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.
Dosage guidance:
Safety: In adults, the risk for pulmonary toxicity increases with cumulative lifetime dose >400 USP units; in pediatric patients, pulmonary function deficits have been seen at cumulative doses ≥60 units/m2 (Ref).
Dosage form information: International considerations: Dosages below are expressed as USP units; 1 USP unit = 1 mg (by potency) = 1,000 international units (Ref). During shortages within the United States, 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.
Clinical considerations: All doses of bleomycin are associated with a minimal emetic potential (Ref); no routine prophylaxis is recommended (Ref).
Germ cell tumors, malignant: Limited data available:
PEB regimen:
Infants: IV: 0.5 mg/kg on day 1 of a 21-day treatment cycle for 4 cycles in combination with cisplatin and etoposide (Ref).
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 (Ref).
CEb regimen:
Children <12 years: IV: 15 units/m2 on day 3 of a 21-day treatment cycle for 4 to 6 cycles depending on risk stratification in combination with carboplatin and etoposide (Ref).
Germ cell tumors, nonseminomatous: Limited data available: Note: Dosing based on trials conducted outside of the United States; dosing presented in units based on milligram potency of product.
VBP regimen: Intermediate risk: Children and Adolescents: IV: 15 units/m2 on days 1 and 2 for 3 to 5 cycles in combination with cisplatin and vinblastine; cycle duration not reported; based on pharmacology of protocol and likely nadir, a 21-day cycle seems likely; however, refer to protocol (Ref).
Hodgkin lymphoma: Limited data available:
Note: Although described in the manufacturer's labeling, test doses may not be predictive of a reaction (Ref) and/or may produce false-negative results; some protocols no longer require; refer to institution/protocol-specific guidelines.
High risk:
ABVE-PC: 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 (Ref).
ABVD: 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, and dacarbazine (Ref).
BEACOPP: 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 (Ref).
Stanford V: Adolescents ≥16 years: IV: 5 units/m2 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 (Ref).
Intermediate risk:
ABVE-PC regimen: 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 (Ref).
COPP/ABV regimen: Note: Dosing based on trials conducted outside of the United States; dosing presented in units based on milligram potency of product. Children and Adolescents: IV: 10 units/m2 on day 8 of a 28-day treatment cycle for 4 to 6 cycles in combination with cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, and vinblastine (Ref).
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 toxicity: Discontinue until determined not to be drug related.
Pulmonary diffusion capacity for carbon monoxide (DLCO) <30% to 35% of baseline: 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 (Ref).
(For additional information see "Bleomycin: Drug information")
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 (Ref). 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.
Gestational trophoblastic neoplasia, high-risk, refractory (off-label use): BEP regimen: IV: 30 units once weekly, on days 1, 8, and 15 of a 3-week treatment cycle (in combination with etoposide, cisplatin, and WBC growth factor support); continue for at least 2 treatment cycles after a normal hCG level; maximum cumulative bleomycin dose: 270 units (Ref).
Hodgkin lymphoma (off-label dosing):
ABVD regimen: IV: 10 units/m2 on days 1 and 15 of a 28-day treatment cycle (in combination with doxorubicin, vinblastine, and dacarbazine) for 2 to 6 cycles (Ref). The number of cycles required and follow-up treatment may be determined by PET scan after 2 cycles (Ref).
BEACOPP and escalated BEACOPP regimens: IV: 10 units/m2 on day 8 of a 21-day treatment cycle (in combination with etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) for 4 to 8 cycles; growth factor support is administered with escalated BEACOPP (Ref).
Escalated BEACOPP plus ABVD regimen: IV: 10 units/m2 on day 8 of a 21-day treatment cycle (in combination with etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone, and growth factor support) for 2 cycles, followed by 2 cycles of the ABVD regimen (Ref).
EBVP regimen: IM, IV: 10 units/m2 on day 1 of a 21-day treatment cycle (in combination with epirubicin, vinblastine, and prednisone) for 6 cycles, then followed by radiation therapy (Ref).
Stanford V regimen: IV: 5 units/m2 dosed weekly on weeks 2, 4, 6, 8, 10, and 12 (in combination with mechlorethamine, vinblastine, vincristine, doxorubicin, etoposide, and prednisone) (Ref).
Test dose for lymphoma patients : Note: Test doses may not be predictive of a reaction (Ref) and/or may produce false-negative results.
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.
Malignant pleural effusion: Intrapleural: 60 units as a single instillation; mix in 50 to 100 mL of NS.
Ovarian germ cell tumors (off-label use): BEP regimen: IV: 30 units/dose on days 1, 8, and 15 of a 21-day treatment cycle for 3 cycles (in combination with etoposide and cisplatin) (Ref) or 15 units/m2 day 1 of a 21-day treatment cycle for 4 cycles (in combination with etoposide and cisplatin) (Ref).
Testicular cancer (off-label dosing): BEP regimen: IV: 30 units/dose on days 1, 8, and 15 of a 21-day treatment cycle for 3 or 4 cycles (in combination with etoposide and cisplatin) (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Altered kidney function:
Manufacturer's labeling (CrCl 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:
CrCl-based dosing:
CrCl 46 to 60 mL/minute: Reduce dose to 70% of normal dose (Ref).
CrCl 31 to 45 mL/minute: Reduce dose to 60% of normal dose (Ref).
CrCl <30 mL/minute: Consider use of alternative drug (Ref).
eGFR-based dosing:
eGFR >50 mL/minute/1.73 m2: No dosage adjustment necessary (Ref).
eGFR 10 to 50 mL/minute/1.73 m2: Reduce dose to 75% of normal dose (Ref).
eGFR <10 mL/minute/1.73 m2: Reduce dose to 50% of normal dose (Ref).
Hemodialysis, intermittent (thrice weekly): Consider reducing dose to 50% of normal dose (Ref).
CRRT: Reduce dose to 75% of normal dose (Ref).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); however, adjustment for hepatic impairment is not necessary (Ref).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%: Dermatologic: Atrophic striae (~50%), erythema of skin (~50%), hyperpigmentation (~50%), skin rash (~50%), skin tenderness (~50%), vesicular eruption (~50%)
1% to 10%:
Hypersensitivity: Anaphylaxis (1%)
Respiratory: Pulmonary toxicity (10%; including dyspnea, pneumonitis, pulmonary fibrosis, rales)
Frequency not defined: Local: Local pain (intrapleural administration)
Postmarketing:
Cardiovascular: Cardiotoxicity (including acute myocardial infarction, coronary artery disease, ischemic heart disease, pericarditis) (Didagelos 2013), chest pain (during infusion), hypotension, phlebitis, Raynaud disease (McGrath 2013)
Dermatologic: Alopecia (Siegel 1990), dermatological reaction (including exfoliation of the skin [particularly on palmar and plantar surfaces], flagellate rash, hyperkeratosis, nailbed changes) (Agrawal 2017, Chen 2007, Lee 2014), pruritus (Lee 2014), skin sclerosis (Kim 1996), Stevens-Johnson syndrome (Giaccone 1986)
Endocrine & metabolic: Weight loss
Gastrointestinal: Anorexia, stomatitis (Siegel 1990), vomiting
Hematologic & oncologic: Hemolytic uremic syndrome (Salhi 2020), thrombotic microangiopathy (Salhi 2020), tumor pain
Hepatic: Hepatotoxicity
Hypersensitivity: Angioedema (Khansur 1984)
Nervous system: Chills, malaise
Renal: Nephrotoxicity
Miscellaneous: Fever, hyperpyrexia (Jhatial 2022)
Hypersensitivity or idiosyncratic reaction to bleomycin or any component of the formulation.
Concerns related to adverse effects:
• Hepatotoxicity: May cause hepatic toxicity.
• Idiosyncratic reaction: 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: 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 bleomycin 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.
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). Pulmonary function deficits at doses as low as 60 to 120 units/m2 in children on formal pulmonary function testing have been reported (COG 2018; Huang 2011).
Other warnings/precautions:
• 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.
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 [preservative free]:
Generic: 15 units (1 ea); 30 units (1 ea)
Yes
Solution (reconstituted) (Bleomycin Sulfate Injection)
15 unit (per each): $36.82 - $68.64
30 unit (per each): $80.03 - $127.32
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Injection:
Generic: 15 units (1 ea)
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.
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.
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).
Store intact vials at 2°C to 8°C (36°F to 46°F). Stable for 24 hours in NS at room temperature.
Palliative treatment of squamous cell carcinoma (of the head and neck, penis, cervix, or vulva), testicular carcinoma, Hodgkin lymphoma, and non-Hodgkin lymphoma; sclerosing agent to control malignant effusions (FDA approved in adults); has also been used in the treatment of germ cell tumors and pediatric Hodgkin lymphoma
Bleomycin may be confused with Cleocin, clindamycin.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes 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).
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
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, patients who could become pregnant 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 (ESMO [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 (ESMO [Peccatori 2013]; Follows 2014).
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), chest x-ray; renal function, hepatic function, vital signs, and temperature initially; CBC with differential and platelet count; check body weight at regular intervals
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])
Altered kidney function: The half-life increases exponentially as CrCl decreases.
Pediatric: Children <3 years of age have a higher total body clearance than adults, 71 mL/minute/m2 vs 51 mL/minute/m2, respectively, following IV bolus administration. Children ≥8 years of age have comparable clearance to adults. In children with normal renal function, plasma concentrations of bleomycin decline biexponentially as in adults. The volume of distribution and terminal half-life of bleomycin in children appear comparable to those in adults (Yee 1983; manufacturer's labeling).
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