It is recommended that bleomycin 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 more 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.
Note: The risk for pulmonary toxicity increases with age >70 years and cumulative lifetime dose of >400 units. International considerations: Dosages below expressed as USP units; 1 USP unit = 1 mg (by potency) = 1,000 international units (Stefanou 2001). During shortages within the US, temporary importation of international products may be allowed by the FDA. The imported bleomycin vial and product labeling may express strength and dosing as international units instead of USP units.
Hodgkin lymphoma (off-label dosing): IV:
ABVD regimen: 10 units/m2 days 1 and 15 of a 28-day treatment cycle (in combination with doxorubicin, vinblastine, and dacarbazine) (Straus 2004)
BEACOPP regimen: 10 units/m2 day 8 of a 21-day treatment cycle (in combination with etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) (Dann 2007, Diehl 2003)
Stanford V regimen: 5 units/m2/dose in weeks 2, 4, 6, 8, 10 and 12 (in combination with mechlorethamine, vinblastine, vincristine, doxorubicin, etoposide, and prednisone) (Horning 2002; Horning 2000)
Test dose for lymphoma patients: IM, IV, SubQ: Due to the possibility of an anaphylactoid reaction, the manufacturer recommends administering bleomycin 2 units or less before the first 2 doses; if no acute reaction occurs, then the regular dosage schedule may be followed. Monitor carefully, particularly following the first 2 doses. Note: Test doses may not be predictive of a reaction (Lam 2005) and/or may produce false-negative results.
Testicular cancer (off-label dosing): IV: BEP regimen: 30 units/dose days 1, 8, and 15 of a 21-day treatment cycle for 4 cycles (in combination with etoposide and cisplatin) (Culine 2008; Nichols 1998)
Malignant pleural effusion: Intrapleural: 60 units as a single instillation; mix in 50 to 100 mL of NS
Ovarian germ cell cancer (off-label use): BEP regimen: IV: 30 units/dose days 1, 8, and 15 of a 21-day treatment cycle for 3 cycles (in combination with etoposide and cisplatin) (Williams 1994) or 15 units/m2 day 1 of a 21-day treatment cycle for 4 cycles (in combination with etoposide and cisplatin) (Cushing 2004)
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Manufacturer's labeling (creatinine clearance should be estimated using the Cockcroft-Gault formula):
CrCl ≥50 mL/minute: No dosage adjustment necessary.
CrCl 40 to 50 mL/minute: Reduce dose to 70% of normal dose
CrCl 30 to 40 mL/minute: Reduce dose to 60% of normal dose
CrCl 20 to 30 mL/minute: Reduce dose to 55% of normal dose
CrCl 10 to 20 mL/minute: Reduce dose to 45% of normal dose
CrCl 5 to 10 mL/minute: Reduce dose to 40% of normal dose
The following adjustments have also been recommended:
Aronoff 2007: Continuous renal replacement therapy (CRRT): Reduce dose to 75% of normal dose
Kintzel 1995:
CrCl 46 to 60 mL/minute: Reduce dose to 70% of normal dose
CrCl 31 to 45 mL/minute: Reduce dose to 60% of normal dose
CrCl <30 mL/minute: Consider use of alternative drug
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); however, adjustment for hepatic impairment is not necessary (King 2001).
(For additional information see "Bleomycin: Pediatric drug information")
Note: The risk for pulmonary toxicity increases with cumulative lifetime dose >400 USP units. International considerations: Dosages below are expressed as USP units; 1 USP unit = 1 mg (by potency) = 1,000 international units (Stefanou 2001). During shortages within the US, temporary importation of international products may be allowed by the FDA. The imported bleomycin vial and product labeling may express strength and dosing as international units instead of USP units. Refer to individual protocols for specific dosage and interval information. All doses of bleomycin are associated with a minimal emetic potential (Dupuis 2011); no routine prophylaxis is recommended (Dupuis 2013).
Test dose for lymphoma patients: Limited data available: Note: Test doses may not be predictive of a reaction (Lam 2005) and/or may produce false-negative results; some protocols no longer require; refer to institution/protocol specific guidelines. Children and Adolescents: IM, IV, SubQ: Because of the possibility of an anaphylactoid reaction, the manufacturer recommends administering 1 to 2 units of bleomycin before the first 1 to 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
Hodgkin lymphoma (combination regimen): Limited data available:
ABVE-PC (intermediate-risk or high-risk Hodgkin lymphoma): Children and Adolescents: IV or SubQ: 5 units/m2 on day 1 and 10 units/m2 on day 8 of a 21-day cycle for 2 to 4 cycles (in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide) (Dharmarajan 2015; Friedman 2014; Schwartz 2009)
ABVD (high-risk Hodgkin lymphoma): Children and Adolescents: IV: 10 units/m2 on days 1 and 15 of a 28-day treatment cycle for 2 to 6 cycles in combination with doxorubicin, vinblastine, dacarbazine (Hutchinson 1998)
BEACOPP (high-risk Hodgkin lymphoma): Children and Adolescents: IV: 10 units/m2 on day 7 of a 21-day treatment cycle for 2 to 4 cycles in combination with etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (Kelly 2002)
Stanford V (high-risk Hodgkin lymphoma): Adolescent ≥16 years: IV: 5 units/m2/dose in weeks 2, 4, 6, 8, 10, and 12 of a 12-week treatment cycle for 1 cycle in combination with mechlorethamine, vinblastine, vincristine, doxorubicin, etoposide, and prednisone (Gordon 2013; Horning 2000; Horning 2002)
Malignant germ cell cancer (combination therapy): Limited data available: PEB regimen (Cushing 2004):
Infants: IV: 0.5 mg/kg on day 1 of a 21-day treatment cycle for 4 cycles in combination with cisplatin and etoposide
Children and Adolescents: IV: 15 units/m2 on day 1 of a 21-day treatment cycle for 4 cycles in combination with cisplatin and etoposide
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosing adjustment for toxicity: The presented dosing adjustments are based on experience in adult patients; specific recommendations for pediatric patients are limited. Refer to specific protocol for management in pediatric patients if available.
Adult:
Pulmonary changes: Discontinue until determined not to be drug-related.
Pulmonary diffusion capacity for carbon monoxide (DLCO) <30% to 35% of baseline in adults: Discontinue treatment.
There are no pediatric specific recommendations; based on experience in adult patients, dosing adjustment suggested.
There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); however, adjustment for hepatic impairment is not necessary (King 2001).
Refer to adult dosing. The incidence of pulmonary toxicity is higher in patients >70 years of age.
ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Fixed doses (dosing which is independent of body weight or BSA), are used in some protocols (eg, testicular cancer); due to toxicity concerns, the same fixed dose should also be considered for obese patients (ASCO [Griggs 2012]).
Pulmonary toxicity: Discontinue until determined not to be drug-related.
Pulmonary diffusion capacity for carbon monoxide (DLCO) <30% to 35% of baseline: Discontinue treatment.
Pulmonary diffusing capacity for carbon monoxide corrected for hemoglobin content [DLCOc] decrease of more than 25% during therapy (compared with baseline): Consider discontinuing bleomycin to avoid further pulmonary toxicity (Lauritsen 2016).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Injection [preservative free]:
Generic: 15 units (1 ea); 30 units (1 ea)
Yes
During shortages within the US, temporary importation of international products may be allowed by the FDA. The imported bleomycin vial and product labeling may express strength and dosing as international units instead of USP units (1,000 international units = 1 USP unit).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Injection:
Generic: 15 units (1 ea)
IV: IV doses should be administered slowly over 10 minutes (according to the manufacturer's labeling).
IM or SubQ: May cause pain at injection site
Intrapleural: 60 units in 50 to 100 mL NS; use of topical anesthetics or opioid analgesia is usually not necessary
Monitor for hypersensitivity, particularly following the first 2 doses in patients with lymphoma.
IM, SubQ: Administer at a concentration of 3 to 15 units/mL; may cause pain at injection site
IV: Administer IV slowly over at least 10 minutes; may be further diluted for administration by continuous IV infusion; slower administration may produce less severe pulmonary toxicity
Hazardous agent (NIOSH 2016 [group 1]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Head and neck cancers: Treatment of squamous cell carcinomas of the head and neck
Hodgkin lymphoma: Treatment of Hodgkin lymphoma
Malignant pleural effusion: Sclerosing agent for malignant pleural effusion
Testicular cancer: Treatment of testicular cancer
Germ cell tumors, malignant
Bleomycin may be confused with Cleocin
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drugs which have a heightened risk of causing significant patient harm when used in error.
Some products available internationally may have vial strength and dosing expressed as international units or milligrams (instead of units or USP units). Refer to prescribing information for specific strength and dosing information.
During shortages within the US, temporary importation of international products may be allowed by the FDA. The imported bleomycin vial and product labeling may express strength and dosing as international units instead of USP units (1,000 international units = 1 USP unit).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Frequency not always defined. The pathogenesis of respiratory adverse effects is not certain, but may be due to damage of pulmonary, vascular, or connective tissue. Response to steroid therapy is variable and somewhat controversial.
>10%:
Cardiovascular: Phlebitis
Central nervous system: Tumor pain
Dermatologic: Hyperpigmentation (50%), atrophic striae (≤50%), erythema (≤50%), exfoliation of the skin (≤50%; particularly on the palmar and plantar surfaces of the hands and feet), hyperkeratosis (≤50%), localized vesiculation (≤50%), skin rash (≤50%), skin sclerosis (≤50%), alopecia (may be dose-related and reversible with discontinuation), nailbed changes (may be dose-related and reversible with discontinuation)
Endocrine & metabolic: Weight loss
Gastrointestinal: Stomatitis (≤30%), mucositis (≤30%), anorexia
Miscellaneous: Febrile reaction (25% to 50%; acute)
1% to 10%:
Dermatologic: Onycholysis, pruritus, thickening of skin
Hypersensitivity: Anaphylactoid reaction (including chills, confusion, fever, hypotension, wheezing; onset may be immediate or delayed for several hours; includes idiosyncratic reaction in 1% of lymphoma patients)
Neuromuscular & skeletal: Scleroderma (diffuse)
Respiratory: Tachypnea (≤5% to 10%), rales (≤5% to 10%), interstitial pneumonitis (acute or chronic: ≤5% to 10%), pulmonary fibrosis (≤5% to 10%), hypoxia (1%)
<1%, postmarketing, and/or case reports: Angioedema, bone marrow depression (rare), cerebrovascular accident, cerebral arteritis, chest pain, coronary artery disease, hepatotoxicity, hyperpigmentation (flagellate), ischemic heart disease, malaise, myocardial infarction, nausea, nephrotoxicity, pericarditis, Raynaud’s phenomenon, scleroderma (scleroderma-like skin changes), Stevens-Johnson syndrome, thrombotic thrombocytopenic purpura, toxic epidermal necrolysis, vomiting
Hypersensitivity to bleomycin or any component of the formulation
Concerns related to adverse effects:
• Hepatotoxicity: May cause hepatic toxicity.
• Idiosyncratic reaction: [US 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 toxicity: [US 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 (especially high inspired oxygen doses). A review of patients receiving bleomycin for the treatment of germ cell tumors suggests risk for pulmonary toxicity is increased in patients >40 years of age, with glomerular filtration rate <80 mL/minute, advanced disease, and cumulative doses >300 units (O’Sullivan 2003). Pulmonary toxicity may include bronchiolitis obliterans and organizing pneumonia (BOOP), eosinophilic hypersensitivity, and interstitial pneumonitis, progressing to pulmonary fibrosis (Sleijfer 2001); pulmonary toxicity may be due to a lack of the enzyme which inactivates bleomycin (bleomycin hydrolase) in the lungs (Morgan 2011; Sleijfer 2001), If pulmonary changes occur, withhold treatment and investigate if drug-related. In a study of patients with testicular cancer receiving bleomycin as part of the BEP regimen, pulmonary function testing (including forced vital capacity [FVC], forced expiratory volume in 1 second [FEV1], and diffusing capacity of the lungs for carbon monoxide [DLCO]) was performed prior to treatment, before each chemotherapy cycle, and then repeated at 1 year, 3 years, and 5 years during follow up; if the carbon monoxide diffusing capacity corrected for hemoglobin content [DLCOc] decreased more than 25% during therapy (compared with baseline), bleomycin was discontinued to avoid further pulmonary toxicity (Lauritsen 2016).
• Renal toxicity: May cause renal toxicity.
Disease-related concerns:
• Hodgkin lymphoma: Positron emission tomography/computed tomography (PET/CT) may have a role in determining early response to therapy in patients with Hodgkin lymphoma; a negative interim PET/CT result after 2 cycles may indicate that bleomycin can be safely omitted from the ABVD treatment regimen (Johnson 2016). Longer follow-up is necessary to determine the effect of bleomycin omission on long-term morbidity and mortality in these patients.
• Renal impairment: Use with caution in patients with renal impairment (CrCl <50 mL/minute), may require dose adjustment.
Special populations:
• Pediatric: In children, a younger age at treatment, cumulative dose ≥400 units/m2 (combined with chest irradiation), and renal impairment are associated with a higher incidence of pulmonary toxicity (Huang, 2011).
Other warnings/precautions:
• Experienced physician: [US Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.
• International issues: Some products available internationally may have vial strength and dosing expressed as international units or milligrams (instead of units or USP units). During shortages within the US, temporary importation of international products may be allowed by the FDA. The imported bleomycin vial and product labeling may express strength and dosing as international units instead of USP units. One USP unit of bleomycin = 1 mg (by potency) = 1,000 international units (Stefanou 2001). Refer to prescribing information for specific dosing information.
• 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.
None known.
Brentuximab Vedotin: May enhance the adverse/toxic effect of Bleomycin. Specifically, the risk for pulmonary toxicity may be increased. Risk X: Avoid combination
Gemcitabine: May enhance the adverse/toxic effect of Bleomycin. The risk of pulmonary toxicity may be increased. Risk C: Monitor therapy
Granulocyte Colony-Stimulating Factors: May enhance the adverse/toxic effect of Bleomycin. Specifically, the risk for pulmonary toxicity may be increased. Management: Avoid use of granulocyte colony-stimulating factors 24 hours before (14 days for pegfilgrastim) and 24 hours after the last dose of bleomycin. Risk D: Consider therapy modification
Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification
Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification
Oxygen: May enhance the adverse/toxic effect of Bleomycin. Specifically, bleomycin pulmonary toxicity may be enhanced. Management: Attempt to keep oxygen at a concentration equal to that of room air (eg, 25%), during surgery and the post-operative period for patients receiving bleomycin. Monitor patients carefully for pulmonary toxicity, especially those receiving fluid replacement. Risk D: Consider therapy modification
Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Risk D: Consider therapy modification
Phenytoin: Bleomycin may decrease the serum concentration of Phenytoin. Risk C: Monitor therapy
According to the manufacturer, women of childbearing potential should avoid becoming pregnant during bleomycin treatment.
Adverse effects were observed in animal reproduction studies. The European Society for Medical Oncology has published guidelines for diagnosis, treatment, and follow-up of cancer during pregnancy; the guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team). In general, if chemotherapy is indicated, it should be avoided in the first trimester and there should be a 3-week time period between the last chemotherapy dose and anticipated delivery, and chemotherapy should not be administered beyond week 33 of gestation (Peccatori 2013). When multiagent therapy is needed to treat Hodgkin lymphoma during pregnancy, bleomycin (as a component of the ABVD [doxorubicin, bleomycin, vinblastine, and dacarbazine] regimen) may be used, starting with the second trimester (Follows 2014; Peccatori 2013).
It is not known if bleomycin is present in breast milk. Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer.
Pulmonary function tests, including total lung volume, forced vital capacity, diffusion capacity for carbon monoxide; vital capacity, total lung capacity and pulmonary capillary blood volume may be better indicators of changes induced by bleomycin (Sleifjer 2001); forced vital capacity [FVC], forced expiratory volume in 1 second [FEV1], and diffusing capacity of the lungs for carbon monoxide [DLCO]) were performed prior to treatment, before each chemotherapy cycle, and then repeated at 1 year, 3 years, and 5 years during follow up for testicular cancer patients receiving bleomycin (Lauritsen 2016); chest x-ray, renal function, liver function. Monitor for signs/symptoms of hypersensitivity; temperature initially; check body weight at regular intervals.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Bleomycin inhibits synthesis of DNA; binds to DNA leading to single- and double-strand breaks; also inhibits (to a lesser degree) RNA and protein synthesis
Absorption: IM, SubQ, and intrapleural administration: 100%, 70%, and 45%, respectively, of IV serum concentrations
Distribution: Vd: IV: 17.5 L/m2
Protein binding: 1%
Metabolism: Enzymatic inactivation by bleomycin hydrolase, a cytosolic cysteine proteinase enzyme; bleomycin hydrolase is widely distributed in normal tissues (except for the skin and lungs)
Half-life elimination: Terminal: IV: 2 hours
Time to peak, serum: IM, SubQ, Intrapleural: 30 to 60 minutes
Excretion: Urine (~65% [IV], 40% [Intrapleural])
Renal function impairment: The half-life increases exponentially as CrCl decreases.
Pediatric: Children younger than 3 years of age have a higher total body clearance than adults.
Solution (reconstituted) (Bleomycin Sulfate Injection)
15 unit (per each): $36.82 - $68.64
30 unit (per each): $80.03 - $127.32
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