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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(blee oh MYE sin)
Generic Available (U.S.)
Yes
Index Terms
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of squamous cell carcinomas of the head and neck, penis, cervix, or vulva, testicular carcinoma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma; sclerosing agent for malignant pleural effusion
Use: Unlabeled/Investigational
Treatment of ovarian germ cell tumors
Pregnancy Risk Factor
D
Pregnancy Considerations
Animal studies have demonstrated teratogenic and abortifacient effects. There are no adequate and well-controlled studies in pregnant women. Women of childbearing potential should avoid becoming pregnant during treatment.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
Due to the potential for serious adverse reactions in the nursing infant, breast-feeding is not recommended.
Contraindications
Hypersensitivity to bleomycin or any component of the formulation
Warnings/Precautions
Boxed warnings:
• Experienced physician: See “Other warnings/precautions” below.
• Idiosyncratic reaction: See “Concerns related to adverse effects” below.
• Pulmonary fibrosis: See “Concerns related to adverse effects” below.
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
• Hepatotoxicity: May cause hepatic toxicity.
• Idiosyncratic reaction: [U.S. Boxed Warning]: A severe idiosyncratic reaction consisting of hypotension, mental confusion, fever, chills, and wheezing (similar to anaphylaxis) has been reported in 1% of lymphoma patients treated with bleomycin. Since these reactions usually occur after the first or second dose, careful monitoring is essential after these doses.
• Pulmonary fibrosis: [U.S. Boxed Warning]: Occurrence of pulmonary fibrosis (commonly presenting as pneumonitis; occasionally progressing to pulmonary fibrosis) is the most severe toxicity. Risk is higher in elderly patients or patients receiving >400 units total lifetime dose; other possible risk factors include smoking and patients with prior radiation therapy or receiving concurrent oxygen.
• Renal toxicity: May cause renal toxicity.
Disease-related concerns:
• Renal impairment: Use with caution in patients with renal impairment (Clcr <50 mL/minute), may require dose adjustment.
Other warnings/precautions:
• Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.
• O2 during surgery: Use caution when administering O2 during surgery to patients who have received bleomycin; the risk of bleomycin-related pulmonary toxicity is increased.
Adverse Reactions
>10%:
Dermatologic: Pain at the tumor site, phlebitis. About 50% of patients develop erythema, rash, striae, induration, hyperkeratosis, vesiculation, and peeling of the skin, particularly on the palmar and plantar surfaces of the hands and feet. Hyperpigmentation (50%), alopecia, nailbed changes may also occur. These effects appear dose related and reversible with discontinuation.
Gastrointestinal: Stomatitis and mucositis (30%), anorexia, weight loss
Respiratory: Tachypnea, rales, acute or chronic interstitial pneumonitis, and pulmonary fibrosis (5% to 10%); hypoxia and death (1%). Symptoms include cough, dyspnea, and bilateral pulmonary infiltrates. The pathogenesis is not certain, but may be due to damage of pulmonary, vascular, or connective tissue. Response to steroid therapy is variable and somewhat controversial.
Miscellaneous: Acute febrile reactions (25% to 50%)
1% to 10%:
Dermatologic: Skin thickening, diffuse scleroderma, onycholysis, pruritus
Miscellaneous: Anaphylactoid-like reactions (characterized by hypotension, confusion, fever, chills, and wheezing; onset may be immediate or delayed for several hours); idiosyncratic reactions (1% in lymphoma patients)
<1%, postmarketing, and/or case reports: Angioedema, cerebrovascular accident, cerebral arteritis, chest pain, coronary artery disease, flagellate hyperpigmentation, hepatotoxicity, malaise, MI, myelosuppression (rare), myocardial ischemia, nausea, pericarditis, Raynaud's phenomenon, renal toxicity, scleroderma-like skin changes, Stevens-Johnson syndrome, thrombotic microangiopathy, toxic epidermal necrolysis, vomiting
Drug Interactions
BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid combination
Cardiac Glycosides: Antineoplastic Agents may decrease the absorption of Cardiac Glycosides. This may only affect digoxin tablets. Exceptions: Digitoxin. Risk C: Monitor therapy
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Risk C: Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Filgrastim: May enhance the adverse/toxic effect of Bleomycin. Specifically, the risk for pulmonary toxicity may be increased. Risk C: Monitor therapy
Gemcitabine: May enhance the adverse/toxic effect of Bleomycin. The risk of pulmonary toxicity may be increased. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk X: Avoid combination
Sargramostim: May enhance the adverse/toxic effect of Bleomycin. Specifically, the risk for pulmonary toxicity may be increased. Risk C: Monitor therapy
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Risk C: Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Risk X: Avoid combination
Storage
Refrigerate intact vials of powder. Intact vials are stable for up to 4 weeks at room temperature. Solutions reconstituted in NS for are stable for up to 28 days refrigerated and 14 days at room temperature; however, the manufacturer recommends stability of 24 hours in NS at room temperature.
Reconstitution
For I.V. use, reconstitute 15-unit vial with 5 mL with NS and the 30-unit vial with 10 mL NS; for I.M. or SubQ use, reconstitute 15-unit vial with 1-5 mL of SWFI, BWFI, or NS and the 30-unit vial with 2-10 mL of SWFI, BWFI, or NS. For intrapleural use, mix in 50-100 mL of NS. Use appropriate precautions for handling and disposal.
Compatibility
Stable in NS; variable stability (consult detailed reference) in D5W.
Y-site administration: Compatible: Allopurinol, amifostine, aztreonam, cefepime, cisplatin, cyclophosphamide, doxorubicin, doxorubicin liposome, droperidol, etoposide phosphate, filgrastim, fludarabine, fluorouracil, gemcitabine, granisetron, heparin, leucovorin calcium, melphalan, methotrexate, metoclopramide, mitomycin, ondansetron, paclitaxel, piperacillin/tazobactam, sargramostim, teniposide, thiotepa, vinblastine, vincristine, vinorelbine.
Compatibility in syringe: Compatible: Cisplatin, cyclophosphamide, doxorubicin, droperidol, fluorouracil, furosemide, heparin, leucovorin calcium, methotrexate, metoclopramide, mitomycin, vinblastine, vincristine.
Compatibility when admixed: Compatible: Amikacin, dexamethasone sodium phosphate, diphenhydramine, fluorouracil, gentamicin, heparin, hydrocortisone sodium phosphate, phenytoin, streptomycin, tobramycin, vinblastine, vincristine. Incompatible: Aminophylline, ascorbic acid injection, cefazolin, diazepam, hydrocortisone sodium succinate, methotrexate, mitomycin, nafcillin, penicillin G sodium, terbutaline.
Mechanism of Action
Inhibits synthesis of DNA; binds to DNA leading to single- and double-strand breaks; also inhibits (to a lesser degree) RNA and protein synthesis
Pharmacodynamics/Kinetics
Absorption: I.M. and intrapleural administration: 30% to 50% of I.V. serum concentrations; intraperitoneal and SubQ routes produce serum concentrations equal to those of I.V.
Distribution: Vd: 22 L/m2; highest concentrations in skin, kidney, lung, heart tissues; lowest in testes and GI tract; does not cross blood-brain barrier
Protein binding: 1%
Metabolism: Via several tissues including hepatic, GI tract, skin, pulmonary, renal, and serum
Half-life elimination: Biphasic (renal function dependent):
Normal renal function: Initial: 1.3 hours; Terminal: 9 hours
End-stage renal disease: Initial: 2 hours; Terminal: 30 hours
Time to peak, serum: I.M.: Within 30 minutes
Excretion: Urine (50% to 70% as active drug)
Dosage
The risk for pulmonary toxicity increases with age >70 years and cumulative lifetime dose of >400 units; 1 unit = 1 mg; details concerning dosage in combination regimens should also be consulted.
Children and Adults: Test dose for lymphoma patients: I.M., I.V., SubQ: Because of the possibility of an anaphylactoid reaction, the manufacturer recommends administering 1-2 units of bleomycin before the first 1-2 doses; monitor vital signs every 15 minutes; wait a minimum of 1 hour before administering remainder of dose; if no acute reaction occurs, then the regular dosage schedule may be followed. Note: Test doses may not be predictive of a reaction (Lam, 2005) and/or may produce false-negative results.
I.V.:
Children: Hodgkin's lymphoma (unlabeled dosing; combination regimen): ABVD: 10 units/m2 days 1 and 15 of a 28-day treatment cycle (Hutchinson, 1998)
Adults:
Hodgkin's lymphoma (unlabeled dosing; combination regimens):
ABVD: 10 units/m2 days 1 and 15 of a 28-day treatment cycle (Straus, 2004)
BEACOPP: 10 units/m2 day 8 of a 21-day treatment cycle (Dann, 2007; Diehl, 2003)
Stanford V: 5 units/m2/dose in weeks 2, 4, 6, 8, 10 and 12 (Horning, 2000; Horning, 2002)
Testicular cancer (unlabeled dosing; combination therapy): 30 units/dose days 1, 8, and 15 of a 21-day treatment cycle for 4 cycles (Culine, 2008; Nichols, 1998)
Ovarian germ cell cancer (unlabeled use; combination therapy): 30 units/dose days 1, 8, and 15 of a 21-day treatment cycle for 3 cycles (Williams, 1994) or 15 units/m2 day 1 of a 21-day treatment cycle for 4 cycles (Cushing, 2004)
Intrapleural: Adults: Malignant pleural effusion: 60 units as a single instillation; mix in 50-100 mL of NS
Dosing adjustment in renal impairment:
The FDA-approved labeling recommends the following adjustments:
Clcr >50 mL/minute: No adjustment required
Clcr 40-50 mL/minute: Administer 70% of normal dose
Clcr 30-40 mL/minute: Administer 60% of normal dose
Clcr 20-30 mL/minute: Administer 55% of normal dose
Clcr 10-20 mL/minute: Administer 45% of normal dose
Clcr 5-10 mL/minute: Administer 40% of normal dose
The following guidelines have been used by some clinicians:
Aronoff, 2007: Adults: Continuous renal replacement therapy (CRRT): Administer 75% of dose
Kintzel, 1995:
Clcr 46-60 mL/minute: Administer 70% of dose
Clcr 31-45 mL/minute: Administer 60% of dose
Clcr <30 mL/minute: Consider use of alternative drug
Dosing adjustment in hepatic impairment: Not studied in patients with hepatic impairment; adjustment for hepatic impairment may be needed.
Dosage: Combination Regimens
Lymphoma, Hodgkin's disease:
ABVD
BEACOPP-14 (Hodgkin's Lymphoma)
BEACOPP Escalated (Hodgkin's Lymphoma)
BEACOPP Standard (Hodgkin's Lymphoma)
MOPP/ABVD
MOPP/ABV Hybrid
Stanford V Regimen
Lymphoma, non-Hodgkin's:
CEPP(B)
COP-BLAM
MACOP-B
m-BACOD
Pro-MACE-CytaBOM
Melanoma:
BOLD
BOLD + Interferon
BOLD (Melanoma)
Osteosarcoma: POG-8651
Ovarian cancer:
BEP (Ovarian Cancer)
BEP (Ovarian Cancer, Testicular Cancer)
Testicular cancer:
BEP (Ovarian Cancer, Testicular Cancer)
BEP (Testicular Cancer)
PVB
VBP
Administration: I.M.
May cause pain at injection site.
Administration: I.V.
I.V. doses should be administered slowly over 10 minutes.
Administration: Other
Intrapleural: 60 units in 50-100 mL NS; use of topical anesthetics or narcotic analgesia is usually not necessary
SubQ: May cause pain at injection site.
Administration: I.V. Detail
pH: 4-6 (reconstituted solution, varies depending on diluent)
Monitoring Parameters
Pulmonary function tests (total lung volume, forced vital capacity, carbon monoxide diffusion), renal function, liver function, chest x-ray, temperature initially; check body weight at regular intervals
Patient Education
This medication can only be administered by injection or infusion; report immediately any redness, burning, pain, or swelling at injection/infusion site. May cause loss of appetite, nausea, or vomiting; mouth sores; fever or chills (will usually resolve); rash, redness, peeling, or increased color of skin; or loss of hair (reversible after cessation of therapy). Report any change in respiratory status; respiratory difficulty; wheezing; air hunger; increased secretions; difficulty expectorating secretions; confusion; unresolved fever or chills; sores in mouth; vaginal itching, burning, or discharge; sudden onset of dizziness; acute headache; or burning, stinging, redness, or swelling at injection site.
Geriatric Considerations
Pulmonary toxicity has been reported more frequently in geriatric patients (>70 years of age).
Anesthesia and Critical Care Concerns/Other Considerations
Clinical Pearls/Comments: The use of oxygen concentrations (>30%) in animals previously treated with bleomycin has been reported to promote pulmonary toxicity. Although this is still controversial, supplemental oxygen should be used judiciously in patients who have received bleomycin.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Stomatitis and mucositis.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
None reported
Mental Health: Effects on Psychiatric Treatment
May rarely produce myelosuppression; use caution with clozapine and carbamazepine
Nursing: Physical Assessment/Monitoring
Evaluate results of pulmonary function tests prior to and at regular intervals during treatment. Pulmonary status should be evaluated for fine rales prior to each treatment (may be the first symptom of pulmonary toxicity). Lymphoma patients should be closely monitored (vital signs every 15 minutes) for 1 hour following test dose before remainder of dose is administered (for first and second dose). Infusion or injection site must be monitored closely to avoid extravasation. Monitor pulmonary, renal, and hepatic function regularly during therapy.
Oncology: Emetic Potential
Very low (<10%)
Oncology: Vesicant
May be an irritant
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution: 15 units, 30 units
References
Aronoff GR, Bennett WM, Berns JS, et al, Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th ed. Philadelphia, PA: American College of Physicians; 2007, p 97.
Azambuja E, Fleck JF, Batista RG, et al, “Bleomycin Lung Toxicity: Who are the Patients With Increased Risk?” Pulm Pharmacol Ther, 2005, 18(5):363-66.
Culine S, Kramar A, Théodore C, et al, “Randomized Trial Comparing Bleomycin/Etoposide/Cisplatin With Alternating Cisplatin/Cyclophosphamide/Doxorubicin and Vinblastine/Bleomycin Regimens of Chemotherapy for Patients With Intermediate- and Poor-Risk Metastatic Nonseminomatous Germ Cell Tumors: Genito-Urinary Group of the French Federation of Cancer Centers Trial T93MP,” J Clin Oncol, 2008, 26(3):421-7.
Cushing B, Giller R, Cullen JW, et al, “Randomized Comparison of Combination Chemotherapy With Etoposide, Bleomycin, and Either High-Dose or Standard-Dose Cisplatin in Children and Adolescents With High-Risk Malignant Germ Cell Tumors: A Pediatric Intergroup Study -- Pediatric Oncology Group 9049 and Children's Cancer Group 8882,” J Clin Oncol, 2004, 22(13):2691-700.
Dann EJ, Bar-Shalom R, Tamir A, et al, “Risk-Adapted BEACOPP Regimen Can Reduce the Cumulative Dose of Chemotherapy for Standard and High-Risk Hodgkin Lymphoma With No Impairment of Outcome,” Blood, 2007, 109(3):905-9.
Diehl V, Franklin J, Pfreundschuh M, et al, “Standard and Increased-Dose BEACOPP Chemotherapy Compared With COPP-ABVD for Advanced Hodgkin's Disease,” N Engl J Med, 2003, 348(24):2386-95.
Floyd JD, Nguyen DT, Lobins RL, et al, “Cardiotoxicity of Cancer Therapy,” J Clin Oncol, 2005, 23(30):7685-96.
Horning SJ, Hoppe RT, Breslin S, et al, “Stanford V and Radiotherapy for Locally Extensive and Advanced Hodgkin's Disease: Mature Results of a Prospective Clinical Trial,” J Clin Oncol, 2002, 20(3):630-7.
Engert A, Franklin J, Eich HT, et al, “Two Cycles of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine Plus Extended-Field Radiotherapy is Superior to Radiotherapy Alone in Early Favorable Hodgkin's Lymphoma: Final Results of the GHSG HD7 Trial,” J Clin Oncol, 2007, 25(23):3495-502.
Horning SJ, Williams J, Bartlett NL, et al, “Assessment of the Stanford V Regimen and Consolidative Radiotherapy for Bulky and Advanced Hodgkin's Disease: Eastern Cooperative Oncology Group Pilot Study E1492,” J Clin Oncol, 2000, 18(5):972-80.
Hoskin PJ, Lowry L, Horwich A, et al, “Randomized Comparison of the Stanford V Regimen and ABVD in the Treatment of Advanced Hodgkin's Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244,” J Clin Oncol, 2009, 27(32):5390-6.
Hutchinson RJ, Fryer CJ, Davis PC, et al, “MOPP or Radiation in Addition to ABVD in the Treatment of Pathologically Staged Advanced Hodgkin's Disease in Children: Results of the Children's Cancer Group Phase III Trial,” J Clin Oncol, 1998, 16(3):897-906.
Ibrahimi OA and Anderson RR, “Images in Clinical Medicine. Bleomycin-Induced Flagellate Hyperpigmentation,” N Engl J Med, 2010, 363(24):e36.
Johnson PW, Radford JA, Cullen MH, et al, “Comparison of ABVD and Alternating or Hybrid Multidrug Regimens for the Treatment of Advanced Hodgkin's Lymphoma: Results of the United Kingdom Lymphoma Group LY09 Trial (ISRCTN97144519),” J Clin Oncol, 2005, 23(36):9208-18.
Kintzel PE and Dorr RT, “Anticancer Drug Renal Toxicity and Elimination: Dosing Guidelines for Altered Renal Function,” Cancer Treat Rev, 1995, 21(1):33-64.
Kung FH, Schwartz CL, Ferree CR,et al, “POG 8625: A Randomized Trial Comparing Chemotherapy With Chemoradiotherapy for Children and Adolescents With Stages I, IIA, IIIA1 Hodgkin Disease: A Report From the Children's Oncology Group,” J Pediatr Hematol Oncol, 2006, 28(6):362-8.
Lam MS, “The Need for Routine Bleomycin Test Dosing in the 21st Century,” Ann Pharmacother, 2005, 39(11):1897-902.
Morgan C, Tillett T, Braybrooke J, et al, “Management of Uncommon Chemotherapy-Induced Emergencies,” Lancet Oncol, 2011 [epub ahead of print].
National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Head and Neck Cancers,” Version 1.2011. Available at http://www.nccn.org/professionals/physician_gls/PDF/head-and-neck.pdf
National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Hodgkin Disease/Lymphoma,” Version 2.2010. Available at http://www.nccn.org/professionals/physician_gls/PDF/hodgkins.pdf
National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Ovarian Cancer,” Version 2.2011. Available at http://www.nccn.org/professionals/physician_gls/PDF/ovarian.pdf
National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Testicular Cancer,” Version 1.2011. Available at http://www.nccn.org/professionals/physician_gls/PDF/testicular.pdf
Nichols CR, Catalano PJ, Crawford ED, et al, “Randomized Comparison of Cisplatin and Etoposide and Either Bleomycin or Ifosfamide in Treatment of Advanced Disseminated Germ Cell Tumors: An Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B Study,” J Clin Oncol, 1998, 16(4):1287-93.
Straus DJ, Portlock CS, Qin J, et al, “Results of aPprospective Randomized Clinical Trial of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine (ABVD) Followed by Radiation Therapy (RT) Versus ABVD Alone for stages I, II, and IIIA Nonbulky Hodgkin Disease,” Blood, 2004, 104(12):3483-9.
Tobias JS, Monson K, Gupta N, et al, “Chemoradiotherapy for Locally Advanced Head and Neck Cancer: 10-year Follow-Up of the UK Head and Neck (UKHAN1) Trial,” Lancet Oncol, 2010, 11(1):66-74.
Wiernik PH, Hong F, Glick JH, et al, “Radiation Therapy Compared With Chemotherapy for Consolidation of Chemotherapy-Induced Remission of Advanced Hodgkin Lymphoma: A Study by the Eastern Co-Operative Oncology Group (E1476) With >20 Years Follow-Up,” Leuk Lymphoma, 2009, 50(10):1632-41.
Williams S, Blessing JA, Liao SY, et al, “Adjuvant Therapy of Ovarian Germ Cell Tumors With Cisplatin, Etoposide, and Bleomycin: A Trial of the Gynecologic Oncology Group,” J Clin Oncol, 1994, 12(4):701-6.
International Brand Names
Lexi-Comp.com
Last full review/revision May 2011
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