Hospira UK Ltd

Fluorouracil 25 mg/ml Solution for Injection or Infusion

Each 1 ml of the solution contains 25 mg of fluorouracil (present as sodium salt).

Excipients: contains 7 mmol (160 mg) sodium per 1g dose.

For a full list of excipients, see section 6.1

Solution for injection or infusion.

Clear, colourless or slightly yellow solution.

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

Routes of Administration:

Selection of an appropriate dose and treatment regime depends 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 1 gram. It is customary to calculate the dose in accordance with the patient's actual bodyweight unless there is obesity, oedema or some form of abnormal fluid retention such as ascites. Ideal weight is used as the basis for calculation in such cases. The initial dose should be reduced by one-third to one half 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 may be used in combination with other cytotoxic chemotherapeutic agents; however, fluorouracil injection should not be mixed directly in the same container with other chemotherapeutic agents or intravenous additives.

Fluorouracil Injection BP can be given by intravenous injection or infusion or intra-arterial regional perfusion.

Adults:

The following regimen 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 but not more than 1 g per infusion diluted in 300 – 500 ml of 5% glucose or 0.9% sodium chloride injection given 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 or a total dose of 12 – 15 g has been reached.

Intravenous Injection:

12 mg/kg bodyweight may be given daily for 3 days and then, if there is no evidence of toxicity, 6 mg/kg on alternate days for 3 further doses. An alternative regimen is 15 mg/kg as a single intravenous injection once a week throughout the course.

Intra-arterial Infusion:

5 - 7.5 mg/kg bodyweight 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.

The initial course of fluorouracil can be repeated after an interval of 4 to 6 weeks from the last dose or, alternatively, treatment can be continued with intravenous injections of 5 – 15 mg/kg bodyweight at weekly intervals.

This sequence constitutes a course of therapy. Some patients have received up to 30 g at a maximum rate of 1 g daily.

A more recent alternative method is to give 15 mg/kg IV once a week throughout the course of treatment. This obviates the need for an initial period of daily administration.

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.

Children:

No recommendations are made regarding the use of fluorouracil in children.

Elderly:

Fluorouracil should be used in the elderly with similar considerations as in younger adults, notwithstanding that the incidence of concomitant medical illness is higher in the former group.

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

• Serious liver impairment

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

• Fluorouracil (5-FU) must not be given to patients homozygotic for dihydropyrimidine dehydrogenase (DPD)

• Fluorouracil is strictly contraindicated in pregnant or breast feeding women

It is recommended that fluorouracil be given only 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 7th and 14th day of the first course, but occasionally being delayed for as long as 20 days. The count usually returns to normal by the 30th 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 haemorrage 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. Treatment should be stopped in case of severe toxicity.

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.

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

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

Combination of 5-fluorouracil and folinic acid

The toxicity profile of 5-fluorouracil may be enhanced or shifted by folinic acid. The most common manifestations are leucopenia, mucositis, stomatitis and/or diarrhoea which may be dose limiting. When 5-fluorouracil and folinic acid are used in combination, the fluorouracil dosage must be reduced more in cases of toxicity than when fluorouracil is used alone. Toxicities observed in patients treated with the combination are qualitatively similar to those observed in patients treated with 5-fluorouracil alone.

Gastrointestinal toxicities are observed more commonly and may be more severe or even life threatening (particularly stomatitis and diarrhoea). In severe cases, 5-fluorouracil and folinic acid must be withdrawn, and supportive intravenous therapy initiated. Patients should be instructed to consult their treating physician immediately if stomatitis (mild to moderate ulcers) and/or diarrhoea (watery stools or bowel movements) two times per day occur.

Particular care should be taken in the treatment of elderly or debilitated patients, as these patients may be at increased risk of severe toxicity.

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.

This medicinal product contains 7 mmol (160 mg) sodium per 1 gram dose. To be taken into consideration by patients on a controlled sodium diet.

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

Both the efficacy and toxicity of 5-fluorouracil may be increased when 5-fluorouracil is used in combination with folinic acid. Side effects may be more pronounced and severe diarrhoea may occur. Life-threatening diarrhoeas have been observed if 600 mg/m² of fluorouracil (i.v. bolus once weekly) is given together with folinic acid.

In combination with other myelosuppressive substances, dosage adjustment is necessary. Concomitant or previous radiation therapy may require dosage reduction. The cardiotoxicity of anthracyclines may be increased.

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 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. Nucleoside analogues, e.g. brivudin and sorivudin, may induce an increase in plasma concentrations of 5-FU or other fluoropyrimidines accompanied by toxicological reactions. Therefore, a time interval of minimum 4 weeks between administration of fluorouracil and brivudin, sorivudin and analogues should be kept.

If applicable, determination of DPD enzyme activity is indicated prior to treatment with 5- fluoropyrimidines.

Cimetidine, metronidazole and interferon may increase the plasma level of 5-fluorouracil, thereby increasing the toxicity of 5-fluorouracil.

In patients receiving phenytoin and 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).

In patients receiving cyclophosphamide, Methotrexate and 5-fluorouracil, addition of thiazide diuretics resulted in a more pronounced decrease of the number of granulocytes when compared to patients not receiving thiazides.

Hepatotoxicity (increase in alkaline phosphatases, transaminases or bilirubin) has been observed commonly in patients receiving 5-fluorouracil in combination with levamisol.

In patients with breast cancer, combination therapy with cyclophosphamide, methotrexate, 5-fluorouracil and tamoxifen has been reported to increase the risk of thromboembolic events.

Serious, potentially life-threatening mucositis may occur following co-administration of vinorelbine and 5-fluorouracil/folinic acid.

Vaccination with live vaccines should be avoided in immunocompromised patients.

No studies on the effects on the ability to drive and use machinery have been performed.

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

Frequencies are defined using the following convention:

Very common (≥ 1/10)

Common (≥ 1/100, < 1/10)

Uncommon (≥ 1/1,000, < 1/100)

Rare (≥ 1/10,000, < 1/1,000)

Very rare (< 1/10,000)

Not known (cannot be estimated from the available data)

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.

Immune system disorders:

Very common:

Bronchospasm, immunosuppression with an increased risk of infection.

Rare:

Generalized allergic reactions, anaphylaxis, anaphylactic shock.

Endocrine disorders:

Rare:

Increase of T4 (total thyroxine). increase of T3 (total triiodthyronin)

Metabolism and nutrition disorders:

Very common

Hyperuricemia.

Psychiatric disorders:

Rare:

Confusion.

Nervous system disorders:

Uncommon:

Nystagmus, headache, dizziness, symptoms of Parkinson's disease, pyramidal signs, euphoria, somnolence

Very rare:

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

Not known:

Peripheral neuropathy may occur, epilepsy.

Eye disorders:

Uncommon

Excessive lacrimation, blurred vision, eye movement disturbance, optic neuritis, diplopia, decrease in visual acuity, photophobia, conjunctivitis, blepharitis, ectropion, dacryostenosis

Cardiac disorders:

Very common:

Ischemic ECG abnormalities.

Common:

Angina pectoris-like chest pain.

Uncommon:

Arrhythmia, myocardial infarction, myocardial ischemia, myocarditis, cardiac insufficiency, dilated 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.

Not known:

intracardiac thrombus.

Vascular disorders:

Rare:

Cerebral, intestinal and peripheral ischemia, Raynaud's syndrome, thromboembolism, thrombophlebitis/ vein tracking

Uncommon:

Hypotension

Gastrointestinal disorders:

Very common:

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

Uncommon:

Dehydration, sepsis, gastrointestinal ulceration and bleeding, sloughing

Hepatobiliary disorders:

Uncommon:

liver cell damage

Very rare

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

Musculoskeletal and connective tissue disorders

Not known:

Drug-induced lupus erythematosus

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 onycholysise.

Reproductive system and breast disorder:

Uncommon:

Spermatogenesis and ovulation disorder

General disorders and administration site conditions:

Very common:

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

Not Known:

Fever

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

E-mail: medsafety@hpra.ie

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.

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 Cerebrospinal Fluid (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 by the usual body mechanisms for uracil.

Fluorouracil has been shown to be carcinogenic in animals (see 4.4)

Sodium Hydroxide

Water for Injections

Fluorouracil is incompatible with carboplatin, cisplatin, cytarabine, diazepam, doxorubicin, other anthracyclines and possibly methotrexate.

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

Unopened: 2 years

Chemical and physical in-use stability has been demonstrated for 5 days at 20-21°C when diluted with 0.9% Sodium Chloride Injection and 5% Glucose Injection.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Do not store above 25°C. Do not refrigerate or freeze. Keep the vials in the outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

Fluorouracil 25 mg/ml Injection is presented in Type I conventional clear glass vials with 1704 rubber stoppers and Type I clear ONCO-TAIN^® vials with rubber stoppers.

Fluorouracil 25 mg/ml Injection is available in the following pack sizes: 10 ml, 20 ml and 100 ml, and in packs of 1, 5 and 10 vials.

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 8.6 to 9.0.

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.

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 instructions on administration, see Section 4.2.

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 the 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 cytotoxic guidelines before commencing.

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 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.

Instructions for Use

Diluents

Fluorouracil Injection B.P. may be diluted with Glucose 5% or Sodium Chloride 0.9% Injection B.P. or Water for Injections B.P. immediately before parenteral use. The remainder of solutions should be discarded after use: do not make up into multidose preparations.

Hospira UK Limited,

Horizon,

Honey Lane,

Hurley,

Maidenhead,

SL6 6RJ,

United Kingdom

PA 437/11/1

Date of first authorisation: 22 May 1986

Date of last renewal: 08 December 2010

04/2017

Ref: gxFU 1_1