Bleonco

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BLEONCO (BLEONCO)

Composition:

Active substance: bleomycin;

1 vial contains bleomycin sulfate equivalent to bleomycin 15 IU.

Excipient: mannite (E 421).

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties: white or cream-colored powder.

Pharmacotherapeutic group.

Antineoplastic agents. Cytotoxic antibiotics and related agents. Other cytotoxic antibiotics.

ATC code L01D C01.

Pharmacological properties.

Pharmacodynamics.

Bleomycin belongs to the group of cytotoxic antibiotics. It is an alkaline water-soluble mixture of structurally related glycopeptide antibiotics with cytostatic activity.

The action of bleomycin is explained by intercalation into single- and double-stranded DNA, causing single- and double-strand breaks. As a result, DNA synthesis and cell division are inhibited. Bleomycin also affects RNA and protein synthesis, but to a lesser extent. The most important factor determining the selective action of bleomycin on various tissues is intracellular inactivation. Squamous epithelial cells have low levels of bleomycin hydrolase and are therefore most sensitive to bleomycin. Chromosomal aberrations (fragmentation, chromatid breaks, and translocations) are frequently observed in sensitive tissues (both normal and neoplastic).

In contrast to most other cytostatics, bleomycin has low myelotoxicity, does not cause immunosuppression, and is not neuro- or cardiotoxic. This toxicity profile of bleomycin allows its use in combination with other anticancer agents.

Pharmacokinetics.

Distribution. Bleomycin rapidly distributes into body tissues, with the highest concentrations found in the skin, lungs, peritoneum, and lymph nodes. Low concentrations are observed in the bone marrow. Bleomycin has not been detected in cerebrospinal fluid after intravenous administration. The volume of distribution of bleomycin in humans is approximately 22 L, exceeding the volume of extracellular fluid. Bleomycin is only minimally bound to plasma proteins.

Biological transformation. The mechanism of bleomycin biotransformation has not been fully elucidated. Inactivation of bleomycin occurs via enzymatic degradation by bleomycin hydrolase, primarily in blood plasma, liver, and other organs, and to a lesser extent in the skin and lungs.

Elimination. The elimination half-life of bleomycin is 2–3 hours. During continuous intravenous infusion, this value may increase up to 9 hours. Approximately two-thirds of the administered dose is excreted unchanged in the urine, likely via glomerular filtration. The majority of the dose is eliminated within 8–12 hours.

The elimination rate is highly dependent on renal function. When standard doses are administered, plasma concentrations of bleomycin are significantly higher in patients with impaired renal function.

Clinical experience indicates that bleomycin is difficult to remove from the body by dialysis.

Clinical Characteristics.

Indications.

• Squamous cell carcinoma of the head and neck, cervix.
• Hodgkin’s disease and non-Hodgkin’s lymphomas.
• Testicular cancer (non-seminomatous and seminomatous tumors).
• Malignant pleural effusion – palliative intrapleural therapy.

Bleomycin is practically always used in combination with other antineoplastic agents and/or radiotherapy.

Contraindications.

• Acute pulmonary infections.
• Marked impairment of lung function and disorders of pulmonary circulation.
• Ataxia-telangiectasia.
• Hypersensitivity to bleomycin.

Interaction with other medicinal products and other forms of interaction.

Combined chemotherapy.

When bleomycin is used as part of combined chemotherapy, its toxicity should be taken into account when selecting and dosing other agents with a similar toxicity profile.

The risk of pulmonary toxicity increases when bleomycin is used in combination with carmustine, mitomycin C, cyclophosphamide, gemcitabine, and methotrexate.

Pulmonary toxicity of bleomycin is particularly enhanced during combined treatment with cisplatin. Therefore, special caution is required with this combination. Scientific literature data indicate that cisplatin should be administered only after bleomycin.

In patients receiving combined therapy with bleomycin and vinca alkaloids for testicular cancer, a Raynaud’s-like syndrome has been observed: ischemia of peripheral body parts, which over time could lead to necrosis of these areas (fingers, toes, nose).

In patients who received combined therapy with cisplatin, vinblastine, and bleomycin, a positive correlation between GFR (glomerular filtration rate) and lung function has been observed. Therefore, bleomycin should be used cautiously in patients with severe renal impairment. In another study, higher doses of cisplatin were associated with decreased creatinine clearance, and consequently, reduced elimination of bleomycin.

Radiation therapy.

Prior or concurrent radiation therapy to the chest area increases the frequency and severity of pulmonary toxic effects.

Prior or concurrent radiation therapy to the head or neck area increases the risk of stomatitis and worsening of angular cheilitis. This may occasionally cause pharyngeal mucositis leading to hoarseness.

Oxygen therapy.

In patients treated with bleomycin, the risk of developing pulmonary toxicity increases when oxygen is administered during surgical procedures. Therefore, oxygen concentrations in breathing mixtures should be reduced both during and after surgery.

Granulocyte colony-stimulating factor (G-CSF)

Increased numbers of neutrophilic granulocytes and stimulation of their ability to generate free oxygen radicals after G-CSF administration may potentiate lung injury when used concomitantly.

Digoxin

Cases of reduced digoxin effect due to decreased oral bioavailability have been reported when used concomitantly with bleomycin.

Phenytoin and fosphenytoin

Cases of decreased phenytoin levels have been reported when used concomitantly with bleomycin. Seizure exacerbation may occur due to reduced phenytoin absorption caused by cytotoxic agents, and there may also be increased toxicity or loss of efficacy of the cytotoxic agent due to enhanced hepatic metabolism induced by phenytoin. Concomitant use is not recommended.

Clozapine

Concomitant use of bleomycin with clozapine should be avoided due to an increased risk of agranulocytosis.

Antibiotics

The bacteriostatic efficacy of gentamicin, amikacin, and ticarcillin may be reduced.

Cyclosporine, tacrolimus

Excessive immunosuppression with risk of lymphoproliferative disorders may occur.

Live vaccines

Administration of live vaccines may result in severe or life-threatening infections in patients whose immune systems are suppressed by chemotherapeutic agents, including bleomycin. Vaccination with live vaccines should be avoided in patients receiving bleomycin. Inactivated vaccines should be used where available (e.g., polio). Administration of yellow fever vaccine during immunosuppressive chemotherapy has led to severe and fatal infections. This risk is increased in subjects who already have immunosuppression due to their underlying disease. This combination must not be used.

Special precautions for use.

Treatment with bleomycin should be carried out under the close supervision of a qualified oncologist experienced in the use of antineoplastic chemotherapeutic agents, preferably in a specialized medical facility.

A careful assessment of the benefit/risk ratio should be performed before administering the drug following radiotherapy to the lungs or mediastinum. Bleomycin should be used cautiously and in reduced doses in patients with impaired renal function. Due to the potential mutagenic effect of bleomycin on germ cells in both men and women, effective contraception must be ensured during therapy and for 6 months after its completion.

Pulmonary toxicity.

During treatment with bleomycin, regular monitoring of lung function and chest X-rays are required.

Pulmonary reactions are the most serious adverse effects, occurring in approximately 10% of treated patients, either during or after completion of therapy. The most common form is interstitial pneumonitis. If not diagnosed promptly and appropriately managed, it may lead to irreversible pulmonary fibrosis. Approximately 1% of patients have died from complications of pulmonary fibrosis.

Patients receiving bleomycin should undergo weekly chest X-rays, continuing for 4 weeks after the end of treatment. Patients should be monitored for approximately 2 months after therapy completion. In cases of concomitant radiotherapy to the chest, chest X-rays should be performed more frequently.

Pulmonary function tests using 100% oxygen should not be administered to patients who have received bleomycin. As an alternative, pulmonary function tests using less than 21% oxygen are recommended. Diffusing capacity of the lungs for carbon monoxide (DLCO) should be analyzed monthly. Pulmonary function tests, particularly measurements of carbon monoxide diffusion and vital lung capacity, allow for early detection of pulmonary toxicity.

Although pulmonary toxicity of bleomycin significantly increases when the cumulative dose exceeds 400 IU (225 IU/m² body surface area), it may occur at much lower doses, especially in elderly patients, patients with impaired renal function, those with pre-existing lung disease, patients who have undergone radiotherapy to the lung area, and those receiving oxygen therapy.

Pulmonary toxicity has also been observed in some cases in younger patients receiving low doses.

Vascular changes in the lungs caused by bleomycin lead to partial destruction of vascular wall elasticity. The earliest symptom of bleomycin-induced lung injury is dyspnea.

If cough, dyspnea, crepitant rales in the lung bases, or a diffuse reticular pattern on chest X-ray (any of these symptoms) appear, administration of the drug should be discontinued until the cause of these manifestations is clarified. If lung damage due to bleomycin is confirmed, bleomycin should not be administered further.

There is no specific treatment for bleomycin-induced pulmonary toxic effects. In some cases, administration of corticosteroids may provide some benefit. Patients should be treated with broad-spectrum antibiotics and corticosteroids.

Elderly patients are more sensitive to bleomycin.

Despite the fact that pulmonary toxicity of bleomycin is associated with exceeding a total dose of 400 IU (approximately 225 IU/m² body surface area), it may also occur with lower doses, particularly in elderly patients, patients with impaired renal function, patients with pre-existing lung diseases, patients who have received concomitant radiotherapy to the chest, and patients requiring oxygen therapy. These patients require careful monitoring, and bleomycin dosage should be reduced or the dosing interval prolonged. Bleomycin should be used with particular caution in patients with lung cancer, as they have an increased incidence of pulmonary toxicity.

Since two-thirds of the administered bleomycin dose is excreted unchanged in urine, renal function significantly affects elimination rate. Plasma concentrations are markedly increased when standard doses are administered to patients with impaired renal function.

Other clinical conditions requiring cautious use include severe heart disease and hepatic dysfunction, as toxicity may be enhanced, as well as infection with Varicella-zoster.

Idiosyncratic reactions / hypersensitivity.

Idiosyncratic reactions clinically resembling anaphylaxis have been reported in approximately 1% of lymphoma patients receiving bleomycin. The reaction may be immediate or occur several hours after administration, usually after the first or second dose. It may present as hypotension, confusion, fever, chills, wheezing, and stridor. Treatment is symptomatic and includes restoration of circulating blood volume, vasopressors, antihistamines, and corticosteroids.

Due to the possibility of an anaphylactoid reaction (reported in 1% of lymphoma patients according to published data), patients should initially receive a test dose of 1–2 units. If no acute reaction occurs, the full dose may be administered.

Disorders of the blood and lymphatic system.

Acute myeloid leukemia and myelodysplastic syndrome have been reported in patients who received concomitant treatment with bleomycin and other antineoplastic agents.

General disorders.

Vascular toxicity has been reported following bleomycin administration, particularly in combination with other antineoplastic agents. Cases were clinically heterogeneous and included myocardial infarction, cerebrovascular accidents, thrombotic microangiopathy, hemolytic uremic syndrome, and cerebral arteritis.

The effect of the drug on gonads should be considered in patients of reproductive age.

Like other cytotoxic agents, bleomycin may trigger tumor lysis syndrome in patients with rapidly growing tumors. Appropriate supportive treatment and pharmacological interventions may prevent or reduce the severity of such complications.

The drug should be used cautiously in patients with creatinine clearance values below 50 ml/min, and renal function should be monitored during bleomycin administration. Dose reduction of bleomycin may be required for these patients.

Intravenous administration.

Vascular pain may occur; therefore, it is important to control the concentration of the drug and the rate of administration. Intravenous infusion should be as slow as possible.

Intramuscular administration.

Avoid repeated injections at the same site, especially in children. If needle insertion causes severe pain or blood refluxes into the syringe, the needle should be immediately withdrawn and reinserted at another site.

When handling cytostatic agents, standard safety procedures should be followed. Contact of bleomycin solutions with skin or mucous membranes must be avoided. If the drug does come into contact with skin or mucous membranes, the affected area should be immediately flushed with large amounts of water.

Unused drug residues and waste should be destroyed by incineration at 800°C.

Use during pregnancy or breastfeeding.

Pregnancy.

The use of bleomycin during pregnancy is contraindicated, as its safety has not been established. There are insufficient data to assess the potential risk of bleomycin use in pregnant women. Bleomycin crosses the placental barrier. Given the pharmacological properties of bleomycin, it is expected to harm the fetus when administered during pregnancy. Therefore, bleomycin should be avoided during pregnancy, especially in the first trimester.

If pregnancy occurs during treatment, the patient should be informed of the risks to the unborn child and closely monitored. Genetic counseling should be considered.

Breastfeeding.

It is unknown whether bleomycin or its metabolites are excreted in human milk. Due to the potential for harmful effects on the infant, breastfeeding is contraindicated during bleomycin therapy.

Breastfeeding should be discontinued during bleomycin treatment.

Effect on fertility.

Both men and women should use adequate contraceptive methods during treatment and for six months after discontinuation of therapy.

Patients who wish to have children after treatment are advised to undergo genetic counseling.

Prior to treatment, patients should be advised to consider sperm cryopreservation due to the possibility of irreversible infertility caused by bleomycin therapy.

Fertility.

Bleomycin treatment may cause irreversible infertility.

Ability to affect reaction speed when driving or operating machinery.

Patients should refrain from driving or operating machinery.

Administration and Dosage

Bleomycin is administered intravenously, intramuscularly, or intrapleurally.

The usual intravenous or intramuscular dose is 10–20 IU/m² once or twice weekly. The maximum daily dose is 20 IU/m². The total cumulative dose should not exceed 400 IU (225 IU/m²).

To prepare for intramuscular injection, the contents of the Bleonco vial should be dissolved in 1–5 mL of 0.9% sodium chloride solution or water for injection. Repeated injections at the same site may cause local reactions; therefore, the injection site should be rotated.

For intravenous injection, the contents of the Bleonco vial should be dissolved in 5–20 mL of 0.9% sodium chloride solution and administered slowly over 5–10 minutes. For intrapleural administration, bleomycin at a dose of 60 IU/m² should be dissolved in 50–100 mL of 0.9% sodium chloride solution and administered via a drainage needle or catheter. In the treatment of lymphoma, therapy should be initiated at a dose of 2 IU/m² for the first two weeks. If no anaphylactoid reactions occur, treatment may continue with the usual doses of 10–20 IU/m² once or twice weekly.

In elderly patients, the total cumulative dose should not exceed 300 IU.

In renal insufficiency, the dose should be adjusted based on serum creatinine concentration. The dose of Bleonco should be reduced when radiation therapy is administered, as irradiated tissues are more sensitive to the drug. When bleomycin is used concomitantly with other antineoplastic agents, pulmonary toxicity may occur even at low doses.

Children

The efficacy and safety of bleomycin in pediatric practice have not been established; therefore, the drug should not be used in patients of this age group.

Overdose

Due to the route of administration and precautionary measures, bleomycin overdose is rare. Acute overdose reactions may manifest as arterial hypotension, fever, tachycardia, and general signs of shock. Treatment is symptomatic. In case of respiratory complications, corticosteroids and broad-spectrum antibiotics are administered.

Adverse Reactions

Like most antineoplastic agents, bleomycin may cause acute and delayed toxic effects.

Fever on the day of injection is the earliest reaction. In 1613 patients receiving bleomycin, the most commonly observed adverse reactions were: pulmonary toxicity in the form of interstitial pneumonia or pulmonary fibrosis (10.2%), skin sclerosis, pigmentation (40.6%), fever and chills (39.8%), alopecia (29.5%), anorexia and weight loss (28.7%), malaise (16.0%), nausea and vomiting (14.6%), stomatitis (13.3%), and nail changes (11.2%). Pain at the injection site or in the tumor area, arterial hypotension, and venous occlusion may occur following intravenous administration.

Raynaud's phenomenon has been reported both during monotherapy with bleomycin and during combination therapy.

The adverse effects of bleomycin listed below are classified by organ systems and frequency of occurrence: very common ≥ 1/10; common ≥ 1/100 and < 1/10; uncommon ≥ 1/1000 and < 1/100; rare ≥ 1/10000 and < 1/1000; very rare < 1/10000; frequency not known.

Infections and infestations

Frequency not known: sepsis.

Benign, malignant and unspecified neoplasms (including cysts and polyps)

Uncommon: tumor pain.

Blood and lymphatic system disorders

Uncommon: myelosuppression, leukopenia, neutropenia, thrombocytopenia, hemorrhage.

Rare: febrile neutropenia.

Frequency not known: pancytopenia, anemia.

Immune system disorders

Common: anaphylaxis, hypersensitivity reactions, idiosyncratic reactions.

Nervous system disorders

Common: headache.

Uncommon: dizziness, confusion.

Cardiac disorders

Rare: myocardial infarction, pericarditis, chest pain.

Vascular disorders

Uncommon: hypotension.

Rare: cerebral infarction, thrombotic microangiopathy, hemolytic-uremic syndrome, cerebral arteritis, Raynaud's phenomenon, arterial thrombosis, deep vein thrombosis.

Frequency not known: peripheral ischemia.

Respiratory system disorders

Very common: interstitial pneumonitis, pulmonary fibrosis, dyspnea.

Common: acute respiratory distress syndrome, respiratory failure, pulmonary embolism.

Gastrointestinal disorders

Very common: decreased appetite, weight loss, nausea, vomiting, mucositis, stomatitis.

Uncommon: angular cheilitis, diarrhea.

Hepatobiliary disorders

Rare: hepatic failure.

Skin and subcutaneous tissue disorders

Very common: erythema, pruritus, striae, blistering, hyperpigmentation, increased sensitivity and swelling of fingertips, hyperkeratosis, alopecia.

Common: exanthema, urticaria, skin redness, induration, edema, flagellate dermatitis.

Uncommon: nail deformity and discoloration, skin edema and blistering at pressure sites.

Rare: scleroderma.

Musculoskeletal and connective tissue disorders

Uncommon: muscle and joint pain.

Renal and urinary disorders

Uncommon: oliguria, dysuria, polyuria, urinary retention.

General disorders and administration site conditions

Common: fever, chills, malaise.

Uncommon: tumor site pain, phlebitis, venous wall hypertrophy and venous access narrowing (with intravenous administration), induction (with intramuscular administration).

Very rare: tumor lysis syndrome.

Description of selected adverse reactions.

Hyperthermic reaction

Body temperature may increase 2–6 hours after the first administration of bleomycin. In cases of persistent fever, antipyretic agents may be required. The frequency of hyperthermic reactions decreases with subsequent administrations of bleomycin.

Fever and chills may develop with a delay of 45 hours or more after drug administration. Since the reaction is dose-dependent, appropriate measures should be taken in case of severe fever, such as administering a reduced dose at shorter intervals or using antihistamines and antipyretics before and/or after drug administration.

Skin and mucous membrane reactions

The most common adverse effects during bleomycin therapy (observed in approximately half of patients) are skin and mucous membrane reactions (skin thickening and induration, hyperkeratosis, skin edema, redness, pruritus, striae, rash, ulceration, hyperpigmentation, increased sensitivity and swelling of the skin of fingertips, nail discoloration, skin edema at pressure sites such as elbows, alopecia, stomatitis). These adverse effects are rarely serious and usually resolve after completion of treatment. Severity of mucosal lesions may increase with combination chemotherapy or concomitant radiotherapy.

Mucosal ulceration occurs more frequently when bleomycin is combined with radiotherapy or another agent toxic to mucous membranes. Skin toxicity develops at a relatively late stage and correlates with cumulative dose. It typically appears during the second and third week after administration of 150 to 200 units of bleomycin.

Gastrointestinal disorders

Nausea and vomiting may occur, particularly with high-dose therapy. In such cases, antiemetics are prescribed. Loss of appetite and weight loss are common and may persist for a long time after treatment ends.

Hematopoietic system

Bleomycin therapy causes only minimal suppression of bone marrow function.

Thrombocytopenia associated with bleomycin treatment is explained not by decreased platelet production but by increased platelet destruction.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions through the national reporting system.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature of 2 to 8 °C. Keep out of reach of children.

Incompatibilities. Bleomycin must not be mixed with solutions of essential amino acids, riboflavin, ascorbic acid, dexamethasone, aminophylline, or furosemide.

5% glucose solution must not be used as a solvent.

Packaging. Lyophilisate in a vial; 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer. VENUS REMEDIES LIMITED.

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