Drug Information

Bleomycin

Bleomycin

ALERT: U.S. Boxed WarningThe FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.

Brand Names: Canada

  • Blenoxane®;
  • Bleomycin Injection, USP
Pharmacologic Category

  • Antineoplastic Agent, Antibiotic
Dosing: AdultThe risk for pulmonary toxicity increases with age >70 years and cumulative lifetime dose of >400 units; 1 unit = 1 mg; details concerning dosage in combination regimens should also be consulted.

Test dose for lymphoma patients: I.M., I.V., SubQ: Because of the possibility of an anaphylactoid reaction, the manufacturer recommends administering 1-2 units of bleomycin before the first 1-2 doses; monitor vital signs every 15 minutes; wait a minimum of 1 hour before administering remainder of dose; if no acute reaction occurs, then the regular dosage schedule may be followed. Note: Test doses may not be predictive of a reaction (Lam, 2005) and/or may produce false-negative results.

Hodgkin’s lymphoma (unlabeled dosing; combination regimens): I.V.:

ABVD: 10 units/m2 days 1 and 15 of a 28-day treatment cycle (Straus, 2004)

BEACOPP: 10 units/m2 day 8 of a 21-day treatment cycle (Dann, 2007; Diehl, 2003)

Stanford V: 5 units/m2/dose in weeks 2, 4, 6, 8, 10 and 12 (Horning, 2002; Horning, 2000)

Testicular cancer (unlabeled dosing; combination therapy): I.V.: 30 units/dose days 1, 8, and 15 of a 21-day treatment cycle for 4 cycles (Culine, 2008; Nichols, 1998)

Ovarian germ cell cancer (unlabeled use; combination therapy): I.V.: 30 units/dose days 1, 8, and 15 of a 21-day treatment cycle for 3 cycles (Williams, 1994) or 15 units/m2 day 1 of a 21-day treatment cycle for 4 cycles (Cushing, 2004)

Malignant pleural effusion: Intrapleural: 60 units as a single instillation; mix in 50-100 mL of NS

Dosing: PediatricThe risk for pulmonary toxicity increases with cumulative lifetime dose of >400 units; 1 unit = 1 mg; details concerning dosage in combination regimens should also be consulted.

Test dose for lymphoma patients: I.M., I.V., SubQ: Because of the possibility of an anaphylactoid reaction, the manufacturer recommends administering 1-2 units of bleomycin before the first 1-2 doses; monitor vital signs every 15 minutes; wait a minimum of 1 hour before administering remainder of dose; if no acute reaction occurs, then the regular dosage schedule may be followed. Note: Test doses may not be predictive of a reaction (Lam, 2005) and/or may produce false-negative results.

Hodgkin’s Lymphoma (unlabeled dosing; combination regimen): I.V.: ABVD: I.V.: 10 units/m2 days 1 and 15 of a 28-day treatment cycle (Hutchinson, 1998)

Dosing: Renal ImpairmentThe FDA-approved labeling recommends the following adjustments:

Clcr >50 mL/minute: No adjustment required

Clcr 40-50 mL/minute: Administer 70% of normal dose

Clcr 30-40 mL/minute: Administer 60% of normal dose

Clcr 20-30 mL/minute: Administer 55% of normal dose

Clcr 10-20 mL/minute: Administer 45% of normal dose

Clcr 5-10 mL/minute: Administer 40% of normal dose

The following guidelines have been used by some clinicians:

Aronoff, 2007: Adults: Continuous renal replacement therapy (CRRT): Administer 75% of dose

Kintzel, 1995:

Clcr 46-60 mL/minute: Administer 70% of dose

Clcr 31-45 mL/minute: Administer 60% of dose

Clcr <30 mL/minute: Consider use of alternative drug

Dosing: Hepatic ImpairmentNot studied in patients with hepatic impairment; adjustment for hepatic impairment may be needed.

Dosage Forms: U.S.Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, powder for reconstitution: 15 units, 30 units

Generic Equivalent Available: U.S.Yes

AdministrationI.V. doses should be administered slowly over 10 minutes.

I.M. or SubQ: May cause pain at injection site

Intrapleural: 60 units in 50-100 mL NS; use of topical anesthetics or narcotic analgesia is usually not necessary

CompatibilityStable in NS; variable stability (consult detailed reference) in D5W.

Y-site administration: Compatible: Allopurinol, amifostine, aztreonam, cefepime, cisplatin, cyclophosphamide, doxorubicin, doxorubicin liposome, droperidol, etoposide phosphate, filgrastim, fludarabine, fluorouracil, gemcitabine, granisetron, heparin, leucovorin calcium, melphalan, methotrexate, metoclopramide, mitomycin, ondansetron, paclitaxel, piperacillin/tazobactam, sargramostim, teniposide, thiotepa, vinblastine, vincristine, vinorelbine.

Compatibility in syringe: Compatible: Cisplatin, cyclophosphamide, doxorubicin, droperidol, fluorouracil, furosemide, heparin, leucovorin calcium, methotrexate, metoclopramide, mitomycin, vinblastine, vincristine.

Compatibility when admixed: Compatible: Amikacin, dexamethasone sodium phosphate, diphenhydramine, fluorouracil, gentamicin, heparin, hydrocortisone sodium phosphate, phenytoin, streptomycin, tobramycin, vinblastine, vincristine. Incompatible: Aminophylline, ascorbic acid injection, cefazolin, diazepam, hydrocortisone sodium succinate, methotrexate, mitomycin, nafcillin, penicillin G sodium, terbutaline.

UseTreatment of squamous cell carcinomas of the head and neck, penis, cervix, or vulva, testicular carcinoma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma; sclerosing agent for malignant pleural effusion

Use - Unlabeled/InvestigationalTreatment of ovarian germ cell tumors

Adverse Reactions Significant>10%:

Dermatologic: Pain at the tumor site, phlebitis. About 50% of patients develop erythema, rash, striae, induration, hyperkeratosis, vesiculation, and peeling of the skin, particularly on the palmar and plantar surfaces of the hands and feet. Hyperpigmentation (50%), alopecia, nailbed changes may also occur. These effects appear dose related and reversible with discontinuation.

Gastrointestinal: Stomatitis and mucositis (30%), anorexia, weight loss

Respiratory: Tachypnea, rales, acute or chronic interstitial pneumonitis, and pulmonary fibrosis (5% to 10%); hypoxia and death (1%). Symptoms include cough, dyspnea, and bilateral pulmonary infiltrates. The pathogenesis is not certain, but may be due to damage of pulmonary, vascular, or connective tissue. Response to steroid therapy is variable and somewhat controversial.

Miscellaneous: Acute febrile reactions (25% to 50%)

1% to 10%:

Dermatologic: Skin thickening, diffuse scleroderma, onycholysis, pruritus

Miscellaneous: Anaphylactoid-like reactions (characterized by hypotension, confusion, fever, chills, and wheezing; onset may be immediate or delayed for several hours); idiosyncratic reactions (1% in lymphoma patients)

<1% (Limited to important or life-threatening): Angioedema, cerebrovascular accident, cerebral arteritis, chest pain, coronary artery disease, flagellate hyperpigmentation, hepatotoxicity, malaise, MI, myelosuppression (rare), myocardial ischemia, nausea, pericarditis, Raynaud’s phenomenon, renal toxicity, scleroderma-like skin changes, Stevens-Johnson syndrome, thrombotic microangiopathy, toxic epidermal necrolysis, vomiting

ContraindicationsHypersensitivity to bleomycin or any component of the formulation

Warnings/PrecautionsBoxed warnings:

• Experienced physician: See “Other warnings/precautions” below.

• Idiosyncratic reaction: See “Concerns related to adverse effects” below.

• Pulmonary toxicity: See “Concerns related to adverse effects” below.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal.

Concerns related to adverse effects:

• Hepatotoxicity: May cause hepatic toxicity.

• Idiosyncratic reaction:[U.S. Boxed Warning] : A severe idiosyncratic reaction consisting of hypotension, mental confusion, fever, chills, and wheezing (similar to anaphylaxis) has been reported in 1% of lymphoma patients treated with bleomycin. Since these reactions usually occur after the first or second dose, careful monitoring is essential after these doses.

• Pulmonary toxicity: [U.S. Boxed Warning] : Occurrence of pulmonary fibrosis (commonly presenting as pneumonitis; occasionally progressing to pulmonary fibrosis) is the most severe toxicity. Risk is higher in elderly patients or patients receiving >400 units total lifetime dose; other possible risk factors include smoking and patients with prior radiation therapy or receiving concurrent oxygen.

• Renal toxicity: May cause renal toxicity.

Disease-related concerns:

• Renal impairment: Use with caution in patients with renal impairment (Clcr <50 mL/minute), may require dose adjustment.

Other warnings/precautions:

• Experienced physician: [U.S. Boxed Warning] : Should be administered under the supervision of an experienced cancer chemotherapy physician.

• O2 during surgery: Use caution when administering O2 during surgery to patients who have received bleomycin; the risk of bleomycin-related pulmonary toxicity is increased.

BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid combination

Cardiac Glycosides: Antineoplastic Agents may decrease the absorption of Cardiac Glycosides. This may only affect digoxin tablets. Exceptions: Digitoxin. Risk C: Monitor therapy

Coccidioidin Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioidin Skin Test. Risk C: Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Risk C: Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification

Filgrastim: May enhance the adverse/toxic effect of Bleomycin. Specifically, the risk for pulmonary toxicity may be increased. Risk C: Monitor therapy

Gemcitabine: May enhance the adverse/toxic effect of Bleomycin. The risk of pulmonary toxicity may be increased. Risk D: Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk D: Consider therapy modification

Sargramostim: May enhance the adverse/toxic effect of Bleomycin. Specifically, the risk for pulmonary toxicity may be increased. Risk C: Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Risk C: Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy

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Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Risk X: Avoid combination

Pregnancy Risk Factor

Drug ratings in pregnancy (US Food & Drug Administration)
Category Interpretation
A Controlled studies show no risk
Controlled studies in pregnant women fail to demonstrate a risk to the fetus in the first trimester with no evidence of risk in later trimesters. The possibility of fetal harm appears remote.
B No evidence of human risk in controlled studies
Either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester and there is no evidence of a risk in later trimesters.
C Risk cannot be ruled out
Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal effects or other) and there are no controlled studies in women, or studies in women and animals are not available. Drugs should be given only if the potential benefits justify the potential risk to the fetus.
D Positive evidence of risk
There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (eg, if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).
X Contraindicated in pregnancy
Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience, or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.
Reproduced with permission from: Lacy CF, Armstrong LL, Goldman MP, Lance LL. Lexi-Comp Drug Information Handbook, 20th Edition. Hudson, OH: Lexi-Comp, 2011. Copyright © 2011.
Pregnancy ImplicationsAnimal studies have demonstrated teratogenic and abortifacient effects. There are no adequate and well-controlled studies in pregnant women. Women of childbearing potential should avoid becoming pregnant during treatment.

LactationExcretion in breast milk unknown/not recommended

Breast-Feeding ConsiderationsDue to the potential for serious adverse reactions in the nursing infant, breast-feeding is not recommended.

Monitoring ParametersPulmonary function tests (total lung volume, forced vital capacity, carbon monoxide diffusion), renal function, liver function, chest x-ray, temperature initially; check body weight at regular intervals

International Brand Names

  • Bemocin (PH);
  • Bileco (AR);
  • Blenamax (AU, MY, RU, TW);
  • Blenoxane (AU, BR, EC, EG, ZA);
  • Bleo (HK);
  • Bleocin (BG, CL, CZ, EE, EG, GR, HK, HN, HU, ID, IN, JP, KP, MY, PE, PL, PT, SG, TH, TR, TW);
  • Bleocin-S (MY);
  • Bleocina (UY);
  • Bleocris (PY);
  • Bleolem (CO, MX, TH);
  • Bleomax (MX);
  • Bleomicina (ES, IT);
  • Bleomycin (AT, CH, DK, FI, GB, NO, SE);
  • Bleomycin PFI (IL);
  • Bleomycine (BE, FR, LU, NL);
  • Bleomycinum (DE);
  • Blexit (CN);
  • Bloicin-S (PH)
Mechanism of ActionInhibits synthesis of DNA; binds to DNA leading to single- and double-strand breaks; also inhibits (to a lesser degree) RNA and protein synthesis

Pharmacodynamics/KineticsAbsorption: I.M. and intrapleural administration: 30% to 50% of I.V. serum concentrations; intraperitoneal and SubQ routes produce serum concentrations equal to those of I.V.

Distribution: Vd: 22 L/m2; highest concentrations in skin, kidney, lung, heart tissues; lowest in testes and GI tract; does not cross blood-brain barrier

Protein binding: 1%

Metabolism: Via several tissues including hepatic, GI tract, skin, pulmonary, renal, and serum

Half-life elimination: Biphasic (renal function dependent):

Normal renal function: Initial: 1.3 hours; Terminal: 9 hours

End-stage renal disease: Initial: 2 hours; Terminal: 30 hours

Time to peak, serum: I.M.: Within 30 minutes

Excretion: Urine (50% to 70% as active drug)

REFERENCES

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