FLUOROURACIL 25 MG / ML INJECTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Fluorouracil 25 mg/ml Injection.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 ml contains 25mg of fluorouracil.

Presentations       250mg / 10ml       500mg / 20ml       2.5g / 100ml

Amount           250mg           500mg           2.5g

fluorouracil present (as sodium salt) per vial

Excipient with known effect

Fluorouracil 250 mg/10 ml contains 40.1 mg of sodium in each vial.

Fluorouracil 500 mg/20 ml contains 80.2 mg of sodium in each vial.

Fluorouracil 2.5 g/100 ml contains 401 mg of sodium in each vial.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

4.1.   Therapeutic indications

4.3 Contraindications

Fluorouracil is contraindicated in patients who/ with:

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

Are seriously debilitated

Are suffering from bone marrow depression after radiotherapy or treatment with other antineoplastic a­gents

Are suffering from a potentially serious infection

Have a poor nutritional state

Are pregnant or breast feeding

Have a known complete absence of dihydropyrimidine dehydrogenase (DPD) activity (see section 4.4)

Have been treated with brivudine, sorivudine or their chemically related analogues, which are potent inhibitors of the enzyme dihydropyrimidine dehydrogenase (DPD), which degrades fluorouracil (see section 4.5). Fluorouracil must not be taken within 4 weeks of treatment with brivudine, sorivudine or their chemically related analogues.

Fluorouracil should not be used in the management of non-malignant disease.

4.4 Special warnings and precautions for use

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.

All patients should be admitted to hospital for initial treatment.

The most pronounced and dose-limiting toxic effects of fluorouracil are on the normal, rapidly proliferating cells of the bone marrow and the lining of the gastrointestinal tract. The immunosuppressive effect of fluorouracil may cause a higher incidence of microbial infections, delayed wound healing and bleeding of the gums.

Haematological effects

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.

Gastrointestinal effects

Treatment should be stopped at the first sign of oral ulceration or if there is evidence of gastrointestinal side effects such as stomatitis, diarrhoea or bleeding from the gastrointestinal tract or haemorrhage at any site, oesophagopharyn­gitis or intractable vomiting. Fluorouracil should be resumed only when the patient has recovered from the above signs. 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.

Radiotherapy

Fluorouracil treatment may potentiate necrosis caused by radiation.

Special risk patients

Fluorouracil should be used with extreme caution in poor risk patients who have recently undergone surgery, have a history of high-dose irradiation of bone marrowbearing areas (pelvis, spine, ribs, etc.) or prior use of another chemotherapeutic agent causing myelosuppression, have a widespread involvement of bone marrow by metastatic tumours, or those with reduced renal or liver function, jaundice or who have a poor nutritional state. Severe toxicity and fatalities are more likely in poor risk patients, but have occasionally occurred in patients who are in relatively good condition. Any form of therapy which adds to the stress of the patient, interferes with nutritional uptake or depresses the bone marrow function, will increase the toxicity of fluorouracil. If therapy is continued careful monitoring of the patient is required.

Cardiotoxicity

Cardiotoxicity has been associated with fluoropyrimidine therapy, including myocardial infarction, angina, arrhythmias, myocarditis, cardiogenic shock, sudden death and electrocardio­graphic changes (including very rare cases of QT prolongation). These adverse events are more common in patients receiving continuous infusion of 5-fluorouracil rather than bolus injection. Prior history of coronary artery disease may be a risk factor for cardiac adverse reactions. Care should therefore be exercised in treating patients who experienced chest pain during courses of treatment, or patients with a history of heart disease. Careful consideration should be given to re-administration of Fluorouracil after a documented cardiovascular reaction (arrhythmia, angina, ST segment changes) as there is a risk of sudden death. Cardiac function should be regularly monitored during treatment with fluorouracil. In case of severe cardiotoxicity the treatment should be discontinued.

Immunosuppressant effects/Increased susceptibility to infections

Vaccination with a live vaccine should be avoided in patients receiving 5-fluorouracil due to the potential for serious or fatal infections. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished. Contact should be avoided with people who have recently been treated with polio virus vaccine.

Patients with leukaemia who are in remission should not receive vaccines containing weakened viruses until three months has elapsed since their last chemotherapy session. Furthermore, immunisation with orally administered vaccines containing the poliomyelitis virus must be postponed for those persons coming into direct contact with the patient, particularly family members.

Hand-foot syndrome

The administration of fluorouracil has been associated with the occurrence of palmarplantar erythrodysesthesia syndrome, also known as hand-foot syndrome.

Continuous-infusion fluorouracil may increase the incidence and severity of palmarplantar erythrodysesthesia. This syndrome has been characterized as a tingling sensation of hands and feet, which may progress over the next few days to pain when holding objects or walking. The palms and soles become symmetrically swollen and erythematous with tenderness of the distal phalanges, possibly accompanied by desquamation. Interruption of therapy is followed by gradual resolution over 5 to 7 days. Supplementation of chemotherapy with oral pyridoxine has been reported to prevent or resolve such symptoms.

Encephalopathy

Cases of encephalopathies (including hyperammonaemic encephalopathy, leukoencephalo­pathy) associated with 5-fluorouracil treatment have been reported from post-marketing sources. Signs or symptoms of encephalopathy are altered mental status, confusion, disorientation, coma or ataxia. If a patient develops any of these symptoms withhold treatment and test serum ammonia levels immediately. In case of elevated serum ammonia levels initiate ammonia-lowering therapy.

Caution is necessary when administering fluorouracil to patients with renal and/or hepatic impairment. Patients with impaired renal and/or hepatic function may have an increased risk for hyperammonaemia and hyperammonaemic encephalopathy.

Dihydropyrimidine dehydrogenase (DPD) deficiency

DPD activity is rate limiting in the catabolism of 5-fluorouracil (see section 5.2). Patients with DPD deficiency are therefore at increased risk of fluoropyrimidines-related toxicity, including for example stomatitis, diarrhoea, mucosal inflammation, neutropenia and neurotoxicity.

DPD-deficiency related toxicity usually occurs during the first cycle of treatment or after dose increase.

Complete DPD deficiency

Complete DPD deficiency is rare (0.01–0.5% of Caucasians). Patients with complete DPD deficiency are at high risk of life-threatening or fatal toxicity and must not be treated with Fluorouracil injection (see section 4.3).

Partial DPD deficiency

Partial DPD deficiency is estimated to affect 3–9% of the Caucasian population. Patients with partial DPD deficiency are at increased risk of severe and potentially life-threatening toxicity. A reduced starting dose should be considered to limit this toxicity. DPD deficiency should be considered as a parameter to be taken into account in conjunction with other routine measures for dose reduction. Initial dose reduction may impact the efficacy of treatment. In the absence of serious toxicity, subsequent doses may be increased with careful monitoring.

Testing for DPD deficiency

Phenotype and/or genotype testing prior to the initiation of treatment with Fluorouracil injection is recommended despite uncertainties regarding optimal pretreatment testing methodologies. Consideration should be given to applicable clinical guidelines.

Genotypic characterisation of DPD deficiency

Pre-treatment testing for rare mutations of the DPYD gene can identify patients with DPD deficiency.

The four DPYD variants c.1905+1G>A [also known as DPYD*2A], c.1679T>G [DPYD*13], c.2846A>T and c.1236G>A/HapB3 can cause complete absence or reduction of DPD enzymatic activity. Other rare variants may also be associated with an increased risk of severe or life-threatening toxicity.

Certain homozygous and compound heterozygous mutations in the DPYD gene locus (e.g. combinations of the four variants with at least one allele of c.1905+1G>A or c.1679T>G) are known to cause complete or near complete absence of DPD enzymatic activity.

Patients with certain heterozygous DPYD variants (including c.1905+1G>A, c.1679T>G, c.2846A>T and c.1236G>A/HapB3 variants) have increased risk of severe toxicity when treated with fluoropyrimidines.

The frequency of the heterozygous c.1905+1G>A g­enotype in the DPYD gene in Caucasian patients is around 1%, 1.1% for c.2846A>T, 2.6–6.3% for c.1236G>A/HapB3 variants and 0.07 to 0.1% for c.1679T>G.

Data on the frequency of the four DPYD variants in other populations than Caucasian is limited. At the present, the four DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T and c.1236G>A/HapB3) are considered virtually absent in populations of African (-American) or Asian origin.

Phenotypic characterisation of DPD deficiency

For phenotypic characterisation of DPD deficiency, the measurement of pre-therapeutic blood levels of the endogenous DPD substrate uracil (U) in plasma is recommended.

Elevated pre-treatment uracil concentrations are associated with an increased risk of toxicity. Despite uncertainties on uracil thresholds defining complete and partial DPD deficiency, a blood uracil level > 16 ng/ml and < 150 ng/ml should be considered indicative of partial DPD deficiency and associated with an increased risk for fluoropyrimidine toxicity. A blood uracil level > 150 ng/ml should be considered indicative of complete DPD deficiency and associated with a risk for life-threatening or fatal fluoropyrimidine toxicity.

5-F'luorouracil Therapeutic drug monitoring (TDM)

TDM of 5-fluorouracil may improve clinical outcomes in patients receiving continuous 5-fluorouracil infusions by reducing toxicities and improving efficacy. AUC is supposed to be between 20 and 30mg x h/L.

Nucleoside analogues, e.g. Brivudine and sorivudine, 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 Brivudine, sorivudine 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.

Photosensitivity reactions:

Some patients may experience photosensitivity reactions following administration of fluorouracil, it is recommended that patients are warned to avoid prolonged exposure to sunlight (see section 4.8).

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 of the nervous system and visual changes which could interfere with driving or the usage of heavy machinery.

4.8 Undesirable effects

The following undesirable effects have been observed and reported during treatment with Fluorouracil Injection with the following frequencies:

Very common (>1/10);

Common (>1/100 to <1/10);

Uncommon (>1/1,000 to <1/100);

Rare (>1/10,000 to <1/1,000);

Very rare (<1/10,000);

Frequency not known (cannot be estimated from the available data).

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

The possibility of overdosage with fluorouracil is unlikely in view of the mode of administration. High dosages or prolonged treatment with fluorouracil can result in life-threatening intoxication symptoms such as; nausea, vomiting, diarrhoea, gastrointestinal ulceration and bleeding, bone marrow depression (including thrombocytopenia, leukopenia, agranulocytosis).

Uridine triacetate is a specific antidote for the treatment of 5-fluorouracil overdose or the treatment of severe early-onset toxicities. It should be administered within 96 hours after end of 5-fluorouracil infusion. In the event uridine triacetate is not available, treatment is symptomatic and supportive.

Patients in which an overdose of fluorouracil is detected should be closely monitored haematologically for at least 4 weeks.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents; Antimetabolites; 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 can also be incorporated into RNA, resulting in formation of defective RNA.

5.2 Pharmacokinetic properties

Absorption and Distribution

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.

Biotransformation

5-fluorouracil is catabolised by the enzyme dihydropyrimidine dehydrogenase (DPD) to the much less toxic dihydro-5-fluorouracil (FUH2). Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureidopropionic acid (FUPA). Finally, P—ureido— propionase cleaves FUPA to a—fluoro—P— alanine (FBAL) which is cleared in the urine.

Dihydropyrimidine dehydrogenase (DPD) activity is the rate limiting step. Deficiency of DPD may lead to increased toxicity of 5-fluorouracil (see section 4.3 and 4.4).

Elimination

Following I.V. administration, the plasma elimination half-life averages about 16 minutes and is dose dependent. Following a single I.V. 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.

Special populations

In patients with hepatic or renal failure, biotransformation and/or elimination of fluorouracil is reduced, requiring a reduction in dose rate (see sections 4.2 and 4.4).

5.3. Preclinical safety data

Preclinical information has not been included because the toxicity profile of fluorouracil has been established after many years of clinical use. Please refer to section 4.

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Sodium hydroxide

Water for Injections.

6.2 Incompatibilities

Admixtures with acidic drugs or drugs that are unstable in the presence of alkali should be avoided. Fluorouracil is reported to be incompatible with cytarabine, diazepam, methotrexate, platinum compounds, doxorubicin (and presumably other anthracyclines that are unstable at alkaline pH), and calcium folinate (leucovorin).

6.3. Shelf life

Before use: 24 months

In use: Chemical and physical in-use stability has been demonstrated for 5 days at 20–21°C.

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 not normally be longer than 24 hours at 2–8 °C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4. Special precautions for storage

Do not store above 25°C. Do not refrigerate or freeze. Keep container in the outer carton.

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.

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

6.5 Nature and contents of container

Type I Conventional Clear Glass Vials with rubber closures.

Type I Clear Onco-Tain® Vials with rubber closures.

250 mg/10ml: Pack Size 5.

500 mg/20ml: Pack Size 10.

2.5 g/100 ml: Pack Size Singles and 10’s.

Not all presentations or pack sizes may be marketed.

6.6 Special precautions for disposal

Cytotoxic Handling Guidelines

Should be administered only by or under the direct supervision of a qualified physician who is experienced in the use of cancer chemotherapeutic agents.

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. A bland cream 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.

Please refer to company for COSHH hazard datasheets.

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 under aseptic conditions in a suite or cabinet dedicated for the assembly of cytotoxics.

c) The personnel carrying out these procedures should be adequately protected with clothing, gloves and eye shield.

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

Disposal

Syringes, Onco^Vials® and adaptors containing remaining solution, absorbent materials, and any other contaminated material should be placed in a thick plastic bag or other impervious container and incinerated at 700°C.

Diluents

Fluorouracil Injection may be diluted with Glucose 5% Injection or Sodium Chloride 0.9% Injection or Water for Injections immediately before parenteral use.

7.

8.

Hospira UK Limited

Horizon

Honey Lane

Hurley

Maidenhead

SL6 6RJ

UK

PL: 04515/0024.

Date of First Authorisation: 20 August 1985

Date of latest renewal: 19 July 2004