progressive movement disorder characterized by tremors, stiffness, slow movements)
• Pyramidal signs
• Blood infection (sepsis)
• Skin inflammation (dermatitis)
• Skin changes. E.g., dry skin, scaly erosion, skin redness, maculopapular and pruritic rash (a skin rash with red bumps and itching)
• A skin rash accompanying certain infectious diseases
• Appearance of hives that cause itching on the skin
• Sensitivity to light (photosensitivity)
• Hyperpigmentation of the skin
• Hyperpigmentation in stripes or depigmentation near the veins
• Nail pigmentation, thickening of the nail bed
• Paronychia (inflammation of the tissue surrounding the fingernails)
• Inflammation of the nail matrix with pus formation and nail detachment
• Disorders of sperm or ovulation
• Increased tear secretion
• Blurred vision
• Inflammation or redness of the coating of the white part of the eye and the lower eyelid
• Disorder of eye movement
• Red eyes (conjunctivitis)
• Optic neuritis (a vision disorder characterized by inflammation of the optic nerve)
• Double vision
• Reduced visual acuity
• Excessive sensitivity of the eyes to light, aversion to sunlight and well-lit places
• Narrowing of the duct that drains tears from the eye (dacryostenosis)
• Eyelid fold outward (ectropion)
• Euphoria

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

• Insufficient blood flow to the brain, intestines, and peripheral organs (extremities)
• Poor blood circulation that causes the fingers of the hands and feet to become numb and pale (Raynaud's syndrome)
• Hypersensitivity
• Inflammation of the veins caused by a blood clot
• Severe allergic reaction throughout the body (anaphylaxis)
• Clot formation in blood vessels, both in veins and arteries
• Mental confusion or disorder of consciousness, especially related to time, place, or identity
• Confusion
• Kidney failure
• Changes in thyroid function - increased T4 and T3 (total thyroxine and triiodothyronine)

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

• Cardiac arrest (sudden stop of heartbeats and cardiac function)
• Sudden cardiac death (unexpected death due to heart problems)
• Symptoms of leukoencephalopathy (diseases affecting the white matter of the brain), including ataxia (loss of ability to coordinate muscle movement)
• Acute cerebellar syndrome
• Difficulty articulating words
• Partial or total loss of ability to communicate verbally or with written words
• Abnormal muscle weakness or fatigue
• Seizure or coma in patients who have received high doses of 5-fluorouracil or in patients with dihydropyrimidine dehydrogenase (DPD) deficiency
• Inflammation of the gallbladder
• Liver cell damage (with fatal outcome)

Unknown: frequency cannot be estimated from available data:

• Blood poisoning (septic shock)
• Neutropenic sepsis (a potentially fatal reaction to an infection that can occur in patients with neutropenia, i.e., low levels of a type of white blood cell that is part of the immune system and fights infections in the blood).
• Lung infection
• Urinary tract infection, bacterial infection of the urinary system
• Bacterial skin infection that causes redness, swelling, and pain in the affected area.
• Reduced number of granulocytes, a type of white blood cell
• Decreased appetite
• Disorientation
• Fever
• Numbness or weakness of arms and legs
• Seizures
• Hyperammonemic encephalopathy (brain dysfunction caused by elevated ammonia)
• Blood clots in the heart cavities that could break loose and block the body's arteries, which, for example, could cause a stroke or lack of blood flow to a limb.
• Inflammation of the heart muscle.
• Skin inflammation that causes scaly red spots possibly accompanied by joint pain and fever (cutaneous lupus erythematosus [CLE])
• Heart disease that manifests with chest pain, difficulty breathing, dizziness, fainting, irregular heartbeats (stress cardiomyopathy)
• Bleeding
• Dark, sticky stools containing partially digested blood
• Chest pain
• Air in the intestinal wall
• Severe disorder characterized by difficulty breathing, vomiting, and abdominal pain with muscle cramps (lactic acidosis)
• Disorder characterized by headache, confusion, seizures, and changes in vision (posterior reversible encephalopathy syndrome [PRES])
• Severe complication with rapid degradation of cancer cells that causes elevated levels of uric acid, potassium, and phosphate (tumor lysis syndrome)
• Discoloration at the injection site
• High levels of triglycerides in the blood, a type of fat
• Pain, redness, or swelling at the infusion site during or shortly after injection/infusion (may be due to the injection not penetrating the vein correctly)
• Vitamin B1 deficiency and Wernicke's encephalopathy (brain damage caused by vitamin B1 deficiency)
• Inflammation of the small and large intestine causing pain and diarrhea, which can cause death of the intestinal tissue (colitis, enterocolitis).

Reporting of adverse effects:

If you experience any type of adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect that does not appear in this prospectus. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: https://www.notificaRAM.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Fluorouracil Accord

• Keep this medicine out of sight and reach of children.
• Do not use this medicine after the expiration date shown on the label and packaging after CAD. The expiration date is the last day of the month indicated.
• Store below 25°C. Do not refrigerate or freeze.
• Store in the original packaging to protect it from light.

For single use. Discard any unused medicine.

Validity period after dilution

Physical-chemical stability has been demonstrated under conditions of use for 24 hours at 25°C with 5% glucose injections or 0.9% sodium chloride or water for injectables with a fluorouracil concentration of 0.98 mg/ml. However, from a microbiological point of view, the product should be used immediately. If not used immediately, the storage times under conditions of use and the conditions prior to use will be the responsibility of the user.

• Do not use if the solution has a brown or dark yellow color.
• Do not use if you notice that the packaging is damaged or particles/crystals are visible.
• Do not throw medicines in the trash or down the drain. All materials used for preparation and administration, or those that have come into contact with cisplatin in any way, must be disposed of in accordance with local requirements for cytotoxics.

6. Container Content and Additional Information

Composition of Fluorouracil Accord

The active ingredient of Fluorouracil Accord is fluorouracil.

The other components are water for injectable preparations, sodium hydroxide, and hydrochloric acid.

Appearance of the Product and Container Content

Each ml of solution contains 50 mg of fluorouracil (as sodium salt formed in situ).

The injectable or infusion solution of fluorouracil is a clear, colorless to pale yellow solution packaged in a type I transparent glass vial with a rubber stopper.

Each 5 ml vial contains 250 mg of fluorouracil.

Each 10 ml vial contains 500 mg of fluorouracil.

Each 20 ml vial contains 1000 mg of fluorouracil.

Each 50 ml vial contains 2500 mg of fluorouracil.

Each 100 ml vial contains 5000 mg of fluorouracil.

Only some package sizes may be marketed.

Marketing Authorization Holder

Accord Healthcare S.L.U.

World Trade Center

Moll de Barcelona, s/n

Edifici Est, 6ª planta

08039 Barcelona

Manufacturer

Accord Healthcare Polska Sp.z o.o.,

ul. Lutomierska 50,95-200 Pabianice,

Poland

or

Accord Healthcare Single Member S.A.

64th Km National Road Athens,

Lamia, Schimatari, 32009,

Greece

This medicinal product has been authorized in the Member States of the European Economic Area under the following names

Date of Last Revision of this Leaflet: February 2025

Detailed information on this medicinal product is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) (http://www.aemps.gob.es/)

This information is intended only for healthcare professionals

INSTRUCTIONS FOR USE/GUIDE FOR HANDLING, PREPARATION, AND DISPOSAL FOR THE USE OF FLUOROURACIL ACCORD

Cytotoxic Handling Guidelines

Fluorouracil should only be administered by a doctor or under the supervision of a qualified doctor with experience in the use of chemotherapeutic agents for the treatment of cancer.

Fluorouracil Accord should only be prepared by professionals who have been trained in the safe preparation of the same. Preparation should be carried out in a laminar flow cabinet or in a dedicated area for the handling of cytotoxics.

If the medicinal product is spilled, operators should use gloves, face masks, eye protection, and a disposable apron and clean up the spilled material with absorbent material stored in the area for this purpose. The area should then be cleaned and all contaminated material should be placed in a cytotoxic waste bag or container and sealed for incineration.

Contamination

Fluorouracil Accord is irritant; contact with skin and mucous membranes should be avoided.

In case of contact with skin or eyes, the affected area should be washed with plenty of water or normal saline. A 1% hydrocortisone cream can be used to treat transient skin itching. Medical advice should be sought if the eyes are affected or if the preparation is inhaled or ingested.

First Aid

Eye contact: wash immediately with plenty of water and consult a doctor.

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

Inhalation or ingestion: consult a doctor.

Disposal

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

Chemical inactivation can be achieved with 5% sodium hypochlorite for 24 hours.

Preparation Guidelines

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

• Operations such as reconstitution of the powder and transfer to syringes should only be performed in the designated area.

• Personnel carrying out these procedures should be adequately protected with special clothing, two pairs of gloves (one latex and one PVC; with the first under the PVC) to cover the different permeabilities to the various antineoplastics, and protective glasses. For the preparation and administration of cytotoxic products, syringes and accessories with Luer Lock closure should always be used.

• Pregnant employees are advised not to handle chemotherapeutic agents.

• Refer to local guidelines before starting.

Instructions for Use

Fluorouracil Accord can be administered by intravenous injection as a bolus, perfusion, or continuous perfusion.

Incompatibilities

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

The formulated solutions are alkaline, and it is recommended to avoid mixing with acidic drugs or preparations.

Given the absence of compatibility studies, this medicinal product should not be mixed with any other medicinal product.

Shelf Life and Storage

Shelf life of unopened vials

2 years. For single use. Discard any unused medicinal product.

Store below 25°C. Do not refrigerate or freeze.

Keep the container in the outer packaging to protect it from light.

In case of formation of a precipitate as a result of exposure to low temperatures, heat to 60°C and shake the product vigorously for redisolution. Let cool to room temperature before use. Discard the medicinal product if the solution turns yellow or brown.

Shelf life after dilution

In use: physical-chemical stability has been demonstrated under conditions of use for 24 hours at 25°C with 5% glucose injections or 0.9% sodium chloride or water for injectable preparations with a fluorouracil concentration of 0.98 mg/ml.

From a microbiological point of view, the product should be used immediately. If not used immediately, the storage times under conditions of use and the conditions prior to use will be the responsibility of the user.