What Is Bleomycin? FDA Approval, Turkish Authorization, and Reimbursement

• FDA Approved: Yes (initial approval: July 19, 1973)
• Product Names, Manufacturers, and Distribution in Turkey: The original product is Blenoxane (Bristol-Myers Squibb). It is also available as Bleocin (İ.E. Ulagay), Bleocel (Koçak Farma), Bleomed (Onko & Koçsel), and Bleotek (Nobel İlaç).
• Active Ingredient: Bleomycin
• Administration: Intravenous (IV), intramuscular (IM), intrapleural
• Class: Antitumor agent
• Category: Chemotherapy medicine
• Approved Cancer Indications: Hodgkin lymphoma, non-Hodgkin lymphoma, germ cell tumors, head and neck cancer, squamous cell carcinomas of the skin, cervix, or vulva, and malignant pleural effusion

What Is Blenoxane?

Blenoxane contains bleomycin, a chemotherapy medicine used for Hodgkin lymphoma, non-Hodgkin lymphoma, germ cell tumors, head and neck cancer, squamous cell carcinomas of the skin, cervix, or vulva, and malignant pleural effusion. It is a small peptide with a molecular weight of 1,500. The medicine binds to DNA, triggering free radical formation and cell death and thereby preventing cancer cells from dividing.

Mechanism of Action

• Opposite ends of the peptide contain DNA-binding and iron-binding regions.
• Iron is a required cofactor for free radical formation and bleomycin's cytotoxic activity.
• Cytotoxic effects arise from reactive oxygen free radicals.
• These cause single- and double-strand DNA breaks, leading to cell death.

FDA (US Food and Drug Administration) Approval History

• July 19, 1973: Approved for Hodgkin lymphoma and testicular cancer.
• June 10, 1975: Additional approval for non-Hodgkin lymphoma and squamous cell head and neck cancer.
• May 14, 1990: Approved as a sclerosing agent for malignant pleural effusion.
• March 22, 2000: Approved for use in combination chemotherapy regimens for germ cell tumors.

Authorization in Turkey

Bleomycin's authorized therapeutic indications in Turkey are stated as follows:

Therapeutic Indications:

• Squamous cell carcinoma affecting the mouth, nasopharynx, paranasal sinuses, larynx, esophagus, external genitalia, cervix, or skin. Differentiated tumors generally respond better than anaplastic tumors.
• Hodgkin disease and other malignant lymphomas, including mycosis fungoides
• Testicular teratoma
• Malignant effusions in serous cavities
• Secondary indications in which some activity has been observed, alone or in combination, include metastatic malignant melanoma and thyroid, lung, and bladder carcinomas.

Related topic: BEP (Bleomycin, Etoposide, Cisplatin) Chemotherapy for Testicular Cancer

Is Bleomycin Reimbursed?

It is listed among medicines for which no indication requirement applies in patients diagnosed with cancer and is covered by SGK reimbursement for all cancer diagnoses.

Resistance Mechanisms

• Increased expression of DNA repair enzymes accelerates repair of bleomycin-induced damage and reduces effectiveness.
• Reduced cellular uptake prevents adequate intracellular concentrations and can cause resistance.

Absorption 

• Oral bioavailability is low, and it is not used orally.
• After IM injection, peak levels occur at approximately 60 minutes but are one-third lower than after IV administration.
• When administered into the pleural cavity for malignant pleural effusion (pleurodesis), approximately 45-50% enters systemic circulation.

Distribution

• It distributes into intracellular and extracellular fluids.
• Plasma protein binding is less than 10%.

Metabolism 

• After IV administration, the medicine is rapidly cleared from circulation.
• The half-life is approximately 3 hours with normal kidney function.
• Bleomycin hydrolase, found particularly in the liver and kidneys, rapidly inactivates it.
• Most elimination is renal: 50-70% is excreted unchanged in urine.
• Impaired kidney function increases toxicity risk, so dose reduction is recommended in renal failure.

Dosage Range 

• Hodgkin lymphoma: 10 units/m² IV on days 1 and 15 of a 28-day cycle (ABVD).
• Testicular cancer: 30 units IV on days 2, 9, and 16 of a 21-day cycle (BEP).
• Intracavitary administration into the pleural cavity: 60 units/m².

Precautions

Respiratory Monitoring:

• Assess DLCO (diffusing capacity for carbon monoxide) and vital capacity before treatment and before each chemotherapy cycle.
• If DLCO falls by more than 15%, stop bleomycin even without respiratory symptoms.
• Pulmonary toxicity risk increases substantially when the total cumulative dose exceeds 400 units.

Lung Imaging:

• Obtain a chest radiograph before treatment and before each cycle.
• Regular monitoring is needed to detect pulmonary toxicity early.

Signs of Pulmonary Dysfunction:

• Closely monitor breathlessness (dyspnea), low blood oxygen (reduced O₂ saturation), and reduced lung expansion.
• If these develop, stop treatment and investigate further.

Use in Kidney Failure:

• Because bleomycin is eliminated through the kidneys, renal failure slows clearance and increases toxicity risk.
• Reduce doses and monitor renal function regularly in these patients.

Anaphylactic Reaction Risk in Lymphoma:

• Patients with lymphoma have an increased risk of anaphylactic reactions.
• Reactions may be immediate or delayed.
• Keep epinephrine, antihistamines, and corticosteroids available for emergency treatment.

Managing Fever and Chills:

• Fever and chills may occur before bleomycin administration.
• Give paracetamol 30 minutes before administration to prevent this effect.

Precautions Before Surgery:

• Patients receiving bleomycin should inform the surgeon and anesthetist before an operation.
• Manage oxygen carefully because high concentrations (FiO₂ >25%) may increase pulmonary toxicity during surgery.

Side Effects

Listed from most common to least common:

1. Skin Reactions: Erythema, hyperpigmentation, striae, blisters, peeling, hyperkeratosis, and ulceration may occur, generally after 150-200 units.
2. Pulmonary Toxicity: Occurs in 10% of patients, presenting with cough, breathlessness, dry crackles, and radiographic infiltrates. Risk increases above age 70 and with cumulative doses >400 units. It may rarely progress to pulmonary fibrosis and cause death in 1%.
3. Hypersensitivity Reactions: Fever and chills may occur in 25%. Anaphylactoid reactions are more common in lymphoma.
4. Cardiovascular Events: Myocardial infarction, stroke, and Raynaud phenomenon have rarely been reported.
5. Bone Marrow Suppression (Myelosuppression): Generally mild.