Fluorouracil Hikma

Package Leaflet: Information for the User

Fluorouracil Hikma

50 mg/ml
Solution for injection/infusion
Generic medicine
Please read all of this leaflet carefully before you are given 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 nurse.
• If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of this leaflet

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

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

Fluorouracil Hikma contains the active substance fluorouracil. It is an anticancer medicine.
Fluorouracil Hikma is used to treat many common cancers, particularly cancers of the
colon, oesophagus, pancreas, stomach, head, neck and breast. It may be used in combination
with other anticancer medicines and with radiotherapy.

2. What you should know before using Fluorouracil Hikma

Do not use Fluorouracil Hikma:

• if you are allergic to fluorouracil or to any of the other ingredients of this medicine (listed in section 6)
• if you have severe infections (e.g. Herpes zoster, chickenpox)
• if your tumour is non-malignant
• if you are severely weakened due to a prolonged illness
• if your bone marrow has been damaged by previous treatments (including radiotherapy)
• if you are currently being treated or have been treated within the last 4 weeks with brivudine for herpes zoster (chickenpox or shingles)
• 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).

Warnings and precautions
Talk to your doctor or nurse before using Fluorouracil Hikma.
Exercise particular caution with Fluorouracil Hikma:

• if the number of blood cells in your body becomes too low (you must have blood tests to monitor these values)
• if you develop mouth ulcers, fever, bleeding anywhere in the body, or feel weak (these symptoms may result from a very low number of blood cells)
• if you have kidney problems
• if you have 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 know you have a partial deficiency in the activity of the enzyme dihydropyrimidine dehydrogenase (DPD)
• if you have a family history of partial or complete deficiency in the activity of the enzyme dihydropyrimidine dehydrogenase (DPD)
• if you have received high-dose pelvic radiation
• if you have gastrointestinal disorders (stomatitis, diarrhoea, gastrointestinal bleeding) or bleeding at any site

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 Hikma, 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 Hikma 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 specialist 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, or visual disturbances. These could be signs of encephalopathy, which may lead to coma and death if not treated.

Other medicines and Fluorouracil Hikma
Before starting treatment, inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. This is extremely important, as taking several medicines together may enhance or reduce their effects.
You must not take brivudine (an antiviral medicine used to treat shingles or chickenpox) at the same time as Fluorouracil Hikma.
If you have taken brivudine, you must wait at least 4 weeks after stopping it before starting fluorouracil therapy. See also section “Do not take Fluorouracil”.
The following medicines affect the action of fluorouracil:

• Methotrexate (an anticancer medicine)
• Metronidazole (an antibiotic)
• Calcium leucovorin (also known as calcium folinate – used to reduce the harmful effects of anticancer medicines)
• Allopurinol (used to treat gout)
• Cimetidine (used to treat stomach ulcers)
• Warfarin (used for platelet treatment)
• Interferon alfa 2a
• Cisplatin (an anticancer medicine)
• Phenytoin (used to control epilepsy/seizures and irregular heart rhythm)
• Vaccines
• Vinorelbine (an anticancer medicine)
• Cyclophosphamide (an anticancer medicine)
• Levamisole (a medicine used to treat worm infections)
• Tamoxifen (an anticancer medicine)

Pregnancy, breastfeeding 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 for at least 6 months after stopping it. If you become pregnant during treatment, inform your doctor immediately and seek genetic counselling.
Since it is not known whether fluorouracil passes into breast milk, breastfeeding must be discontinued if you are being treated with Fluorouracil Hikma.
If you are a man, you should avoid fathering a child during treatment and for up to 6 months after stopping treatment with Fluorouracil Hikma. Sperm preservation before treatment is recommended due to the risk of irreversible infertility following therapy with Fluorouracil Hikma.
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 events affecting your nervous system and changes in vision. If you experience any of these effects, do not drive or use tools or machines, as this may impair your ability to drive or operate machinery.

Fluorouracil Hikma contains sodium
This medicinal product contains less than 1 mmol of sodium (23 mg) per millilitre, i.e. essentially “sodium-free”.

3. How to use Fluorouracil Hikma

The dose of medicine you will be given depends on your medical condition,
your body weight, whether you have recently undergone surgery, and how well
your kidneys and liver are functioning. It also depends on the results of your blood
tests. Your initial course of treatment will be administered daily or at weekly
intervals. Further administrations will depend on your response to
treatment. You may also receive treatment in combination with radiotherapy.
The medicine may be diluted with water for injectable preparations, a glucose solution,
or sodium chloride solution before administration. It is administered into a vein or
an artery. If given into a vein, it may be administered as a standard injection or as
a slow infusion through an intravenous drip (infusion). If administered into an artery, it will be given
as an infusion.
If you are given more Fluorouracil Hikma than you should
Since this medicine will be administered while you are in hospital, it is unlikely that you will receive
too little or too much medicine. However, inform your doctor or pharmacist if you have any concerns.
You will need to have blood tests during and after treatment with
Fluorouracil Hikma to monitor your blood cell levels.
Treatment must be discontinued if your white blood cell count drops too low.
Nausea, vomiting, diarrhoea, severe mucositis, and gastrointestinal ulceration may occur if
you are given too much Fluorouracil Hikma. If you have any doubts about using this
product, consult your doctor.

4. Possible side effects

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

• severe allergic reaction – you may experience 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,
• shortness of breath,
• your bowel movements are bloody or black,
• your mouth becomes painful or develops ulcers,
• numbness, tingling, or tremors in the hands or feet,
• increased heart rate and breathlessness,
• feeling confused or unsteady on your feet, coordination problems in arms and legs, difficulty thinking or speaking, vision or memory problems.
• If severe stomatitis (ulcers in the mouth and/or throat), mucositis, diarrhoea, neutropenia (increased risk of infections), or neurotoxicity occur during the first treatment cycle, this may be due to DPD deficiency (see Section 2: Warnings and precautions).

These are serious side effects. You may require urgent medical treatment.

Very common side effects (more than 1 in 10 patients):

• ischaemic changes on ECG (inadequate blood supply to an organ, usually due to blockage of an artery)
• Neutropenia (abnormally low levels of neutrophils in the blood)
• Leucopenia (abnormally low white blood cell count)
• Anaemia (a condition in which the red blood cell mass in the blood is insufficient)
• Pancytopenia (a disorder in which the bone marrow greatly reduces or stops production of blood cells)
• Reduced production of blood cells
• High fever and a sharp drop in circulating white blood cells
• Inflammation of the lining of the mouth and digestive tract
• Pharyngitis (inflammation of the mucous membranes of the pharynx)
• Inflammation of the rectum or anus
• Loss of appetite
• Watery diarrhoea
• Nausea
• Vomiting
• Hair loss
• Hand-foot syndrome, a skin toxicity reaction
• Delayed wound healing
• Nosebleeds
• Fatigue
• General weakness
• Tiredness
• Lack of energy
• Inflammation of the mucosal lining of any structure in the mouth
• Oesophagitis (inflammation of the oesophagus)
• Increased uric acid levels in the blood
• Infections

Common side effects (up to 1 in 10 patients):

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

Uncommon side effects (up to 1 in 100 patients):

• Abnormal heart rhythms
• Heart attack
• Myocardial ischaemia (loss of oxygen to the heart muscle)
• Myocarditis (inflammatory disease of the heart muscle)
• Heart failure
• Dilated 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 or body tissues
• Gastrointestinal ulceration and bleeding, skin loss
• Rhythmic eye movements
• Headache
• Feeling of imbalance and unsteadiness
• Parkinsonism symptoms (a progressive movement disorder characterised by tremors, rigidity, and slow movements)
• Pyramidal symptoms
• Feeling unwell
• Skin inflammation
• Skin changes such as dry skin, cracking, erosion, skin redness, pruritic maculopapular rash (rash starting from the lower limbs and progressing to arms and chest)
• A skin rash associated with certain infectious diseases
• Itchy bruise-like spots appearing on the skin
• Photosensitivity
• Hyperpigmentation of the skin
• Striped hyperpigmentation or depigmentation near veins
• Nail changes (e.g. diffuse superficial blue pigmentation, hyperpigmentation; nail dystrophy, pain and thickening of the nail bed)
• Paronychia (inflammation of tissue around the nail)
• Nail matrix inflammation with pus formation and nail shedding
• Disorders in sperm or egg production
• Tearing
• Blurred vision
• Inflammation or redness of the lining of the white part of the eye and the lower eyelid
• Eye movement disorders
• Optic neuritis (a visual disorder characterised by inflammation of the optic nerve)
• Double vision
• Reduced visual acuity
• Excessive sensitivity to light and discomfort in sunlight or brightly lit environments
• Ocular disorder characterised by chronic inflammation of the lower eyelid
• Everted lower eyelid
• Blocked tear ducts
• A layer or mass of dead tissue separated from surrounding living tissue, as seen in wounds, ulcers, or inflammation
• Liver cell damage

Rare side effects (up to 1 in 1,000 patients):

• Generalised allergic reaction
• Inadequate blood supply to the brain, intestines, and peripheral organs
• Discoloration of fingers, toes, and occasionally other areas
• Blood clot formation within blood vessels, which may occur in both arteries and veins
• Swelling (inflammation) of a vein due to a blood clot (thrombophlebitis)
• Severe, whole-body allergic reaction (anaphylaxis)
• Systemic vasodilation (dilation of blood vessels) leading to low blood pressure
• Confusion
• Increased T4 (total thyroxine), increased T3 (total triiodothyronine)

Very rare side effects (up to 1 in 10,000 patients):

• Cardiac arrest (sudden cessation of heartbeat and heart 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 movements)
• Difficulty articulating words
• Confusion
• Altered mental state or awareness, especially regarding time, place, or identity
• Abnormal muscle weakness or fatigue
• Acute cerebellar syndrome
• Partial or complete loss of ability to communicate verbally or in writing
• Seizures or coma in patients receiving high doses of 5-fluorouracil or in patients with dihydropyrimidine dehydrogenase (DPD) deficiency
• Kidney failure
• Liver cell damage (cases with fatal outcome)
• Inflammation of the gallbladder
• Slow and progressive destruction of the small bile ducts

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

• Fever
• Numbness or weakness in arms and legs
• 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, and irregular heartbeat (stress cardiomyopathy)
• Air in the intestinal wall
• A serious condition presenting with breathing difficulties, vomiting, and abdominal pain with muscle cramps (lactic acidosis)
• A condition characterised by headache, confusion, seizures, and visual disturbances (posterior reversible encephalopathy syndrome [PRES])
• A serious complication involving rapid breakdown of tumour cells, leading to high levels of uric acid, potassium, and phosphate (tumour lysis syndrome)
• Elevated triglyceride levels (a type of fat)
• Pain, redness, or swelling at the infusion site during or shortly after injection/infusion (likely due to improper venous access)
• 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, please inform your doctor or nurse. You may also report side effects directly via the national reporting system at:
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 Hikma

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and the carton after
EXP.
Store below 25°C. Do not refrigerate or freeze.
Keep the container in the outer packaging to protect the medicine from light.
For single use only. Discard any unused portion of the medicine.
Do not use the product if the solution appears brown or dark yellow.
Do not use this medicine if you notice that the container is damaged or if particles or
crystals are visible.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist
how to dispose of medicines no longer in use. This will help protect the environment.

6. Package contents and other information

What Fluorouracil Hikma contains

• The active substance is fluorouracil.
• The other components are trometamol, sodium hydroxide, and water for injections.

Description of the appearance of Fluorouracil Hikma and contents of the pack
Fluorouracil Hikma, 50 mg/ml, solution for injection or for infusion is a clear, colourless or almost colourless solution in a type I glass vial closed with a stopper.
1 ml of solution contains 50 mg of fluorouracil (as sodium salt formed in situ).
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 100 ml vial contains 5000 mg of fluorouracil.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Hikma Farmacêutica (Portugal), S.A.
Estrada do Rio da Mó, 8, 8A and 8B – Fervença
2705-906 Terrugem SNT
Portugal

Manufacturer
Thymoorgan Pharmazie GmbH
Schiffgraben 23
38690 Goslar
Germany
Hikma Farmacêutica (Portugal), S.A.
Estrada do Rio da Mó 8, 8A and 8B
2705-906 Terrugem SNT
Portugal

This medicinal product is authorised in the European Economic Area Member States under the following names:
Italy: Fluorouracil Hikma 50 mg/ml Solution for injection/infusion
Portugal: Fluorouracilo Hikma, 50 mg/ml, Solução injetável ou para perfusão
United Kingdom: Fluorouracil 50 mg/ml, Solution for injection/infusion

The following information is intended for healthcare professionals only:

INSTRUCTIONS FOR USE/HANDLING, PREPARATION, AND DISPOSAL
GUIDELINES FOR FLUOROURACIL INJECTION
Guidelines for handling cytotoxic substances
Fluorouracil Hikma must be administered only under the supervision of qualified physicians experienced in the use of antineoplastic agents.

Preparation (guidelines):
Contamination
In case of contact with skin or eyes, the affected area must be washed immediately with copious amounts of water or normal saline solution. A 1% hydrocortisone cream may be used to treat transient skin irritation. If eyes are affected, or if the preparation is inhaled or ingested, medical advice must be sought immediately.

In case of spillage, personnel must wear gloves, mask, eye protection, and disposable gowns. Absorbent material stored in the designated area should be used to soak up the spilled product. The area should then be cleaned thoroughly, and all contaminated materials placed into a cytotoxic spill bag or container, sealed, and incinerated.

First aid
Eye contact: Immediately flush eyes with water and seek medical advice.
Skin contact: Wash thoroughly with soap and water and remove contaminated clothing.
Inhalation, ingestion: Seek medical advice immediately.

Disposal
Syringes, vials, absorbent materials, solution, and any other contaminated materials must be placed in a thick plastic bag or another impermeable container, clearly labeled as cytotoxic waste, and incinerated at a temperature of at least 700°C.

Chemical inactivation can be achieved using a 5% sodium hypochlorite solution within 24 hours.

a) Chemotherapeutic agents must be prepared for administration only by healthcare personnel adequately trained in the safe handling of such preparations.
b) Procedures such as reconstitution of powder and transfer into syringes must be carried out only in designated areas.
c) Personnel performing these procedures must be adequately protected with special protective clothing, two pairs of gloves (latex under PVC gloves) to account for differing permeability characteristics of various antineoplastic agents, and eye protection. Luer-lock syringes and connectors must always be used both during preparation and administration of cytotoxic drugs.
d) Pregnant personnel must be advised not to handle chemotherapeutic agents.
e) Refer to local guidelines before starting procedures.

Instructions for use

Fluorouracil Hikma may be administered by intravenous injection or intravenous or

intra-arterial infusion.
Incompatibilities
Fluorouracil is incompatible with folic acid, 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 mixtures with acidic drugs or acidic preparations should be avoided. In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Shelf life and storage conditions
Shelf life of the unopened vial:
250 mg/5 ml: 18 months
500 mg/10 ml: 2 years
1000 mg/20 ml: 2 years
5000 mg/100 ml: 2 years

Shelf life after dilution
During use: Chemical and physical stability during use has been demonstrated for 5 days at 20°C – 25°C and at 2° - 8°C with water for injections, 5% glucose solutions, and 0.9% sodium chloride solutions at fluorouracil concentrations of 0.5 mg/ml, 2.0 mg/ml, and 4.0 mg/ml.
From a microbiological standpoint, the product should be used immediately. If not used immediately, the storage times before use and the conditions are the responsibility of the user and normally should not exceed 24 hours at 2 – 8°C, unless dilution has taken place under controlled and validated aseptic conditions.