Ftorolek (Solution) Instructions for Use

Marketing Authorization Holder

Pharmatsel, LLC (Russia)

Manufactured By

Biolek Joint-Stock Company, JSC (Ukraine)

ATC Code

L01BC02 (Fluorouracil)

Active Substance

Fluorouracil (Rec.INN registered by WHO)

Dosage Form

Ftorolek

Solution for intravascular and intracavitary administration 50 mg/ml: amp. 5 ml 10 pcs., fl. 5, 10 or 20 ml 1 or 10 pcs.

Dosage Form, Packaging, and Composition

Solution for intravascular and intracavitary administration transparent, slightly yellowish.

Excipients: sodium hydroxide 15.37 mg, water for injections up to 1 ml.

5 ml – ampoules (10) – cardboard packs.
5 ml – vials (1) – cardboard packs.
5 ml – vials (10) – cardboard packs.
10 ml – vials (1) – cardboard packs.
10 ml – vials (10) – cardboard packs.
20 ml – vials (1) – cardboard packs.
20 ml – vials (10) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Antimetabolite

Pharmacotherapeutic Group

Antineoplastic agent, antimetabolite

Pharmacological Action

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

Pharmacokinetics

After IV or IA administration, Fluorouracil is biotransformed and distributed in rapidly proliferating tissues, such as bone marrow, gastrointestinal mucosa, and tumor tissues. V_d is 0.12 L/kg of body weight, plasma protein binding is about 10%. It easily penetrates the blood-brain barrier, entering the cerebrospinal fluid and brain tissues. It is metabolized mainly in the liver. T_1/2 of fluorouracil depends on the administered dose and is 8-22 min. About 7-20% of fluorouracil is excreted through the kidneys unchanged within 6 hours (90% is excreted within the first hour), 60-80% is excreted through the respiratory tract in the form of CO₂, a small amount is excreted with bile. The renal clearance of fluorouracil is 170-180 ml/min.

Indications

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

ICD codes

Dosage Regimen

Administer intravenously as a bolus injection or by slow infusion, intra-arterially, or intracavitarily.

Determine the dosage individually based on the specific cancer type, disease stage, patient’s hematological status, and the chosen anticancer therapy protocol.

For intravenous bolus administration, a common initial dose is 12 mg/kg of body weight once daily for four to five consecutive days. Do not exceed a single dose of 800 mg.

If toxicity does not occur, administer a dose of 6 mg/kg on the 7th, 9th, and 11th days, and then on the 13th day. Alternatively, after the initial course, administer 10-15 mg/kg as a single dose once per week.

For continuous intravenous infusion, a typical regimen is 20-25 mg/kg of body weight administered over 24 hours for four to five consecutive days.

For intracavitary administration, such as for malignant effusions, instill 500-750 mg after fluid aspiration. Repeat the administration at intervals of 7-10 days.

Adjust or discontinue therapy immediately upon observing severe gastrointestinal toxicity (e.g., stomatitis, esophagopharyngitis, diarrhea), hematological toxicity (e.g., leukocyte count below 3500/mm³ or a rapidly falling count, platelet count below 100,000/mm³), or hemorrhage.

Perform complete blood counts with differential and platelet counts before each dose and regularly throughout the treatment cycle.

Monitor patients with a history of cardiovascular disease closely for signs of cardiotoxicity, such as angina pectoris or ECG changes.

Adverse Reactions

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

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

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

From metabolism very common – hyperuricemia.

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

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

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

From the respiratory system very common – bronchospasm.

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

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

From the urinary system uncommon – renal failure.

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

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

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

Contraindications

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

With caution

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

Use in Pregnancy and Lactation

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

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

Use in Hepatic Impairment

Contraindicated in severe liver dysfunction. It should be used with caution in patients with mild to moderate hepatic failure.

Use in Renal Impairment

Contraindicated in severe renal dysfunction. It should be used with caution in patients with mild to moderate hepatic failure.

Pediatric Use

Contraindicated for use in children.

Special Precautions

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

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

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

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

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

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

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

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

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

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

Effect on ability to drive vehicles and mechanisms

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

Drug Interactions

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

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