Bleomycin

Usage

Bleomycin is an anti-neoplastic medication used to treat several types of cancer, including:

• Squamous cell carcinomas of the head and neck, skin, penis, cervix, and vulva
• Hodgkin’s lymphoma
• Non-Hodgkin’s lymphoma
• Testicular cancer
• Malignant pleural effusions (as a sclerosing agent)

Pharmacological Classification: Antineoplastic agent, specifically a glycopeptide antibiotic with cytotoxic properties.

Mechanism of Action: Bleomycin exerts its antineoplastic effects primarily by causing DNA strand breaks and inhibiting DNA synthesis. It also appears to chelate metal ions, potentially contributing to its cytotoxic activity.

Alternate Names

Bleomycin sulfate.

Brand Names: Blenoxane, Bleo 15k.

How It Works

Pharmacodynamics: Bleomycin’s primary mechanism of action involves binding to DNA and inducing single- and double-strand breaks, preventing cell replication. It does not appear to significantly affect RNA or protein synthesis.

Pharmacokinetics:

• Absorption: Absorption varies depending on the route of administration. Intravenous administration results in rapid and complete systemic availability. Intramuscular and subcutaneous routes show good absorption. Intrapleural administration leads to partial systemic absorption (around 45%).
• Metabolism: Bleomycin is metabolized minimally, primarily by a hydrolase enzyme, bleomycin hydrolase, which is present in various tissues but at lower concentrations in the skin and lungs.
• Elimination: Primarily renal excretion (60-70% as unchanged drug), hence dose adjustment is needed in patients with renal impairment. A small amount might be excreted in breastmilk.

Mode of Action: Bleomycin binds to DNA, leading to free radical formation, ultimately causing DNA fragmentation and inhibiting DNA synthesis.

Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Bleomycin’s main action is direct DNA damage; it does not primarily act through receptor binding, enzyme inhibition, or neurotransmitter modulation.

Elimination Pathways: Primarily renal excretion, with a small amount of metabolism via the bleomycin hydrolase.

Dosage

Bleomycin dosing is complex and requires careful consideration of patient-specific factors. Consult current protocols and guidelines for detailed information and appropriate regimen. Dosing is expressed in International Units (IU) or sometimes in units (U). 1 mg is approximately equivalent to 1 IU or 1 U.

Standard Dosage

Adults:

• Squamous cell carcinoma, non-Hodgkin’s lymphoma, testicular carcinoma: 0.25 to 0.5 units/kg (10 to 20 units/m²) IV, IM, or SC weekly or twice weekly.
• Hodgkin’s Disease: Similar to above, followed by a maintenance dose of 1 unit daily or 5 units weekly IV or IM after 50% response.
• Malignant Pleural Effusion: 60 units in 50-100 mL of normal saline as a single intrapleural instillation. May repeat at intervals if fluid reaccumulates.

Children: Not recommended for pediatric use due to limited safety and efficacy data. Use only in exceptional circumstances at specialized facilities, adapting adult dosing based on body surface area.

Special Cases:

• Elderly Patients (≥60 years): Reduce the total cumulative dose due to increased risk of pulmonary toxicity. Specific adjustments are based on age (see below).
• Patients with Renal Impairment: Adjust the dosage based on creatinine clearance. Significant dose reduction is needed for creatinine clearance <50 mL/min.
• Patients with Hepatic Dysfunction: No dose adjustment is typically necessary.
• Patients with Comorbid Conditions: Consider comorbid conditions such as pulmonary or cardiovascular disease, which may increase the risk of adverse events.

Clinical Use Cases

Bleomycin dosing in these settings should be guided by established clinical protocols:

• Intubation: Not specifically indicated for intubation.
• Surgical Procedures: Not typically administered during surgical procedures.
• Mechanical Ventilation: No specific dosage adjustments related to mechanical ventilation. Monitor for pulmonary toxicity, especially with high FiO2.
• Intensive Care Unit (ICU) Use: No specific ICU dosing guidelines. Close monitoring is essential.
• Emergency Situations: Not typically used in emergency situations.

Dosage Adjustments

Adjustments based on renal function, age, and other clinical considerations are crucial. Lifetime cumulative dose should generally not exceed 400 units due to the risk of pulmonary fibrosis. For elderly patients, adjust the total dose as follows:

• ≥80 years: 100,000 IU total, 15,000 IU/week.
• 70-79 years: 150,000 - 200,000 IU total, 30,000 IU/week.
• 60-69 years: 200,000 - 300,000 IU total, 30,000 - 60,000 IU/week.

Side Effects

Common Side Effects

• Fever and chills (approximately 50% of patients)
• Skin reactions (rash, hyperpigmentation, itching, nail changes)
• Mucositis/Stomatitis
• Anorexia and weight loss
• Nausea and vomiting
• Alopecia (hair loss)
• Pulmonary function changes

Rare but Serious Side Effects

• Pulmonary fibrosis (potentially fatal)
• Anaphylactoid reactions (hypotension, confusion, wheezing, chills)
• Raynaud’s phenomenon

Long-Term Effects

• Pulmonary fibrosis
• Secondary malignancies

Adverse Drug Reactions (ADR)

• Pulmonary toxicity (including pneumonitis and fibrosis)
• Hypersensitivity reactions

Contraindications

• Known hypersensitivity to bleomycin
• Severe pulmonary impairment

Drug Interactions

• Other antineoplastic agents: Increased risk of pulmonary toxicity (especially with cisplatin, vinblastine)
• Nephrotoxic drugs: Decreased bleomycin clearance (e.g., cisplatin, aminoglycosides)
• Oxygen therapy and other drugs affecting pulmonary function: Increased risk of pulmonary toxicity
• Live vaccines: Reduced vaccine efficacy and risk of infection
• Phenytoin: Reduced phenytoin absorption

Pregnancy and Breastfeeding

• Pregnancy Safety Category: D (Australia); Not assigned (US FDA). Contraindicated. Bleomycin is teratogenic and can cause fetal harm. Avoid pregnancy during and for 6 months after treatment.
• Breastfeeding: Contraindicated. Bleomycin may be excreted in breast milk and pose a risk to the infant.

Drug Profile Summary

• Mechanism of Action: DNA strand breakage, inhibiting DNA synthesis
• Side Effects: Fever, chills, skin reactions, mucositis, pulmonary toxicity (rare but serious)
• Contraindications: Hypersensitivity, severe pulmonary impairment
• Drug Interactions: Other antineoplastic agents, nephrotoxic drugs, oxygen therapy
• Pregnancy & Breastfeeding: Contraindicated
• Dosage: Varies depending on indication and patient factors (see Dosage section)
• Monitoring Parameters: Pulmonary function tests, renal function tests, complete blood count.

Popular Combinations

Bleomycin is often used in combination chemotherapy regimens. Examples include:

• BEP (Bleomycin, Etoposide, Cisplatin): For testicular cancer.
• ABVD (Adriamycin, Bleomycin, Vinblastine, Dacarbazine): For Hodgkin’s lymphoma.

Precautions

• General Precautions: Assess renal and pulmonary function before and during treatment.
• Specific Populations:
  • Pregnant Women: Contraindicated.
  • Breastfeeding Mothers: Contraindicated.
  • Children & Elderly: Use with caution and adjust dosage.
• Lifestyle Considerations: Avoid smoking, which may exacerbate pulmonary toxicity.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Bleomycin?

A: Dosage is dependent on the type of cancer, patient’s overall condition, and other factors. Standard doses range from 0.25 to 0.5 units/kg (10 to 20 units/m²) administered intravenously, intramuscularly, or subcutaneously weekly or twice weekly.

Q2: What are the major side effects of Bleomycin?

A: Common side effects include fever, chills, skin changes, mucositis, and nausea/vomiting. A rare but serious side effect is pulmonary toxicity, including pneumonitis and fibrosis.

Q3: How does Bleomycin work against cancer?

A: Bleomycin damages the DNA of cancer cells, preventing them from dividing and growing.

Q4: What are the contraindications for using Bleomycin?

A: Bleomycin is contraindicated in patients with known hypersensitivity to the drug and those with severe pulmonary impairment.

Q5: Can Bleomycin be used during pregnancy or breastfeeding?

A: No, Bleomycin is contraindicated during pregnancy and breastfeeding due to its potential to cause fetal harm and potential presence in breast milk.

Q6: How is Bleomycin administered?

A: Bleomycin can be administered intravenously, intramuscularly, subcutaneously, or intrapleurally, depending on the indication.

Q7: Does Bleomycin interact with other medications?

A: Yes, Bleomycin can interact with other antineoplastic agents, nephrotoxic drugs, oxygen therapy, and certain other medications. Consult drug interaction resources for a comprehensive list.

Q8: What monitoring is required during Bleomycin treatment?

A: Patients receiving Bleomycin should undergo regular monitoring of pulmonary function tests, renal function tests, and complete blood count.

Q9: What is the maximum cumulative lifetime dose for Bleomycin?

A: The maximum recommended lifetime cumulative dose is generally 400 units, although lower doses are recommended for elderly patients.

Q10: Are there specific dosage adjustments for elderly patients?

A: Yes, due to an increased risk of pulmonary toxicity, lower cumulative doses are recommended for patients over 60 years of age, with further reductions based on the age bracket (see dosage section).