Fluorouracil AHCL

Package leaflet: Information for the patient

Fluorouracil AHCL 50 mg/ml, Solution for injection or infusion

Generic medicine
Please read all of this leaflet carefully before you use this medicine because it contains important information for you

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not give it to other people, even if they have the same symptoms as you, because it could be dangerous.
• If you experience any adverse reaction, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

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

The name of your medicine is **‘**Fluorouracil AHCL 50 mg/ml, Solution for injection or infusion’, but in the following sections
of this leaflet it will be referred to as 'Fluorouracil AHCL'.
What Fluorouracil AHCL is
Fluorouracil AHCL contains the active substance fluorouracil. It is an anticancer medicine.
What Fluorouracil AHCL is used for
Fluorouracil AHCL is used to treat many common types of cancer, particularly cancers of the colon,
oesophagus, pancreas, stomach, head and neck, and breast. It may be used in combination with
other anticancer medicines and with radiotherapy.
Contact your doctor if you do not feel better or if you feel worse.

2. What you need to know before using Fluorouracil AHCL

Do not use Fluorouracil AHCL

• if you are allergic (hypersensitive) to fluorouracil or to any of the other ingredients of Fluorouracil AHCL (listed in section 6).
• if you have serious infections (e.g. Herpes zoster, chickenpox).
• if your tumour is not malignant.
• if you have been severely weakened by prolonged illness.
• if your bone marrow has been damaged by previous treatments (including radiotherapy).
• if you are currently taking brivudine, sorivudine or analogues (an antiviral medicine).
• if you are pregnant or breastfeeding.
• if you have severe impairment of liver function.
• if you are homozygous for the enzyme dihydropyrimidine dehydrogenase (DPD).
• if you know you have no activity of the enzyme dihydropyrimidine dehydrogenase (DPD) (complete absence of DPD activity).

Inform your doctor if any of the above conditions apply to you before using this medicine.
Warnings and precautions:
Talk to your doctor, pharmacist or nurse before using Fluorouracil AHCL. Be especially careful
with Fluorouracil AHCL:

• if your bone marrow is not producing blood cells normally (your doctor will perform a blood test to check this).
• if you have oral ulcers, fever, widespread bleeding or weakness (these symptoms may be due to very low blood cell counts).
• if you have any kidney problems.
• if you have any liver problems, including jaundice (yellowing of the skin).
• if you have heart problems. Inform your doctor if you experience chest pain during treatment.
• if you have previously suffered from angina (chest pain) or have a history of heart disease, as you may have an increased risk of angina attack or heart attack, or show signs of heart problems during an ECG test.
• if you have reduced activity/deficiency of the DPD enzyme (dihydropyrimidine dehydrogenase).
• if you have received high-dose radiation therapy to the pelvis.
• if you are generally in poor health and have lost a lot of weight.
• if you have had surgery within the last 30 days.
• if you experience gastrointestinal side effects (stomatitis, diarrhoea, gastrointestinal tract bleeding) or widespread bleeding.
• if you know you have partial deficiency in the activity of the enzyme dihydropyrimidine dehydrogenase (DPD).
• if you have heart problems. Inform your doctor if you experience chest pain during treatment.
• if you have a family member with partial or complete absence of dihydropyrimidine dehydrogenase (DPD) enzyme activity.

DPD deficiency: DPD deficiency is a genetic condition that usually does not cause health problems unless certain medicines are taken. If you have DPD deficiency and take Fluorouracil AHCL, you are at increased risk of developing severe adverse reactions (listed in section 4 Possible side effects). Testing for DPD deficiency is recommended before starting treatment. Do not take Fluorouracil AHCL if you have no enzyme activity. If you have reduced enzyme activity (partial deficiency), your doctor may prescribe a lower dose. Even if DPD deficiency test results are negative, severe or potentially life-threatening adverse reactions may still occur.
Contact your doctor immediately if you are concerned about any side effects or if you notice any additional side effects not listed 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 confusion, disorientation or other altered mental status, difficulty with balance or coordination, visual disturbances.
These could be signs of encephalopathy, which may lead to coma and death if untreated.
Inform your doctor if any of the above conditions apply to you before using this medicine.
Fluorouracil may cause sensitivity to sunlight. This may increase skin reactions. To avoid this, you should avoid direct sunlight as much as possible during treatment and must not use sunlamps or sunbeds.
Exposure to UV radiation (e.g. natural sunlight, tanning beds) should be avoided.
Other medicines and Fluorouracil AHCL
Inform your doctor or pharmacist if you are taking, have recently taken or might take any other medicines:
Special care is needed if you are taking/using other medicines, as some may interact with Fluorouracil AHCL:

• Methotrexate, cyclophosphamide, cisplatin, vinorelbine (anticancer medicines)
• Metronidazole (an antibiotic)
• Folinic acid (also known as calcium folinate or calcium leucovorin – used to reduce harmful effects of anticancer medicines)
• Allopurinol (used to treat gout)
• Cimetidine (used to treat gastric ulcers)
• Warfarin (used to treat blood clots)
• Interferon alfa (used in the treatment of lymphomas and chronic hepatitis)
• Brivudine, sorivudine and other analogues (antiviral medicines)
• Phenytoin (used to control epilepsy/seizures and irregular heart rhythm)
• Vaccines
• Radiotherapy
• Levamisole (a medicine used to treat helminthic infections)
• Tamoxifen (used in certain types of breast cancer)
• Clozapine (used for certain psychiatric disorders).

Inform your doctor or pharmacist if you are taking, have recently taken or might take these or any other medicines, including those without a prescription.
Pregnancy, breastfeeding and fertility:
Fluorouracil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. If you are pregnant or planning to become pregnant, you must not use this medicine.
If you are a woman of childbearing potential, you must use effective contraception during treatment with this medicine and for up to 6 months after treatment ends. If pregnancy occurs during treatment, inform your doctor and seek genetic counselling.
Since it is not known whether fluorouracil passes into breast milk, breastfeeding must be discontinued if the mother is treated with Fluorouracil AHCL.
If you are a man, you must avoid fathering a child during treatment and for up to 6 months after stopping treatment with Fluorouracil AHCL. Sperm preservation before treatment is advised due to the possibility of irreversible infertility caused by Fluorouracil AHCL therapy.
Ask your doctor for advice before taking any medicine.
Driving and using machines:
Do not drive or operate machinery because fluorouracil may cause side effects such as nausea and vomiting. It may also cause adverse effects on the nervous system and visual disturbances. If you experience any of these effects, do not drive or operate tools or machines, as the medicine may impair your ability to drive or operate machinery.
Fluorouracil AHCL contains sodium
Fluorouracil AHCL contains 7.78 mmol (178.2 mg) of sodium per maximum daily dose (600 mg/m²). This should be taken into account in patients on a controlled-sodium diet.

3. How to use Fluorouracil AHCL

The dose of medicine you will be given depends on your medical condition, body weight, any recent surgical procedures you have undergone, and the function of your liver and kidneys. It will also depend on the results of your blood tests. The first treatment cycle may be administered daily or at weekly intervals. Further cycles may be given depending on your response to treatment. You may also receive treatment in combination with radiotherapy.
Before administration, the medicine may be diluted with glucose solution, sodium chloride solution, or water for injections. It will be given into a vein either as a standard injection or as a slow injection through a drip (infusion).
If you receive more Fluorouracil AHCL than you should
Since the medicine will be administered during a hospital stay, it is unlikely that you will receive too low or too high a dose; however, speak to your doctor or pharmacist if you have any concerns.
You will need to have blood tests during and after treatment with Fluorouracil AHCL to monitor your blood cell levels. Treatment may need to be interrupted if your white blood cell count is too low.
Nausea, vomiting, diarrhoea, severe mucositis, and gastrointestinal ulceration and bleeding may occur if you receive an excessive dose of fluorouracil. If you have any doubts about using this medicine, consult your doctor.
If you forget to use Fluorouracil AHCL
Do not take a double dose to make up for a missed dose.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
If any of the following occur, inform your doctor immediately:

• Severe allergic reaction – sudden itching (hives), swelling of the hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty swallowing or breathing), and you may feel like you are about to faint.
• Chest pain
• Bloody or black stools
• Mouth becomes sore or develops ulcers
• Numbness, tingling or tremors in the hands or feet
• Heart attack or other heart problems such as rapid heartbeat and shortness of breath
• Symptoms of leukoencephalopathy (brain disease) – weakness, coordination problems in arms and legs, difficulty thinking/speaking, vision/memory problems, seizures, headache
• Shortness of breath

These are serious side effects. You may need urgent medical treatment.
If you experience any of the following symptoms, inform your doctor as soon as possible:
Very common: may affect more than 1 in 10 people

• Changes in ECG (electrocardiogram – a test to monitor heart rhythm and electrical activity)
• Myelosuppression (a disorder in which the bone marrow produces a reduced number of all types of blood cells [pancytopenia])
• Neutropenia and leucopenia (abnormally low levels of white blood cell types in the blood)
• Thrombocytopenia (reduced number of platelets in the blood, reducing the blood’s ability to clot)
• Severe drop in circulating granulated white blood cells (agranulocytosis)
• Anaemia (a condition in which red blood cells are reduced)
• Increased risk of infection due to immunosuppression
• Wheezing (bronchospasm)
• Nausea
• Vomiting
• Diarrhoea
• Infections
• Loss of appetite
• Delayed wound healing
• Inflammation of the mucous lining of any structure in the mouth, throat and digestive tract, e.g. oesophagus, rectum or anus
• Increased uric acid levels in the blood
• Nosebleeds
• Hair loss
• Hand-foot syndrome (toxic skin reaction with redness and swelling of hands and feet)
• Tiredness and lack of energy
• General weakness

Common: may affect up to 1 in 10 people

• Angina pectoris (severe chest pain associated with insufficient blood supply to the heart)
• Low white blood cell count accompanied by fever

Uncommon: may affect up to 1 in 100 people

• Abnormal heart rhythm
• Heart attack
• Myocardial ischemia (loss of oxygen to the heart muscle)
• Myocarditis (inflammatory disease of the heart muscle)
• Heart failure
• Congestive cardiomyopathy (a type of heart disease in which the heart muscle is abnormally enlarged, thickened and/or stiffened)
• Cardiogenic shock
• Low blood pressure
• Drowsiness
• Dehydration
• Bacterial infection in the bloodstream
• Gastrointestinal ulceration and bleeding, skin loss
• Gastrointestinal haemorrhage
• Rhythmic eye movements (nystagmus)
• Headache
• Sensations of imbalance and instability
• Symptoms of Parkinson’s disease (a progressive movement disorder characterised by tremors, stiffness, slow movements)
• Nausea
• Bloodstream infection (sepsis)
• Skin inflammation (dermatitis)
• Skin changes, e.g. dry skin, skin fissures, erosion of skin in some infectious diseases, skin redness, pruritic maculopapular rash (rash starting on lower limbs, spreading to arms and then to chest)
• Itchy sores appearing on the skin
• Light sensitivity (photosensitivity)
• Hyperpigmentation of the skin
• Hyperpigmentation or depigmentation near veins
• Nail pigmentation disorder
• Paronychia (inflammation of the tissue surrounding the nails)
• Inflammation of the nail matrix with pus formation and nail loss
• Ovarian or sperm cell production disorder
• Liver cell damage
• Increased tearing
• Blurred vision
• Inflammation or redness of the lining of the white of the eye and the inner surface of the lower eyelid
• Eye movement disorders
• Optic neuritis (a vision disorder characterised by inflammation of the optic nerve)
• Double vision
• Decreased visual acuity
• Excessive sensitivity to light and aversion to sunlight and bright environments
• Chronic inflammatory eye diseases affecting eyelid margins
• Everted lower eyelids
• Blockage of the tear duct
• A layer or mass of dead tissue separated from surrounding living tissue, as seen in wounds, ulcers or inflammation
• Euphoria

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

• Poor blood circulation in the brain, causing fingers of hands and feet to become numb and pale (Raynaud's syndrome)
• Swelling (inflammation) of a vein due to a blood clot (thrombophlebitis)
• Severe systemic allergic reactions throughout the body (anaphylaxis)
• Blood clot formation in blood vessels, which may affect arteries or veins
• Changes in thyroid function – increased T4 and T3 (total thyroxine and triiodothyronine)
• Systemic vasodilation (widening of blood vessels) leading to low blood pressure
• Confusional state
• Renal failure

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

• Cardiac arrest (sudden cessation of heartbeat and heart function)
• Sudden cardiac death (sudden death due to heart problems)
• Symptoms of leukoencephalopathy (a disease affecting the white matter of the brain), including ataxia (loss of ability to coordinate muscle movements)
• Acute cerebellar syndrome
• Difficulty in articulating speech
• Mental confusion or altered awareness, especially regarding time, place and identity
• Partial or complete loss of ability to communicate verbally or in writing
• Seizures in patients receiving high doses of 5-fluorouracil or in patients with dihydropyrimidine dehydrogenase enzyme deficiency
• Liver cell damage (cases with fatal outcome)
• Inflammation of the gallbladder
• Progressive destruction of bile ducts
• Coma

Not known: frequency cannot be estimated from available data

• Fever
• Numbness or weakness in arms and legs
• Seizures
• Cutaneous lupus erythematosus
• Hyperammonaemic encephalopathy (brain dysfunction caused by high levels of ammonia)
• Skin inflammation causing red, scaly patches, which may occur together with joint pain and fever (cutaneous lupus erythematosus [CLE])
• Heart disease presenting with chest pain, shortness of breath, dizziness, fainting, irregular heartbeat (stress cardiomyopathy)
• Air in the intestinal wall
• Serious condition presenting with breathing difficulties, vomiting and abdominal pain with muscle cramps (lactic acidosis)
• Condition characterised by headache, confusion, seizures and vision changes (posterior reversible encephalopathy syndrome [PRES])
• Serious complication with rapid breakdown of tumour cells causing high levels of uric acid, potassium and phosphate (tumour lysis syndrome)
• Discoloration at the injection site
• Elevated 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 incorrect administration into the vein)
• Vitamin B1 deficiency and Wernicke’s encephalopathy (brain damage caused by vitamin B1 deficiency)
• Inflammation of the small and large intestine causing pain and diarrhoea, which may lead to intestinal tissue death (colitis, enterocolitis)

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or visit the website: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse .
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Fluorouracil AHCL

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the label or carton after Exp. The expiry date refers to the last day of that month.
Store below 25°C. Do not refrigerate or freeze.
Keep the vial in the outer packaging to protect the medicine from light.
For single use only. Discard any unused portion.

Period of validity after dilution
Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C with 5% glucose or 0.9% sodium chloride for injections or water for injectable preparations at a concentration of 0.98 mg/ml of fluorouracil. From a microbiological standpoint, the product should be used immediately. If not used immediately, the duration and conditions of in-use storage prior to use are the responsibility of the user.

Do not use if the product solution appears brown or dark yellow.
Do not use if the container is damaged or if particles/crystals are visible.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What Fluorouracil AHCL contains:

• The active substance in Fluorouracil AHCL is fluorouracil.
• The other components are water for injections, sodium hydroxide, and hydrochloric acid.

Description of the appearance of Fluorouracil AHCL and contents of the pack:
1 ml of solution contains 50 mg of fluorouracil (as sodium salt formed in situ).
Fluorouracil AHCL for injection or infusion is a clear, colourless to slightly yellow solution, contained in a clear type I 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
Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer:
Marketing Authorisation Holder
Accord Healthcare S.L.U.
World Trade Center,
Moll de Barcelona,
s/n, Edifici Est 6ª planta,
08039 Barcelona,
Spain

Manufacturer
Accord Healthcare Polska Sp.z o.o.,
ul. Lutomierska, 50,
95-200, Pabianice
Poland
Accord Healthcare Single Member S.A.
64th Km National Road Athens,
Lamia, Schimatari, 32009, Greece

This medicinal product is authorised in the European Economic Area Member States under the following
names.

The following information is intended exclusively for doctors or healthcare professionals:

INSTRUCTIONS FOR USE/HANDLING, PREPARATION AND DISPOSAL FOR

FLUOROURACIL AHCL

Guidelines for Handling Cytotoxic Drugs
Fluorouracil must be administered only by, or under the supervision of, a qualified physician experienced in the use of antineoplastic chemotherapeutic agents.
Fluorouracil AHCL must be prepared for administration exclusively by personnel trained and qualified in the safe handling of this preparation. Preparation must be carried out only in an aseptic environment or in a dedicated area designated for cytotoxic drug compounding.

In case of spillage, personnel must wear gloves, mask, protective goggles, and disposable gown, and collect the spilled solution using absorbent material kept in the area specifically designated for this purpose. The area must then be cleaned thoroughly, and all contaminated materials must be placed into a plastic bag or container designated for cytotoxic waste, sealed, and incinerated.

Contamination
Fluorouracil is an irritant substance; avoid contact with skin and mucous membranes.
In case of contact with skin or eyes, the affected area must be thoroughly washed with water or normal saline solution. For transient skin irritation, a cream containing 1% hydrocortisone may be applied. In case of eye contact, or in case of inhalation or ingestion, seek immediate medical attention.

First Aid
Eye contact: Immediately irrigate with water and consult a physician.
Skin contact: Wash thoroughly with soap and water and remove contaminated clothing.
Inhalation, ingestion: Seek medical advice immediately.

Disposal
Syringes, containers, absorbent materials, solutions, and any other contaminated materials must be placed in a strong plastic bag or other impermeable container clearly marked as cytotoxic waste and incinerated at a minimum temperature of 700°C.
Chemical inactivation can be achieved using 5% sodium hypochlorite over a period of 24 hours.

Preparation Guidelines
a) Chemotherapeutic agents must be prepared for administration only by trained personnel competent in the safe handling of such preparations.
b) Procedures such as reconstitution of powder and transfer to syringes must be performed exclusively in a designated area.
c) Personnel performing these operations must be adequately protected with special protective clothing, two pairs of gloves (one pair of latex gloves worn under one pair of PVC gloves) to compensate for differences in permeability to various antineoplastic agents, and protective goggles. Syringes and equipment with Luer-Lock connectors must always be used when preparing and administering cytotoxic products.
d) Pregnant women are advised not to handle chemotherapeutic agents.
e) Before starting, refer to applicable local guidelines.

Instructions for Use
Fluorouracil AHCL may be administered by intravenous injection as a bolus, infusion, or continuous infusion.

Incompatibilities
Fluorouracil is incompatible with leucovorin calcium, 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 mixing with acidic drugs or preparations is not recommended.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Shelf Life and Storage
Shelf life of unopened vial:
2 years. For single use only. Discard any unused portion.
Store below 25°C. Do not refrigerate or freeze. Keep the container in its outer packaging to protect from light.
If a precipitate forms due to exposure to low temperatures, it can be redissolved by heating to 60°C with vigorous shaking. Allow to cool to body temperature before use. The product must be discarded if the solution turns brown or dark yellow.

Shelf life after dilution
During use: Chemical and physical stability has been demonstrated for 24 hours at 25°C when diluted with 5% glucose, 0.9% sodium chloride for injection, or water for injections, at a fluorouracil concentration of 0.98 mg/ml.
From a microbiological standpoint, the product should be used immediately. If not used immediately, the duration and conditions of storage prior to use are the responsibility of the user.