Flura-5

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLURA-5 (FLURA-5)

Composition:

Active substance: 1 ml of solution contains 50 mg of fluorouracil;

Excipients: sodium hydroxide, tromethamine, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical characteristics: colorless or almost colorless solution.

Pharmacotherapeutic group. Antineoplastic agents. Antimetabolites. Structural analogues of pyrimidine. ATC code L01B C02.

Pharmacological properties.

Pharmacodynamics.

Fluorouracil is an antineoplastic agent belonging to the group of antimetabolites. As a pyrimidine antagonist, it interferes with DNA synthesis and thereby inhibits cell division. Fluorouracil itself does not possess antineoplastic activity. Antitumor effects are manifested in the body after enzymatic transformation of fluorouracil into phosphorylated forms – 5-fluorouridine and 5-fluorodeoxyuridine.

Pharmacokinetics.

Absorption

There is a high inter- and intra-individual variability in fluorouracil absorption from the gastrointestinal tract following oral administration. Fluorouracil is also subject to "first-pass" metabolism in the liver. The bioavailability of fluorouracil ranges from 0% to 80%. Fluorouracil is administered only intravenously or intra-arterially.

5-Fluorouracil is catabolized by the enzyme dihydropyrimidine dehydrogenase (DPD) into the much less toxic dihydro-5-fluorouracil (FUH2). Dihydropyrimidinase cleaves the pyrimidine ring to form 5-fluoro-ureidopropionic acid (FUPA). Finally, β-ureidopropionase breaks down FUPA into α-fluoro-β-alanine (FBAL), which is excreted in urine. DPD activity is the rate-limiting factor in fluorouracil clearance. DPD deficiency may lead to increased toxicity of 5-fluorouracil.

Distribution

Following intravenous administration, fluorouracil is distributed throughout the body, particularly in rapidly proliferating tissues such as bone marrow, gastrointestinal mucosa, and neoplastic tissues. Fluorouracil crosses the blood-brain and placental barriers. The volume of distribution of fluorouracil is 0.12 L/kg of body weight, and plasma protein binding is approximately 10%.

Biological transformation

Metabolism of fluorouracil occurs in the liver and resembles that of uracil. Rapid enzymatic transformation of fluorouracil into the active metabolite dihydro-5-fluorouracil takes place, which has a significantly longer half-life than fluorouracil. During metabolism, non-toxic compounds such as carbon dioxide and urea are also formed.

Elimination

The mean elimination half-life of fluorouracil from plasma is 10–20 minutes and depends on the dose. Unchanged fluorouracil is not detectable in plasma 3 hours after intravenous administration.

Fluorouracil is primarily excreted via the lungs as carbon dioxide (60–80%). It is also excreted by the kidneys in unchanged form (7–20%) at a rate of approximately 170–180 mL/min. In patients with impaired renal function, elimination of fluorouracil is slower.

Clinical characteristics.

Indications.

Treatment of breast cancer and colorectal cancer (as monotherapy or in combination with other antineoplastic agents).

Treatment of gastric cancer, head and neck cancer, and pancreatic cancer.

Contraindications.

• Hypersensitivity to fluorouracil or to any component of the medicinal product.
• Significant deviations in blood cell counts.
• Bone marrow suppression, especially following radiotherapy or treatment with other antineoplastic agents.
• Pseudomembranous enterocolitis.
• Myelosuppression.
• Significant deviations in blood cell counts.
• Bleeding.
• Stomatitis, mucosal ulcers of the oral cavity and gastrointestinal tract.
• Severe diarrhea.
• Severe hepatic and/or renal dysfunction.
• Severe infectious diseases (e.g., herpes zoster, varicella).
• Severe exhaustion (cachexia).
• Plasma bilirubin level > 85 µmol/L.
• During fluorouracil treatment, vaccination with live vaccines must be avoided.
• Pregnancy or breastfeeding.
• Known complete deficiency of dihydropyrimidine dehydrogenase (DPD) enzyme activity.

Fluorouracil must not be administered concomitantly with brivudine, sorivudine, or their analogs. Brivudine, sorivudine, and analogs are potent inhibitors of the enzyme dihydropyrimidine dehydrogenase (DPD), which metabolizes fluorouracil.

In patients with dihydropyrimidine dehydrogenase (DPD) deficiency, therapeutic doses of 5-fluorouracil may lead to enhanced adverse effects. If serious adverse reactions occur, DPD enzyme activity screening may be indicated. Patients with DPD deficiency should not be treated with 5-fluorouracil.

Vaccination with live vaccines should not be administered concurrently with 5-fluorouracil therapy. All contact with oral polio vaccines should be avoided.

Note

Fluorouracil should not be administered to patients with DPD enzyme deficiency.

Special safety precautions.

As with all cytotoxic agents, handling of the drug requires adherence to safety procedures: use of protective clothing (gowns, caps, masks, goggles, and disposable gloves), preferably in a specially designated area.

Contact of fluorouracil solutions with skin or mucous membranes must be avoided. If such contact occurs, thoroughly wash with soap and water. In case of eye exposure, rinse eyes immediately with copious amounts of water and seek medical attention promptly. Pregnant healthcare personnel must not handle this drug.

Inactivation: 700 °C; sodium hypochlorite (aqueous solution of natrii hypochlorosi), diluted 10 parts with water; concentrated NaOH for several hours.

The prepared solution should be used immediately after reconstitution.

Reduced efficacy due to adsorption of 5-fluorouracil onto glass infusion containers has been reported in the scientific literature.

Appropriate regulations for handling and disposal of cytostatic agents must be followed.

Unused medicinal product or contaminated materials must be disposed of in accordance with local requirements.

Interaction with other medicinal products and other forms of interaction.

Combined therapy of fluorouracil with calcium folinate (folic acid) has been described in medical literature. The clinical consequence of this interaction may be severe, sometimes fatal, diarrhea. Increased numbers of fatal cases have been reported, particularly with regimens involving weekly intravenous (i.v.) bolus injection of 600 mg 5-fluorouracil per 1 m² body surface area in combination with calcium folinate.

The efficacy and toxicity of therapy increase when fluorouracil is used in combination with other cytotoxic agents (cyclophosphamide, vincristine, methotrexate, cisplatin, doxorubicin), interferon-α, or folic acid. When used in combination with other agents that suppress bone marrow function, dose adjustments of fluorouracil are required. Dose reductions may also be necessary during concomitant or prior radiotherapy. Fluorouracil may enhance skin radiation reactions during radiotherapy.

Cardiotoxicity of anthracyclines may be potentiated when used concomitantly with fluorouracil. Aminophenazone, phenylbutazone, and sulfonamides must not be taken before or during fluorouracil treatment. Concomitant administration of allopurinol may reduce both the toxicity and efficacy of fluorouracil therapy.

Chlordiazepoxide, disulfiram, griseofulvin, and isoniazid may enhance the therapeutic effect of fluorouracil.

Fluorouracil impairs general defense mechanisms of the body, thereby reducing immune response. Administration of live vaccines during fluorouracil therapy may lead to enhanced viral replication.

Hemolytic-uremic syndrome has been reported after prolonged treatment with fluorouracil in combination with mitomycin.

Cimetidine, metronidazole, allopurinol, and interferon may increase plasma concentrations of fluorouracil, leading to increased toxicity.

Levamisole may enhance the hepatotoxicity of fluorouracil.

Thiazides may potentiate the myelotoxicity of antineoplastic agents.

Vinorelbine in combination with fluorouracil and folic acid may cause severe mucositis.

Gemcitabine may increase systemic exposure to fluorouracil.

The enzyme dihydropyrimidine dehydrogenase (DPD) plays a key role in the metabolism of fluorouracil. Nucleoside analogs such as brivudine and sorivudine may lead to a sharp increase in plasma concentrations of fluorouracil or other fluoropyrimidines, thereby increasing toxicity. For this reason, a minimum interval of 4 weeks must be maintained between administration of fluorouracil and brivudine, sorivudine, or their analogs. If necessary, DPD enzyme activity should be tested before initiating therapy with 5-fluoropyrimidines. In case of accidental administration of brivudine to patients receiving fluorouracil therapy, effective measures must be taken immediately to reduce fluorouracil toxicity. Immediate hospitalization is recommended. All measures should focus on preventing systemic infections and dehydration.

Concomitant use of phenytoin and fluorouracil has been associated with increased plasma phenytoin levels, leading to symptoms of phenytoin intoxication.

In women receiving a thiazide diuretic in addition to cyclophosphamide, methotrexate, and fluorouracil, a greater reduction in granulocyte count has been observed compared to similar cytotoxic cycles without thiazide.

Isolated cases of decreased prothrombin time (Quick’s test) have been reported in patients receiving warfarin and additionally treated with fluorouracil as monotherapy or in combination with levamisole.

In women with breast cancer receiving a combination of cyclophosphamide, methotrexate, fluorouracil, and tamoxifen, an increased risk of thromboembolic events has been observed.

Concomitant administration of vinorelbine and fluorouracil/folic acid may lead to severe mucositis, potentially resulting in fatal outcome.

Quantitative methods for determining bilirubin and urinary 5-hydroxyindoleacetic acid may yield falsely elevated or false-positive results.

General warnings regarding cytostatics.

Cytostatic agents may reduce antibody formation following influenza vaccination. Cytostatics increase the risk of infection after vaccination with live vaccines.

Special precautions for use.

Treatment with the drug must be conducted under the supervision of a qualified oncologist experienced in the use of potent antimetabolites. Fluorouracil therapy should be initiated in an inpatient setting.

Gastrointestinal mucosal damage during fluorouracil therapy requires symptomatic management depending on severity, for example, fluid replacement. Mild diarrhea can be managed with antidiarrheal agents. However, this is insufficient for the treatment of moderate to severe diarrhea.

Prior to and during fluorouracil therapy, the following clinical evaluations should be performed:

• Daily examination of the oral cavity and pharynx to detect possible signs of mucosal damage;
• Complete blood count, including counts of blood cells and platelets, before each fluorouracil administration;
• Biochemical assessment of fluid and electrolyte balance;
• Liver function tests;
• Serum uric acid level determination;
• Fecal occult blood test.

Treatment should be immediately discontinued if any of the following symptoms occur: gastrointestinal adverse reactions (stomatitis, mucositis, severe diarrhea, severe vomiting, ulceration, bleeding), leukocyte count < 3000/μL, platelet count < 80,000/μL, adverse reactions involving the central nervous system (including ataxia and tremor), or cardiac system.

Treatment may be resumed only after resolution of adverse reactions and if the patient's general condition permits. Reinitiation of therapy is not recommended in cases of severe gastrointestinal, cardiac, or neurological toxicity.

When fluorouracil is used concomitantly with oral anticoagulants, careful monitoring of the prothrombin index (prothrombin time by Quick) is required.

Live vaccines should not be administered during fluorouracil therapy. During treatment with fluorouracil, patients should avoid contact with individuals who have received the polio vaccine.

Leukopenia typically develops during adequate fluorouracil treatment. The nadir of leukocyte count usually occurs on days 7 and 14 of the first treatment cycle, although occasionally it may occur up to 20 days after administration. Leukocyte counts usually return to normal by day 30.

Daily monitoring of platelet and leukocyte counts is recommended. Treatment should be discontinued if platelet count falls below < 100 × 10⁹/L or leukocyte count below < 3 × 10⁹/L. If leukocyte count decreases below 2 × 10⁹/L, especially in the presence of granulocytopenia, hospitalization in an isolation unit is recommended, along with measures to prevent systemic infections. Treatment should also be discontinued at the first signs of stomatitis or oral ulceration, severe diarrhea, gastrointestinal ulceration, gastrointestinal bleeding, or any bleeding or hemorrhage regardless of location.

Fluorouracil has a narrow "therapeutic window"—the difference between therapeutic and toxic doses is small. Achieving a therapeutic effect without some degree of toxicity is unlikely; therefore, careful patient selection and dose adjustment are essential. Fluorouracil should be administered with caution in patients with impaired renal or hepatic function, or jaundice. Caution is also required when treating patients who experienced chest pain during previous treatment cycles or those with a history of cardiac disease. In cases of severe cardiotoxicity, fluorouracil therapy should be discontinued. Fluorouracil may exert cardiotoxic effects even in patients without a history of heart disease.

Special caution is required when treating high-risk patients (those who have received high-dose pelvic radiotherapy, alkylating agents, or those who have undergone adrenalectomy or hypophysectomy).

When used in combination with methotrexate, to achieve optimal efficacy, methotrexate should not be administered within 24 hours prior to 5-fluorouracil (not the reverse!).

Patients with dihydropyrimidine dehydrogenase (DPD) deficiency or low DPD activity, regardless of cause (including after use of DPD inhibitors such as eniluracil or the antiviral agent sorivudine), are at particularly high risk of developing severe and prolonged adverse reactions during 5-fluorouracil treatment. Therefore, initial screening for DPD activity is recommended. If severe adverse reactions occur soon after initiation of 5-fluorouracil therapy, DPD deficiency should be considered. Patients with DPD deficiency should not be treated with 5-fluorouracil.

Due to the potential for anaphylactic reactions, measures for shock management should be available before administering 5-fluorouracil.

5-Fluorouracil may be mutagenic. Male patients undergoing treatment with 5-fluorouracil are advised to avoid fathering a child during treatment and for 6 months after treatment ends, and to seek medical advice regarding sperm cryopreservation due to the potential for severe impairment of spermatogenesis. Female patients should not become pregnant during 5-fluorouracil therapy—effective contraception should be used.

When planning pregnancy after discontinuation of treatment, genetic counseling is recommended.

Gastrointestinal mucosal damage requires symptomatic management depending on severity, for example, fluid replacement. Mild diarrhea may be managed with antidiarrheal agents. However, these are insufficient for moderate to severe diarrhea.

Patients should be additionally warned about the possible development of stomatitis/mucositis, diarrhea, and bleeding (particularly gastrointestinal). Medical attention should be sought promptly upon onset of any symptoms.

Cardiotoxicity

Cardiotoxicity associated with fluoropyrimidine therapy includes myocardial infarction, angina, arrhythmias, myocarditis, cardiogenic shock, sudden death, stress-induced cardiomyopathy (Takotsubo syndrome), and electrocardiographic changes (including very rare cases of QT prolongation). These adverse effects occur more frequently in patients receiving continuous infusion 5-fluorouracil rather than bolus injections. A history of ischemic heart disease may be a risk factor for cardiovascular adverse reactions. Therefore, caution is warranted in patients reporting chest pain during treatment or those with a history of cardiac disease. Cardiac function should be monitored regularly during fluorouracil therapy. In case of severe cardiotoxicity, treatment should be discontinued.

Encephalopathy

Post-marketing experience has reported cases of encephalopathy (including hyperammonemic encephalopathy, leukoencephalopathy, posterior reversible encephalopathy syndrome, and Wernicke's encephalopathy) associated with 5-fluorouracil treatment. Symptoms of encephalopathy include altered mental status, confusion, disorientation, coma, or ataxia. If any of these symptoms develop, treatment should be immediately suspended, and serum ammonia and vitamin B1 levels should be evaluated. Appropriate therapy should be initiated if elevated ammonia or vitamin B1 deficiency is detected. Hyperammonemic encephalopathy often occurs concurrently with lactic acidosis.

Caution is required when administering fluorouracil to patients with impaired renal and/or hepatic function, as they may be at increased risk of hyperammonemia and hyperammonemic encephalopathy.

Tumor lysis syndrome

Post-marketing experience has reported cases of tumor lysis syndrome associated with fluorouracil use. Close monitoring is required in patients at increased risk of tumor lysis syndrome (e.g., patients with renal impairment, hyperuricemia, high tumor burden, or rapidly progressing disease). Preventive measures (such as hydration and correction of elevated uric acid levels) should be considered.

Deficiency of dihydropyrimidine dehydrogenase (DPD)

The enzyme dihydropyrimidine dehydrogenase (DPD) plays a key role in the metabolism of 5-fluorouracil. Nucleoside analogs such as brivudine and sorivudine may increase plasma concentrations of 5-fluorouracil and other fluoropyrimidines, thereby increasing their toxicity.

Therefore, an interval of at least 4 weeks should be maintained between administration of 5-fluorouracil and brivudine, sorivudine, eniluracil, or related analogs.

Testing for DPD deficiency

Phenotypic and/or genotypic testing is recommended before initiating 5-fluorouracil therapy, despite uncertainties regarding optimal pre-treatment testing methods. Relevant clinical guidelines should be considered. Impaired renal function may elevate blood uracil levels, increasing the risk of misdiagnosis in patients with partial or severe renal impairment.

In cases of accidental administration of brivudine to patients receiving 5-fluorouracil, effective measures to reduce 5-fluorouracil toxicity should be taken. Immediate hospitalization is recommended. All possible measures should be taken to prevent systemic infections and dehydration.

Rare, unexpected, and severe toxicity (e.g., stomatitis, diarrhea, mucositis, neutropenia, neurotoxicity) associated with 5-FU is explained by limited DPD activity. Patients with low or absent DPD activity—the enzyme responsible for fluorouracil clearance—are at increased risk of severe, life-threatening, or fatal adverse reactions. Although DPD deficiency cannot always be precisely determined, it is known that patients with certain homozygous or specific heterozygous mutations in the DPYD gene (e.g., DPYD*2A, c.1679T>G, c.2846A>T, and c.1236G>A/HapB3), which may result in complete or near-complete absence of DPD enzymatic activity (as confirmed by laboratory testing), are at the highest risk of life-threatening or fatal adverse reactions and should not be treated with fluorouracil. Standard dosing has not been proven safe in patients with complete absence of DPD activity.

It has been demonstrated that patients with certain heterozygous DPYD variants (including DPYD*2A, c.1679T>G, c.2846A>T, and c.1236G>A/HapB3) have an increased risk of severe toxicity during fluoropyrimidine treatment.

The frequency of the heterozygous DPYD*2A genotype in Caucasian patients is approximately 1%, 1.1% for c.2846A>T, 2.6–6.3% for c.1236G>A/HapB3 variants, and 0.07–0.1% for c.1679T>G. Genotyping for these alleles is recommended to identify patients at increased risk of severe toxicity. Data on the frequency of these DPYD variants in non-Caucasian populations are limited. Other rare variants may also be associated with increased risk of severe toxicity.

For patients with partial DPD deficiency (e.g., heterozygous mutations in the DPYD gene) where the benefit of 5-fluorouracil treatment outweighs the risks (considering the suitability of alternative non-fluoropyrimidine chemotherapy regimens), treatment should be administered with particular caution, under continuous monitoring, and with dose adjustments based on toxicity. A reduced initial dose should be considered in such patients to prevent severe toxicity. Insufficient data exist to recommend a specific dose for patients with partially reduced DPD activity confirmed by specific testing. The DPYD*2A and c.1679T>G variants are associated with greater reduction in enzymatic activity and higher risk of adverse effects compared to other variants. The impact of dose reduction on efficacy is currently unknown. Therefore, dose escalation may be considered in the absence of severe toxicity, provided the patient is closely monitored. Patients with a negative test for the aforementioned alleles may still be at risk of developing severe adverse effects.

Life-threatening toxicity, manifesting as acute overdose, may occur in patients with undetermined DPD deficiency who have received 5-fluorouracil, as well as in patients with negative testing for specific DPYD variants. In cases of acute toxicity of grade 2–4, treatment must be immediately suspended. The decision to permanently discontinue the drug should be based on clinical assessment of the onset, duration, and severity of observed toxicity.

Phenotypic characterization of DPD deficiency

For phenotypic assessment of DPD deficiency, measurement of plasma levels of the endogenous DPD substrate uracil (U) prior to treatment initiation is recommended. Elevated pre-treatment uracil levels are associated with increased risk of toxicity. Although definitive threshold values for uracil levels defining complete or partial DPD deficiency have not been established, a plasma uracil level ≥ 16 ng/mL and < 150 ng/mL should be considered indicative of partial DPD deficiency and associated with increased risk of fluoropyrimidine toxicity. A plasma uracil level ≥ 150 ng/mL should be considered indicative of complete DPD deficiency and associated with life-threatening or fatal fluoropyrimidine toxicity. Uracil levels in patients with renal impairment should be interpreted with caution (see "Testing for DPD deficiency" above).

Use during pregnancy or breastfeeding.

Pregnancy. The drug must not be used during pregnancy. Women of childbearing potential should use effective contraception. If pregnancy occurs during treatment, genetic counseling is recommended. 5-Fluorouracil may cause potentially severe fetal harm when administered during pregnancy.

Breastfeeding. The drug must not be used during breastfeeding.

Fertility. Fluorouracil may have a negative impact on the reproductive system. Men receiving fluorouracil therapy are advised not to father children during treatment and for 6 months after treatment completion. Men should be advised to consult specialists about sperm cryopreservation before starting treatment, as fluorouracil use may lead to irreversible infertility.

Ability to affect reaction speed when driving or operating machinery.

Fluorouracil may cause nausea and vomiting, thereby impairing the ability to drive or operate machinery. Patients should refrain from driving and operating complex machinery while receiving fluorouracil therapy.

Administration and Dosage

Doses and treatment regimens are determined individually depending on the patient's condition and type of cancer, as well as whether Fluora-5 is used as monotherapy or in combination with other treatments. The exact dosage should be obtained from therapeutic protocols proven effective in treating the specific disease.

Treatment with Fluora-5 should be initiated under hospital conditions. The total daily dose for adults should not exceed 1 g.

Typically, doses for adults are calculated per 1 kg of actual body weight; however, for patients with excessive body weight, edema, ascites, or other forms of pathological fluid retention, doses should be calculated based on ideal body weight.

The drug should be administered via intravenous injection, intravenous infusion, or intra-arterial infusion.

Below are approximate dosage recommendations.

Treatment of colorectal cancer

During the initial course of therapy, the drug may be administered via intravenous infusion or injection. Infusions are preferred, as they result in fewer toxic effects.

Intravenous infusions. A daily dose of 15 mg/kg body weight (600 mg/m² body surface area), but not exceeding 1 g per infusion, should be diluted in 300–500 mL of 5% glucose solution or 0.9% sodium chloride solution. The infusion solution should be administered intravenously over 4 hours. The same dose should be given on subsequent days until toxic effects appear or the total cumulative dose reaches 12–15 g. Some patients have received up to 30 g of fluorouracil, at 1 g per day (maximum daily dose). If adverse hematological or gastrointestinal side effects occur, the next dose should be delayed until hematological parameters normalize and toxic effects resolve. Alternatively, the drug may be administered via continuous 24-hour intravenous infusions.

Intravenous injections. 12 mg/kg body weight (480 mg/m² body surface area) should be administered daily via intravenous injection for 3 consecutive days. If signs of toxicity occur, the drug may be continued at a dose of 6 mg/kg body weight (240 mg/m² body surface area) on days 5, 7, and 9 of the cycle. For maintenance therapy, administer 5–10 mg/kg body weight (200–400 mg/m² body surface area) once weekly.

If adverse side effects occur, the next administration should be postponed until toxic effects subside.

Treatment of breast cancer

For treatment of breast cancer, the drug should be used in combination with other chemotherapeutic agents, for example, methotrexate and cyclophosphamide or doxorubicin and cyclophosphamide.

In such treatment regimens, the drug should be administered intravenously at 10–15 mg/kg body weight (400–600 mg/m² body surface area) on day 1 and day 8 of a 28-day cycle.

The drug may also be administered via continuous 24-hour intravenous infusions, with the usual dose being 8.25 mg/kg body weight (350 mg/m² body surface area).

Other administration methods

Intra-arterial infusions. A daily dose of 5–7.5 mg/kg body weight (200–300 mg/m² body surface area) should be administered via continuous 24-hour intra-arterial infusion. In some cases, regional intra-arterial infusions may be used for treatment of primary tumors or metastases.

Special patient groups

Dose reduction is recommended in cases of cachexia, major surgical procedures within the previous 30 days, bone marrow suppression, or impaired liver or kidney function.

Dose adjustment is not required for elderly patients.

Instructions for personnel

The solution should be drawn from the vial immediately before use. If a precipitate forms due to cooling, it should be dissolved by heating to 60°C and vigorous shaking. Before administration, the solution should be cooled to body temperature.

Children.

Guidelines for fluorouracil treatment in children have not been established.

Overdose.

Symptoms

Acute: Psychotic reactions, drowsiness, enhanced effects of sedatives, increased toxicity of alcohol.

If sedation is required, diazepam may be administered intravenously in small doses (e.g., starting at 5 mg), with continuous monitoring of cardiovascular and respiratory functions.

Chronic: Bone marrow suppression, potentially progressing to agranulocytosis and severe thrombocytopenia, tendency to bleeding, gastrointestinal ulcers, diarrhea, alopecia.

Signs of intoxication: The following adverse reactions occur with increasing overdose:

• Nausea;
• Vomiting;
• Diarrhea;
• Severe mucosal inflammation;
• Gastrointestinal ulceration and gastrointestinal bleeding;
• Myelosuppression (thrombocytopenia, leukopenia, agranulocytosis).

Treatment

There is no specific antidote for fluorouracil. As a preventive measure, transfusions of leukocyte or platelet concentrates may/should be used. Adequate hydration and diuresis should be maintained, and electrolyte imbalances should be corrected. Hemodialysis is usually not required. The patient should remain under close medical supervision to detect hematological and delayed gastrointestinal complications as early as possible. Further treatment is symptomatic.

If signs of intoxication occur, fluorouracil administration should be stopped immediately. Symptomatic therapeutic measures should be initiated promptly.

Severe myelosuppression should be treated in a hospital setting. Treatment of myelosuppression includes, if necessary, replacement of lost blood components and antibacterial therapy. Placement of the patient in a sterile environment may be required.

Hematological monitoring should be continued for 4 weeks after an overdose event.

If continuation of 5-fluorouracil therapy is necessary despite cardiac side effects, vasodilators should be prescribed to prevent coronary artery spasm.

Adverse Reactions

The most common and serious adverse reactions associated with fluorouracil use are toxic effects on the bone marrow and gastrointestinal disturbances.

Infections and infestations

Infections, fever, infectious diseases, sepsis.

Blood and lymphatic system disorders

Myelosuppression (one of the dose-limiting toxicities), neutropenia and thrombocytopenia (both ranging from moderate to very severe), leukopenia, agranulocytosis, anemia, febrile neutropenia, immunosuppression, epistaxis, and pancytopenia.

Leukopenia is most pronounced 9–14 days after administration; white blood cell counts usually return to normal within 30 days.

The severity (NCI grades I–IV, according to the U.S. National Cancer Institute scale) of myelosuppression depends on the route of administration (intravenous bolus or continuous intravenous infusion) and dosage. Neutropenia develops after each therapeutic cycle with intravenous bolus administration of fluorouracil at appropriate doses (maximum decrease in neutrophil counts: on day 9–14 (–20) of treatment; recovery to normal levels: usually after day 30).

Immune system disorders

Immunosuppression with increased susceptibility to infections. Generalized allergic reactions, anaphylaxis, and anaphylactic shock may occur.

Metabolic and nutritional disorders

Hyperuricemia.

The risk of developing severe and prolonged adverse reactions shortly after initiation of fluorouracil therapy is highest in patients with low dihydropyrimidine dehydrogenase (DPD) activity (due to any cause, including use of DPD inhibitors such as eniluracil or the antiviral agent sorivudine).

DPD activity should be monitored at the beginning of treatment.

Frequency unknown – lactic acidosis, tumor lysis syndrome, hypertriglyceridemia, vitamin B1 deficiency.

Psychiatric disorders

Confusion.

Nervous system disorders

A transient reversible cerebral syndrome may occur, characterized by ataxia, confusion, extrapyramidal and corticospinal motor disturbances, nystagmus, headache, dizziness, Parkinson-like symptoms, pyramidal signs, euphoria, somnolence, disorientation, acute cerebellar syndrome.

Dysgeusia, peripheral neuropathy. Cases of leukoencephalopathy symptoms, including reversible ataxia after immediate discontinuation, have been reported.

Speech difficulties, acute cerebellar syndrome, dysarthria, confusion, disorientation, myasthenia, aphasia, seizures, or coma have been reported in patients receiving high-dose 5-fluorouracil, as well as in patients with dihydropyrimidine dehydrogenase deficiency, renal insufficiency, or hyperammonemic encephalopathy.

Symptoms of leukoencephalopathy such as memory loss, paresthesia, lethargy, muscle weakness, speech disturbances, coma, and seizures have been reported. The risk of leukoencephalopathy is higher in patients with dihydropyrimidine dehydrogenase deficiency. Diffusion-weighted imaging is recommended for diagnosis of leukoencephalopathy. Cases of cerebral infarction have been observed during combination chemotherapy (particularly fluorouracil in combination with mitomycin C or cisplatin).

Frequency unknown – posterior reversible encephalopathy syndrome, Wernicke's encephalopathy.

Ophthalmological disorders

Excessive tearing and lacrimal duct stenosis, blurred vision, ocular motor disturbances, optic neuritis, diplopia, decreased visual acuity, photophobia, conjunctivitis, blepharitis, cicatricial ectropion, fibrosis of lacrimal canaliculi, cataract, blindness (at high doses).

Cardiac disorders

ECG changes typical of ischemia, chest pain resembling angina, arrhythmia, myocardial infarction, myocardial ischemia, myocarditis, heart failure, dilated cardiomyopathy, and cardiogenic shock, cardiac arrest, and sudden cardiac death.

Cardiotoxic adverse effects predominantly occur during or within a few hours after the first therapeutic cycle.

Patients with pre-existing ischemic heart disease or cardiomyopathy are at higher risk of developing cardiotoxic adverse effects.

Pericarditis.

Frequency unknown – stress-induced cardiomyopathy (Takotsubo syndrome).

Vascular disorders

Epistaxis, arterial hypotension, thrombophlebitis, cerebral ischemia, intestinal ischemia, peripheral ischemia, Raynaud's syndrome, thromboembolism, venous dilation, peripheral neuropathy, vasculitis.

Respiratory system disorders

Bronchospasm, pneumonitis (cough, dyspnea).

Gastrointestinal disorders

Gastrointestinal disturbances are very common and may be life-threatening.

Mucosal inflammation (e.g., stomatitis, esophagitis, pharyngitis, proctitis). Diarrhea, heartburn, taste disturbances, anorexia, watery diarrhea, nausea, vomiting (can be managed with antiemetic and antidiarrheal agents). Gastrointestinal ulceration, gastrointestinal hemorrhage, dehydration, sepsis, ulcer formation, gastrointestinal bleeding, and expulsion of necrotic material.

Severe proctitis and diarrhea, nausea, and vomiting have been reported, progressing from mild to very severe.

The severity (NCI grades I–IV) of gastrointestinal adverse effects depends on the route of administration and dosage. When continuous infusion is used for fluorouracil administration, stomatitis more frequently becomes the dose-limiting toxicity than myelosuppression.

Frequency unknown – intestinal pneumatosis, enterocolitis, colitis (including necrotizing colitis).

Hepatobiliary disorders

Hepatic cytolysis syndrome. Liver necrosis (sometimes fatal), biliary sclerosis, cholecystitis. Cases of hepatocellular damage and isolated cases of liver necrosis, sometimes fatal, have been observed.

Skin and subcutaneous tissue disorders

Alopecia (reversible). Dermatitis, delayed wound healing, skin changes (e.g., dryness, fissures, erosions, erythema, rash, pruritus, photosensitivity, skin allergic reactions, pigmentation, hyperpigmentation or depigmentation in streaks near veins), nail changes (e.g., diffuse blue surface pigmentation, hyperpigmentation), nail loss, nail dystrophy, pain and thickening of the nail plate (paronychia), onycholysis, telangiectasia, urticaria. A notable complication associated with high-dose bolus administration and prolonged continuous infusions of fluorouracil is hand-foot syndrome (palmar-plantar erythrodysesthesia).

The syndrome begins with dysesthesia of palms and soles, progressing to redness, pain, peeling, and tenderness. Concomitant symmetrical swelling and erythema of palms and soles occur. The so-called "hand-foot syndrome" is characterized by dysesthesia, redness, swelling, pain, and peeling of the skin on palms and soles and occurs very frequently after continuous intravenous infusion and frequently after intravenous bolus injection.

Frequency unknown – cutaneous lupus erythematosus.

Musculoskeletal and connective tissue disorders

Nasal bone necrosis, muscle weakness.

Renal and urinary system disorders

Renal failure, hyperuricemia.

Endocrine system disorders

Elevated serum total thyroxine (T4) and total triiodothyronine (T3) levels without increased free T4 or TSH, in the absence of clinical signs of hyperthyroidism.

Reproductive system disorders

Impairment of spermatogenesis and ovulation.

General disorders and administration site conditions

Increased fatigue, exhaustion, general asthenia, apathy, fever, injection site reactions.

Frequency unknown — local reaction due to extravasation (pain, swelling, erythema).

Laboratory findings

Isolated cases of prolonged prothrombin time have been reported during concomitant use of fluorouracil and warfarin.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25°C. Keep out of reach of children.

Incompatibilities.

The medicinal product must be diluted with 0.9% sodium chloride solution or 5% glucose solution.

No incompatibility has been detected with any of the tested carrier solutions.

Incompatibilities reported with the following substances

Cisplatin, cytarabine, diazepam, doxorubicin, droperidol, filgrastim, gallium nitrate, leucovorin, methotrexate, metoclopramide, morphine, ondansetron, parenteral nutrition solutions, vinorelbine.

Compatibility with calcium folinate

A mixture of 1000 mg calcium folinate (100 mL of 10 mg/mL calcium folinate), 5000 mg Fluri-5 (100 mL of 50 mg/mL Fluri-5), and 40 mL of 0.9% sodium chloride solution is stable in an infusion pump (e.g., "Easy pump" type) at room temperature for 48 hours.

The drug must not be mixed with other medicinal products in the same container.

Packaging. 5 mL or 10 mL in a vial; 1 vial per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Venus Remedies Limited.

Venus Remedies Limited.

Manufacturer's address and place of business.

Hill Top Industrial Estate, Jharmajri, EPIP Phase-I (Extn.), Bhatoli Kalan, Baddi, Distt. Solan, Himachal Pradesh, 173205, India.