New Zealand - English - Medsafe (Medicines Safety Authority)
NEW ZEALAND DATA SHEET
1. PRODUCT NAME
Fluorouracil 25 mg/ml Solution for injection.
Fluorouracil 50 mg/ml Solution for injection.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each mL of DBL
Fluorouracil containing 25 mg or 50 mg of fluorouracil.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Solution for injection.
DBL™ Fluorouracil Injection BP is a clear, colourless to slightly yellow solution.
Fluorouracil is a sterile preservative free solution of 5-Fluorouracil in Water for
Injection, prepared with the aid of Sodium Hydroxide.
The pH of the solution is approximately 8.9.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Fluorouracil Injection is indicated alone or in combination for the palliative
treatment of malignant tumours, particularly of the breast, colon or rectum; and in the
treatment of gastric, primary hepatic, pancreatic, uterine (cervical particularly), ovarian
and bladder carcinomas.
4.2 Dose and method of administration
The dosage being based on the patient's actual weight. Ideal weight is used only if the
patient is obese or if there has been a spurious weight gain due to oedema, ascites or other
forms of abnormal fluid retention.
The total daily dose of fluorouracil should not exceed 1 gram. The initial recommended
doses should be reduced by one third to a half if any of the following conditions are
poor nutritional state
after major surgery (within previous 30 days)
inadequate bone marrow function (W.B.C. count less than 5,000 per mm³; platelet
count less than 100,000 per mm
impaired hepatic and/or renal function.
The following regimes have been recommended for use of fluorouracil as a single agent
15 mg/kg bodyweight (to a maximum of 1 g daily) diluted in 300-500mL of 5% glucose
given over a period of 4 hours. The infusion may be repeated daily until the first
gastrointestinal side effects appear (stomatitis, diarrhoea, leucopenia, thrombocytopenia).
Treatment must be discontinued until the side effects have receded (until the W.B.C.
count has risen to 3,000 - 4,000 per mm³ and the platelet count to 80,000 - 100,000 per
). The patient may then be placed on a maintenance therapy programme.
12 mg/kg bodyweight daily for 3 consecutive days.
Providing there are no signs of toxic effects, the patient may then be given 6mg/kg I.V.
on the 5
If after the 9
day there is still no sign of toxicity, the patient may be placed on
maintenance therapy is started.
5 - 10 mg/kg bodyweight by I.V. injection once a week. Toxic symptoms seldom occur
during maintenance therapy. If, however, they do appear, therapy must be discontinued
until the symptoms regress.
Methods of Administration
Fluorouracil may be used in combination with other cytostatic agents or radiotherapy. In
such cases doses should be correspondingly reduced. DBL
Fluorouracil Injection may
also be administered as a 24 hour intra-arterial continuous drip infusion (5 - 7. mg/kg
Fluorouracil is contraindicated in patients who are debilitated, who are suffering from
bone marrow depression following radiotherapy or therapy with other antineoplastic
agents, and in patients who are pregnant.
Fluorouracil must not be taken within 4 weeks of treatment with brivudine, sorivudine or
their chemically related analogues. Brivudine, sorivudine and their analogues are potent
fluorouracil (see Section 4.5).
4.4 Special warnings and precautions for use
It is recommended that fluorouracil be given only by or under strict supervision of a
qualified physician who is well acquainted with the use of potent antimetabolites.
Because of the possibility of severe toxic reactions, all patients should be hospitalised, at
least during the initial course of therapy.
Fluorouracil should not be re-administered after a documented cardiovascular reaction
(arrhythmia, angina, ST segment changes) as there is a risk of sudden death.
Any form of therapy which adds to the stress of the patient, interferes with nutritional
uptake or depresses bone marrow function, will increase the toxicity of fluorouracil.
Adequate treatment with fluorouracil is usually followed by leucopenia, the lowest white
blood cell (W.B.C.) count commonly being observed between the 9
day of the
first course, but occasionally being delayed for as long as 20 days. The count usually
returns to normal by the 30
day. Daily monitoring of platelets and W.B.C. counts are
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 W.B.C. count falls below 2,000 per
mm³, it is recommended that the patient be placed in protective isolation in the hospital
and given the appropriate preventative treatment for systemic infection.
Treatment should also be discontinued at the first sign of oral ulceration or if there is
evidence of gastrointestinal side effects such as stomatitis, diarrhoea or bleeding from the
Patients taking phenytoin concomitantly with fluorouracil should undergo regular testing
because of the possibility of an elevated plasma level of phenytoin (see section 4.5).
Fluorouracil has a narrow margin of safety and is a highly toxic drug. Fluorouracil
therapy should be discontinued promptly whenever one of the following signs of toxicity
vomiting, diarrhoea, melena haemorrhage, oral ulceration, evidence of gastrointestinal
ulceration or bleeding. 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
Cytotoxic agents, including fluorouracil, may produce myelosuppression (including, but
Leucopenia and thrombocytopenia commonly follow treatment with fluorouracil.
Clinical consequences of sever myelosuppression include infections. Viral, bacterial, fungal
and/or parasitic infections, either localized or systemic, may be associated with the use of
fluorouracil alone or in combination with other immunosuppressive agents. These infections
may be mild, but can be severe and at times fatal.
There is an increased risk of death associated with re-administration of fluorouracil in
patients with a documented cardiovascular reaction (See section 4.8).
administration of fluorouracil. Attention should therefore be paid to patients who experience
chest pain during treatment, and patients with a history of heart disease.
Renal and hepatic impairment
Fluorouracil should be used with caution in patients with renal and/or hepatic dysfunction.
Dihydropyrimidine dehydrogenase deficiency
with fluorouracil has been
attributed to deficiency
dehydrogenase (DPD) activity. Fatal outcome has been reported in some cases. Absence
of this catabolic enzyme appears to result in prolonged clearance of fluorouracil. Special
May depress bone marrow function and increase the toxicity of fluorouracil. Extreme
caution is necessary when administering fluorouracil to patients who have had high dose
pelvic irradiation, or have been previously treated with alkylating agents. Fluorouracil
chemotherapeutic agents may depress bone marrow function and increase the toxicity of
fluorouracil, it is recommended that patients are warned to avoid prolonged exposure to
sunlight (see section 4.8).
Immunosuppressant effects/increased susceptibility to infections
Administration of live or live-attenuated vaccines in patients immunocompromised by
chemotherapeutic agents including fluorouracil, may result in serious or fatal infections.
Vaccination with a live vaccine should be avoided in patients receiving fluorouracil. Killed
or inactivated vaccines may be administered; however, the response to such vaccines may be
The administration of fluorouracil has been associated with the occurrence of palmar-
plantar erythrodysesthesia syndrome, also known as hand-foot syndrome. Continuous-
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
Effects on laboratory tests
Fluorouracil could interfere with diagnostic tests of thyroid function by causing rises in total
thyroxine and liothyronine due to increased globulin binding. Plasma albumin may be
decreased because of drug-induced protein malabsorption.
Use in elderly
Fluorouracil should be used with caution in elderly patients. Aged 70 years or older and
fluorouracil based chemotherapy. Close monitoring for multiple organ toxicities and
vigorous supportive care of those with toxicity are necessary.
4.5 Interaction with other medicines and other forms of interaction
: All myelosuppressive drugs (e.g., Cytotoxic agents used in combination
chemotherapy) can increase hematotoxicity of fluorouracil.
combination should be used with caution as it is reported to increase the gastrointestinal
toxicity of fluorouracil.
fluorouracil. Studies of this possibility have reported conflicting results.
Various agents have been reported to biochemically modulate the antitumour efficacy or
toxicity of fluorouracil. Common drugs include methotrexate, metronidazole, leucovorin.
Pretreatment with cimetidine prior to IV fluorouracil increased the AUC by 27%. The
total body clearance was reduced by 28%.
Increased phenytoin plasma concentrations have been reported during concomitant use of
phenytoin with capecitabine or its metabolite fluorouracil. Formal interaction studies
between phenytoin and capecitabine have not been conducted, but the mechanism of
interaction is presumed to be inhibition of CYP2C9 isoenzyme system by capecitabine.
capecitabine or fluorouracil should be regularly monitored for increased phenytoin levels
(see section 4.4).
Brivudine and sorivudine.
Brivudine, sorivudine or their chemically related analogues
irreversibly inhibit DPD, resulting in a significant increase in fluorouracil exposure. This
may lead to increased fluoropyrimidine-related toxicities with potentially fatal outcome.
Therefore, either a different antiviral therapy may be used or there should be an interval
of at least 4 weeks between the administration of brivudine, sorivudine, or the analogues
and the start of fluorouracil treatment (see Section 4.3). In the case of accidental
administration of nucleoside analogues that inhibit DPD activity to patients treated with
Immediate hospitalization is recommended.
. Radiation therapy on the bone marrow, especially to the area of the
chest and mediastinum, may potentiate the bone marrow effects of fluorouracil.
reported during concomitant use of warfarin and fluorouracil or its analogues. In these
cases, fluorouracil has usually been administered as one component of an antineoplastic
coumarin-derivative therapy should be monitored regularly in patients taking fluorouracil.
Fluorouracil treatment may interfere with some laboratory tests.
Increases in total serum thyroxine concentration (due to increased binding to globulin)
have been reported.
4.6 Fertility, pregnancy and lactation
Fluorouracil has not been adequately studied in animals to permit an evaluation of its
effects on fertility and general reproductive performance. However, doses of 125 or
250mg/kg, administered intraperitoneally, have been shown to induce chromosomal
aberrations and changes in chromosomal organisation of spermatogonia in rats.
Spermatogonial differentiation was also inhibited by fluorouracil, resulting in transient
infertility. However, in studies with a strain of mouse which is sensitive to the induction
of sperm head abnormalities after exposure to a
range of chemical mutagens
carcinogens, fluorouracil did not produce any abnormalities at oral doses of up to
80mg/kg/day. In female rats, fluorouracil, administered intraperitoneally at weekly doses
significantly reduced the incidence of fertile matings, delayed the development of pre-
and post-implantation embryos, increased the incidence of pre-implantation lethality and
induced chromosomal anomalies in these embryos. In a limited study in rabbits, a single
25mg/kg dose of fluorouracil or 5 daily doses of 5mg/kg had no effect on ovulation,
appeared not to affect implantation and had only a limited effect in producing zygote
destruction. Compounds such as fluorouracil, which interfere with DNA, RNA and
protein synthesis, might be expected to have adverse effects on gametogenesis.
In general, use of a contraceptive is recommended during cytotoxic drug therapy.
Pregnancy - Category D
This category specifies drugs which have caused an increased incidence of human fetal
Safety for use in pregnancy has not been established. Fluorouracil should only be used in
women of child bearing potential if the expected benefits outweigh the risks of therapy, and
adequate contraception is used. If the patient becomes pregnant whilst receiving the drug she
should be advised of the potential hazards on the fetus. Men undergoing fluorouracil
treatment should also ensure they use effective contraceptive measures.
Fluorouracil is therefore strictly contraindicated in pregnancy.
It is not known whether fluorouracil is excreted in breast milk. To avoid possible harmful
effects in the infant, breast-feeding is not advised during fluorouracil therapy.
4.7 Effects on ability to drive and use machines
The effect of fluorouracil on the ability to drive and use machinery has not been
4.8 Undesirable effects
The ratio between effective and toxic dose is small and therapy with fluorouracil is
usually accompanied by some degree of adverse effects. Patients should be carefully
observed and dosage adjustment may have to be made. Deaths have been reported.
Infections and Infestations
Septic shock, sepsis, neutropenic sepsis, pneumonia, superinfection, urinary tract infection,
catheter related infection, cellulitis, pharyngitis and other infections.
Blood and lymphatic system disorders
Leucopenia, primarily granulocytopenia commonly occurs. The nadir for white blood cell
count usually occurs from the 9
to the 14
day after initiation of therapy, but may occur
Thrombocytopenia may also occur, with the lowest platelet counts occurring from the 7
day of therapy.
Nervous system disorders
Combination therapy with 5-fluorouracil and levamisole has been associated
Symptoms may include memory loss, confusion, paraesthesia, lethargy, muscle weakness,
pleiocytosis, and computed tomography and magnetic resonance scans may show lesions in
the white matter suggestive of demyelination. If this syndrome occurs, treatment should be
discontinued immediately. The condition is at least partially reversible if 5-fluorouracil and
levamisole are discontinued and corticosteroids given.
Disorientation, confusion, euphoria, ataxia, nystagmus, headache, slurred
speech, dizziness, unsteadiness and acute cerebellar syndrome have occurred in patients
receiving fluorouracil. These symptoms may persist after therapy is discontinued.
Systemic fluorouracil treatment has been associated with various types of ocular toxicity.
Additionally several other reports have been noted including excessive lacrimation,
dacryostenosis, visual changes and photophobia.
There have been reports of myocardial infarction*, angina pectoris*, cardiac shock*,
cardiac failure*, cardiomyopathy*, myocarditis*, pericarditis*, chest pain, tachycardia,
breathlessness, arrhythmia and E.C.G. changes (ST segment changes) after administration
of fluorouracil. There have been reports of sudden death in patients readministered
fluorouracil after a documented cardiovascular reaction.
The most pronounced dose-limiting toxic effects of fluorouracil are on the normal,
rapidly proliferating tissues of the bone marrow and the lining of the gastrointestinal tract.
Diarrhoea, nausea and vomiting are seen commonly during therapy and may be treated
symptomatically. Nausea and vomiting may be controlled with an appropriate antiemetic.
oesophagitis, therefore the dose may require adjustment or therapy may need to be
discontinued. Gastrointestinal side effects may be exacerbated if fluorouracil is given
with folinic acid (leucovorin).
Skin and subcutaneous tissue disorders
Alopecia may be seen in a substantial number of cases, but is reversible. Dermatitis,
hyperpigmentation, changes in the nail beds and ataxia have been reported. Skin rashes
channels have also been reported. Continuous-infusion fluorouracil may increase incidence
and severity of palmar-plantar erythrodysesthesia. Photosensitivity reaction.
Local injection site reaction. Fevers have also been reported. Rarely, anaphylaxis or
generalised allergic reactions have occurred in patients receiving fluorouracil. Pyrexia
and chest pain.
Listed cardiac disorders associated with 5-flouorouracil, may lead to cardiac arrest.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It
allows continued monitoring of the benefit/risk balance of the medicine. Healthcare
administration. High dosages or prolonged treatment with fluorouracil can result in life-
vomiting, diarrhoea, gastrointestinal ulcers and hemorrhage and myelosuppression (include
thrombocytopenia, leucopenia and granulocytopenia).
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 who have been exposed to an overdose of fluorouracil
should be monitored haematologically for at least 4 weeks. Should abnormalities appear,
appropriate therapy should be utilised.
For advice on the management of overdose please contact the National Poisons Centre on
0800 POISON (0800 764766).
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
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.
5.2 Pharmacokinetic properties
After intravenous administration, fluorouracil is distributed through the body water and
disappears from the blood within 4 hours. It is preferentially taken up by actively dividing
tissues and tumours after conversion to its nucleotide. Fluorouracil readily enters the
About 20% is excreted unchanged in the urine and the remainder is mostly metabolised in
the liver by the usual body mechanisms for uracil.
5.3 Preclinical safety data
Long term studies in animals to evaluate the carcinogenic potential of fluorouracil have
not been conducted. However, there was no evidence of carcinogenicity in small groups
of rats given fluorouracil orally at doses of 0.01, 0.3, 1 or 3 mg per rat 5 days per week
for 52 weeks, followed by a 6 month observation period. On the basis of the available
data, no evaluation can be made of the carcinogenic risk of fluorouracil to humans.
Oncogenic transformation of fibroblasts from mouse embryo has been induced
fluorouracil, but the relationship between oncogenicity and mutagenicity is not clear. A
positive effect was observed in the micronucleus test on bone marrow cells of the mouse,
and fluorouracil at very high concentrations produced chromosomal breaks in hamster
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Water for injection
Admixture with acidic drugs or drugs that decompose in an alkaline environment 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) or levoleucovorin
6.3 Shelf life
18 months (only for 250 mg/5 mL)
6.4 Special precautions for storage
Store at 8 - 25°C. Do not refrigerate. Protect from light.
6.5 Nature and contents of container
DBL™ Fluorouracil Injection BP is available in clear glass vials containing 25 mg/mL or 50
mg/mL of fluorouracil in the following presentations and pack sizes.
500 mg/20 mL
10 x 20mL vials
250 mg/5 mL
5 x 5mL vials
2.5 g/100 mL
1 x 100mL vial
500 mg/10 mL
5 x 10mL vials
1 g/20 mL
5 x 20mL vials
2.5 g/50 mL
1 x 50mL vial
250 mg/10 mL
5 x 10 mL vials