Fluorouracil (Solution) Instructions for Use

ATC Code

L01BC02 (Fluorouracil)

Active Substance

Fluorouracil (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antitumor drug. Antimetabolite

Pharmacotherapeutic Group

Antineoplastic agents; antimetabolites; pyrimidine analogues

Pharmacological Action

Antitumor agent from the group of antimetabolites. It inhibits the process of cell division by blocking DNA synthesis (due to inhibition of the enzyme thymidylate synthase activity) and the formation of structurally imperfect RNA (due to the incorporation of fluorouracil into its structure).

Pharmacokinetics

After IV or intra-arterial administration, Fluorouracil is biotransformed and distributed in rapidly proliferating tissues, such as bone marrow, gastrointestinal mucosa, and tumor tissues. The V_d is 0.12 L/kg of body weight, binding to plasma proteins is about 10%. It easily penetrates the blood-brain barrier, entering the cerebrospinal fluid and brain tissues.

It is metabolized mainly in the liver. The T_1/2 of fluorouracil depends on the administered dose and is 8-22 min. About 7-20% of fluorouracil is excreted through the kidneys unchanged within 6 hours (90% is excreted within the first hour), 60-80% is excreted through the respiratory tract in the form of CO₂, a small amount is excreted with bile. The renal clearance of fluorouracil is 170-180 mL/min.

Indications

Colon and rectal cancer, breast cancer, esophageal cancer, stomach cancer, pancreatic cancer, primary liver cancer, ovarian cancer, cervical cancer, bladder cancer, malignant tumors of the head and neck, prostate cancer, adrenal cancer, vulvar cancer, penile cancer, carcinoid.

ICD codes

Dosage Regimen

Administer Fluorouracil solution intravenously (as a bolus or by slow infusion), intra-arterially, or intracavitarily.

Determine the dosage regimen individually based on the specific malignancy, disease stage, patient performance status, and the chosen anticancer therapy protocol.

For intravenous bolus administration, a common initial dose is 12 mg/kg body weight once daily for 4-5 consecutive days. The maximum single dose should not exceed 800 mg. If no toxicity is observed, administer 6 mg/kg on days 1, 3, 5, and 7. Do not repeat courses more frequently than every 4 weeks.

For intravenous infusion regimens, administer 15 mg/kg (up to 1 g total) by slow IV infusion over 1-4 hours once per week or utilize a continuous 24-hour infusion of 1,000 mg/m²/day for 4-5 days. Adjust subsequent doses based on tolerance and hematological recovery.

For intra-arterial infusion, use 0.45-0.60 mg/kg/day by continuous infusion. Adjust the dose based on regional perfusion and local toxicity.

For intracavitary administration (e.g., pleural, peritoneal), instill 500-750 mg after drainage of the malignant effusion. The frequency of administration is determined by the rate of fluid reaccumulation and patient tolerance.

Modify or withhold doses based on hematological toxicity. Withhold therapy if the white blood cell count falls below 3,500/mm³ or the platelet count falls below 100,000/mm³. Do not administer if the WBC is below 2,000/mm³ or platelets are below 50,000/mm³.

Monitor for gastrointestinal toxicity (stomatitis, diarrhea, vomiting). Discontinue therapy immediately at the first sign of severe stomatitis, intractable vomiting, diarrhea (more than 3-5 stools per day), or gastrointestinal ulceration and bleeding.

Assess dihydropyrimidine dehydrogenase (DPD) enzyme activity prior to initiation if possible. Do not administer to patients with known complete DPD deficiency due to the high risk of severe, life-threatening toxicity. Use extreme caution and consider dose reduction in patients with partial DPD deficiency.

In patients with impaired renal or hepatic function, use with extreme caution and consider dose reduction. Contraindicated in severe hepatic or renal impairment.

Discontinue treatment in case of cardiotoxicity (e.g., angina, ECG changes suggestive of ischemia).

Adverse Reactions

From the hematopoietic system: very common – dose-limiting leukopenia, neutropenia, thrombocytopenia, anemia, epistaxis; common – febrile neutropenia; very rare – agranulocytosis, pancytopenia.

From the immune system: very common – immunosuppression with an increased frequency of infectious diseases; rare – generalized allergic reactions, anaphylactic shock; frequency unknown – development of secondary infections, sepsis.

From the endocrine system: frequency unknown – increase in total thyroxine and triiodothyronine in blood plasma, without an increase in free total thyroxine and TSH and without clinical signs of hyperthyroidism.

From the metabolism: very common – hyperuricemia.

From the nervous system: uncommon – nystagmus, headache, vertigo, parkinsonism, pyramidal symptoms, transient reversible cerebral syndrome, drowsiness, euphoria, retrobulbar neuritis; rare – peripheral neuropathy (when used in combination with radiation therapy); very rare – dysgeusia, ataxia, speech impairment, confusion, disorientation, myasthenia, aphasia, seizures, coma, cerebral infarction (with combined therapy with mitomycin or cisplatin); frequency unknown – hepatic encephalopathy.

From the organ of vision: uncommon – conjunctivitis, excessive lacrimation, blurred vision, decreased visual acuity, blepharitis, ectropion, photophobia, optic neuritis, diplopia, limited eye mobility, visual impairment, cortical blindness (at high doses).

From the cardiovascular system: very common – ischemic changes on ECG; common – pain in the heart area; uncommon – decreased blood pressure, arrhythmias, ischemia, myocardial infarction, myocarditis, dilated cardiomyopathy, cardiogenic shock, heart failure; rare – thrombophlebitis; very rare – angina pectoris, cardiac arrest, sudden cardiac death; frequency unknown – pericarditis, impaired peripheral, cerebral and intestinal circulation, Raynaud’s syndrome, thromboembolism.

From the respiratory system: very common – bronchospasm.

From the digestive system: very common – decreased appetite, erosive and ulcerative lesions of the gastrointestinal tract, diarrhea, nausea, vomiting, anorexia; uncommon – dehydration, sepsis, gastrointestinal bleeding, detachment of necrotic mucous membrane epithelium; frequency unknown – heartburn.

From the liver and biliary tract: uncommon – liver cell damage, non-calculous cholecystitis; very rare – liver necrosis (including fatal).

From the urinary system: uncommon – renal failure.

From the reproductive system: uncommon – reversible suppression of gonadal function, leading to amenorrhea or azoospermia.

From the skin and subcutaneous tissues: very common – reversible alopecia, prolonged wound healing, palmar-plantar erythrodysesthesia syndrome; uncommon – exanthema, hyperpigmentation or depigmentation of the skin in the form of stripes near the veins, dry skin, skin cracks, erythema, skin itching, maculopapular rash, telangiectasias, change and shedding of nail plates, photosensitivity, dermatitis, urticaria.

Other: very common – increased fatigue, asthenia, fever, weakness, decreased motivation; frequency unknown – thrombophlebitis at the injection site.

Contraindications

Hypersensitivity to fluorouracil; severe leukopenia, neutropenia, thrombocytopenia, bone marrow suppression, active bleeding, stomatitis, ulcerations of the oral and gastrointestinal mucosa, pseudomembranous enterocolitis, severe infections, severe liver dysfunction, severe renal dysfunction; pregnancy, breastfeeding period (during therapy and for 2 weeks after the last administration of fluorouracil); childhood; combination with dihydropyrimidine dehydrogenase inhibitors (brivudine, sorivudine); established complete deficiency of dihydropyrimidine dehydrogenase (DPD) activity; debilitated patients.

With caution

In patients with mild to moderate renal failure; with mild to moderate hepatic failure; acute infectious diseases of viral, fungal or bacterial nature (including tuberculosis, chickenpox, herpes zoster); history of cardiovascular diseases; bone marrow infiltration by tumor cells, previously performed radiation therapy or chemotherapy; in patients with partial DPD deficiency.

Use in Pregnancy and Lactation

Fluorouracil is contraindicated for use during pregnancy. If it is necessary to use during lactation, breastfeeding should be discontinued.

Women of reproductive age should use reliable methods of contraception during treatment with fluorouracil and for at least 6 months after the end of therapy. If a patient becomes pregnant during treatment with fluorouracil, genetic counseling should be considered.

Use in Hepatic Impairment

Contraindicated in severe liver dysfunction. Use with caution in patients with mild to moderate hepatic failure.

Use in Renal Impairment

Contraindicated in severe renal dysfunction. Use with caution in patients with mild to moderate renal failure.

Pediatric Use

Contraindicated in children.

Special Precautions

Treatment with fluorouracil should be carried out under the supervision of an oncologist with experience in the use of antimetabolites. Given the risk of severe toxic reactions, including fatal ones, the physician must inform the patient in detail about the possible risk and necessary safety measures. Treatment should be started in a hospital setting.

Before starting and during therapy with fluorouracil, peripheral blood counts, liver and kidney function laboratory parameters should be monitored.

Caution should be exercised when treating patients experiencing heart pain during treatment courses, or in patients with a history of heart disease. Heart function should be monitored regularly. In case of severe cardiotoxicity, treatment should be discontinued.

If symptoms of encephalopathy develop, treatment should be immediately suspended and the plasma ammonia level should be determined. If the plasma ammonia concentration is elevated, therapy to reduce it should be initiated.

Caution should be exercised when using fluorouracil in patients with mild to moderate renal and/or hepatic failure. In patients with reduced renal/hepatic function, the risk of hyperammonemia and hepatic encephalopathy increases.

In patients with reduced or absent activity of DPD, the enzyme involved in the catabolism of fluorouracil, there is an increased risk of severe, life-threatening or fatal adverse reactions caused by the use of fluorouracil.

With simultaneous use of fluorouracil and oral anticoagulants, blood clotting (e.g., prothrombin index) should be carefully monitored.

Fluorouracil may reduce the immunological response to vaccination. The use of live vaccines during treatment with fluorouracil may lead to enhanced virus replication. The use of live vaccines is contraindicated during the use of fluorouracil; contact with people recently vaccinated against polio should also be avoided.

Men and women of reproductive age should use reliable methods of contraception during treatment with fluorouracil and for at least 6 months after the end of therapy. Men should consult a doctor about the possibility of sperm cryopreservation before starting treatment due to possible irreversible infertility as a result of fluorouracil use.

All measures must be taken to prevent the fluorouracil solution from getting on the skin and mucous membranes. If fluorouracil gets on the skin or mucous membranes, they should be thoroughly washed with soap and water; if it gets on the eye mucosa – with plenty of water.

Effect on ability to drive vehicles and mechanisms

During the use of fluorouracil, patients should exercise caution when driving vehicles and mechanisms, as well as when engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Drug Interactions

With simultaneous use, calcium folinate enhances the therapeutic and toxic effects of fluorouracil. Severe diarrhea, sometimes fatal, may occur as a clinical manifestation of this interaction.

When fluorouracil is used in combination with other cytostatics and interferon-alpha, both the antitumor effect and the toxicity of fluorouracil may be enhanced.

When fluorouracil is used in combination with radiation therapy, the skin toxicity of the latter may be enhanced.

With long-term combined use with mitomycin, the appearance of hemolytic-uremic syndrome was observed.

With simultaneous use of fluorouracil and anthracyclines, the cardiotoxic effect of the latter may be enhanced.

With simultaneous use with inhibitors of the enzyme dihydropyrimidine dehydrogenase, responsible for the catabolism of endogenous and fluorinated pyrimidines (brivudine, sorivudine), the toxicity of fluorouracil is significantly increased. The interval between the use of fluorouracil and brivudine, sorivudine or their analogues should be at least 4 weeks.

With simultaneous use of phenytoin and fluorouracil, the plasma concentration of phenytoin increases, which may lead to symptoms of intoxication.

With simultaneous use, chlordiazepoxide, disulfiram, griseofulvin and isoniazid may enhance the activity of fluorouracil.

With simultaneous use, levamisole may enhance the hepatotoxicity of fluorouracil.

There are reports of a decrease in Quick’s blood clotting time with simultaneous use of warfarin and fluorouracil, as well as in combination with levamisole.

With simultaneous use, metronidazole, cimetidine, interferons and allopurinol may increase the plasma concentration of fluorouracil, thereby increasing its toxic effects.

In female patients taking thiazide diuretics together with cyclophosphamide, methotrexate and fluorouracil, a more pronounced decrease in the number of granulocytes was noted compared to the same cytostatic therapy without the use of thiazide diuretics.

With simultaneous use of vinorelbine and fluorouracil/folinic acid, severe inflammation of the oral and gastrointestinal mucous membranes may develop, including fatal.

In patients with breast cancer receiving combined therapy with cyclophosphamide, methotrexate, fluorouracil and tamoxifen, the risk of thromboembolic complications increases.

When using fluorouracil, false-positive results are possible when determining bilirubin and 5-hydroxyindoleacetic acid in urine.

Fluorouracil should not be mixed with solutions containing other chemotherapeutic substances.

Fluorouracil is incompatible with the following agents: cisplatin, cytarabine, diazepam, doxorubicin, droperidol, filgrastim, gallium nitrate, leucovorin, methotrexate, metoclopramide, morphine, ondansetron, parenteral nutrition solutions, vinorelbine.

Storage Conditions

Store at 15°C (59°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.