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bleomycin

( blee-oh-MY-sin )
Other Name(s): Blenoxane® (multiple brands available)
Appearance: Clear, colourless solution ; may be mixed into larger bags of fluids
A - Drug Name

bleomycin

SYNONYM(S):   bLM; BLEO

COMMON TRADE NAME(S):   Blenoxane® (multiple brands available)

 
B - Mechanism of Action and Pharmacokinetics

Bleomycin is an antibiotic complex produced by fermentation from Streptomyces verticillus. It causes single- and double-strand DNA breaks through formation of an intermediate iron complex. DNA synthesis, and to a lesser degree, RNA and protein synthesis are inhibited. Bleomycin is cell cycle phase-specific.



Absorption
Oral: no
Distribution

High concentrations in skin, lung, kidney, peritoneum and lymphatics; crosses placenta; 45% absorbed systemically after intrapleural injection.

Cross blood brain barrier? no
Volume of distribution 13-29 L/m2
PPB < 10 %
Metabolism

Inactivated by enzymes in many tissues, including liver / GI.

Active metabolites Bleomycin-iron complex
Inactive metabolites yes
Elimination

Excreted by kidneys; terminal half-life increases exponentially as creatinine clearance falls.

Urine 60-70% unchanged
Half-life 2-5 hours (IV)
Clearance 3 L/h/m2
 
C - Indications and Status
Health Canada Approvals:

  • Squamous cell cancer - head and neck, skin, penis, cervix and vulva
  • Hodgkin's and Non-Hodgkin's lymphoma
  • Testicular cancer
  • Malignant pleural effusion


Other Uses:

  • Germ Cell Cancer
 
D - Adverse Effects

Emetogenic Potential:  

Minimal

Extravasation Potential:   None

ORGAN SITE SIDE EFFECT* (%) ONSET**
Cardiovascular Arterial thromboembolism E
Hypotension (rare) I
Other (Pleuropericarditis- rare) E
Dermatological Alopecia (partial) E
Nail disorder E  D
Pruritus E
Radiation recall reaction (rare) I
Rash E
Skin hyperpigmentation E  D
Gastrointestinal Anorexia (common) E
Mucositis (30%) E
Nausea (mild, common) I
Vomiting (mild, common) I
Weight loss E
General Fever, chills (common) I
Tumor pain E
Hematological Disseminated intravascular coagulation (rare) E
Hemolytic uremic syndrome (rare) E
Hepatobiliary ↑ LFTs (unusual) E
Hypersensitivity Anaphylaxis (1%) (lymphoma patients) I
Injection site Phlebitis (infrequent) I  E
Renal Other (abnormal renal function- rare) E
Respiratory Pneumonitis (10%) (1% fatal) D
Vascular Peripheral ischemia (Raynaud's) E


* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
Dose-limiting side effects are underlined.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

Skin and mucosal changes are the most frequent side effects, occurring in approximately 50% of treated patients and are dose-related. Topical steroids may be useful. Skin ulceration and/or peeling on fingertips may be painful and can require discontinuation of bleomycin. Bleomycin can cause unusual pigmentation on the trunk consisting of linear streaks with crisscross patterns in 8-20% of patients.

Fever and chills occur in approximately 50% of patients. These reactions usually occur starting a few hours after treatment, and may last up to 4-12 hours. Pre-treatment with hydrocortisone 100 mg (Solu-Cortef®) IV significantly decreases severity of the reaction. Acetaminophen q3-4h prn can be used to control fever if it occurs. Anaphylaxis is reported in 1% of patients with lymphoma after the 1st or 2nd dose; it may be immediate or delayed for several hours.

Bleomycin lung toxicity occurs in 10% of patients and is fatal in 1%. Changes in pulmonary functions tests occur in 20% of patients receiving bleomycin. Early and late pulmonary toxicity have distinct pathologic and radiographic features. Symptoms may develop as long as 1-3 months after discontinuation of treatment. The incidence of pulmonary toxicity increases significantly at a cumulative dose of >400 U. Risk factors include age >70 years, pre-existing pulmonary disease, coexisting renal failure, prior or concomitant thoracic radiation therapy, subsequent high-dose oxygen exposure (e.g. during anesthesia), smoking or previous exposure to bleomycin within 6 months. Bolus dosing increases the risk of pulmonary toxicity.

Bleomycin therapy should be withheld if the pulmonary diffusion capacity for carbon monoxide (DLCO) falls to 30-35% of initial value, if the forced vital capacity (FVC) falls significantly, or if there are any clinical or radiographic features indicating pulmonary toxicity. Pneumonitis due to bleomycin should be treated with corticosteroids in an effort to prevent progression to fibrosis. Corticosteroids have been of questionable value once interstitial fibrosis has occurred. Patients should be warned that uncontrolled oxygen should be avoided except briefly in an emergency and to avoid increased oxygen pressure as in scuba diving.

Bleomycin has the potential to enhance radiation injury to tissues. While often called radiation recall reactions, the timing of the radiation may be before, concurrent with or even after the administration of bleomycin. Recurrent injury to a previously radiated site may occur weeks to months following radiation.

 
E - Dosing

Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Patients with lymphoma should receive reduced doses for the 1st two doses because of the risk of anaphylaxis.

Maximum lifetime doses should not exceed 400 U (200mg/m2). Not to exceed 100 mg/m2 in patients with prior or concurrent lung radiation and in patients over 70 years.



Adults:

 

 


Intravenous: 10-20 units/m² (or give IM/SC) Weekly or twice weekly

Intrapleural: 60 units (instilled via intercostal drain diluted in normal saline; consult recommendations for details)

Dosage with Toxicity:

Toxicity Grade / Counts x 109/L

Action / % previous dose

 

Pulmonary:
Pneumonitis;  
DLCO ≤ 35% of baseline;
Rapid ↓in FVC

Discontinue and investigate.  If confirmed treat with corticosteroids.

 

Cardiac :  ECG changes;  pleuropericarditis

Hold and investigate; consider ↓ infusion rate or discontinue.

Grade 3 (related organ)

75%

Grade 4 (related organ)

Discontinue



Dosage with Hepatic Impairment:

No adjustment required.



Dosage with Renal Impairment:

Creatinine clearance (mL/min)

% usual dose

10 – 50

75%

< 10

50%



Children:

Refer to protocols being used.



 
F - Administration Guidelines

  • If the patient is known to have hypersensitivity to other drugs, the first dose may be preceded by 1mg test dose given in sidearm of running IV and 30 minutes observation for hypersensitivity.

IM, SC:

  • Reconstitute in 1-5mL sterile water for injection, bacteriostatic water for injection or normal saline for injection

IV:

  • Reconstitute with 5-10mL Normal Saline.
  • May be given by direct IV push over 10 minutes, followed by a Saline flush, if no IV line has been set up.
  • Or may further dilute in 100mL Normal Saline and infuse over 10-15 minutes. 

Intrapleural:

  • Dissolve drug in 50 – 100 mL Normal Saline
  • Instill via an indwelling thoracostomy tube after drainage. Frequent repositioning of patient. Drain after 4 hours.


 
G - Special Precautions
Other:

Bleomycin is contraindicated in patients who have demonstrated hypersensitivity to the drug or to its excipients. Caution should be exercised when used concomitantly with nephrotoxic drugs as they may reduce bleomycin clearance. Bleomycin should be used with extreme caution in patients with pre-existing renal or pulmonary disease, and in patients over the age of 70. Patients should avoid high FIO2 for at least a year after completion (i.e. during anesthesia).

The manufacturer suggests that patients with lymphoma should receive their first 2 doses of bleomycin at reduced dose (2 units) because of the risk of an anaphylaxis-like syndrome. If no reaction occurs, subsequent doses can be given at full dose.

Bleomycin modifies the structure of DNA, and has the potential to be carcinogenic. It is mutagenic and teratogenic and should not be used in pregnancy. Adequate contraception should be used by both sexes during bleomycin treatment and for at least 6 months after the last dose. Bleomycin’s effects on fertility have not been established. Breast feeding is not recommended due to the potential secretion into breast milk.

 
H - Interactions

AGENT EFFECT MECHANISM MANAGEMENT
Cisplatin or other nephrotoxins ↓ clearance of bleomycin in patients treated previously or concurrently with cisplatin cisplatin-induced decrease in GFR monitor for excessive bleomycin toxicity, especially pulmonary
digoxin ↓ effect of digoxin ↓ absorption of digoxin monitor
phenytoin ↓ efficacy of phenytoin ↓ absorption of phenytoin monitor phenytoin serum levels; adjust phenytoin dose if required.
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type Monitor Frequency
Chest x-rays monitoring for pulmonary changes Intermittent
Liver function tests (if failure suspected) Baseline and regular
Renal function tests (if failure suspected) Baseline and regular

Clinical assessment of skin, pulmonary, mucositis, idiosyncratic reactions

At each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version



Suggested Clinical Monitoring

Monitor Type Monitor Frequency
Pulmonary tests, including DLCO, if patient has pre-existing pulmonary dysfunction, or has had prior pulmonary radiation, if age >70, or if total cumulative Bleomycin dose >400 mg routine (monthly)
 
K - References

Cancer Drug Manual (the Manual), 1994, British Columbia Cancer Agency (BCCA)

Bleomycin: e-Drugdex, Micromedex Healthcare Series.

Chen YB, Rahemtullah A, Breeden E, et al. Bleomycin-induced flagellate erythema. J Clin Oncol 2007; 25(7): 898-900.

Compendium of Pharmaceuticals and Specialties. 2006. Blenoxane®. Canadian Pharmacists Association.

Product Monograph: Bleomycin for Injection. Pharmaceutical Partners of Canada Inc., January 14, 2008.

Product Monograph: Bleomycin sulphate for injection. Hospira Healthcare Corp., June 1, 2007.

Sebti SM and Lazo JS. Metabolic inactivation of bleomycin analogs by bleomycin hydrolase. Pharmac Ther 1988; 38: 321-9.

 


October 2017 edited indications

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

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The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

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