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Fluorouracil Injection

Page 1 of 19



5-fluorouracil Ph.Eur.

50 mg/mL Injection USP

Antineoplastic Agent

Sandoz Canada Inc.

Date of Revision: April 3, 2012

145 Jules-Léger

Boucherville, QC

J4B 7K8

Submission Control No: 145218

Fluorouracil Injection

Page 2 of 19

Fluorouracil Injection

(5-fluorouracil Ph.Eur.)












Fluorouracil (5-fluorouracil) is a fluorinated pyrimidine antimetabolite which is structurally

similar to uracil, one of the necessary building blocks in cellular division and growth.

Figure 1

Its usefulness is based on uracil being utilized preferentially for nucleic acid biosynthesis in

some tumors. 5-fluorouracil is metabolized to 5-fluorouridine triphosphate (F-UTP),

2-deoxyfluorouridine monophosphate (Fd-UMP), and 2-deoxyfluorouridine triphosphate

(Fd-UTP) in cells to concentrations that result in both DNA-directed and RNA-directed

cytotoxicities (see Figure 1). Fd-UMP is the intracellular cytotoxic form of 5-fluorouracil. It

competes with the natural substrate d-UMP (deoxyuridine monophosphate) for the catalytic site

Fluorouracil Injection

Page 3 of 19

on thymidylate synthetase (a key enzyme in DNA synthesis), forming a covalent complex with

the enzyme that is unable to undergo the normal catalytic reaction of converting d-UMP to

d-TMP. The presence of a reduced folate cofactor is required for tight binding of Fd-UMP to

thymidylate synthetase. Folinic acid (leucovorin), which is metabolized to 5,10-methylene-

tetrahydropteroylglutamine (a reduced folate), is able to modulate the antineoplastic effect of

5-fluorouracil by promoting the formation and stabilization of the ternary complex formed

between Fd-UMP and thymidylate synthetase. In this way, leucovorin produces a synergistic

effect on 5-fluorouracil therapy.

At the same time, 5-fluorouracil interferes with the mechanism of action of RNA, resulting from

the formation of «fraudulent» RNA by the incorporation of F-UTP in the ribonucleotides.

Incorporation into RNA has been associated with toxicity and has major effects on both the

processing and functions of RNA.

By interference with the formation of DNA and RNA, 5-fluorouracil provokes unbalanced

growth and death of cells. The effects of DNA and RNA deprivation are most marked on those

cells which grow rapidly and which take up 5-fluorouracil rapidly.

While there is no evidence that 5-fluorouracil prolongs survival time generally, the usefulness of

the drug has been demonstrated by the relief of pain and other symptoms in certain types of

human malignancies. There have also occasionally been regression of tumors.

The steady-state plasma concentrations of 5-fluorouracil following bolus i.v. doses of

400-600 mg/m

(10-15 mg/kg) range from 0.1-1.0 mM. Following continuous infusion of

1,100 mg/m

/day, plasma concentrations of 0.5-2.5 µM are observed. 5-fluorouracil readily

penetrates the blood-brain barrier and CSF concentrations of about 7 µM are reached within

30 minutes after intraveneous administration. The volume of distribution of 5-fluorouracil ranges

from 0.1 to 0.4 L/kg. The elimination half-life is 6-20 minutes and is dose-dependent.

Following an i.v. injection, no intact drug can be detected in the plasma after three hours. For

bolus doses, 5-fluorouracil plasma clearance is 0.5 to 1.4 L/min. Clearance values are 10- to

60-fold higher following i.v. infusion. This non-linearity likely represents saturation of a

metabolic or transport process at higher drug concentrations. Plasma protein binding of

5-fluorouracil is 10%.

The metabolism of 5-fluorouracil occurs mainly in the liver and results in degradation products

(e.g., carbon dioxide, urea, alpha-fluoro-beta-alanine) which are inactive. Approximately 15%

of the dose is excreted intact in the urine in 6 hours and over 90% of this is excreted intact in the

first hour; 60 to 80% is excreted as respiratory carbon dioxide in 8 to 12 hours.

Fluorouracil Injection

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Fluorouracil Injection (5-fluorouracil) is indicated in the palliative management of carcinoma of

the breast, colon, rectum, stomach and pancreas. In clinical practice, 5-fluorouracil is often

combined with other cytotoxic agents such as methotrexate, cyclophosphamide, cisplatin,

vincristine, mitomycin, adriamycin, levamisole and interferon alpha-2a; or drugs which may

enhance its effect on killing tumor cells such as calcium leucovorin.

Various combinations of 5-fluorouracil/interferon and 5-fluorouracil/leucovorin/interferon are

also used in clinical practice.

Fluorouracil Injection does not replace surgery or other recognized forms of therapy and should

be used only when these measures are not possible or have been tried and have failed.


Fluorouracil (5-fluorouracil) therapy is contraindicated in pregnant women, for patients in a poor

nutritional state, those with severely depressed bone marrow function, with potentially serious

infections, or those with a known hypersensitivity to 5-fluorouracil.


Fluorouracil (5-fluorouracil) should be given only by or under the supervision of a qualified

physician who is experienced in cancer chemotherapy and well-versed in the use of potent


The drug should be used with extreme caution in patients who have undergone recent major

surgery; those with a history of high dose irradiation to bone marrow-bearing areas (pelvis,

spine, ribs, etc.) or previous use of other myelosuppressive chemotherapeutic agents; those with

a widespread involvement of bone marrow by metastatic tumors; or those with renal or liver

impairment. Although severe toxicity is more likely in debilitated patients, fatalities may be

encountered occasionally even in patients in relatively good condition.

5-fluorouracil should be used with great care in patients who are known or suspected to have a

dihydropyrimidine dehydrogenase deficiency, as these patients are at a greater risk of

experiencing symptoms of toxicity.

Usage in Pregnancy:

Although it is not known whether 5-fluorouracil crosses the human

placenta, it has been shown to cross the rat placenta and enter into the fetal circulation of this

rodent. Positive teratologic findings have been observed in animals (see TOXICOLOGY,

Teratology). Therefore, this drug should not be used during pregnancy.

Fluorouracil Injection

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Nursing Mothers:

It is not known whether 5-fluorouracil is excreted in human milk. Because

5-fluorouracil inhibits DNA, RNA and protein synthesis, mothers should not nurse while

receiving this drug.


Positive mutagenic findings have been observed in the usual mutagenicity

screening tests (see TOXICOLOGY, Mutagenicity).

Drug Interactions - Combined Therapy

Leucovorin (folinic acid) and 5-fluorouracil are routinely used together in the treatment of

colorectal cancer. There is biochemical rationale for the synergism produced by the combination

of 5-fluorouracil and leucovorin. Leucovorin is metabolized to a reduced folate co-factor that is

necessary for maximal inhibition of thymidylate synthetase by Fd-UMP, the active metabolite of

5-fluorouracil. Studies with tumour lines in vitro have confirmed this effect and several clinical

studies have shown evidence that there may be some increased therapeutic benefit from

providing a source of reduced folate.

Clinical trials have been reported using sequenced methotrexate/fluorouracil in head and neck,

breast and colorectal cancers. Methotrexate has been shown to improve the effectiveness of

5-fluorouracil against tumor cells in vitro and in vivo. The sequence of administration is of

importance. Administration of methotrexate followed by 5-fluorouracil leads to a synergistic

interaction. Biochemical modulation might occur both through effects on RNA and DNA

synthesis and enhancement of 5-fluorouracil uptake. The importance of the time interval

between methotrexate and 5-fluorouracil exposure in the treatment of metastatic colon cancer

has been demonstrated. When these two agents are separated by 24 hours as compared with 1

hour, the response rate, time to progression and survival are significantly improved. However,

different tumors may respond differently to changes in the time interval between methotrexate

and 5-fluorouracil.

Any form of therapy which adds to the stress of the patient, interferes with nutrition, or depresses

bone marrow function, may increase the toxicity of 5-fluorouracil.

When combining 5-fluorouracil with other anticancer agents (such as methotrexate,

cyclophosphamide, cisplatin, vincristine, mitomycin, adriamycin, levamisole or interferon

alpha-2a) and leucovorin, drug interactions increasing both the efficacy and/or toxicity have

been reported. A hemolytic-uremic syndrome has been reported to occur after long-term use of

5-fluorouracil in combination with mitomycin.


Fluorouracil (5-fluorouracil) should be administered by individuals experienced in the use of

antineoplastic therapy. Fluorouracil is both an irritant and a highly toxic drug. Professional staff

administering 5-fluorouracil should exercise particular care to prevent spillage and contact with

the drug. Should skin contact occur, the area should be vigorously washed with soap and cold

water and the material used for cleansing disposed by incineration. In the case of contact with

the eyes, irrigate immediately with water and contact a physician. If inhaled or ingested, seek

Fluorouracil Injection

Page 6 of 19

immediate medical attention. (see PHARMACEUTICAL INFORMATION, Special


5-fluorouracil is a highly toxic drug with a narrow margin of safety. Therefore, patients should

be carefully supervised. Therapy should be properly adjusted or discontinued if:

Significant stomatitis, mucositis or esophagitis, severe diarrhea or vomiting, or

gastrointestinal ulcers or bleeding occurs.

Leukopenia (WBC count under 3 000/mm

), thrombocytopenia (platelet count under

80 000/mm

), or granulocytopenia (under 1 500/mm

Central or peripheral nervous system toxicity, including ataxia, tremor.

Cardiac toxicity.

Therapeutic response is unlikely to occur without some evidence of toxicity. Patients should be

informed of expected toxic effects, particularly oral manifestations (see Adverse Reactions).

Because of the possibility of leukopenia, frequent blood counts (every two or three days) are

essential during initial therapy. If the count falls, it is advisable to obtain differentials with each

count. If the count is less than 1 500/mm

with marked granulocytopenia (less than 1 000/mm

it is recommended that the patient be carefully followed and considered for prophylactic

antibiotics. During maintenance therapy, counts before each course are sufficient.

In the case of severe gastrointestinal, cardiac or neurological toxicity, continued treatment with

5-fluorouracil is not recommended.

Severe hematological effects, gastrointestinal hemorrhage and even death may result from the

use of 5-fluorouracil despite meticulous selection of patients and careful adjustment of dosage,

but severe toxicity is more frequent in poor risk patients.

Laboratory Test Interactions

The results of tests for bilirubin (icteric index), and for 5-hydroxyindole acetic acid in the urine,

may be increased or false positive.


Stomatitis, mucositis and esophagopharyngitis (which may lead to sloughing and ulceration),

diarrhea, anorexia, nausea and emesis are commonly seen during therapy with Fluorouracil

(5-fluorouracil). Allergic reactions including anaphylaxis, bronchospasm, urticaria and pruritus

have also been reported. If anaphylactic shock occurs, the usual countermeasures should be

employed. Diarrhea usually responds to antidiarrheal agents. Uncontrolled nausea and vomiting

can be treated with antiemetic agents.

Leukopenia with neutropenia usually follows each course of adequate therapy with

5-fluorouracil. The lowest white blood cell counts are commonly observed between the 9

days after the first dose, although the maximal depression may occasionally be delayed for

Fluorouracil Injection

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as long as 20 days. By the 30

day, the count usually returns to the normal range. Pancytopenia,

agranulocytosis, anemia, hemolytic anemia and thrombocytopenia have also been reported. Due

to immunosuppression, infections (sometimes serious), may develop in patients treated with


Alopecia and dermatitis may be seen in a substantial number of cases. Patients should be alerted

to the possibility of alopecia, but since the alopecia is reported to be reversible, special measures

do not seem to be indicated. The dermatitis seen most often is a pruritic maculopapular rash

appearing usually on the extremities and sometimes on the trunk. It is generally reversible and

responsive to symptomatic treatment.

Other Adverse Reactions


Myocardial ischemia, angina, precordial pain, cardiac arrhythmias, ischemia

and heart failure resulting rarely in death.


Gastrointestinal ulceration and bleeding.

Central nervous system:

Ataxia, dysarthria, nystagmus, disorientation, headache, confusion,

euphoria, acute cerebellar syndrome (which may persist following discontinuation of treament).

Extra pyramidal or cortical dysfunction (usually reversible). Isolated cases of

leucoencephalopathy have also been reported.


Dry skin; fissuring; photosensitivity as manifested by erythema or increased

pigmentation of the skin; palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), as

manifested by tingling of the hands and feet followed by pain, erythema and swelling.

Palmar-plantar erythrodysesthesia syndrome gradually resolves 5 to 7 days after interruption of

therapy. This syndrome may be treated with the concomitant oral administration of pyridoxine

at doses of 100 to 150 mg per day.


Visual changes; photophobia; oculomotor disturbances and lacrimation, optic

neuritis. Lacrimal duct stenosis (canalicular fibrosis) associated with prolonged administration

of fluorouracil has been reported as rare. This condition is reversible upon reduction or

temporary cessation of 5-fluorouracil therapy, but on occasion may necessitate surgical



Thrombophlebitis, epistaxis, nail changes (including loss of nails), chest pain,

vein pigmentation. Hepatocellular damage and, in very rare cases, fatal hepatic necrosis have

been observed.

Fluorouracil Injection

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You can report any suspected adverse reactions associated with the use of health products to the Canada Vigilance

Program by one of the following 3 ways:

Report online at www.healthcanada.gc.ca/medeffect

Call toll-free at 1-866-234-2345

Complete a Canada Vigilance Reporting Form and:

- Fax toll-free to 1-866-678-6789, or

- Mail to: Canada Vigilance Program

Health Canada

Postal Locator 0701D

Ottawa, ON K1A 0K9

Postage paid labels, Canada Vigilance Reporting Form and the adverse reaction reporting guidelines are available on

the MedEffect

Canada Web site at www.healthcanada.gc.ca/medeffect.

NOTE: Should you require information related to the management of side effects, contact your health professional.

The Canada Vigilance Program does not provide medical advice.


The main symptoms of overdose are nausea, vomiting, diarrhea, stomatitis, esophagopharyngitis,

gastrointestinal ulceration and bleeding, hemorrhage from any site and bone marrow depression

(including thrombocytopenia, leukopenia and agranulocytosis). No specific antidotal therapy

exists. Patients who have been exposed to an overdose of Fluorouracil (5-fluorouracil) should be

monitored hematologically with regular white cell counts, differentials and platelet counts.

Should abnormalities appear, appropriate symptomatic therapy should be utilized. Suitable

counter measures are withdrawal of medication or dosage reduction and, depending on the

symptoms, blood transfusions, leukocyte or platelet infusions or antiinfective therapy. Nausea,

vomiting and diarrhea may be controlled by appropriate therapy.

For management of a suspected drug overdose, contact your regional Poison Control Centre.


Criteria for the selection of patients: In order to be considered for Fluorouracil Injection

(5-fluorouracil) therapy, a prospective patient must meet the following:

No history of high irradiation to major bone marrow-bearing areas.

Adequate bone marrow function, i.e., a white blood cell count of 3 000/mm

or over,

a granulocyte count of 1 500/mm

or over and a platelet count of 80 000/mm

or over.

Adequate hepatic and renal functions.

Fluorouracil Injection

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Fluorouracil Injection (5-fluorouracil) should only be administered intravenously, and care

should be taken to avoid extravasation. No dilution of the solution is required when Fluorouracil

Injection is given by direct intravenous injection.

In most cases, dosage should be based on the patient's actual weight or actual body surface area.

However, if the patient is obese or if there has been a spurious weight gain due to edema, ascites

or other forms of abnormal fluid retention, the ideal weight or ideal body surface area should be

used. Following major weight loss, the dose of 5-fluorouracil should be reduced.

It is recommended that each patient be carefully evaluated prior to treatment, in order to estimate

as accurately as possible the optimum initial dosage of Fluorouracil Injection. Likewise, the

duration of therapy must be determined by a specialist, based on the type and course of the



: The following dosage schedules may be used.

General Recommendations

IV Injection

800 mg/m

(19 mg/kg) single dose.

480 mg/m

(12 mg/kg) per day on days 1, 2, 3, 4 followed by 240 mg/m

(6 mg/kg) per day

on days 6, 8, 10 and 12. Repeat course every 30 days.

300-450 mg/m

(7-11 mg/kg) per day for 5 days. Repeat every 4 weeks.

400-480 mg/m

(10-12 mg/kg) or 500-600 mg/m

(12-15 mg/kg) per week.

IV Infusion

Administration by infusion may result in slightly less toxicity. Fluorouracil Injection may be

diluted with 300 to 500 mL of 5% dextrose solution.

480 mg/m

(12 mg/kg) over a period of 4 hours daily until signs of toxicity are observed,

usually within 8 to 15 days.

1 000-2 000 mg/m

(24-49 mg/kg) over a period of 24 hours daily for 5 days. Repeat course

every 4 weeks.

Combination therapy with folinic acid

IV injection 370-400 mg/m

(9-10 mg/kg) for 5 days plus folinic acid 200-500 mg/m

(5-12 mg/kg) for 5 days. Repeat course every 4 weeks.

The patient must be monitored for toxic signs. Drug therapy should be appropriately adjusted or

discontinued should toxic signs such as gastrointestinal bleeding become manifested.

Recommandations for Poor Risk Patients

For poor risk patients, the following dosage schedules may be used:

IV Injection

240 mg/m

(6 mg/kg) per day on days 1, 2, 3 followed by 120 mg/m

(3 mg/kg) per day on days

5, 7, 9. Repeat course every 30 days.

Fluorouracil Injection

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IV Infusion

240 mg/m

(6 mg/kg) over a period of 4 hours daily until signs of toxicity are observed, usually

within 8 to 15 days.

Renal Impairment:

Due to the impairment of bone marrow function in azotemia, secondary to kidney failure, a dose

adjustment appropriate to the degree of renal failure and to the reaction of the individual patient

to Fluorouracil Injection is recommended.

Liver Impairment:

Since 5-fluorouracil is metabolized mainly in the liver, a dosage reduction should be considered

when liver function is impaired.


The patient's reaction to the previous course should be taken into account when

determining the dosage. Some patients have received from 9 to 45 courses of

treatment over periods ranging from 12 to 60 months.

Frequent blood counts (every two or three days) are essential during initial therapy. During

maintenance therapy, counts before each course are sufficient.

Therapy should be properly adjusted or discontinued whenever any of the following signs of

toxicity appear:

Significant stomatitis, mucositis or esophagitis, severe diarrhea or vomiting, or

gastrointestinal ulcers or bleeding occurs.

Leukopenia (WBC count under 3 000/mm

), thrombocytopenia (platelet count under

80 000/mm

), or granulocytopenia (under 1 500/mm

Central or peripheral nervous system toxicity, including ataxia, tremor.

Cardiac toxicity.

Dosage Reduction in Combination Therapy:

When Fluorouracil Injection is combined with other cytostatics of similar toxicity profile or with

radiotherapy, the recommended dosage should be reduced accordingly.

Fluorouracil Injection

Page 11 of 19


Drug Substance

Common Name:

Fluorouracil Ph.Eur.

Chemical Name:

5-fluoro-2,4 (1H, 3H)-pyrimidinedione

Structural Formula:

Molecular Formula:

Molecular Weight:


Physical Form:

White to almost white, almost odourless, crystalline powder.


Sparingly soluble in water, slightly soluble in alcohol, almost

insoluble in chloroform and ether.


Fluorouracil contains 50 mg of fluorouracil per mL of water for injection; sodium hydroxide is

added to solubilize the compound and to adjust the pH to approximately 9.2.


Store between 15 and 25°C. Do not freeze or refrigerate.

Although Fluorouracil Injection (5- fluorouracil) solution may discolour slightly during storage,

the potency, and safety are not adversely affected, and are maintained until the expiry date.

If a precipitate occurs during storage, resolubilize by heating to 60°C with vigorous shaking;

allow to cool to body temperature before using.


No dilution of the solution is required when Fluorouracil Injection is given by direct intravenous


Fluorouracil Injection

Page 12 of 19

Fluorouracil Injection may be diluted with 300 to 500 mL of 5% dextrose and administered by

infusion over a period of either 4 or 24 hours (see Dosage and Administration). Infusions

prepared with 5% dextrose solution should be used within 24 hours.

Special Instructions:

As for all antineoplastic agents, personnel handling these agents should wear

polyvinylchloride gloves, safety glasses, disposable gowns and masks and should work in

vertical laminar flow hood.

Fluorouracil is both an irritant and a highly toxic drug. Professional staff administering

antineoplastic agents should exercise particular care to percent spillage and contact with the

drug. Should skin contact occur, the area should be vigorously washed with soap and water.

In the case of contact with the eyes, irrigate immediately with water and contact a

physician. If inhaled or ingested, seek immediate medical attention.

As 5-fluorouracil is frequently adsorbed by regular glass surfaces, silanized glass should be

used when 5-fluorouracil is given. All materials which have come in contact with cytotoxic

agents including needles, syringes, open ampoules or vials, polyvinylchloride gloves,

gowns, masks and materials used for cleansing, should be segregated and incinerated at 1

000°C or more. If incineration is not possible, add household bleach (sodium hypochlorite

solution) or 0.1 molar sodium hydroxide solution and place the sealed container in a landfill


Personnel regularly involved in the preparation and handling of cytotoxic agents should

have bi-annual blood examinations.


Fluorouracil Injection is available in:

10 mL single-dose vials containing 500 mg fluorouracil, in packs of 5 vials.

100 mL Pharmacy bulk vial containing 5 000 mg fluorouracil, in packs of 1 vial.

LATEX-FREE stoppers: stoppers contain no dry natural rubber



5-fluorouracil has wide range of activity against the majority of solid and ascitic forms of

epithelial and mesenchymal transplantable tumors of mice, rats and hamsters. Examples of these

transplantable tumors include Flexner-Jobling carcinoma, Walker 256 carcinoma, Yoshida

ascites tumor, Shay's chloroleukemia, Sarcoma 180, Ehrlich ascites carcinoma, L-1210 leukemia,

E0771, mammary adeno-carcinoma 755 and Sarcoma A-1. 5-fluorouracil is ineffective in

Fluorouracil Injection

Page 13 of 19

spontaneous mammary tumors, human epidermoid carcinoma, Harding-Passey melanoma,

myeloid leukemia Db 1490, and 5-fluorouracil resistant strains of Ehrlich carcinoma and

leukemia L-1210.

Tissue Cultures

5-fluorouracil inhibits the growth of Hela and H. Ep. #1 cells, both of which are epithelial-like

stains derived from human cervical carcinomas, in tissue culture. The minimum active

concentration inhibiting the growth of Hela cells ranges from 0.1 to 1.0 mcg/mL depending on

the media used in the study. For H. Ep. #1 cells, the minimum active concentration is

1.0 mcg/mL.


5-fluorouracil is a potent inhibitor of the growth of the bacteria,

Lactobacillus leichmannii

Lactobacillus plantarum

Lactobacillus casei

Streptococcus faecalis

, and the yeast,

Saccharomyces carlsbergensis

. The mode of action of 5-fluorouracil in these microorganisms

appears to be that the drug is converted into 5-fluoro-2'-deoxyuridylic acid, a highly potent

irreversible inhibitor of the enzyme thymidylate synthetase, the catalyst needed in the

methylation of deoxyuridylic acid to thymidylic acid, an important reaction in the formation of



In man, the biochemical effects of 5-fluorouracil in the anabolic pathway are:

Inhibition of the incorporation of uracil and orotic acid in the synthesis of RNA thus

inhibiting its synthesis.

Synthesis of an unnatural RNA by incorporation of 5-fluorouracil into the molecule.

Inhibition of the methylation of deoxyuridylic acid to thymidylic acid thereby inhibiting the

synthesis of DNA.

5-fluorouracil is converted into fluorouridine and further into the mono-, di-, and triphosphates

of fluorouridine. 5-fluorouridine monophosphate is then reduced to 5-fluoro-2'-deoxyuridine

monophosphate, the apparent lethal nucleotide, which inhibits the enzyme thymidylate

synthetase required in the DNA synthesis. The inhibition of DNA synthesis is considered to be

chiefly responsible for the antineoplastic activity of 5-fluorouracil in man, since concentrations

which inhibit DNA still permit RNA synthesis.

The catabolic pathway of 5-fluorouracil is analogous to that of uracil, forming the following

degradative products: dihydrofluorouracil, alpha-fluoro-beta-ureidopropionic acid,

alpha-fluoro-beta-guanidopropionic acid, alpha-fluoro-beta-alanine, urea, and CO


Short-Term Toxicity

values of 5-fluorouracil in difference species via different routes of administration are as


Fluorouracil Injection

Page 14 of 19

(mg/kg ± S.E.)







340 ± 17

> 250

> 500

266 ± 25


165 ± 26

303 ± 51


27 ± 5.1

24 ± 1.9


31.5 ± 3.8

29 ± 3.1

The toxicity of 5-fluorouracil shows pronounced species differences. Dogs, cats and rabbits

display acute intoxication resembling fluoroacetate poisoning. Convulsions are observed in cats

and dogs while cardiac failure appears in rabbits. Mice, rats and monkeys tolerate 5-fluorouracil

better than dogs, cats and rabbits.

Long-Term Toxicity

Excessive dosage of 5-fluorouracil in mice, rats and monkeys leads to chronic intoxication

characterized by depression of cells of the bone marrow and damage to cells of the

gastrointestinal mucosa. The bone marrow damage caused by overdosage is reversible upon

discontinuation of 5-fluorouracil.

The approximate doses which are tolerated for varying periods of time in different species are

shown in the following table:


Dose (mg/kg/day)

No. of Days

Route of












One of the three monkeys receiving 12 mg/kg/day demonstrated severe toxicity and had to

be sacrificed after 6 weeks of treatment.

Five days/week dosing for 13 consecutive weeks.


Animal studies have demonstrated an increased incidence of some tumors in mice, but not in

rats, after long-term treatment with 5-fluorouracil. Fifty male and fifty female BALB/C mice

were administered 5-fluorouracil i.p. at a dose of 30 mg/kg body weight once a week to test the

carcinogenicity of 5-fluorouracil. A significant increase in lung tumors in both sexes and tumors

of the lymphoreticular system in female mice was observed.

No evidence of carcinogenicity was reported in four groups of Fischer rats administered

5-fluorouracil by gastric intubation 5 times per week for 52 weeks, at a dose of 3.0, 1.0, 0.01 and

0.3 mg/animal per day followed by a 6 month observation period. In another study, male BR46

rats were administered weekly with i.v. injections of 33 mg/kg body weight for 52 weeks,

followed by observations for the remainder of their lifetimes with no evidence of carcinogenesis.

Fluorouracil Injection

Page 15 of 19


Oncogenic transformation of fibroblasts from mouse embryo has been induced in vitro by

5-fluorouracil, but the relationship between oncogenicity and mutagenicity is not clear.

5-fluorouracil is mutagenic to several strains of

Salmonella typhimurium

, including TA 1535,

TA 1537 and TA 1538, and to

Saccharomyces cerevisiae

, although no evidence of mutagenicity

was found with

Salmonella typhimurium

strains TA 92, TA 98 and TA 100. A positive effect

was observed in the micronucleus test on bone marrow sells of the mouse. 5-fluorouracil, at

very high concentrations, produced chromosomal breaks in hamster fibroblasts

in vitro.


5-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 250 mg/kg,

administered intraperitoneally, have been shown to induce chromosomal aberrations and changes

in chromosomal organization of spermatogonia in rats. Spermatogonial differentiation was also

inhibited by 5-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 and carcinogens, 5-fluorouracil did not produce any abnormalities at oral

doses of up to 80 mg/kg/day. In female rats, 5-fluorouracil, administered intraperitoneally at

weekly doses of 25 or 50 mg/kg for three weeks during the pre-ovulatory phase of oogenesis,

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 the limited study in rabbits, a single 25 mg/kg

dose of 5-fluorouracil or 5 daily doses of 5 mg/kg had no effect on ovulation, appeared not to

affect implantation and had only a limited effect in producing zygote destruction. Agents such

as 5-fluorouracil, which interfere with DNA, RNA and protein synthesis, might be expected to

have adverse effects on gametogenesis.


5-fluorouracil is teratogenic in laboratory animals. 5-fluorouracil exhibited maximum

teratogenicity when given to mice as single intraperitoneal injections of 10 to 40 mg/kg on day

10 or 12 of gestation. Similarly, intraperitoneal doses of 12 to 37 mg/kg given to rats between

days 9 and 12 of gestation and intramuscular doses of 3 to 9 mg given to hamsters between days

8 and 11 of gestation were teratogenic. Malformations included cleft palates, skeletal defects

and deformed appendages, paws and tails. The dosages which were teratogenic in animals are 1

to 3 times the maximum recommended human therapeutic dose. In monkeys, divided doses of

40 mg/kg given between days 20 and 24 of gestation were not teratogenic.

5-fluorouracil has not been studied in animals for its effects on peri- and post-natal development.

However, 5-fluorouracil has been shown to cross the placenta and enter into fetal circulation in

the rat. Administration of 5-fluorouracil has resulted in increased resorptions and

embryolethality in rats. In monkeys, maternal doses higher than 40 mg/kg resulted in abortion of

all embryos exposed to 5-fluorouracil. Compounds which inhibit DNA, RNA and protein

synthesis might be expected to have adverse effects on peri- and post-natal development.

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