Fluorouracil fares

INSTRUCTIONS for medical use of the medicinal product Fluorouracil PhaRes (Fluorouracil PhaRes)

Composition:

active substance: 5-fluorouracil;

1 ml of solution contains 50 mg of 5-fluorouracil;

excipients: sodium hydroxide, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless to slightly yellowish solution.

Pharmacotherapeutic group. Antineoplastic agents. Antimetabolites. Pyrimidine analogues. ATC code L01BC02.

Pharmacological properties

Pharmacodynamics

Fluorouracil is a fluorinated pyrimidine derivative that has no intrinsic antineoplastic activity.

Antitumor activity is manifested in the body after enzymatic transformation of fluorouracil into phosphorylated forms: 5-fluorouridine (FUTP) and 5-fluoro-2'-deoxyuridine monophosphate (FdUMP). At least three mechanisms of action are proposed: inhibition of DNA synthesis (by FdUMP inhibition of thymidylate synthetase); inhibition of RNA synthesis (by incorporation of FUTP into structurally defective RNA); and DNA strand breakage following incorporation of fluorodeoxyuridine triphosphate (phosphorylated FdUMP) into DNA.

The inhibitory effects are particularly pronounced in rapidly proliferating cells, which consequently take up fluorouracil to a greater extent.

Pharmacokinetics

After intravenous administration of fluorouracil, the elimination half-life (first phase) is 10–20 minutes and depends on the dose; the half-life in the second phase has been reported to range from 8 to 40 minutes. Fluorouracil is not detectable in blood plasma 3 hours after intravenous administration.

Distribution

After administration, fluorouracil distributes into all body fluids. Fluorouracil crosses the blood-brain barrier.

Metabolism

Approximately 85% of the administered dose is metabolized. Intracellularly, fluorouracil is converted into active metabolites: 5-fluorouridine triphosphate (FUTP) and 5-fluoro-2'-deoxyuridine monophosphate (FdUMP). In addition to active metabolites, fluorouracil is transformed into inactive metabolites (main metabolites: 5-fluorouridine, 5-fluoro-2'-deoxyuridine) and metabolized to uracil in the liver. Carbon dioxide, urea, and other metabolites are also formed.

Elimination

After intravenous administration of fluorouracil, approximately 15% of the dose is excreted unchanged in urine within 6 hours; over 90% of the dose is eliminated from the body within the first hour.

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

Clinical characteristics.

Indications.

Adjuvant or palliative treatment:

• of progressive colorectal cancer;
• of progressive gastric cancer;
• of progressive pancreatic cancer;
• of progressive and/or metastatic breast cancer.

Contraindications.

Hypersensitivity to fluorouracil or to any of the excipients.

Bone marrow suppression.

Significant deviations from normal levels of blood cellular elements.

Severe hepatic dysfunction.

Severe infections.

State of severe debilitation.

Complete deficiency of dihydropyrimidine dehydrogenase (DPD) (see section "Special precautions").

Pregnancy or breastfeeding.

Do not use concomitantly with brivudine, sorivudine, or their analogs (brivudine, sorivudine, and analogs are potent inhibitors of the enzyme dihydropyrimidine dehydrogenase, which degrades fluorouracil).

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

Special precautions.

As with all cytotoxic agents, handling of Fluorouracil Phares requires adherence to safety procedures: use of protective clothing (gowns, caps, masks, goggles, and disposable gloves), and, if possible, work should be performed in a specially designated area.

Contact of fluorouracil solutions with skin or mucous membranes must be avoided. If contact occurs, affected areas should be thoroughly washed with soap and water. In case of eye exposure, eyes should be irrigated immediately with copious amounts of water and medical advice should be sought urgently. Pregnant healthcare personnel should not handle this drug.

Unused medication or waste materials must be disposed of in accordance with local regulations.

Interaction with other medicinal products and other forms of interaction.

A clinically significant interaction has been described between brivudine and fluoropyrimidines (e.g., capecitabine, fluorouracil, tegafur), resulting from brivudine’s inhibition of dihydropyrimidine dehydrogenase. This interaction leads to increased fluoropyrimidine toxicity and can be potentially fatal. Therefore, a minimum interval of 4 weeks must be maintained between administration of fluorouracil and brivudine, sorivudine, or their analogs. Brivudine treatment may be initiated

24 hours after the last dose of fluorouracil.

All therapeutic interventions that worsen the patient's condition or impair bone marrow function (e.g., other cytostatic agents) may increase fluorouracil toxicity.

Fluorouracil may enhance the skin toxicity of radiation therapy.

The efficacy and toxicity of 5-fluorouracil may be increased when 5-fluorouracil is used in combination with folic acid. The clinical consequence of this interaction is considered to be increased gastrointestinal toxicity with severe, life-threatening diarrhea. Increased mortality has been reported with administration of 600 mg/m² fluorouracil (intravenous bolus once weekly) in combination with folic acid.

Increased plasma concentrations of phenytoin have been reported when phenytoin and fluorouracil are administered concurrently, leading to symptoms of phenytoin intoxication.

Cimetidine, metronidazole, or interferon may increase plasma concentrations of fluorouracil and enhance its toxic effects.

In patients receiving cyclophosphamide, methotrexate, and 5-fluorouracil, addition of thiazide diuretics has led to a more pronounced decrease in granulocyte count compared to patients not taking thiazides.

In isolated cases, patients receiving warfarin and fluorouracil either as monotherapy or in combination with levamisole showed a reduction in prothrombin time.

Hepatotoxicity (elevated levels of alkaline phosphatase, transaminases, or bilirubin) has frequently been observed in patients receiving 5-fluorouracil in combination with levamisole.

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

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

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

Gemcitabine may increase systemic exposure to fluorouracil.

Dose adjustment is required when used in combination with other myelosuppressive agents. Concomitant or prior radiotherapy may require dose reduction. Cardiotoxicity of anthracyclines may be increased.

Significant reduction in fluorouracil clearance with subsequent increase in serum fluorouracil levels and increased toxicity has been observed during concomitant therapy with metronidazole. Therefore, simultaneous administration of these drugs should be avoided.

Aminophenazone, phenylbutazone, and sulfonamides should not be taken before or during fluorouracil therapy. Concomitant use of allopurinol may reduce both toxicity and efficacy of fluorouracil.

The efficacy of fluorouracil may be reduced by administration of chlordiazepoxide, disulfiram, griseofulvin, and isoniazid.

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

Dose reduction of fluorouracil is required when administered concurrently with or following radiotherapy.

General information for cytostatic agents.

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

Special precautions for use.

Treatment with Fluorouracil PharEks should be carried out under supervision of a qualified oncologist experienced in the use of antimetabolites (in a hospital setting). Initiation of fluorouracil therapy must occur in a hospital environment.

With adequate fluorouracil treatment, leukopenia typically develops. The lowest leukocyte count is usually observed between days 7 and 14 of the first treatment cycle, although the nadir may sometimes occur up to 20 days after administration. Leukocyte counts usually return to normal by day 30.

Fluorouracil treatment must be discontinued immediately if any of the following signs of toxicity occur: leukopenia (< 2000/μL); thrombocytopenia (< 50,000/μL); stomatitis, esophagitis; vomiting uncontrolled by antiemetic agents; diarrhea; gastrointestinal ulceration or bleeding; other hemorrhages; neurotoxic disorders; or cardiotoxic disorders.

After blood parameters have recovered (leukocytes ≥ 3000/μL or platelets ≥ 70,000/μL), treatment may be resumed at a reduced dose, provided no other adverse reactions requiring discontinuation are present.

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. In cases of severe toxicity, treatment should be discontinued.

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 compared to bolus injections. A history of ischemic heart disease may be a risk factor for some cardiovascular adverse reactions. Therefore, caution is advised in patients who report chest pain during treatment or who have a history of cardiac disease. Cardiac function should be monitored regularly during fluorouracil therapy. Treatment should be discontinued in case of severe cardiotoxicity.

Encephalopathy

Post-marketing experience has reported cases of encephalopathy (including hyperammonemic encephalopathy, leukoencephalopathy, posterior reversible encephalopathy syndrome) associated with 5-fluorouracil therapy. 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 levels should be assessed. If hyperammonemia is confirmed, appropriate measures to reduce ammonia levels should be initiated. Hyperammonemic encephalopathy often occurs concomitantly with lactic acidosis.

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 (e.g., those with renal impairment, hyperuricemia, high tumor burden, or rapidly progressing disease) should be closely monitored. Prophylactic measures (e.g., hydration, correction of elevated uric acid levels) may be appropriate.

Deficiency of dihydropyrimidine dehydrogenase (DPD)

DPD activity is the rate-limiting factor in the catabolism of 5-fluorouracil. Therefore, patients with DPD deficiency are at increased risk of fluoropyrimidine-related toxicity, including stomatitis, diarrhea, mucositis, neutropenia, and neurotoxicity. Toxicity associated with DPD deficiency typically occurs during the first treatment cycle or after dose escalation.

Complete DPD deficiency

Complete DPD deficiency is rare (0.01–0.5% in individuals of Caucasian ethnicity). Patients with complete DPD deficiency are at increased risk of life-threatening or fatal toxicity and should not receive Fluorouracil PharEks.

Partial DPD deficiency

Partial DPD deficiency occurs in 3–9% of individuals of Caucasian ethnicity. Patients with partial DPD deficiency are at increased risk of severe and potentially life-threatening toxicity. To reduce this risk, a lower initial dose should be considered. However, dose reduction may affect treatment efficacy. Subsequent doses may be increased in the absence of severe toxicity, provided close monitoring is maintained.

Testing for DPD deficiency

Testing for DPD phenotype and/or genotype is recommended prior to initiating Fluorouracil PharEks, despite uncertainties regarding optimal testing methodologies. Relevant clinical guidelines should be considered.

Genotypic characterization of DPD deficiency

Pre-treatment testing for rare DPYD gene mutations can identify patients with DPYD deficiency. Four DPYD variants—c.1905+1G>A (also known as DPYD*2A), c.1679T>G (DPYD*13), c.2846A>T, and c.1236G>A/HapB3—may result in complete or reduced DPD enzymatic activity. Other rare variants may also be associated with increased risk of severe or life-threatening toxicity. Homozygous or compound heterozygous mutations in the DPYD gene (e.g., combinations of the four variants with at least one c.1905+1G>A or c.1679T>G allele) are known to cause complete or near-complete absence of DPD enzymatic activity. Patients with certain heterozygous DPYD variants (including c.1905+1G>A, c.1679T>G, c.2846A>T, and c.1236G>A/HapB3) are at increased risk of severe toxicity during fluoropyrimidine therapy. The frequency of heterozygous c.1905+1G>A genotype in Caucasians is approximately 1%, c.2846A>T — 1.1%, c.1236G>A/HapB3 — 2.6–6.3%, and c.1679T>G — 0.07–0.1%.

Data on the frequency of these four DPYD variants in non-Caucasian populations are limited. To date, the four DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T, and c.1236G>A/HapB3) are considered virtually absent in individuals of African or Asian ethnicity.

Phenotypic characterization of DPD deficiency

For phenotypic assessment of DPD deficiency, measurement of baseline plasma uracil levels—the endogenous substrate of DPD—is recommended. Elevated uracil concentrations prior to treatment initiation are associated with increased risk of toxicity. Despite uncertainty regarding threshold values defining complete or partial DPD deficiency, a DPD level in blood ≥ 16 ng/mL and < 150 ng/mL should be considered indicative of partial DPD deficiency and associated with increased risk of fluoropyrimidine toxicity. A uracil level in blood ≥ 150 ng/mL should be considered indicative of complete absence of DPD activity and associated with life-threatening or fatal fluoropyrimidine toxicity.

Therapeutic drug monitoring of 5-fluorouracil

Therapeutic drug monitoring of 5-fluorouracil may improve clinical outcomes, reduce toxicity, and enhance efficacy in patients receiving regular 5-fluorouracil infusions. The target AUC is expected to range between 20 and 30 mg×h/L.

Brivudine

Fluorouracil PharEks must not be used concomitantly with brivudine. Fatal outcomes have been reported due to this drug interaction. Therefore, a minimum interval of 4 weeks must be maintained between administration of fluorouracil and brivudine. Brivudine therapy may be initiated 24 hours after the last dose of fluorouracil.

If brivudine is administered to patients receiving fluorouracil, effective measures must be taken to reduce fluorouracil toxicity. Immediate hospitalization is recommended. Management should focus on prevention of systemic infections and dehydration.

Patients receiving phenytoin concomitantly with fluorouracil should be closely monitored, as increased plasma phenytoin concentrations may occur.

Intestinal wall damage during fluorouracil therapy requires symptomatic treatment depending on severity, such as fluid replacement. Mild diarrhea may be managed with antidiarrheal agents. However, this is insufficient for moderate or severe diarrhea.

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

• Daily examination of the oral cavity and pharynx to detect possible mucosal lesions;
• Complete blood count, including counts of blood cells and platelets, prior to each fluorouracil administration;
• Biochemical assessment of fluid and electrolyte balance;
• Liver function tests.

Careful monitoring of the prothrombin index is required when fluorouracil is used concomitantly with oral anticoagulants.

Patients should be additionally warned about the possible occurrence of stomatitis/mucositis, diarrhea, and bleeding (particularly gastrointestinal). They should be advised to contact their physician promptly upon onset of any symptoms.

Combination of fluorouracil and folic acid

The toxicity profile of fluorouracil may be enhanced or altered when used concomitantly with folic acid. The most common manifestations are leukopenia, mucositis, stomatitis, and/or diarrhea, which may be dose-limiting. When fluorouracil is used in combination with folic acid, the fluorouracil dose should be reduced more substantially in case of toxicity than when fluorouracil is used alone. The toxic effects observed in patients receiving this combination are qualitatively similar to those seen with fluorouracil monotherapy. Gastrointestinal toxicity occurs more frequently and may be more severe or even life-threatening (particularly stomatitis and diarrhea). In severe cases, fluorouracil and folic acid should be discontinued and supportive intravenous therapy initiated. Patients should be instructed to immediately inform their physician if stomatitis (ulcers of mild to moderate degree) and/or diarrhea (watery stools) occur.

Patients should avoid prolonged sun exposure due to the risk of photosensitization. The drug should be used with caution in patients who have received high-dose radiation therapy to the pelvic area.

Particular attention should be paid when treating elderly or debilitated patients, as they may be at increased risk of severe toxicity. Women of childbearing potential and men should be advised to use effective contraception during fluorouracil therapy and for 6 months after completion of treatment.

The medicinal product contains less than 1 mmol (23 mg) of sodium per 1 mL.

Use during pregnancy or breastfeeding

Pregnancy

Fluorouracil must not be used during pregnancy. Women of childbearing potential should be advised to avoid pregnancy and to use effective contraception during fluorouracil therapy and for 6 months after completion of treatment. If Fluorouracil PharEks is administered during pregnancy or if a patient becomes pregnant while receiving the drug, she should be informed of the potential risk to the fetus and the need for genetic counseling.

Breastfeeding

Fluorouracil PharEks must not be used during breastfeeding.

Fertility

Fluorouracil may have mutagenic effects. Men receiving fluorouracil should be advised to use reliable contraception during therapy and for 6 months after discontinuation. Sperm cryopreservation should be considered prior to treatment initiation due to the potential for irreversible infertility caused by fluorouracil therapy.

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 or operating machinery while receiving fluorouracil therapy.

Administration and Dosage

Fluorouracil should be administered only under the supervision of a qualified physician experienced in the use of antineoplastic chemotherapy. Treatment with fluorouracil should be initiated in a hospital setting.

Fluorouracil is used as monotherapy and as part of combination chemotherapy. Since administration methods and dosage recommendations for fluorouracil vary significantly, only general dosage guidelines can be provided.

The exact dosage must be determined according to therapeutic protocols proven effective in treating the specific disease.

Colorectal Cancer

Fluorouracil is used for the treatment of colorectal cancer as monotherapy or in combination with other therapies. The usual daily dose range of fluorouracil is 370–600 mg/m² of body surface area administered by intravenous bolus injection, or 200–750 mg/m² of body surface area administered by continuous intravenous infusion.

Gastric Cancer

Administer as monotherapy or as part of combination chemotherapy at a daily dose of 500–600 mg/m² of body surface area by intravenous bolus injection.

Pancreatic Cancer

Administer as monotherapy at a daily dose of 400–500 mg/m² of body surface area by intravenous bolus injection, or at a dose of 1000 mg/m² of body surface area by continuous intravenous infusion.

Breast Cancer

In combination chemotherapy regimens, administer at a daily dose of 500–600 mg/m² of body surface area intravenously.

Discontinuation of Treatment and Dose Reduction

Treatment with fluorouracil must be immediately discontinued if any of the following signs of toxicity occur: leukopenia (< 2000/μL); thrombocytopenia (< 50,000/μL); stomatitis, esophagitis; vomiting uncontrolled by antiemetic agents; diarrhea; gastrointestinal ulceration and bleeding; other hemorrhages; neurotoxic disorders; cardiotoxic disorders.

After recovery of blood parameters (leukocytes ≥ 3000/μL or platelets ≥ 70,000/μL), treatment may be resumed at a reduced dose (see Table 1), provided no other adverse reactions requiring treatment discontinuation are present.

Table 1

Renal or hepatic insufficiency

Dose reduction is not required in case of impaired liver or kidney function alone. Dose reduction should be considered only when both hepatic and renal functions are impaired simultaneously; in severe cases, the dose should be reduced by 1/3–1/2.

Administration method

Fluorouracil should usually be administered intravenously as a bolus injection or by continuous infusion.

It is very important to strictly adhere to the duration of injection/infusion and the selected treatment regimen.

Fluorouracil must be administered strictly by intravenous infusion.

Duration of use

The decision regarding duration of treatment is made by the physician depending on the treatment protocol. Therapy should be discontinued in case of lack of response to treatment, disease progression, or occurrence of adverse reactions that preclude continuation of therapy.

The solution should be drawn from the vial/ampoule immediately before use.

If a precipitate forms in the preparation due to cooling, it should be dissolved by heating to 60 °C with vigorous shaking. Before administration, the preparation should be cooled to body temperature.

Children

There are no recommendations for treatment in children; therefore, the medicinal product should not be used in pediatric practice.

Overdose

Symptoms: Symptoms and signs of fluorouracil overdose are qualitatively similar to adverse reactions but are usually more pronounced. In particular, the following adverse reactions may occur: nausea, vomiting, diarrhea, gastrointestinal ulcers and bleeding, bone marrow suppression (including thrombocytopenia, leukopenia, and agranulocytosis).

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

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

Hematological monitoring should be performed for 4 weeks after overdose.

Adverse Reactions

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

The following frequency categories of adverse reactions are provided:

Very common: ≥1/10;
Common: >1/100, <1/10;
Uncommon: ≥1/1000, <1/100;
Rare: ≥1/10,000, <1/1000;
Very rare: <1/10,000;
Frequency not known (cannot be estimated based on available data).

Infections and infestations

Very common: infections.
Common: immunosuppression with increased risk of infection.
Rare: sepsis.

Blood and lymphatic system disorders

Very common: myelosuppression (one of the dose-limiting adverse effects), neutropenia and thrombocytopenia (both ranging from moderate to very severe), leucopenia, anemia, immunosuppression.
Common: febrile neutropenia.
Rare: agranulocytosis, pancytopenia.

The severity (grades I–IV according to the National Cancer Institute, NCI, USA scale) of myelosuppression depends on the route of administration (intravenous bolus injection or continuous intravenous infusion) and dosage of the drug.

Neutropenia develops after each therapeutic cycle with intravenous bolus administration of fluorouracil at appropriate doses (maximum decrease in neutrophil counts: on days 9–14 (-20); recovery to normal levels: usually after day 30).

Immune system disorders

Rare: generalized allergic reactions, anaphylaxis, anaphylactic shock.

Endocrine system disorders

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

Metabolic and nutritional disorders

Common: hyperuricemia.
Frequency not known: lactic acidosis, tumor lysis syndrome.

Nervous system disorders

Uncommon: nystagmus, headache, dizziness, Parkinson-like symptoms, pyramidal signs, euphoria, somnolence.
Very rare: dysgeusia, peripheral neuropathy. Cases of reversible leukoencephalopathy symptoms, including ataxia, have been reported, resolving after immediate discontinuation. Neurological symptoms such as speech difficulties, acute cerebellar syndrome, dysarthria, confusion, disorientation, myasthenia, aphasia, seizures, or coma have been observed in patients receiving high doses of 5-fluorouracil and in patients with dihydropyrimidine dehydrogenase deficiency or renal impairment.
Frequency not known: hyperammonaemic encephalopathy, posterior reversible encephalopathy syndrome.

Eye disorders

Rare: excessive tearing, blurred vision, eye movement disorders, optic neuritis, diplopia, decreased visual acuity, photophobia, conjunctivitis, blepharitis; ectropion due to scarring, and fibrosis of lacrimal glands.

Cardiac disorders

Common: ECG changes characteristic of ischemia.
Uncommon: chest pain resembling angina.
Rare: arrhythmia, myocardial infarction, myocarditis, heart failure, dilated cardiomyopathy, cardiogenic shock.
Very rare: cardiac arrest, sudden cardiac death.
Frequency not known: pericarditis, stress-induced cardiomyopathy (Takotsubo syndrome).

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

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

Vascular disorders

Rare: thrombophlebitis.
Frequency not known: cerebral ischemia, intestinal ischemia, peripheral ischemia, Raynaud's syndrome, thromboembolism.

Respiratory, thoracic and mediastinal disorders

Common: bronchospasm, epistaxis.

Gastrointestinal disorders

Common: mucositis (stomatitis, esophagitis, proctitis), watery diarrhea, nausea, vomiting.
Rare: dehydration, gastrointestinal ulceration and bleeding.

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

Cases of mucositis (stomatitis, esophagitis, proctitis), watery diarrhea, nausea, and vomiting have been reported, ranging from mild to very severe, as well as acalculous cholecystitis.

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, which becomes the dose-limiting factor.

Frequency not known: intestinal pneumatosis.

Hepatobiliary disorders

Rare cases of hepatocellular damage and isolated cases of liver necrosis, sometimes fatal, have been observed.
Uncommon: hepatic cytolysis.
Very rare: liver necrosis (sometimes fatal), bile duct sclerosis, cholecystitis.

Skin and subcutaneous tissue disorders

Common: alopecia (mostly reversible).
Rare: dermatitis, exanthema, 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 superficial blue pigmentation, hyperpigmentation, nail dystrophy), pain and thickening of the nail plate (paronychia), and onycholysis.

Hand-foot syndrome (palmar-plantar erythrodysesthesia) has been observed during prolonged continuous infusion at high doses. The syndrome begins with dysesthesia of palms and soles, progressing to redness, pain, peeling, and tenderness, accompanied by symmetrical swelling and erythema of palms and soles.

Frequency not known: cutaneous lupus erythematosus.

General disorders and administration site conditions

Common: slow wound healing, exhaustion, general asthenia, fatigue, apathy, chills.

Musculoskeletal and connective tissue disorders

Uncommon: necrosis of nasal bones, muscle weakness.

Psychiatric disorders

Rare: confusion.
Very rare: disorientation.

Renal and urinary disorders

Uncommon: renal failure.

Reproductive system disorders

Uncommon: impaired spermatogenesis and ovulation.

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

Reporting of adverse reactions

Reporting of adverse reactions after marketing authorization of the medicinal product is very important. It allows continued monitoring of the benefit-risk balance of the medicinal product. In case of any adverse reactions, healthcare professionals should be informed.

Reporting of adverse reactions after marketing authorization is of great importance. It enables ongoing monitoring of the benefit-risk profile of the medicinal product. Medical and pharmaceutical professionals, as well as 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, protected from light, at temperatures not exceeding 25 °C, in a place inaccessible to children. Do not cool or freeze.

Incompatibilities

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

Fluorouracil Fares should not be mixed with other substances during infusion, as precipitation may occur.

Incompatibilities have been reported with the following substances: cisplatin, cytarabine, diazepam, doxorubicin, droperidol, filgrastim, gallium nitrate, calcium folinate, methotrexate, metoclopramide, morphine, ondansetron, parenteral nutrition solutions, vinorelbine.

Packaging

5 ml, 10 ml, 20 ml or 100 ml in a vial; 1 vial per cardboard box.

Prescription category

Prescription only.

Manufacturer

Haupt Pharma Wolfenbüttel GmbH.

Manufacturer's address and place of business

Pfaffenrieder Strasse 5, Wolfratshausen, Bavaria, 82515, Germany.