FLUOROURACIL Solution for injection or infusion Ref.[7972] Active ingredients: Fluorouracil

Posology

5-fluorouracil should be administered only under the supervision of a qualified physician with extensive experience in cytotoxic treatment.

Patients must be carefully and frequently monitored during the treatment. The risks and benefits to individual patients should be carefully considered before each treatment.

Method of administration

5-fluorouracil can be administered by intravenous injection as bolus, infusion or continuous infusion for up to several days.

"These are general advices. Please refer to a local or international guideline for a more (up to date) recommendation."

Precautions to be taken before handling or administering the medicinal product and

For instructions on dilution of the medicinal product before administration, see section 6.6

Intravenous administration

The dose of 5-fluorouracil and the treatment schedule depends on the chosen treatment regimen, the indication, the general status and previous treatment of the patient. Treatment regimens vary in the combination of 5-fluorouracil with other cytotoxic agents or dose of concomitantly used folinic acid.

The number of cycles used should be decided by the treating clinician depending on local treatment protocols and guidelines; taking into consideration treatment success and tolerability in individual patients.

Initial treatment should be given in hospital.

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

1. Cachexia
2. Major surgery within preceding 30 days
3. Reduced bone marrow function
4. Impaired hepatic or renal function

Adults and elderly patients receiving 5-fluorouracil should be monitored prior to each dose for haematological (platelet, leucocyte, and granulocyte counts), gastrointestinal (stomatitis, diarrhoea, bleeding from the gastrointestinal tract), and neurological toxicity, and, if necessary, the dose of 5-fluorouracil may be either reduced or withheld.

Necessity of dosage adjustment or discontinuation of the medicinal product depends on the occurrence of undesirable effects. Haematological toxicities such as reduced leukocytes (≤ 3500/mm³) and/or platelet counts (≤ 100000/mm³) can require treatment interruption. Resumption of treatment must be decided by the treating clinician depending upon the clinical scenario.

Colorectal cancer

5-fluorouracil is used in the treatment of colon and rectal cancers in a number of treatment regimens. 5-fluorouracil is preferably used along with folinic acid. Commonly used treatment regimens also combine 5-fluorouracil and folinic acid with other chemotherapeutic agents such as Irinotecan (FOLFIRI and FLIRI), Oxaliplatin (FOLFOX) or both Irinotecan and Oxaliplatin (FOLFIRINOX).

The commonly used dose range of 5-fluorouracil varies from 200-600mg/m² of body surface. The dose also varies depending administration as intravenous bolus or as continuous intravenous infusion.

The dose schedules also vary depending on the chemotherapy regimen, and 5-fluorouracil dose could be repeated weekly, bimonthly or monthly.

The number of cycles varies with the treatment regimens used and also depends on the clinical decision based on treatment success and tolerability.

Breast cancer

5-fluorouracil is commonly used in chemotherapy regimens in combination with cyclophosphamide and methotrexate (CMF), or epirubicin, cyclophosphamide (FEC) or methotrexate and leucovorin (MFL). The usual dose range is 500- 600 mg/m² body surface as an intravenous bolus and repeated every 3–4 weeks as necessary. In adjuvant treatment of primary invasive breast cancer, duration of treatment will usually continue for 6 cycles.

Gastric cancer and cancer of gastroesophageal junction

Peri-operative chemotherapy with ECF regimen (epirubicin, cisplatin, 5-fluorouracil) is currently recommended. The recommended dose of 5-fluorouracil is 200 mg/m² body surface per day given as continuous intravenous infusion for 3 weeks. 6 cycles are recommended but this depends on treatment success and tolerability of medicinal product by the patient.

Oesophageal cancer

5-fluorouracil is commonly used in combination with cisplatin; or cisplatin and epirubicin; or epirubicin and oxaliplatin. Dose varies between 200- 1000 mg/m² body surface per day as continuous intravenous infusion over several days and repeated cyclically depending upon regimen.

For cancers involving lower part of oesophagus, peri-operative chemotherapy with ECF regimen (epirubicin, cisplatin, 5-fluorouracil) is commonly recommended. The recommended dose of 5-fluorouracil is 200 mg/m² body surface per day given as continuous intravenous infusion for 3 weeks and repeated cyclically.

Concerning administration of 5-fluorouracil/cisplatin in combination with radiotherapy, please refer to the literature.

Pancreatic cancer

5-fluorouracil is preferably used in combination with folinic acid or gemcitabine. Dose varies between 200- 500 mg/m² body surface per day as intravenous bolus injection or intravenous infusion, depending on the regimen and repeated cyclically.

Head and neck cancer

5-fluorouracil is preferably used in combination with cisplatin or carboplatin. Dose varies between 600- 1200 mg/m² body surface per day as continuous intravenous infusion over several days and repeated cyclically depending upon regimen.

Concerning administration of 5-fluorouracil/ cisplatin or carboplatin in combination with radiotherapy, please refer to the literature.

Special populations

Renal or hepatic impairment

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

Paediatric population

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

Elderly

No dosage adjustment necessary.

The symptoms and signs of overdosage are qualitatively similar to the adverse reactions but commonly are more pronounced particularly, the following adverse reactions might occur:

Nausea, vomiting, diarrhoea, gastrointestinal ulceration and bleeding, bone marrow depression (including thrombocytopenia, leukopenia, agranulocytosis).

Treatment consists of drug discontinuation and supportive measures (see section 4.4).

Patients who have been exposed to an overdose of fluorouracil should be monitored haematologically for at least four weeks. Should abnormalities appear, appropriate therapy should be utilised.

Shelf life of unopened vial: 2 years.

Vial after first opening: Use immidiately after opening

Shelf Life after dilution:

In use: Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C with Glucose 5% or Sodium Chloride 0.9% Injection or Water for Injections at concentration 0.98 mg/ml of fluorouracil.

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

Store below 25°C. Do not refrigerate or freeze. Keep vial in the outer carton in order to protect from light.

The pH of Fluorouracil Injection is 8.9 and the drug has maximal stability over the pH range 8.6 to 9.4.

For storage condition of the diluted medicinal product, see section 6.3.

If a precipitate has formed as a result of exposure to low temperatures, redissolve by heating to 60°C accompanied by vigorous shaking. Allow to cool to body temperature prior to use.

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

Fluorouracil Injection 50 mg/ml, 5 ml is filled in 5 ml Type I clear glass vials with rubber closure.

Fluorouracil Injection 50 mg/ml, 10 ml is filled in 10 ml Type I clear glass vials with rubber closure.

Fluorouracil Injection 50 mg/ml, 20 ml is filled in 20 ml Type I clear glass vials with rubber closure.

Fluorouracil Injection 50 mg/ml, 50 ml is filled in 50 ml Type I clear glass vials with rubber closure.

Fluorouracil Injection 50 mg/ml, 100ml is filled in 100 ml Type I clear glass vials with rubber closure.

Pack sizes:

Pack of 1X 5 ml vial
Pack of 1X 10 ml vial
Pack of 1X 20 ml vial
Pack of 1X 50 ml vial
Pack of 1X 100 ml vial

Not all pack sizes may be marketed.

Cytotoxic Handling Guidelines

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

Fluorouracil Injection should only be prepared for administration by professionals who have been trained in the safe use of the preparation. Preparation should only be carried out in an aseptic cabinet or suite dedicated for the assembly of cytotoxics.

In the event of spillage, operators should put on gloves, face mask, eye protection and disposable apron and mop up the spilled material with an absorbent material kept in the area for that purpose. The area should then be cleaned and all contaminated material transferred to a cytotoxic spillage bag or bin and sealed for incineration.

Contamination

Fluorouracil is an irritant, contact with skin and mucous membranes should be avoided.

In the event of contact with the skin or eyes, the affected area should be washed with copious amounts of water or normal saline. Hydrocortisone cream 1% may be used to treat the transient stinging of the skin. Medical advice should be sought if the eyes are affected or if the preparation is inhaled or ingested.

First Aid

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

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

Inhalation, Ingestion: Seek medical advice.

Preparation Guidelines

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

b) Operations such as reconstitution of powder and transfer to syringes should be carried out only in the designated area.

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

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

e) Refer to local guidelines before commencing.

Disposal

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

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

Instruction for Use

Diluents

Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C with Glucose 5% or Sodium Chloride 0.9% Injection or Water for Injections at concentration 0.98 mg/ml of fluorouracil.

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

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

The remainder of solutions should be discarded after use: do not make up into multidose preparations.