Bleomycin

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Bleomycin
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]

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Black Box Warning

ConditionName:
See full prescribing information for complete Boxed Warning.
* It is recommended that Bleomycin for Injection, USP be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.
  • Pulmonary fibrosis is the most severe toxicity associated with bleomycin. The most frequent presentation is pneumonitis occasionally progressing to pulmonary fibrosis. Its occurrence is higher in elderly patients and in those receiving greater than 400 units total dose, but pulmonary toxicity has been observed in young patients and those treated with low doses.
  • A severe idiosyncratic reaction consisting of hypotension, mental confusion, fever, chills, and wheezing has been reported in approximately 1% of lymphoma patients treated with bleomycin.

Overview

Bleomycin is a antibiotic, antineoplasic agent that is FDA approved for the treatment of Squamous Cell Carcinoma, Hodgkin’s disease, non-Hodgkin’s lymphoma, Testicular Carcinoma, Malignant Pleural Effusion. There is a Black Box Warning for this drug as shown here. Common adverse reactions include pneumonitis, pulmonary fibrosis, rash, hyperpigmentation of skin.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indications

  • Bleomycin for Injection, USP should be considered a palliative treatment. It has been shown to be useful in the management of the following neoplasms either as a single agent or in proven combinations with other approved chemotherapeutic agents:
Squamous Cell Carcinoma
  • Head and neck (including mouth, tongue, tonsil, nasopharynx, oropharynx, sinus, palate, lip, buccal mucosa, gingivae, epiglottis, skin, larynx), penis, cervix, and vulva. The response to Bleomycin for Injection is poorer in patients with previously irradiated head and neck cancer.

Lymphomas: Hodgkin’s disease, non-Hodgkin’s lymphoma.

Testicular Carcinoma
  • Embryonal cell, choriocarcinoma, and teratocarcinoma
  • Bleomycin for Injection, USP has also been shown to be useful in the management of:
Malignant Pleural Effusion
  • Bleomycin for Injection is effective as a sclerosing agent for the treatment of malignant pleural effusion and prevention of recurrent pleural effusions.

Dosage

  • Because of the possibility of an anaphylactoid reaction, lymphoma patients should be treated with 2 units or less for the first 2 doses. If no acute reaction occurs, then the regular dosage schedule may be followed.
  • The following dose schedule is recommended:
Squamous cell carcinoma, non-Hodgkin’s lymphoma, testicular carcinoma
  • 0.25 to 0.5 units/kg (10 to 20 units/m2) given intravenously, intramuscularly, or subcutaneously weekly or twice weekly.
Hodgkin’s Disease
  • 0.25 to 0.5 units/kg (10 to 20 units/m2) given intravenously, intramuscularly, or subcutaneously weekly or twice weekly. After a 50% response, a maintenance dose of 1 unit daily or 5 units weekly intravenously or intramuscularly should be given.
  • Pulmonary toxicity of Bleomycin for Injection, USP appears to be dose-related with a striking increase when the total dose is over 400 units. Total doses over 400 units should be given with great caution.
  • When Bleomycin for Injection, USP is used in combination with other antineoplastic agents, pulmonary toxicities may occur at lower doses.
  • Improvement of Hodgkin’s disease and testicular tumors is prompt and noted within 2 weeks. If no improvement is seen by this time, improvement is unlikely. Squamous cell cancers respond more slowly, sometimes requiring as long as 3 weeks before any improvement is noted.
Malignant Pleural Effusion
  • 60 units administered as a single dose bolus intrapleural injection
Use in Patients with Renal Insufficiency
  • The following dosing reductions are proposed for patients with creatinine clearance (CrCL) values of less than 50 mL/min:
  • CrCL can be estimated from the individual patient’s measured serum creatinine (Scr) values using the Cockcroft and Gault formula:
Males CrCL = [weight x (140 – Age)]/(72 x Scr)
Females CrCL = 0.85 x [weight x (140 – Age)]/(72 x Scr)
Where CrCL in mL/min/1.73m2, weight in kg, age in years, and Scr in mg/dL.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Bleomycin in adult patients.

Non–Guideline-Supported Use

  • AIDS-related Kaposi's sarcoma[1][2]
  • Carcinoma of esophagus[3][4]
  • Cystic craniopharyngioma[5][6][7]
  • Germ cell tumor of ovary[8][9]
  • Gestational trophoblastic neoplasia[10]
  • Malignant effusion - Peritoneal effusion[11]
  • Malignant melanoma[12][13]
  • Malignant pericardial effusion[14]
  • Malignant tumor of thyroid gland[15]
  • Mycosis fungoides, Advanced stage, in combination with other agents[16]

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding FDA-Labeled Use of Bleomycin in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Bleomycin in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Bleomycin in pediatric patients.

Contraindications

  • Bleomycin for Injection is contraindicated in patients who have demonstrated a hypersensitive or an idiosyncratic reaction to it.

Warnings

ConditionName:
See full prescribing information for complete Boxed Warning.
* It is recommended that Bleomycin for Injection, USP be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.
  • Pulmonary fibrosis is the most severe toxicity associated with bleomycin. The most frequent presentation is pneumonitis occasionally progressing to pulmonary fibrosis. Its occurrence is higher in elderly patients and in those receiving greater than 400 units total dose, but pulmonary toxicity has been observed in young patients and those treated with low doses.
  • A severe idiosyncratic reaction consisting of hypotension, mental confusion, fever, chills, and wheezing has been reported in approximately 1% of lymphoma patients treated with bleomycin.
  • Patients receiving bleomycin must be observed carefully and frequently during and after therapy. It should be used with extreme caution in patients with significant impairment of renal function or compromised pulmonary function.
  • Pulmonary toxicities occur in 10% of treated patients. In approximately 1%, the nonspecific pneumonitis induced by bleomycin progresses to pulmonary fibrosis and death. Although this is age and dose related, the toxicity is unpredictable. Frequent roentgenograms are recommended.
  • A severe idiosyncratic reaction (similar to anaphylaxis) consisting of hypotension, mental confusion, fever, chills, and wheezing has been reported in approximately 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.
  • Renal or hepatic toxicity, beginning as a deterioration in renal or liver function tests, have been reported. These toxicities may occur at any time after initiation of therapy.

Precautions

  • Patients with creatinine clearance values of less than 50 mL/min should be treated with caution and their renal function should be carefully monitored during the administration of bleomycin. Lower doses of bleomycin may be required in these patients than those with normal renal function

Adverse Reactions

Clinical Trials Experience

Pulmonary
  • The most serious side effects are pulmonary adverse reactions, occurring in approximately 10% of treated patients. The most frequent presentation is pneumonitis occasionally progressing to pulmonary fibrosis. Approximately 1% of patients treated have died of pulmonary fibrosis. Pulmonary toxicity is both dose and age related, being more common in patients over 70 years of age and in those receiving over 400 units total dose. This toxicity, however, is unpredictable and has been seen in young patients receiving low doses. Some published reports have suggested that the risk of pulmonary toxicity may be increased when bleomycin is used in combination with G-CSF (filgrastim) or other cytokines. However, randomized clinical studies completed to date have not demonstrated an increased risk of pulmonary complications in patients treated with bleomycin and G-CSF.
  • Because of lack of specificity of the clinical syndrome, the identification of patients with pulmonary toxicity due to bleomycin has been extremely difficult. The earliest symptom associated with bleomycin pulmonary toxicity is dyspnea. The earliest sign is fine rales.
  • Radiographically, bleomycin-induced pneumonitis produces nonspecific patchy opacities, usually of the lower lung fields. The most common changes in pulmonary function tests are a decrease in total lung volume and a decrease in vital capacity. However, these changes are not predictive of the development of pulmonary fibrosis.
  • The microscopic tissue changes due to bleomycin toxicity include bronchiolar squamous metaplasia, reactive macrophages, atypical alveolar epithelial cells, fibrinous edema, and interstitial fibrosis. The acute stage may involve capillary changes and subsequent fibrinous exudation into alveoli producing a change similar to hyaline membrane formation and progressing to a diffuse interstitial fibrosis resembling the Hamman-Rich syndrome. These microscopic findings are nonspecific; e.g., similar changes are seen in radiation pneumonitis and pneumocystic pneumonitis.
  • To monitor the onset of pulmonary toxicity, roentgenograms of the chest should be taken every 1 to 2 weeks (see WARNINGS). If pulmonary changes are noted, treatment should be discontinued until it can be determined if they are drug related. Recent studies have suggested that sequential measurement of the pulmonary diffusion capacity for carbon monoxide (DLco) during treatment with bleomycin may be an indicator of subclinical pulmonary toxicity. It is recommended that the DLco be monitored monthly if it is to be employed to detect pulmonary toxicities, and thus the drug should be discontinued when the DLco falls below 30% to 35% of the pretreatment value.
  • Because of bleomycin’s sensitization of lung tissue, patients who have received bleomycin are at greater risk of developing pulmonary toxicity when oxygen is administered in surgery. While long exposure to very high oxygen concentrations is a known cause of lung damage, after bleomycin administration, lung damage can occur at lower concentrations that are usually considered safe. Suggested preventive measures are:
  • Maintain FlO2 at concentrations approximating that of room air (25%) during surgery and the postoperative period.
  • Monitor carefully fluid replacement, focusing more on colloid administration rather than crystalloid.
  • Sudden onset of an acute chest pain syndrome suggestive of pleuropericarditis has been reported during bleomycin infusions. Although each patient must be individually evaluated, further courses of bleomycin do not appear to be contraindicated.
  • Pulmonary adverse events which may be related to the intrapleural administration of bleomycin have been reported.
Idiosyncratic Reactions
  • In approximately 1% of the lymphoma patients treated with bleomycin, an idiosyncratic reaction, similar to anaphylaxis clinically, has been reported. The reaction may be immediate or delayed for several hours, and usually occurs after the first or second dose (see WARNINGS). It consists of hypotension, mental confusion, fever, chills, and wheezing. Treatment is symptomatic including volume expansion, pressor agents, antihistamines, and corticosteroids.
Integument and Mucous Membranes
  • These adverse reactions have been reported in approximately 50% of treated patients. They consist of erythema, rash, striae, vesiculation, hyperpigmentation, and tenderness of the skin. Hyperkeratosis, nail changes, alopecia, pruritus, and stomatitis have also been reported. It was necessary to discontinue bleomycin therapy in 2% of treated patients because of these toxicities.
  • Scleroderma-like skin changes have been reported.
  • Skin toxicity is a relatively late manifestation usually developing in the second and third week of treatment after 150 to 200 units of bleomycin have been administered and appears to be related to the cumulative dose.
  • Intrapleural administration of bleomycin has been associated with local pain. Hypotension possibly requiring symptomatic treatment has been reported. Death has been reported in association with bleomycin pleurodesis in seriously ill patients.
Other
  • Vascular toxicities coincident with the use of bleomycin in combination with other antineoplastic agents have been reported. The events are clinically heterogeneous and may include myocardial infarction, cerebrovascular accident, thrombotic microangiopathy (HUS), or cerebral arteritis. Various mechanisms have been proposed for these vascular complications. There are also reports of Raynaud’s phenomenon occurring in patients treated with bleomycin in combination with vinblastine with or without cisplatin or, in a few cases, with bleomycin as a single agent. It is currently unknown if the cause of Raynaud’s phenomenon in these cases is the disease, underlying vascular compromise, bleomycin, vinblastine, hypomagnesemia, or a combination of any of these factors.
  • Fever, chills, and vomiting have been reported. Anorexia and weight loss have been reported and may persist long after termination of this medication. Pain at tumor site, phlebitis, and other local reactions have been reported.
  • Malaise has been reported.

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Bleomycin in the drug label.

Drug Interactions

Drugs that Can Affect Renal Clearance
  • Because bleomycin is eliminated predominantly through renal excretion, the administration of nephrotoxic drugs with bleomycin may affect its renal clearance. Specifically, in one report of 2 children receiving concomitant cisplatin with bleomycin, total body clearance of bleomycin decreased from 39 to 18 mL/min/m2 as the cumulative dose of cisplatin exceeded 300 mg/m2. Terminal half-life of bleomycin also increased from 4.4 to 6 hours. Fatal bleomycin pulmonary toxicity has been reported in a patient with unrecognized cisplatin-induced oliguric renal failure.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): D

  • Bleomycin can cause fetal harm when administered to a pregnant woman. It has been shown to be teratogenic in rats. Administration of intraperitoneal doses of 1.5 mg/kg/day to rats (about 1.6 times the recommended human dose on a unit/m2 basis) on days 6 to 15 of gestation caused skeletal malformations, shortened innominate artery and hydroureter. Bleomycin is abortifacient but not teratogenic in rabbits at intravenous doses of 1.2 mg/kg/day (about 2.4 times the recommended human dose on a unit/m2 basis) given on gestation days 6 to 18.
  • There have been no studies in pregnant women. If bleomycin is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with bleomycin.


Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bleomycin in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Bleomycin during labor and delivery.

Nursing Mothers

  • It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued by women receiving bleomycin therapy.

Pediatric Use

  • Safety and effectiveness of bleomycin in pediatric patients have not been established.

Geriatic Use

  • In clinical trials, pulmonary toxicity was more common in patients older than 70 years than in younger patients (see BOXED WARNING, WARNINGS, and ADVERSE REACTIONS, PULMONARY). Other reported clinical experience has not identified other differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
  • Bleomycin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Gender

There is no FDA guidance on the use of Bleomycin with respect to specific gender populations.

Race

There is no FDA guidance on the use of Bleomycin with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Bleomycin in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Bleomycin in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Bleomycin in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Bleomycin in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Oral
  • Intravenous

Monitoring

There is limited information regarding Monitoring of Bleomycin in the drug label.

  • Description

IV Compatibility

There is limited information regarding IV Compatibility of Bleomycin in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

  • Description

Management

  • Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Bleomycin in the drug label.

Pharmacology

There is limited information regarding Bleomycin Pharmacology in the drug label.

Mechanism of Action

Structure

File:Bleomycin01.png
This image is provided by the National Library of Medicine.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Bleomycin in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Bleomycin in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Bleomycin in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Bleomycin in the drug label.

How Supplied

Storage

There is limited information regarding Bleomycin Storage in the drug label.

Images

Drug Images

{{#ask: Page Name::Bleomycin |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}

Package and Label Display Panel

{{#ask: Label Page::Bleomycin |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}

Patient Counseling Information

There is limited information regarding Patient Counseling Information of Bleomycin in the drug label.

Precautions with Alcohol

  • Alcohol-Bleomycin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Look-Alike Drug Names

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

  1. ↑ Poignonec S, Lachiver LD, Lamas G, Coutellier A, Caumes E, Soudant J (1995). "Intralesional bleomycin for acquired immunodeficiency syndrome-associated cutaneous Kaposi's sarcoma". Arch Dermatol. 131 (2): 228. PMID 7531965.
  2. ↑ Brambilla L, Boneschi V, Beretta G, Finzi AF (1984). "Intralesional chemotherapy for Kaposi's sarcoma". Dermatologica. 169 (3): 150–5. PMID 6207059.
  3. ↑ Coonley CJ, Bains M, Hilaris B, Chapman R, Kelsen DP (1984). "Cisplatin and bleomycin in the treatment of esophageal carcinoma. A final report". Cancer. 54 (11): 2351–5. PMID 6208990.
  4. ↑ Dinwoodie WR, Bartolucci AA, Lyman GH, Velez-Garcia E, Martelo OJ, Sarma PR (1986). "Phase II evaluation of cisplatin, bleomycin, and vindesine in advanced squamous cell carcinoma of the esophagus: a Southeastern Cancer Study Group Trial". Cancer Treat Rep. 70 (2): 267–70. PMID 2418969.
  5. ↑ Hukin J, Steinbok P, Lafay-Cousin L, Hendson G, Strother D, Mercier C; et al. (2007). "Intracystic bleomycin therapy for craniopharyngioma in children: the Canadian experience". Cancer. 109 (10): 2124–31. doi:10.1002/cncr.22633. PMID 17407137.
  6. ↑ Mottolese C, Stan H, Hermier M, Berlier P, Convert J, Frappaz D; et al. (2001). "Intracystic chemotherapy with bleomycin in the treatment of craniopharyngiomas". Childs Nerv Syst. 17 (12): 724–30. doi:10.1007/s00381-001-0524-5. PMID 11862438.
  7. ↑ Hader WJ, Steinbok P, Hukin J, Fryer C (2000). "Intratumoral therapy with bleomycin for cystic craniopharyngiomas in children". Pediatr Neurosurg. 33 (4): 211–8. doi:55955 Check |doi= value (help). PMID 11124639.
  8. ↑ Gershenson DM, Morris M, Burke TW, Levenback C, Matthews CM, Wharton JT (1996). "Treatment of poor-prognosis sex cord-stromal tumors of the ovary with the combination of bleomycin, etoposide, and cisplatin". Obstet Gynecol. 87 (4): 527–31. doi:10.1016/0029-7844(95)00491-2. PMID 8602303.
  9. ↑ Williams SD, Birch R, Einhorn LH, Irwin L, Greco FA, Loehrer PJ (1987). "Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide". N Engl J Med. 316 (23): 1435–40. doi:10.1056/NEJM198706043162302. PMID 2437455.
  10. ↑ Chen LP, Cai SM, Fan JX, Li ZT (1995). "PEBA regimen (cisplatin, etoposide, bleomycin, and adriamycin) in the treatment of drug-resistant choriocarcinoma". Gynecol Oncol. 56 (2): 231–4. PMID 7534740.
  11. ↑ Maiche AG (1994). "Management of peritoneal effusions with intracavitary mitoxantrone or bleomycin". Anticancer Drugs. 5 (3): 305–8. PMID 7522646.
  12. ↑ Luikart SD, Kennealey GT, Kirkwood JM (1984). "Randomized phase III trial of vinblastine, bleomycin, and cis-dichlorodiammine-platinum versus dacarbazine in malignant melanoma". J Clin Oncol. 2 (3): 164–8. PMID 6199481.
  13. ↑ Punt CJ, van Herpen CM, Jansen RL, Vreugdenhil G, Muller EW, de Mulder PH (1997). "Chemoimmunotherapy with bleomycin, vincristine, lomustine, dacarbazine (BOLD) plus interferon alpha for metastatic melanoma: a multicentre phase II study". Br J Cancer. 76 (2): 266–9. PMC 2223935. PMID 9231931.
  14. ↑ Liu G, Crump M, Goss PE, Dancey J, Shepherd FA (1996). "Prospective comparison of the sclerosing agents doxycycline and bleomycin for the primary management of malignant pericardial effusion and cardiac tamponade". J Clin Oncol. 14 (12): 3141–7. PMID 8955660.
  15. ↑ De Besi P, Busnardo B, Toso S, Girelli ME, Nacamulli D, Simioni N; et al. (1991). "Combined chemotherapy with bleomycin, adriamycin, and platinum in advanced thyroid cancer". J Endocrinol Invest. 14 (6): 475–80. PMID 1723086.
  16. ↑ Fierro MT, Doveil GC, Quaglino P, Savoia P, Verrone A, Bernengo MG (1997). "Combination of etoposide, idarubicin, cyclophosphamide, vincristine, prednisone and bleomycin (VICOP-B) in the treatment of advanced cutaneous T-cell lymphoma". Dermatology. 194 (3): 268–72. PMID 9187846.
  17. ↑ Empty citation (help)
  18. ↑ "http://www.ismp.org". External link in |title= (help)

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