Fluorouracil 50 mg/ml Solution for Injection or Infusion

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 1 g of Fluorouracil.

Each 50 ml vial contains 2.5 g of Fluorouracil.

Each 100 ml vial contains 5 g of Fluorouracil.

For a full list of excipients, see section 6.1.

Solution for Injection or Infusion.

A clear colourless solution with a pH in the range of 8.5 to 9.1.

Fluorouracil Injection may be used alone or in combination, for its palliative action in the management of common malignancies particularly cancer of the colon, and breast.

Selection of an appropriate dose and treatment regime depend upon the condition of the patient, the type of carcinoma being treated and whether Fluorouracil is to be administered alone or in combination with other therapy. Initial treatment should be given in hospital and the total daily dose should not exceed 1gram. It is customary to calculate the dose in accordance with patient's actual weight unless there is obesity, oedema or some other form of abnormal fluid retention such as ascites. In this case, ideal weight is used as the basis for calculation.

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

Fluorouracil Injection can be given by intravenous injection or, intravenous or intra-arterial infusion.

ADULT DOSE

The following regimens have been recommended for use as a single agent¬.

Initial Treatment:

This may be in the form of an infusion or an injection, the former usually being preferred because of lesser toxicity.

Intravenous Infusion:

15 mg/kg bodyweight or 600 mg /m2 but not more than 1 g per infusion, diluted in 500 ml of 5% glucose or 0.9% NaCl injection and given by intravenous infusion at a rate of 40 drops per minute over 4 hours. Alternatively the daily dose may be infused over 30-60 minutes or may be given as a continuous infusion over 24 hours. The infusion may be repeated daily until there is evidence of toxicity (stomatitis, diarrhoea, leucopenia or thrombocytopenia) or a total dose of 12-15 g has been reached.

Intravenous Injection:

12 mg/kg bodyweight or 480 mg/m2 may be given daily for 3 days and then, if there is no evidence of toxicity (stomatitis, diarrhoea, leucopenia or thrombocytopenia), 6 mg/kg or 240 mg/m2 on alternate days for 3 further doses (day 5-7-9). An alternative regime is 15 mg/kg as a single intravenous injection once a week throughout the course.

Intra-arterial Infusion:

5/7.5 mg/kg bodyweight or 200-300 mg/m2 daily may be given by 24 hour continuous intra-arterial infusion.

Maintenance Therapy:

An initial intensive course may be followed by maintenance therapy providing there are no significant toxic effects. In all instances, toxic side effects must disappear before maintenance therapy is started.

Treatment can be continued with intravenous injections of 5 – 10 mg/kg bodyweight or 200-400 mg /m2 at weekly intervals.

In combination with Irradiation:

Irradiation combined with 5-FU has been found to be useful in the treatment of certain types of metastatic lesions in the lungs and for the relief of pain caused by recurrent, inoperable growth. The standard dose of 5-FU should be used.

Combination with other cytostatic agents:

Fluorouracil can be used with other cytostatic agents. In this case the standard dose is reduced.

Special populations

Renal or hepatic impairment

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

CHILDREN

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

ELDERLY

No dosage adjustment necessary.

Hypersensitivity to the Fluorouracil or to any of the excipients.

Fluorouracil is contraindicated in the following

• Serious infections (e.g. Herpes zoster, chickenpox).

• Seriously debilitated patients.

• Bone marrow depression after radiotherapy or treatment with other antineoplastic agents.

• Management of non-malignant disease

5-Fluorouracil (5-FU) must not be given in combination with brivudin, sorivudin and analogues. Brivudin, sorivudin und analogues are potent inhibitors of the 5-FU-metabolising enzyme dihydropyrimidine dehydrogenase (DPD) (see section 4.4 and 4.5).

Fluorouracil is strictly contraindicated in pregnant or breast feeding women.

It is recommended that Fluorouracil should only be given by, or under the strict supervision of, a qualified physician who is conversant with the use of potent antimetabolites and has the facilities for regular monitoring of clinical, biochemical and haematological effects during and after administration.

All patients should be admitted to hospital for initial treatment.

Adequate treatment with Fluorouracil is usually followed by leucopenia, the lowest white blood cell (W.B.C.) count commonly being observed between the 7^th and 14^th day of the first course, but occasionally being delayed for as long as 20 days. The count usually returns to normal by the 30^th day. Daily monitoring of platelet and W.B.C. count is recommended and treatment should be stopped if platelets fall below 100,000 per mm³ or the W.B.C. count falls below 3,500 per mm³. If the total count is less than 2000 per mm³, and especially if there is granulocytopenia, it is recommended that the patient be placed in protective isolation in the hospital and treated with appropriate measures to prevent systemic infection.

Treatment should also be stopped at the first sign of oral ulceration or if there is evidence of gastrointestinal side effects such as stomatitis, diarrhoea, bleeding from the G.I. tract or haemorrhage at any site. The ratio between effective and toxic dose is small and therapeutic response is unlikely without some degree of toxicity. Care must be taken therefore, in the selection of patients and adjustment of dosage.

Fluorouracil should be used with caution in patients with reduced renal or liver function or jaundice. Isolated cases of angina, ECG abnormalities and rarely, myocardial infarction have been reported following administration of Fluorouracil. Care should therefore be exercised in treating patients who experience chest pain during courses of treatment, or patients with a history of heart disease.

Dihydropyrimidine dehydrogenase (DPD) plays an important role in the metabolism of fluorouracil. There have been reports of increased fluorouracil toxicity in patients who have reduced activity/deficiency of DPD. If applicable, determination of DPD enzyme activity is indicated prior to the treatment with 5-fluoropyrimidines.

Nucleoside analogues, e.g. brivudin and sorivudin, which affect DPD activity may cause increased plasma concentrations and increased toxicity of fluoropyrimidines (see section 4.5). Therefore, an interval of at least 4 weeks between administration of fluorouracil and brivudin, sorivudin or analogues should be kept. In the case of accidental administration of nucleoside analogues to patients treated with fluorouracil, effective measures should be taken to reduce fluorouracil toxicity. Immediate hospitalisation is recommended. Any measure to prevent systemic infections and dehydration should be commenced.

Vaccination with a live vaccine should be avoided in patients receiving 5-fluorouracil due to the potential for serious or fatal infections. Contact should be avoided with people who have recently been treated with polio virus vaccine.

It is not advisable to prolonged exposure to sunlight because of the risk of photosensitivity.

Use with caution in patients who have had high-dose pelvic radiation.

Women of childbearing potential and men have to use effective contraception during and up to 6 months after treatment.

Patients taking phenytoin concomitantly with fluorouracil should undergo regular testing because of the possibility of an elevated plasma level of phenytoin.

Various agents have been reported to biochemically modulate the anti tumour efficacy or toxicity of Fluorouracil. Common drugs include methotrexate, metronidazole, leucovorin interferon alfa and allopurinol.

Fluorouracil should be avoided in combination with clozapine due to increased risk of agranulocytosis.

Increased incidence of cerebral infarction has been reported in oropharyngeal cancer patients treated with 5-Fluorouracil and cisplatin.

Marked elevations of prothrombin time and INR have been reported in a few patients stabilised on warfarin therapy following initiation of Fluorouracil regimes.

The enzyme dihydropyrimidindehydrogenase (DPD) plays an important role in the metabolism of Fluorouracil. Medicinal products that affect DPD activity, such as the nucleoside analogues brivudin, sorivudin and chemically related analogues, may cause marked increases in fluorouracil plasma concentrations and thereby increase toxicity. A time interval of minimum 4 weeks between the intake of fluorouracil and brivudin, sorivudin and analogues is recommended (see section 4.4).

Cimetidine has been reported to increase plasma concentrations of Fluorouracil, possibly by reduced hepatic metabolism.

In patients receiving phenytoin and 5-Fluorouracil concomitantly, an increase of phenytoin plasma concentration has been reported resulting in symptoms of phenytoin toxicity.

Fluorouracil enhances the action of other cytostatic drugs and irradiation therapy (see section 4.2).

Vaccination with live vaccines should be avoided in immunocompromised patients.

Women of childbearing potential should be advised to avoid becoming pregnant and use an effective method of contraception during treatment with Fluorouracil and up to 6 months afterwards (see section 4.4). If the drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be fully informed of the potential hazard to the foetus and genetic counsellation is recommended. Fluorouracil should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

There are no adequate and well-controlled studies in pregnant women, however, fatal defects and miscarriages have been reported.

Men treated with Fluorouracil are advised not to father a child during and for up to 6 months following cessation of treatment (see section 4.4). Advice on conservation of sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with Fluorouracil.

Since it is not known whether Fluorouracil passes into breast milk, breast-feeding must be discontinued if the mother is treated with Fluorouracil.

Fluorouracil may induce side effects such as nausea and vomiting. It can also produce adverse event on nervous system and visual changes which could interfere driving or the usage of heavy machinery.

Frequencies are defined using the following convention:

Very common (1/10),

Common ( 1/100 to < 1/10),

Uncommon ( 1/1000 to < 1/100),

Rare ( 1/10000 to < 1/1000),

Very rare (< 1/10000),

Not known (cannot be estimated from the available data).

Cardiac disorders:

Very common

Common

Angina pectoris-like chest pain.

Uncommon

Arrhythmia, myocardial infarction, myocardial ishchemia myocarditis, heart insufficiency, dilative cardiomyopathy, cardiac shock.

Very rare

Cardiac arrest, sudden cardiac death

Cardiotoxic adverse events mostly occur during or within hours following the first treatment cycle. There is an increased risk of cardiotoxicity in patients with previous coronary heart disease or cardiomyopathy.

Blood and lymphatic system disorders:

Very common

Myelosuppression (Onset: 7-10 days, Nadir: 9-14 days, Recovery: 21-28 days), neutropenia, thrombocytopenia, leucopenia, agranulocytosis, anaemia and pancytopenia.

Psychiatric disorders:

Rare:

Confusion.

Nervous system disorders:

Uncommon

Very rare

Symptoms of leucoencephalopathy including ataxie, Acute cerebellar syndrome, dysarthrie, confusion, disorientation, myasthenia, aphasia, convulsion or coma in patients receiving high doses of 5-fluorouracil and in patients with dihydropyrimidine dehydrogenase deficiency, kidney failure.

Eye disorders:

Uncommon

Gastrointestinal disorders:

Very common

Gastrointestinal adverse events are very common and may be life-threatening. Mucositis (stomatitis, eosophagitis, pharyngitis, proctitis), anorexia, watery diarrhoea, nausea, vomiting.

Uncommon

Skin and subcutaneous tissue disorders:

Very common

Alopecia.

Palmar-plantar erythrodysaesthesia syndrome (hand-foot syndrome) has been noted with protracted and high dose continuous infusion.

The syndrome begins with dysaesthesia of the palms and soles that progress to pain and tenderness. There is associated symmetrical swelling and erythema of the hand and foot.

Uncommon

Dermatitis, skin alterations (e.g. dry skin, fissure erosion, erythema, pruritic maculopapular rash), exanthema, urticaria, photosensitivity, hyperpigmentation of the skin, streaky hyperpigmentation or depigmentation near the veins. Changes in the nails (e.g. diffuse superficial blue pigmentation, hyperpigmentation, nail dystrophy, pain and thickening of the nail bed, paronychia) and onycholyse.

Metabolism and nutrition disorders:

Very common

Hyperuricaemia.

Vascular disorders:

Rare

Uncommon

Hypotension

General disorders and administration site conditions:

Very common

Delayed wound healing, epistaxis, fatigue, general weakness, tiredness, lack of energy.

Immune system disorders:

Very common

Bronchospasm, immunosuppression with an increased risk of infection.

Rare

Generalized allergic reactions, anaphylaxis, anaphylactic shock.

Hepatobiliary disorders:

Uncommon

liver cell damage

Very rare

Liver necrosis (cases with fatal outcome), Biliary sclerosis, Cholecystitis

Reproductive system and breast disorder:

Uncommon

Spermatogenesis and ovulation disorder

Endocrine disorders:

Rare:

Increase of T4 (total thyroxin), increase of T3 (total trijodthyronin).

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).

No specific antidotal therapy exists.

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.

Pharmacotherapeutic group: Pyrimidine analogues

ATC code: L01BC02.

Fluorouracil is an analogue of uracil, a component of ribonucleic acid. The drug is believed to function as an antimetabolite. After intracellular conversion to the active deoxynucleotide, it interferes with the synthesis of DNA by blocking the conversion of deoxyuridylic acid to thymidylic acid by the cellular enzyme thymidylate synthetase. Fluorouracil may also interfere with RNA synthesis.

After intravenous administration, Fluorouracil is distributed through the body water and disappears from the blood within 3 hours. It is preferentially taken up by actively dividing tissues and tumours after conversion to its nucleotide. Fluorouracil readily enters the C.S.F. and brain tissue.

Following IV administration, the plasma elimination half-life averages about 16 minutes and is dose dependant. Following a single IV dose of Fluorouracil approximately 15 % of the dose is excreted unchanged in the urine within 6 hours; over 90% of this is excreted in the first hour. The remainder is mostly metabolised in the liver to inactive metabolites by the usual body mechanisms for uracil. Hepatic impairment may result in slower metabolism of Fluorouracil and may require dose adjustment

Preclinical information has not been included, as the clinical toxicity profile of fluorouracil has been established after many years of clinical use.

Sodium hydroxide (For pH adjustment)

Hydrochloric acid (For pH adjustment)

Water for Injections

Fluorouracil is incompatible with Calcium folinate, Carboplatin, Cisplatin, Cytarabine, Diazepam, Doxorubicin, Droperidol, Filgrastim, Gallium nitrate, Methotrexate, Metoclopramide, Morphine, Ondansetrone, parenteral nutrition, Vinorelbin, other Anthracyclines.

Formulated solutions are alkaline and it is recommended that admixture with acidic drugs or preparations should be avoided.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Shelf life of unopened vial:

2 years.

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 B.P or Water for Injections B.P 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 and would normally not be longer than 24 hours at 2-8°C, unless dilution has taken place in controlled and validated aseptic conditions.

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

Keep container in the outer carton in order to protect from light.

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 Ph.Eur Type I clear glass vials with rubber closure.

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

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

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

Fluorouracil Injection 50 mg/ml, 100ml is filled in 100 ml Ph.Eur 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.

The pH of Fluorouracil Injection is 8.9 and the drug has maximal stability over the pH range 8.5 and 9.1.

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

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.

Administration

For instruction on administration, see section 4.2.

Preparation (guidelines):

Contamination

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.

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.

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.

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.

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.

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 B.P or Water for Injections B.P 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 and would normally not be longer than 24 hours at 2-8°C, unless dilution has taken place in controlled and validated aseptic conditions.

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.

Accord Healthcare Limited,

319, Pinner Road,

North Harrow,

Middlesex, HA1 4HF,

United Kingdom

PL 20075/0078

10/06/2009

24/07/2011