Blenamax (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Pharmachemie, B.V. (Netherlands)

ATC Code

L01DC01 (Bleomycin)

Active Substance

Bleomycin (Rec.INN registered by WHO)

Dosage Form

Blenamax

Lyophilizate for the preparation of solution for injections 15 IU: fl. 1 pc.

Dosage Form, Packaging, and Composition

Lyophilizate for the preparation of solution for injections in the form of a powder or porous mass of white or white with a yellowish tint.

Colorless glass vials (1) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic antibiotic

Pharmacotherapeutic Group

Antineoplastic agent, antibiotic

Pharmacological Action

Bleomycin belongs to the group of antineoplastic antibiotics and is a mixture of structurally related water-soluble salts of glycopeptide antibiotics.

The mechanism of action of bleomycin is based on DNA fragmentation and destruction of its helical structure, which leads to inhibition of cell division. Bleomycin has a lesser effect on RNA and protein synthesis.

It has a selective effect on tumors of epidermal origin due to its ability to accumulate in skin cells. The selectivity of action is explained by the low content of the inactivating enzyme bleomycin hydrolase in tumor cells.

Unlike most other cytostatics, Bleomycin is less toxic to the bone marrow, does not have an immunosuppressive effect, and is not a neurotoxic or cardiotoxic drug.

When administered intrapleurally, it exhibits sclerosing properties.

Pharmacokinetics

After intramuscular administration of the drug at a dose of 15 IU/m² of body surface area, C_max in plasma is reached after 30 minutes.

Bleomycin is rapidly distributed in body tissues with the highest concentration in the skin, lungs, kidneys, peritoneum, and lymph nodes. With intrapleural instillation, systemic absorption is 45%. It does not penetrate the blood-brain barrier. Binding to plasma proteins is insignificant.

To date, the mechanism of biotransformation of bleomycin is unknown. Inactivation of the drug is carried out with the participation of the enzyme bleomycin hydrolase, mainly in the blood plasma, liver and other organs, and to a lesser extent in the skin and lungs.

The T_1/2 of bleomycin is about 2-3 hours. Approximately 60-70% of the administered amount of bleomycin with normal renal function is excreted unchanged in the urine, apparently due to glomerular filtration.

The plasma concentration of the drug increases sharply when the usual dose of bleomycin is administered to patients with impaired renal function. With a creatinine clearance < 35 ml/min, only 20% of the drug is excreted in the urine.

Indications

In combination with other cytostatics and/or radiation therapy for the treatment of

• Squamous cell carcinomas of the head and neck, esophagus, lungs, cervix, vulva;
• Skin cancer;
• Penile cancer;
• Germ cell tumors;
• Kidney cancer;
• Hodgkin’s disease and non-Hodgkin’s lymphomas (including lymphosarcoma and reticulosarcoma);
• Malignant testicular tumors;
• Malignant pleurisy (as a sclerosing agent).

ICD codes

Dosage Regimen

Blenamax can be administered intramuscularly, intravenously, subcutaneously, or intrapleurally.

In each individual case, when choosing the dose and regimen of Blenamax administration, data from specialized literature should be used. Doses are calculated per unit of total body surface area.

Recommended doses

• Intramuscularly or subcutaneously (in 1-5 ml of water for injections or 0.9% sodium chloride solution, alternating injection sites) at a dose of 10-20 IU/m² once or twice a week;
• Intravenously as a bolus (in 5-10 ml of 0.9% sodium chloride solution or water for injections over 5-10 minutes) at a dose of 10-20 IU/m² once or twice a week;
• Intravenously as a 6-24-hour infusion (in 200-1000 ml of 0.9% sodium chloride solution) at a dose of 10-20 IU/m² for 4-7 days every 3-4 weeks;
• Intrapleurally (in 50-100 ml of 0.9% sodium chloride solution after evacuation of the maximum possible amount of exudate) 60 IU once.

Due to the increased risk of anaphylactic reaction in patients with malignant lymphomas, the initial dose may be reduced (for example, to 2-3 IU/m²). In the absence of an acute reaction to the drug administration, further therapy can be continued at the usual dose.

The total cumulative dose of Blenamax should not exceed 400 IU, and further continuation of the drug administration can only be carried out after assessment of lung function. When using the drug in combination with other antineoplastic drugs, pulmonary toxicity may occur at lower cumulative doses of Blenamax.

In elderly patients, the drug dose is determined as follows

Administration of Blenamax to children can only be carried out in special cases. The drug dose is determined based on the unit of total body surface area.

In patients with impaired renal function, the dose of Blenamax is calculated as follows

• With a serum creatinine level of 130-180 µmol/l, the drug dose should be reduced by 50%.
• With a serum creatinine level of more than 180 µmol/l, the drug administration is postponed until the creatinine level indicators normalize.

Adverse Reactions

Hematopoietic system: Bleomycin practically does not suppress bone marrow hematopoiesis. Slight reversible thrombocytopenia may rarely be observed.

Immune system: urticaria, anaphylactic reactions (decreased blood pressure, confusion, fever, chills, wheezing). Such reactions were observed in approximately 1% of patients with malignant lymphomas, usually after the first or second administration of the drug.

Nervous system: headache, dizziness, paresthesia and hyperesthesia.

Cardiovascular system: episodes of acute dystonia have been described in patients with lymphogranulomatosis treated with high doses of bleomycin. Decreased blood pressure (with intravenous administration). Rarely, as a result of vascular disorders, cerebral arteritis, thrombotic microangiopathy, myocardial infarction, stroke, Raynaud’s syndrome may be observed.

Respiratory system: in 2-10% of cases, interstitial pneumonia (appearance of shortness of breath, cough, wheezing in the lungs), often resulting in pulmonary fibrosis or even with a fatal outcome (1%).

Skin and skin appendages: dyskeratosis in the area of the elbow or knee joints, palms, fingers, buttocks, shoulder blades; hyperemia, rash, striae, hyperpigmentation, skin itching, deformation and brittleness of nails, hyperesthesia of the skin and distal (nail) phalanges, redness of the fingertips, alopecia. Skin disorders occur in approximately 50% of cases, usually after reaching a cumulative dose of bleomycin of 150-200 IU. In rare cases, they are pronounced and usually disappear after completion of the course of treatment. Isolated reports of the development of scleroderma in individuals receiving Bleomycin have been received.

Gastrointestinal tract: anorexia, nausea, vomiting, diarrhea, stomatitis, weight loss (with long-term use).

Local reactions: local thrombophlebitis, venous occlusions usually develop with intravenous administration of the drug. When administered into the pleural cavity, pain at the injection site may be observed.

Other: pleuropericarditis, increased fatigue, pain in the area of tumor formations; changes in liver and kidney function tests, bone and joint pain.

Fever (increased temperature with chills) is observed in 20-60% of patients, usually 2-6 hours after the first injection of bleomycin. The frequency of fever development during subsequent injections of bleomycin is significantly reduced.

Contraindications

• Acute pulmonary infections;
• Severe impaired lung function;
• Severe impaired renal function;
• Ataxia telangiectasia (Louis-Bar syndrome);
• Pregnancy and lactation;
• Hypersensitivity to bleomycin.

With caution in case of concomitant or prior radiation therapy, acute infectious or viral diseases, impaired renal function, in childhood.

Use in Renal Impairment

In patients with impaired renal function, the dose of Blenamax is calculated as follows

• With a serum creatinine level of 130-180 µmol/l, the drug dose should be reduced by 50%.
• With a serum creatinine level of more than 180 µmol/l, the drug administration is postponed until the creatinine level indicators normalize.

Pediatric Use

Administration of Blenamax to children can only be carried out in special cases. The drug dose is determined based on the unit of total body surface area.

Geriatric Use

In elderly patients, the drug dose is determined as follows

Special Precautions

Treatment should be carried out under the supervision of a physician experienced in antineoplastic therapy.

Patients receiving bleomycin treatment should regularly undergo respiratory function tests, as well as radiological examination of the chest organs.

If cough, shortness of breath, wheezing, or radiological signs of interstitial pneumonia appear, the administration of bleomycin should be discontinued until the manifestations of the drug’s toxic effects are eliminated. If necessary, antibiotics and glucocorticosteroids should be prescribed.

The toxicity of bleomycin increases when the cumulative dose of 400 IU (225 IU/m²) is reached; however, the toxic dose may be significantly lower in elderly patients, in patients with impaired renal function, with a history of lung diseases, in case of previous lung irradiation, and also smoking. Sensitivity to bleomycin is increased in elderly patients. Antipyretics can be taken to relieve fever. The plasma concentration of bleomycin increases sharply when the drug is administered to patients with impaired renal function.

Due to the potential teratogenic effect of bleomycin on male and female reproductive cells, reliable methods of contraception should be used during treatment with bleomycin and for three months after completion of treatment.

Standard precautions should be observed during the preparation of the drug solution and its administration. If the drug comes into contact with the skin or mucous membranes, these areas should be rinsed with plenty of water.

Overdose

Immediate symptoms in case of overdose are decreased blood pressure, fever, rapid pulse, and general symptoms of shock. There is no specific antidote.

Treatment is symptomatic. For bronchopulmonary complications, patients should be prescribed treatment with glucocorticosteroids and broad-spectrum antibiotics.

Drug Interactions

Bleomycin reduces the bioavailability of digoxin and affects its efficacy.

When bleomycin is combined with vinca alkaloids, Raynaud’s syndrome may develop.

Bleomycin reduces the plasma level of phenytoin.

Concomitant use of bleomycin with nephrotoxic drugs (cisplatin) leads to a decrease in the clearance of bleomycin. Concomitant use of cisplatin and bleomycin may lead to severe and even fatal pulmonary toxicity.

With simultaneous administration of bleomycin with carmustine, mitomycin, cyclophosphamide and methotrexate, filgrastim and other cytokines, as well as with previous or concurrent radiation therapy to the chest area, the risk of pulmonary toxicity increases.

Patients who have been treated with bleomycin have an increased risk of pulmonary toxicity when using oxygen during anesthesia for surgical interventions. Such patients are recommended to reduce the oxygen concentration during and after surgery.

Vaccination with live vaccines while using bleomycin may lead to intensification of the replication process of the vaccine virus, enhancement of its side/adverse effects and/or reduction of antibody production in the patient’s body in response to vaccine administration.

Storage Conditions

Store in a light-protected place, out of reach of children, at a temperature of 2 to 8°C (46.4°F).

Shelf Life

Shelf life – 3 years.

After reconstitution, the drug is stable in 0.9% sodium chloride solution for 24 hours at a temperature of 2°C (35.6°F) to 8°C (46.4°F) or 12 hours at a temperature of (15-25°C (-13°F)) provided sterility is maintained.

Dispensing Status

The drug is dispensed by prescription.

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.