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Bleomycin: Pediatric drug information

Bleomycin: Pediatric drug information
(For additional information see "Bleomycin: Drug information" and see "Bleomycin: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Experienced physician:

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 toxicity:

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.

Idiosyncratic reaction:

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.

Therapeutic Category
  • Antineoplastic Agent, Antibiotic
Dosing: Pediatric

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.

Dosing: Kidney Impairment: Pediatric

There are no pediatric specific recommendations; based on experience in adult patients, dosing adjustment suggested.

Dosing: Hepatic Impairment: Pediatric

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).

Dosing: Adult

(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 (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.

Dosing: Kidney Impairment: Adult

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

Dosing: Hepatic Impairment: Adult

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).

Dosage Forms: US

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)

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Injection:

Generic: 15 units (1 ea)

Dosage Forms Considerations

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).

Administration: Pediatric

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

Administration: Adult

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 Drugs Handling Considerations

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).

Storage/Stability

Store intact vials at 2°C to 8°C (36°F to 46°F). Stable for 24 hours in NS at room temperature.

Use

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

Medication Safety Issues
Sound-alike/look-alike issues:

Bleomycin may be confused with Cleocin

High alert medication:

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.

International issues:

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.

Other safety concerns:

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).

Adverse Reactions

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

Contraindications

Hypersensitivity to bleomycin or any component of the formulation

Warnings/Precautions

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.

Metabolism/Transport Effects

None known.

Drug Interactions

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

Reproductive Considerations

According to the manufacturer, women of childbearing potential should avoid becoming pregnant during bleomycin treatment.

Pregnancy Considerations

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).

Monitoring Parameters

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

Mechanism of Action

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

Pharmacokinetics (Adult data unless noted)

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])

Pharmacokinetics: Additional Considerations

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.

Pricing: US

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.

Brand Names: International
  • Bemocin (ZW);
  • Bileco (AR);
  • Blemisin (RO);
  • Blenamax (AU, HK, ID, MY, RU, SG, TW, ZA);
  • Blenoxane (BR, EC, ZA);
  • Bleo (GB);
  • Bleo 15K (AU);
  • Bleochem (IN);
  • Bleocin (AE, BG, CZ, EE, GR, HK, HN, HU, ID, IN, JO, JP, KR, LB, LK, LT, MY, PE, PL, PT, SA, SG, TH, TR, TW, VN);
  • Bleocina (UY);
  • Bleocip (EG, ET, LB, VE, ZW);
  • Bleocris (AR, PY);
  • Bleolem (CO, MX, TH, ZA);
  • Bleomax (CR, DO, GT, HN, IN, MX, NI, PA, SV);
  • Bleomedac (DE, NL, SK);
  • Bleomicina (ES, IT);
  • Bleomycin (AT, CH, DK, FI, NO, SE);
  • Bleomycin PFI (IL);
  • Bleomycine (BE, FR, LU);
  • Blkesol (ZW);
  • Blocamicina (AR);
  • Bloicin-S (EG, PH);
  • Blomindex (CR, DO, GT, HN, NI, PA, SV);
  • Bonar (BR);
  • Cinaleo (BR);
  • Kupbloicin (VN);
  • Lyoble (LK);
  • Naprobleo (ET);
  • Naproplat (ET);
  • Nikableomicina (CL);
  • Tevableo (BR)


For country abbreviations used in Lexicomp (show table)

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