Patient Information Leaflet

Fluorouracil Teva 250 mg/5 ml solution for infusion, 500 mg/10 ml solution for infusion, 1 g/20 ml solution for infusion, 5 g/100 ml solution for infusion

Please read all of this leaflet carefully before you start using this medicine, as it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor, pharmacist, or nurse.
This medicine has been prescribed for you only. Do not give it to other people, even if they have the same symptoms as yours, as it may be harmful to them.
If you experience any side effects, including those not listed in this leaflet, inform your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet:

What Fluorouracil Teva is and what it is used for
What you need to know before using Fluorouracil Teva
How to use Fluorouracil Teva
Possible side effects
How to store Fluorouracil Teva
Contents of the pack and other information

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

Fluorouracil Teva contains fluorouracil, a substance capable of inhibiting and fighting the growth of tumours, used in the treatment of breast cancer, the second part of the intestine (colon and rectum), stomach and pancreatic cancer.
This medicine is used in patients who cannot be treated surgically or by other means.
Contact your doctor if you do not feel better or if you feel worse.

2. What you should know before using Fluorouracil Teva

Do not use Fluorouracil Teva

if you are allergic to the active substance or to any of the other ingredients of this medicine (listed in section 6);
if you are severely debilitated (e.g. malnourished);
if your bone marrow function – that is, your bone marrow's ability to produce functioning blood cells – is reduced, for example due to previous chemotherapy or radiotherapy;
if you currently have severe infections (e.g. Herpes zoster, varicella);
if you are being treated or have been treated within the last 4 weeks with brivudine, sorivudine or their analogues (antiviral drugs);
if you know you have no activity of the enzyme dihydropyrimidine dehydrogenase (DPD);
if you have a so-called "homozygous" mutation of the enzyme dihydropyrimidine dehydrogenase (DPD);
if your tumour is not malignant;
if you have severe impairment of liver function;
if you are breastfeeding.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before taking Fluorouracil Teva, particularly:

if you have heart problems. Inform your doctor also 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 member with partial or complete absence of dihydropyrimidine dehydrogenase (DPD) enzyme activity.

DPD deficiency: DPD deficiency is a genetic condition that generally does not cause health problems unless certain medications are taken. If you have DPD deficiency and take Fluorouracil Teva, you are at higher 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 Teva 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 tests are negative, severe or potentially life-threatening adverse effects may still occur.
Contact your specialist immediately if you develop 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.
Your doctor should pay particular attention and carefully consider whether to treat you with Fluorouracil Teva if you are a patient who:

previously received high-dose radiotherapy in the pelvic area (lower trunk, corresponding to the pelvis);
previously received treatment with alkylating antitumour drugs;
has widespread metastases in the bone marrow;
has reduced kidney or liver function, including jaundice (yellowing of the skin).

Fluorouracil Teva must be administered only by a physician experienced in the use of antineoplastic agents, or under such a physician’s supervision.
You should be hospitalised, at least during the initial treatment cycle, due to the potential toxic effects of this drug. Indeed, despite appropriate dose adjustment and careful assessment of your clinical condition, it is rare for treatment with Fluorouracil Teva to be effective without some toxicity symptoms developing. In more severe cases, gastrointestinal bleeding (haemorrhage), blood toxicity signs, and even death may occur; therefore, your doctor may decide to discontinue treatment with this medicine. Furthermore, any condition that may increase your level of stress, interfere with your nutritional status, or affect your bone marrow function increases the toxicity of the medicine (see also section “Other medicines and Fluorouracil Teva”).
During treatment with Fluorouracil Teva, you must not receive any vaccinations to avoid the risk of severe or fatal reactions (see also section “Other medicines and Fluorouracil Teva”), and you should avoid prolonged exposure to sunlight due to the risk of photosensitivity.
During treatment with Fluorouracil Teva, your doctor will perform frequent blood tests to monitor your blood counts, i.e. the number of red blood cells, white blood cells, and platelets in your blood.
If even one of the following symptoms occurs, treatment with Fluorouracil Teva will be immediately suspended:

oral ulcerations and gastrointestinal side effects such as inflammation of the mouth or throat (stomatitis and oesophagopharyngitis);
too rapid or excessive reduction in white blood cell count (leucopenia with white blood cell count below 3,500);
uncontrolled vomiting;
frequent bowel movements, diarrhoea, and watery stools;
gastrointestinal ulcers and bleeding;
decreased platelet count (thrombocytopenia);
widespread bleeding (haemorrhage);
heart-related disorders;
nervous system disorders.

Fluorouracil administration has been associated with a condition known as “hand-foot syndrome” (palmar-plantar erythrodysesthesia; see also section “Possible side effects”). This syndrome is characterised by a tingling sensation in the hands and feet, which may progress within a few days to pain when handling objects or walking. The palms of the hands and soles of the feet may become swollen, with skin irritation, sometimes accompanied by symmetrical desquamation. Discontinuation of treatment leads to gradual resolution within 5–7 days.
Additionally, during treatment with this medicine, changes in certain blood parameters may occur: decreased white blood cells and platelets (leucopenia), increased alkaline phosphatase, transaminases, bilirubin, and lactate dehydrogenase, as well as decreased plasma albumin.
Furthermore, urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) may increase.

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

Other medicines and Fluorouracil Teva
Inform your doctor if you are taking, have recently taken, or might take any other medicines.
You must not take brivudine, sorivudine or their analogues (antiviral drugs used to treat shingles or chickenpox) concurrently with fluorouracil treatment (including during treatment-free intervals when no fluorouracil tablets are taken).
If you have taken brivudine, sorivudine or their analogues, you must wait at least 4 weeks after stopping them before starting fluorouracil therapy. See also section “Do not use Fluorouracil Teva”.
The following medicines may increase the toxic effects of fluorouracil:

calcium folinate/folinic acid;
immunosuppressive/myelosuppressive drugs, including radiotherapy: sometimes prescribed together with or consecutively to fluorouracil to enhance treatment efficacy. In such cases, a dose reduction may be necessary.

It is also important to note that treatment with fluorouracil may lower your normal immune defences and thus alter your response to vaccinations (killed virus/live attenuated virus vaccines). For this reason, your doctor will carefully evaluate whether and when to vaccinate you. Moreover, if someone in close contact with you intends to receive an oral polio vaccine (live attenuated), you should discuss this with your doctor and may need to ask that person to postpone vaccination until your health improves.
Patients with leukaemia in remission should not receive live attenuated virus vaccines within three months of their last chemotherapy session.
Also inform your doctor or pharmacist if you are taking the following medicines, as they may affect fluorouracil’s action:

allopurinol (used to treat gout);
cimetidine (used to treat gastric ulcers);
metronidazole (an antibiotic);
interferon (an antiviral);
blood-thinning medicines (anticoagulants), e.g. warfarin;
medicines called thiazide diuretics (used to treat hypertension);
levamisole (a medicine used to treat infections);
tamoxifen, cyclophosphamide (antitumour medicines);
clozapine (an antipsychotic medicine);
phenytoin (a medicine used to control epilepsy/seizures and irregular heart rhythm);
vinorelbine (an antitumour medicine);
methotrexate (an antitumour medicine);
leucovorin (a medicine also known as calcium folinate, used to reduce harmful effects of antitumour medicines).

Diagnostic tests
During treatment with Fluorouracil Teva, increases may occur in certain blood enzymes such as alkaline phosphatase, transaminases, lactate dehydrogenase, and bilirubin, as well as in urinary 5-hydroxyindoleacetic acid (5-HIAA). A decrease in plasma albumin, a protein present in blood plasma, may also occur.

Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you may be pregnant, plan to become pregnant, or are breastfeeding, consult your doctor before using this medicine.

Pregnancy
Fluorouracil should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
If you are a woman of childbearing potential, you must use effective contraception during treatment and for 6 months after treatment ends. If pregnancy occurs during treatment, contact your doctor immediately. Your doctor will inform you about the potential risks to the foetus and may recommend genetic counselling by a specialist.

Breastfeeding
Fluorouracil is strictly contraindicated in breastfeeding women. It is not known whether fluorouracil passes into breast milk; therefore, breastfeeding must be discontinued before starting treatment with Fluorouracil Teva.

Fertility
If you are a man, you should avoid fathering a child during treatment and for 3 months after stopping treatment with Fluorouracil Teva. Sperm banking before treatment is recommended due to the possibility of irreversible infertility caused by fluorouracil therapy.

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 use tools or machines, as the medicine may impair your ability to drive or operate machinery.

Fluorouracil Teva contains sodium
This medicine contains 8.2 mg of sodium per ml, i.e. 164 mg of sodium per maximum dose of 1000 mg fluorouracil (20 mL), equivalent to 8.23% of the maximum daily intake recommended in an adult’s diet.

3. How to use Fluorouracil Teva

Fluorouracil Teva will be administered by intravenous infusion by trained healthcare personnel.
The dose will be determined by your doctor, as it must be calculated with the utmost precision based on your body weight, your general health status (including any recent surgical procedures, and liver and kidney function), and the therapeutic plan established for your clinical condition.
The dose may subsequently be adjusted according to your response to the first treatment cycle.
During treatment, you will undergo regular medical examinations and tests to monitor the appropriate progress of therapy.
If you are elderly and have reduced kidney function, your doctor will reduce the dose of the medicine.

The normally recommended doses are:
Initial dosing
The recommended dose is 12 mg/kg body weight once daily for 4 days. The daily dose should not exceed 800 mg. Your doctor may decide to continue administering the drug beyond 4 days, depending on your individual response and clinical condition.
In at-risk patients and those who are particularly debilitated, the recommended dose is 6 mg/kg daily for 3 days. The total daily dose should not exceed 400 mg. Your doctor may decide to continue administering the drug beyond 3 days, depending on your individual response and clinical condition.

Maintenance therapy
Treatment may continue with the initial dose if toxicity is not a concern, repeating administration every 30 days after the last treatment.
If toxicity occurs, once signs of toxicity have subsided, the recommended dose is 10–15 mg/kg weekly as a single administration. The total weekly dose should not exceed 1 g.
In at-risk and particularly debilitated patients, the dose will be reduced.
In any case, the dose administered in each treatment cycle will be adjusted based on the reactions observed during previous treatment.

Infusion
Your doctor will determine the dose most suitable for your condition, and the medicine will be administered through a slow injection (infusion) directly into a vein. A series of infusions constitutes one “treatment cycle.” The interval between two treatment cycles should be 4–6 weeks.

If you use more Fluorouracil Teva than you should
Due to the conditions under which it is administered, it is unlikely that you would receive more Fluorouracil Teva than intended. However, please be aware that the following reactions may occur if you receive an excessive dose of fluorouracil: nausea, vomiting, diarrhoea, inflammation of the stomach and intestinal lining with possible bleeding (gastrointestinal ulceration), and reduced bone marrow function (the ability of the bone marrow to produce blood cells). If these conditions occur, treatment will be discontinued and supportive measures will be initiated. Your health status will be monitored for at least 4 weeks.

If you stop treatment with Fluorouracil Teva
Consult your doctor if you intend to discontinue treatment.
If you have any doubts about how to use this medicine, ask your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will experience them.
Treatment with fluorouracil will be discontinued if signs of severe drug-related toxicity occur.
If severe stomatitis (ulcers in the mouth and/or throat), mucosal inflammation, 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”).
If any of the following occur, inform your doctor immediately:

chest pain;
shortness of breath.

Possible side effects include the following:
Very common (may affect more than 1 in 10 people):

infections;
inadequate bone marrow function (bone marrow failure);
decrease in the number of white blood cells called neutrophils (neutropenia);
decrease in the number of platelets (thrombocytopenia);
decrease in the number of white blood cells (leucopenia);
decrease in the number of white blood cells called granulocytes (agranulocytosis);
anaemia;
decrease in the number of all blood cells (pancytopenia);
inflammation of the oral cavity (stomatitis), oesophagus (oesophagitis), pharynx (pharyngitis), rectum and anus (proctitis);
diarrhoea, nausea and vomiting;
increased uric acid in the blood (hyperuricaemia);
reduced or absent appetite (anorexia);
reduced normal immune defences (immunosuppression);
hair loss, particularly in women (alopecia);
tingling sensation in the hands and feet, which may rapidly progress within a few days to pain when handling objects or walking (palmar-plantar erythrodysaesthesia, also known as “hand-foot syndrome”);
delayed wound healing;
malaise, weakness (asthenia) and fatigue;
nosebleeds (epistaxis);
abnormal contraction of bronchial muscles (bronchospasm);
ischaemic abnormalities in the electrocardiogram (insufficient blood supply to an organ, usually due to a blocked artery).

Common (may affect up to 1 in 10 people)

inflammation of the tongue (glossitis), gastric mucosa (gastritis) and intestinal mucosa (enteritis, duodenitis and duodenal ulcer);
abdominal pain;
low levels of white blood cells accompanied by fever (febrile neutropenia);
skin inflammation (dermatitis);
chest pain similar to that associated with insufficient blood supply to the heart (angina pectoris).

Uncommon (may affect up to 1 in 100 people)

bacterial infection in the bloodstream or body tissues (sepsis);
abnormalities in heart rhythm (arrhythmia); myocardial infarction; oxygen deprivation to the heart muscle (myocardial ischaemia); inflammatory disease of the heart muscle (myocarditis); heart failure; heart disease in which the heart muscle is abnormally thickened, enlarged and/or stiffened (congestive cardiomyopathy); cardiogenic shock;
inflammation of the stomach and intestinal wall with possible bleeding (gastrointestinal ulceration and haemorrhage);
exfoliation of the gastrointestinal mucosa;
dehydration;
rhythmic, involuntary oscillating eye movements (nystagmus);
headache (cephalalgia);
sensation of imbalance and instability (dizziness);
symptoms of Parkinson’s disease (a progressive movement disorder characterised by tremors, stiffness, and slowness of movement);
central motor-type syndrome (pyramidal syndrome);
drowsiness;
dry skin, skin fissures and erosion, skin redness, pruritic maculopapular skin rash (rash starting on the lower limbs, spreading to the arms and then to the chest); skin rash; appearance of itchy sores on the skin (urticaria); photosensitivity; skin hyperpigmentation;
hyperpigmentation or depigmentation near veins;
nail pigmentation, nail dystrophy, nail bed disorder; inflammation of the tissue surrounding the nails (paronychia); inflammation of the nail matrix with pus formation and nail loss (onycholysis);
lacrimation; blurred vision; abnormal eye movements; optic neuritis (a vision disorder characterised by inflammation of the optic nerve); double vision (diplopia); decreased visual acuity; excessive sensitivity to light (photophobia); inflammation or redness of the lining of the white part of the eye (conjunctivitis) and of the eyelid margin (blepharitis); outward turning of the lower eyelids (ectropion); blockage of the tear duct (acquired dacryostenosis);
euphoria;
disorder of ovarian or sperm cell production (azoospermia);
drop in blood pressure (hypotension);
damage to liver cells (hepatocellular injury).

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

inadequate blood circulation in the intestine (intestinal ischaemia), brain (cerebral ischaemia), and peripheral organs (peripheral ischaemia);
kidney failure;
hypersensitivity; severe systemic allergic reaction (anaphylaxis); anaphylactic shock;
confusion;
blood clot formation in blood vessels, which may affect arteries or veins (thromboembolism); inflammation of veins leading to blood clot formation (thrombophlebitis);
discolouration of fingers and toes, and occasionally other areas (Raynaud’s phenomenon);
increase in total thyroxine (T4) and total triiodothyronine (T3).

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

sudden cessation of heartbeat and cardiac function (cardiac arrest); sudden death due to heart problems (sudden cardiac death);
symptoms of leukoencephalopathy (a disease affecting the brain’s white matter), including ataxia (loss of ability to coordinate muscle movements);
brain damage (acute cerebellar syndrome that may persist after treatment ends);
difficulty in articulating speech (dysarthria);
partial or complete loss of ability to communicate verbally or use written language (aphasia);
seizures or coma;
muscle weakness;
disorientation;
damage to liver cells (cases with fatal outcome); slow and progressive destruction of bile ducts (biliary sclerosis); inflammation of the gallbladder (cholecystitis, even in the absence of gallstones).

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

formation of blood clots in one of the heart ventricles (cardiac ventricular thrombosis);
inflammation of the membrane lining the heart, called pericardium (pericarditis); alteration in liver structure (intra- and extrahepatic sclerosis);
drowsiness (lethargy);
impaired vision;
dilation of blood vessels (aneurysm);
reduced blood flow (ischaemia);
blockage of blood vessels (arterial thrombosis, embolism);
bleeding at the infusion cannula site;
blockage of the infusion cannula;
development of rheumatic diseases (fibromyalgia);
abscess;
infections at the cannula insertion site;
changes in the electrocardiogram trace;
hyperammonaemic encephalopathy (brain dysfunction caused by high levels of ammonia);
numbness or weakness in the arms and legs (peripheral neuropathy);
fever;
change in the colour of the vein near the injection sites;
difficulty breathing, such as breathlessness (dyspnoea);
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;
serious condition presenting with breathing difficulties, vomiting, and abdominal pain with muscle cramps (lactic acidosis);
condition characterised by headache, confusion, seizures, and visual disturbances (posterior reversible encephalopathy syndrome (PRES));
serious complication with rapid breakdown of tumour cells leading to high levels of uric acid, potassium and phosphate (tumour lysis syndrome);
elevated levels of triglycerides, a type of fat;
pain, redness or swelling at the infusion site during or shortly after injection/infusion (likely due to improper injection 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, pharmacist or nurse. You can 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 Teva

Store at a temperature between 15°C and 25°C. Keep the medicine in the original packaging to protect it from light.
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging after "Exp.".
The expiry date refers to the last day of that month.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Fluorouracil Teva contains
Fluorouracil Teva 250 mg/5 ml infusion solution
The active substance is fluorouracil. One vial contains 250 mg of fluorouracil.
Fluorouracil Teva 500 mg/10 ml infusion solution
The active substance is fluorouracil. One vial contains 500 mg of fluorouracil.
Fluorouracil Teva 1 g/20 ml infusion solution
The active substance is fluorouracil. One vial contains 1 g of fluorouracil.
Fluorouracil Teva 5 g/100 ml infusion solution
The active substance is fluorouracil. One vial contains 5 g of fluorouracil.
The other components are sodium hydroxide, hydrochloric acid, water for injections.

Description of the appearance of Fluorouracil Teva and contents of the pack
Fluorouracil Teva 250 mg/5 ml infusion solution is supplied in a carton containing one 5 ml glass vial.
Fluorouracil Teva 500 mg/10 ml infusion solution is supplied in a carton containing one 10 ml glass vial.
Fluorouracil Teva 1 g/20 ml infusion solution is supplied in a carton containing one 20 ml glass vial.
Fluorouracil Teva 5 g/100 ml infusion solution is supplied in a carton containing one 100 ml glass vial.

Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
Teva Italia S.r.l. - Piazzale Luigi Cadorna, 4 – 20123 Milano, Italy
Manufacturer
Pharmachemie B.V. - Swensweg, 5 - 2031 GA Haarlem, The Netherlands

The following information is intended exclusively for healthcare professionals.

Dosage and method of administration
Parenteral medicinal products should be inspected visually for particulate matter or discoloration prior to manipulation and administration.
The fluorouracil infusion solution may change color during storage; however, this does not compromise the product's validity or safety.
If a precipitate forms in the solution due to exposure to low temperatures, warm it to 60°C and shake vigorously. Cool to body temperature before use.

Compatibility
Fluorouracil Teva may be diluted with 0.9% sodium chloride for injection or 5% dextrose for injection. The resulting solution is stable for 48 hours when stored at room temperature and protected from light.

Incompatibilities
Do not mix fluorouracil for injection with intravenous infusion additives or other chemotherapeutic agents.

Special precautions for handling
As with all cytotoxic preparations, special care must be taken to ensure correct and safe handling.

The drug should only be handled by adequately trained personnel. Pregnant women must not handle the drug.
Handling must be performed in a designated area, using a vertical laminar flow hood. The work surface should be covered with disposable, plastic-backed absorbent paper.
Appropriate protective clothing must be worn, such as plastic gloves, protective goggles, and a face mask. In case of eye contact, rinse thoroughly under running water or with physiological saline solution.
Luer-lock devices must be used on all syringes and equipment. Aerosol formation can be minimized by using needles with a large internal diameter and vented needles.
All unused materials, needles, syringes, vials, and other items that have come into contact with cytotoxic drugs must be kept separate, placed in sealed polypropylene bags, and incinerated at a temperature exceeding 1000°C. Excreta should be handled similarly. Liquid waste should be flushed away with a large volume of water.