Fluorouracil-farmeks

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FTOURACIL-PHARMEKS (FLUOROURACIL-PHARMEX)

Composition:

Active substance: fluorouracil (fluorouracil);

1 ml of concentrate for infusion solution contains 50 mg of fluorouracil;

Excipients: sodium hydroxide, water for injections.

Pharmaceutical form. Concentrate for infusion solution.

Main physicochemical properties: clear, colorless or slightly yellowish liquid.

Crystalline precipitate may form if stored below 15 °C. The precipitate can be redissolved by heating the vial containing the product to 60 °C in a water bath, accompanied by vigorous shaking. Cool to body temperature before administration.

Pharmacotherapeutic group. Antineoplastic agents. Antimetabolites. Pyrimidine analogues. ATC code L01B C02.

Pharmacological properties.

Pharmacodynamics.

Fluorouracil is an antineoplastic agent of the antimetabolite group. As a pyrimidine antagonist, it interferes with DNA synthesis and thereby inhibits cell division. Fluorouracil itself does not exhibit 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 high inter- and intra-individual variability in fluorouracil absorption from the gastrointestinal tract following oral administration. Fluorouracil also undergoes extensive first-pass metabolism in the liver. Its bioavailability ranges from 0 to 80%. Fluorouracil is therefore approved only for intravenous and intra-arterial administration.

5-Fluorouracil is catabolized by the enzyme dihydropyrimidine dehydrogenase (DPD) to dihydro-5-fluorouracil (FUH2), which is significantly less toxic. Dihydropyrimidinase then 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

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

Biological transformation

Metabolism of fluorouracil occurs primarily in the liver and is similar to that of uracil. Rapid enzymatic conversion of fluorouracil into its active metabolite dihydro-5-fluorouracil occurs, 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 is dose-dependent. Unchanged fluorouracil is no longer detectable in plasma 3 hours after intravenous administration.

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

Clinical characteristics.

Indications.

Adjuvant or palliative treatment of:

• advanced colorectal cancer;
• advanced gastric cancer;
• advanced pancreatic cancer;
• advanced and/or metastatic breast cancer;
• advanced head and neck tumors.

Contraindications.

• Hypersensitivity to fluorouracil or to any of the components of the drug.
• Significant abnormalities in blood cell counts.
• Bone marrow suppression, particularly following radiotherapy or treatment with other antineoplastic agents.
• Bleeding.
• Severe impairment of liver and/or kidney function.
• Severe infectious diseases (e.g., herpes zoster, varicella).
• Stomatitis, mucosal ulcers of the mouth and gastrointestinal tract.
• Pseudomembranous enterocolitis.

-Myelosuppression.

• Severe diarrhea.
• 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) 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 degrades fluorouracil.

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

Live vaccination should not be administered concurrently with 5-fluorouracil therapy. All contact with polio vaccines should be avoided.

Special safety precautions.

As with handling other cytotoxic agents, safety precautions must be observed when manipulating Fluorouracil-Pharmex: protective clothing (gowns, caps, masks, goggles, and disposable gloves) should be used, and handling should be performed, if possible, in a specially designated area.

Contact of fluorouracil solution with skin and mucous membranes must be avoided. If such contact occurs, the affected areas should be thoroughly washed with soap and water. In case of contact with the eyes, they should be rinsed immediately with copious amounts of water and medical advice sought promptly. Pregnant healthcare personnel must not handle the drug.

Inactivation: 700 °C; sodium hypochlorite diluted with 10 parts water; concentrated NaOH for several hours.

The prepared solution should be used immediately after preparation.

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

Handling and disposal regulations for 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.

Combination 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 in association with the administration regimen of intravenous bolus injection of 600 mg fluorouracil per square meter of body surface area once weekly in combination with calcium folinate.

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

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

In women who received a thiazide-type diuretic in addition to cyclophosphamide, methotrexate, and fluorouracil, a greater reduction in granulocyte count was observed compared to similar cycles of cytostatics without thiazide.

Isolated cases of decreased prothrombin time (Quick) have been reported in patients receiving warfarin who additionally received fluorouracil as monotherapy or in combination with levamisole.

Cardiotoxicity of anthracyclines may be enhanced when used in combination with fluorouracil. Aminophenazone, phenylbutazone, and sulfonamides must not be taken before or during fluorouracil treatment. Concurrent use of allopurinol may reduce the toxicity and efficacy of fluorouracil therapy.

Chlordiazepoxide, disulfiram, griseofulvin, and isoniazid may enhance the efficacy of fluorouracil therapy.

Fluorouracil suppresses general defense mechanisms of the body, thus reducing immune response. Administration of live vaccines during fluorouracil treatment may lead to enhanced viral replication.

Development of hemolytic-uremic syndrome has been reported after prolonged treatment with fluorouracil in combination with mitomycin.

Levamisole may enhance the hepatotoxicity of fluorouracil.

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

Gemcitabine may increase systemic exposure to fluorouracil.

The DPD enzyme plays a key role in the metabolism of fluorouracil. Nucleoside analogs such as brivudine and sorivudine may lead to a sudden increase in plasma concentration of fluorouracil or other fluoropyrimidines, thereby increasing toxicity accordingly. For this reason, a minimum interval of four weeks must be maintained between administration of fluorouracil and brivudine, sorivudine, or their analogs. If necessary, testing of DPD enzyme activity should be performed before initiating therapy with fluoropyrimidines. In case of accidental administration of brivudine to patients receiving fluorouracil treatment, effective measures must be taken to reduce fluorouracil toxicity. Immediate hospitalization is recommended. All measures should aim at preventing systemic infections and dehydration.

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

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

When vinorelbine and fluorouracil/folic acid are used concomitantly, severe mucositis may develop, potentially leading to fatal outcome.

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

General guidelines for cytostatic agents.

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

Special precautions for use.

Treatment with Fluorouracil-Pharmex should be carried out under the supervision of a qualified oncologist experienced in the use of potent antimetabolites. Treatment with fluorouracil should be initiated in a hospital setting.

Gastrointestinal wall damage during fluorouracil therapy requires symptomatic management depending on the 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 examinations 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;
• Measurement of serum uric acid levels;
• Fecal occult blood test.

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

Careful monitoring of the prothrombin index (prothrombin time according to Quick) is required when fluorouracil is used concomitantly with oral anticoagulants.

Live vaccines should not be administered during fluorouracil therapy. Patients should avoid contact with individuals who have recently received oral polio vaccine during treatment with fluorouracil.

Leukopenia typically develops during adequate fluorouracil therapy. The lowest leukocyte count usually occurs around days 7 and 14 of the first treatment cycle, although it may sometimes 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 x 10⁹/L or leukocyte count below < 3 x 10⁹/L. If leukocyte count decreases below 2 x 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 in the event of hemorrhage or bleeding at any site.

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, as well as in patients with jaundice. Caution is also required when treating patients who have experienced chest pain during previous treatment cycles or those with a history of cardiovascular disease. In cases of severe cardiotoxicity, fluorouracil therapy must be discontinued. Fluorouracil may exert cardiotoxic effects even in patients without a history of heart disease.

Particular 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 combining fluorouracil with methotrexate, methotrexate should not be administered within 24 hours before fluorouracil (not vice versa) to achieve optimal efficacy.

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 fluorouracil therapy. Therefore, initial screening for DPD activity is recommended. If severe adverse reactions occur soon after initiating fluorouracil therapy, DPD deficiency should be considered. Patients with DPD deficiency should not be treated with fluorouracil.

Due to the risk of anaphylactic reactions, appropriate resuscitation measures must be available before administering fluorouracil.

Fluorouracil may be mutagenic. Male patients undergoing fluorouracil therapy should avoid fathering a child during treatment and for 6 months after treatment ends, and should seek medical advice regarding sperm preservation due to the potential for severe impairment of spermatogenesis. Female patients should avoid pregnancy during fluorouracil therapy and must use effective contraception.

Genetic counseling is recommended when planning pregnancy after discontinuation of treatment.

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

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

Cardiotoxicity

Cardiotoxicity associated with fluoropyrimidine therapy includes myocardial infarction, angina pectoris, 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 some cardiovascular adverse reactions. Therefore, caution is advised in patients reporting chest pain during treatment and in those with a history of cardiac disease. Cardiac function should be monitored regularly during fluorouracil therapy. In cases of severe cardiotoxicity, treatment must be discontinued.

Encephalopathy

Post-marketing experience has reported cases of encephalopathy (including hyperammonemic encephalopathy, leukoencephalopathy, posterior reversible encephalopathy syndrome (PRES), and Wernicke's encephalopathy) associated with 5-fluorouracil therapy. Signs or 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. If serum ammonia is elevated or vitamin B1 deficiency is present, appropriate therapy should be initiated. 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.

Deficiency of dihydropyrimidine dehydrogenase (DPD)

The enzyme dihydropyrimidine dehydrogenase (DPD) plays a key role in the degradation of 5-fluorouracil. Nucleoside analogs, such as brivudine and sorivudine, can 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 similar agents.

If necessary, DPD enzyme activity should be assessed before initiating 5-fluorouracil. In cases of accidental administration of brivudine to patients receiving 5-fluorouracil, effective measures to reduce 5-fluorouracil toxicity should be implemented. Immediate hospitalization is recommended. All possible measures should be taken to prevent systemic infections and dehydration.

Testing for DPD deficiency

Phenotypic and/or genotypic testing is recommended before initiating treatment with 5-fluorouracil, despite uncertainties regarding optimal testing methodologies. Relevant clinical guidelines should be considered.

Impaired renal function may lead to elevated blood uracil levels, increasing the risk of diagnostic errors in patients with DPD deficiency who also have moderate to severe renal impairment.

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 eliminating fluorouracil—are at increased risk of severe, life-threatening, or fatal adverse reactions caused by fluorouracil. Although DPD deficiency cannot always be precisely determined, 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 evidenced by laboratory testing), have the highest risk of life-threatening or fatal adverse reactions and should not be treated with 5-fluorouracil. The recommended dosing has not been proven safe in patients with complete absence of DPD activity.

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 therapy.

The frequency of the heterozygous DPYD*2A genotype in patients of Caucasian descent is approximately 1%, 1.1% for c.1679T>G, 2.6–6.3% for c.1236G>A/HapB3 variants, and 0.07–0.1% for c.2846A>T. 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 an increased risk of serious toxicity.

For patients with partial DPD deficiency (e.g., heterozygous mutations in the DPYD gene) in whom the benefit of 5-fluorouracil therapy outweighs the risks (considering the suitability of alternative non-fluoropyrimidine chemotherapy regimens), treatment should be administered with special caution, under continuous monitoring, and with dose adjustments based on toxicity. A reduced initial dose should be considered for such patients to prevent serious toxicity. Insufficient data exist to recommend a specific dose for patients with partially confirmed DPD activity via specific testing. The DPYD*2A and c.1679T>G variants have been reported to cause greater reduction in enzymatic activity compared to other variants, with higher risk of adverse effects. The impact of dose reduction on efficacy is currently unknown. Therefore, if no serious toxicity occurs, the dose may be increased under careful patient monitoring. Patients with a negative test for the above-mentioned 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 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), is recommended before initiating treatment. Elevated uracil concentrations prior to treatment are associated with an increased risk of toxicity. Despite uncertainty regarding threshold values defining complete or partial DPD deficiency, a plasma uracil level ≥ 16 ng/mL and < 150 ng/mL should be considered indicative of partial DPD deficiency and associated with an 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 should be interpreted cautiously in patients with impaired renal function (see "Testing for DPD deficiency" above).

Tumor lysis syndrome

Post-marketing reports have documented cases of tumor lysis syndrome associated with fluorouracil use. Patients at increased risk of tumor lysis syndrome (particularly those with renal impairment, hyperuricemia, high tumor burden, or rapidly progressing disease) should be closely monitored. Preventive measures (such as hydration and correction of elevated uric acid levels) should be considered.

Fluorouracil-Pharmex contains the following amount of sodium:

5 mL of solution contains 1.7 mmol (or 39.1 mg) of sodium;

10 mL of solution contains 3.4 mmol (or 78.2 mg) of sodium;

Caution is advised when administering to patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Pregnancy. Fluorouracil-Pharmex must not be used during pregnancy. Women of reproductive potential must use effective contraception. If pregnancy occurs during treatment, genetic counseling is recommended. 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 should avoid fathering a child during treatment and for 6 months after treatment ends. Men should be advised to consult specialists about sperm cryopreservation before starting treatment, as fluorouracil 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 receiving fluorouracil therapy should refrain from driving and operating complex machinery.

Administration and Dosage

The dosage and treatment regimen are determined individually by a physician depending on the patient's condition and type of cancer, as well as whether Fluorouracil-Pharmex is used as monotherapy or in combination with other treatments. For precise dosing, refer to therapeutic protocols proven effective in treating the specific disease.

Initiation of treatment with Fluorouracil-Pharmex must be performed 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, in patients with excess body weight, edema, ascites, or other forms of pathological fluid retention, doses should be calculated based on ideal body weight.

Fluorouracil-Pharmex is administered via intravenous (i.v.) injections, intravenous infusions, or intra-arterial infusions.

Below are general dosage recommendations.

Initial therapy with daily administration:

• As an i.v. infusion: 15 mg/kg or 600 mg/m² over 4 hours daily until side effects appear;
• As an i.v. injection: slow i.v. injection (over 2–3 minutes) of 12 mg/kg or 480 mg/m² on days 1, 2, and 3.

If no signs of toxicity are observed, administer 6 mg/kg or 240 mg/m² on days 5, 7, and 9.

Initial weekly therapy:

Slow i.v. injection of 15 mg/kg or 600 mg/m² once weekly.

Maintenance therapy:

Once remission is achieved or after reduction of side effects—specifically when white blood cell count increases to 3000–4000/µL and platelet count to 80,000–100,000/µL—administer 5–10 mg/kg or 200–400 mg/m² i.v. once weekly.

The maximum daily dose should not exceed 1 g. All doses are intended for patients with normal body weight. Dose adjustments are required for obese patients, or those with ascites or edema.

When fluorouracil is combined with other cytostatic agents having a similar side effect profile or with radiation therapy, the dose should be appropriately reduced. In such cases, the drug should be administered as a 24-hour continuous intravenous infusion.

Treatment of colorectal cancer

During the initial treatment course, the drug may be administered via infusion or injection. Infusion is preferred, as it results in fewer toxic effects.

Intravenous infusions. Daily dose of 15 mg/kg body weight (600 mg/m² body surface area), but not exceeding 1 g per infusion, 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. Continue administration at the same dose daily until toxic effects appear or until the 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, further administration should be postponed until hematological parameters recover and toxic effects resolve. Alternatively, Fluorouracil-Pharmex may be administered via continuous 24-hour intravenous infusion.

Intravenous injections. Administer 12 mg/kg body weight (480 mg/m² body surface area) daily via intravenous injection for 3 consecutive days. If no signs of toxicity are observed, continue with 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, further administration should be postponed until toxic effects subside.

Treatment of breast cancer

For treatment of breast cancer, Fluorouracil-Pharmex should be used in combination with other chemotherapeutic agents, such as methotrexate and cyclophosphamide, or doxorubicin and cyclophosphamide.

In such regimens, administer Fluorouracil-Pharmex intravenously at 10–15 mg/kg body weight (400–600 mg/m² body surface area) on days 1 and 8 of a 28-day treatment cycle.

Fluorouracil-Pharmex may also be administered via continuous 24-hour intravenous infusions, with a typical dose of 8.25 mg/kg body weight (350 mg/m² body surface area).

Administration method

Fluorouracil must be administered strictly via intravenous infusion. The drug should be administered via infusions or injections after dilution in 0.9% sodium chloride solution or 5% glucose solution.

Extravascular administration must be avoided.

Special dosage instructions

Recommended doses should be reduced by one-third or one-half in cases of cachexia, following major surgery, myelosuppression (white blood cells < 4000/µL, platelets < 100,000/µL), or severe hepatic or renal impairment.

Renal or hepatic dysfunction

Exercise caution in patients with impaired renal or hepatic function and reduce the dose as necessary.

Special patient groups

Dosage adjustment is not required in elderly patients.

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 with vigorous shaking. The solution should be cooled to body temperature before administration.

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 leading to agranulocytosis and severe thrombocytopenia, bleeding tendency, gastrointestinal ulcers, diarrhea, alopecia.

Signs of intoxication: The following adverse reactions intensify with increasing overdose: nausea, vomiting, diarrhea, severe mucosal inflammation, gastrointestinal ulceration and bleeding, myelosuppression (thrombocytopenia, leukopenia, agranulocytosis).

Treatment

There is no specific antidote for fluorouracil. Prophylactically, transfusions of leukocyte or platelet concentrates may be used. Adequate hydration and diuresis should be maintained, and electrolyte imbalances corrected. Hemodialysis is generally not required. The patient must remain under close medical supervision to promptly detect hematological and delayed gastrointestinal complications. Further treatment is symptomatic.

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

Pronounced myelosuppression should be treated in a hospital setting. Therapy includes, if necessary, blood component replacement and antibacterial treatment. Placement of the patient in a sterile environment may be required.

Hematological monitoring should continue for 4 weeks after overdose.

If fluorouracil therapy must be continued despite cardiac side effects, vasodilators should be prescribed to prevent coronary artery spasm.

Adverse reactions.

The most common and serious adverse reactions associated with the use of fluorouracil are bone marrow toxicity and gastrointestinal disturbances.

The following frequency categories of adverse reactions are used:

Very common (≥1/10); common (>1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).

Infections and infestations

Very common: infections.

Uncommon: malaise.

Frequency not known: infectious diseases, sepsis.

Blood and lymphatic system disorders

Very common: myelosuppression (one of the dose-limiting side effects), neutropenia and thrombocytopenia (both ranging from moderate to very severe), leukopenia, anemia, epistaxis, immunosuppression.

Common: febrile neutropenia.

Very rare: agranulocytosis, pancytopenia.

Leukopenia is most pronounced 9–14 days after administration; leukocyte counts usually return to normal by day 30.

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

Immune system disorders

Very common: immunosuppression with increased frequency of infections.

Rare: generalized allergic reactions, anaphylaxis, anaphylactic shock.

Metabolic and nutritional disorders

Very common: hyperuricemia.

Frequency not known: lactic acidosis, tumor lysis syndrome, hypertriglyceridemia, vitamin B1 deficiency.

Psychiatric disorders

Rare: confusion.

Nervous system disorders

Uncommon: nystagmus, headache, dizziness, Parkinsonism, pyramidal symptoms, euphoria, somnolence.

Very rare: dysgeusia, peripheral neuropathy. Cases of leukoencephalopathy symptoms, including ataxia, have been reported; these are reversible upon immediate discontinuation of fluorouracil therapy. Speech difficulties, acute cerebellar syndrome, dysarthria, confusion, disorientation, myasthenia, aphasia, seizures, or coma have been reported in patients receiving high doses of 5-fluorouracil and in patients with dihydropyrimidine dehydrogenase deficiency, renal impairment.

Frequency not known: posterior reversible encephalopathy syndrome.

Frequency not known: hyperammonemic encephalopathy, Wernicke's encephalopathy.

Eye disorders

Uncommon: excessive tearing and lacrimal duct stenosis, blurred vision, impaired eye movements, optic neuritis, diplopia, decreased visual acuity, photophobia, conjunctivitis, eyelid inflammation, ectropion due to cicatricial changes, and fibrosis of lacrimal glands.

Cardiac disorders

Very common: ECG changes characteristic of ischemia.

Common: chest pain resembling angina.

Uncommon: arrhythmia, myocardial infarction, myocardial ischemia, myocarditis, heart failure, dilated cardiomyopathy, cardiogenic shock.

Very rare: cardiac arrest and sudden cardiac death.

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

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

Frequency not known: pericarditis, bradycardia, stress cardiomyopathy (Takotsubo syndrome).

Vascular disorders

Uncommon: hypotension.

Rare: cerebral ischemia, intestinal ischemia, peripheral ischemia, Raynaud's syndrome, thromboembolism, thrombophlebitis.

Respiratory, thoracic and mediastinal disorders

Very common: bronchospasm.

Gastrointestinal disorders

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

Very common: mucositis (stomatitis, pharyngitis, esophagitis, proctitis), anorexia, watery diarrhea, nausea, vomiting (can be managed with antiemetic and antidiarrheal agents, respectively).

Uncommon: dehydration, sepsis, gastrointestinal ulceration and bleeding, expulsion of necrotic material.

There have been reports of severe proctitis and diarrhea, nausea, and vomiting progressing from mild to very severe.

The severity (grades I–IV according to the National Cancer Institute classification) of gastrointestinal adverse reactions depends on the dose and route of administration. With continuous intravenous infusion, stomatitis is more likely than myelosuppression and becomes the dose-limiting factor.

Rarely, cases of hepatic cell damage and isolated cases of liver necrosis, sometimes fatal, have been observed.

Frequency not known: intestinal pneumatosis, enterocolitis, colitis (including necrotizing colitis).

Hepatobiliary disorders

Uncommon: hepatic cytolysis syndrome.

Very rare: liver necrosis (sometimes fatal), biliary sclerosis, cholecystitis.

Skin and subcutaneous tissue disorders

Very common: alopecia, delayed wound healing.

Uncommon: dermatitis, skin changes (including dryness, fissures, erosions, erythema, rash, pruritus, photosensitivity, skin allergic reactions, pigmentation, hyperpigmentation or depigmentation in streaks near veins), nail changes (e.g., diffuse bluish surface pigmentation, hyperpigmentation, nail dystrophy), pain and thickening of the nail plate (paronychia), and onycholysis.

An unusual complication following 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, desquamation, and tenderness. Concomitant symmetrical swelling and erythema of palms and soles have been observed. The so-called "hand-foot syndrome" is characterized by dysesthesia, redness, swelling, pain, and desquamation of the skin on palms and soles and occurs very commonly after continuous intravenous infusion, and frequently after intravenous bolus injection.

Frequency not known: cutaneous lupus erythematosus.

Musculoskeletal and connective tissue disorders

Uncommon: nasal bone necrosis, muscle weakness.

Renal and urinary disorders

Uncommon: renal failure, hyperuricemia.

Endocrine disorders

Frequency not known: increased serum total thyroxine (T4) and total triiodothyronine (T3) without increase in free T4 or thyroid-stimulating hormone, and without clinical signs of hyperthyroidism.

Reproductive system disorders

Uncommon: impaired spermatogenesis and ovulation.

General disorders and administration site conditions

Very common: asthenia, general fatigue, exhaustion, apathy, malaise.

Frequency not known: local reaction due to extravasation (pain, swelling, erythema).

Laboratory findings

Very rare: isolated cases of prolonged prothrombin time have been reported with concomitant use of fluorouracil and warfarin.

Reporting of adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25°C. Do not refrigerate or freeze. Keep out of reach of children.

Incompatibilities.

Fluorouracil-Farmeks must be diluted with 0.9% sodium chloride solution or 5% glucose solution.

Fluorouracil should not be diluted with strong buffer solutions with pH < 8, as fluorouracil may precipitate in such environments. Do not mix with other chemotherapeutic solutions.

Reported incompatibilities with the following substances:

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

Incompatibility with calcium folinate

Fluorouracil must not be mixed in the same infusion with calcium folinate, as precipitation may occur. 5-fluorouracil 50 mg/mL and calcium folinate 20 mg/mL, with or without 5% dextrose in water, were found to be incompatible when mixed in various proportions and stored at 4°C, 23°C, or 32°C in polyvinyl chloride containers. Fluorouracil should not be mixed with other chemotherapeutic solutions.

Infusion solutions with concentrations of 0.35 mg/mL and 15.0 mg/mL, prepared by diluting Fluorouracil-Farmeks with 5% glucose solution or 0.9% sodium chloride solution, are chemically and physically stable for 28 days when stored at room temperature in a light-protected environment. Use only clear solutions.

Precipitation in the form of crystals may occur if stored below 15°C. However, crystals can be redissolved by heating to 60°C in a water bath with vigorous shaking. Cool to body temperature before injection.

Packaging. 5 mL or 10 mL in a vial. 5 vials in a blister pack, 2 blister packs in a cardboard box.

Prescription status. Prescription only.

Manufacturer. LLC "FARMEKS GROUP".

Manufacturer's address and location of business activity.

100 Shevchenka Street, Boryspil, Kyiv Oblast, 08301, Ukraine.