Les renseignements du Formulaire de médicaments s’adressent aux professionnels de la santé. Il ne s’agit pas d’un avis médical. Certains des renseignements, y compris ceux sur le financement des médicaments anticancéreux, ne s’appliquent pas à tous les patients. Les plans de traitement du cancer sont propres à chaque patient. Si vous êtes un patient, veuillez parler avec votre équipe soignante pour comprendre comment ces renseignements s’appliquent à vous.
bleomycin
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.
Oral: no
Well absorbed after parenteral (IV, Subcut, IM) administration. About 45% of the dose is absorbed into the circulation after intrapleural administration. Absorption from subcut is delayed and may resemble a slow IV infusion.
Rapid distribution to tissues. High concentrations in skin, lung, kidney, peritoneum and lymphatics.
Low concentrations are found in the bone marrow.
| Cross blood brain barrier? | no |
| PPB |
Limited |
Inactivated by hydrolases in many tissues. The liver and GI tract show the highest rate of inactivation, while skin, lungs and kidneys show a lower rate.
Squamous cells are highly sensitive to bleomycin due to their low bleomycin hydrolase content.
| Active metabolites |
yes |
| Inactive metabolites | yes |
Excreted by kidneys; terminal half-life increases exponentially as creatinine clearance falls. Elimination during the first 24 hours is lower after most intracavitary administrations than after IV administration.
| Urine |
66% unchanged |
| Half-life |
2-5 hours (IV bolus) |
- Squamous cell cancer - head and neck, skin, penis, cervix and vulva
- Hodgkin and Non-Hodgkin lymphoma (including lymphosarcoma and reticulum cell sarcoma)
- Testicular cancer
- Malignant pleural effusion
The response is poorer in patients with head and neck cancer who have received previous radiotherapy.
Other Uses:
- Germ Cell Cancers
Emetogenic Potential:
Extravasation Potential: None
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arterial thromboembolism (rare) | E | |||
| Hypotension (rare) | I | ||||
| Other - Pleuropericarditis (rare) | E | ||||
| Venous thromboembolism (<10%) | E | ||||
| Dermatological | Alopecia (30%) (partial) | E | |||
| Nail disorder (11%) | E D | ||||
| Other - Hyperkeratosis (≤ 50%; hands, nails) | E D | ||||
| Radiation recall reaction (rare) | I | ||||
| Rash , pruritis (8%; skin folds, friction areas) | E | ||||
| Skin hyperpigmentation (41%) skin folds, nail cuticles, friction areas, IM injection sites | E D | ||||
| Gastrointestinal | Anorexia, weight loss (29%) | E | |||
| Mucositis (30%) | E | ||||
| Nausea, vomiting (15%) | I | ||||
| General | Fatigue (16%) | E | |||
| Fever, chills (50% with IV; 25% with IM) | I | ||||
| Tumor pain (rare) | E | ||||
| Hematological | Hemolytic uremic syndrome (rare) | E | |||
| Hepatobiliary | ↑ LFTs (rare) | E | |||
| Hypersensitivity | Anaphylaxis (<10%) (lymphoma patients 1%) | I | |||
| Injection site | Phlebitis (rare) | I E | |||
| Renal | Creatinine increased (rare) | E | |||
| Respiratory | Pneumonitis (10%) (1% fatal) | D | |||
| Vascular | Peripheral ischemia (Raynaud's; with vinblastine) | 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.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for bleomycin include fever/chills, skin hyperpigmentation, hyperkeratosis, alopecia (partial), mucositis, anorexia, fatigue, nausea/vomiting, nail disorder, and pneumonitis.
Skin and mucosal changes are the most frequent side effects, occurring in approximately 50% of treated patients and include stomatitis, alopecia, hyperpigmentation, ulceration, erythema, hyperkeratosis, nail changes, rash, vesiculation, tenderness, pruritus, peeling, striae and bleeding. Hypoesthesia may occur at the onset of skin toxicity, and may progress to hyperesthesia. Adverse mucocutaneous effects usually develop in the 2nd or 3rd week of bleomycin treatment. These appear to be dose-related and are usually observed after 150-200 units of bleomycin have been administered. Discontinuation of bleomycin due to these toxicities has occurred in 2% of patients. Bleomycin can cause unusual pigmentation on the trunk consisting of linear streaks with crisscross patterns in 8-22% 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. 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. Dyspnea and fine rales are early symptoms of pulmonary toxicity. The clinical symptoms, radiologic and microscopic findings are not specific to bleomycin lung toxicity. 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. It has also been observed occasionally in young patients receiving low doses.
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. Appropriate antibiotic therapy should be given for infectious pneumonitis. 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.
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy.
Maximum lifetime doses should not exceed 400 units (or 200 units/m2; less for patients with lung function or renal impairment), due to increased pulmonary toxicity risk. Not to exceed 100 units/m2 in patients with prior or concurrent lung radiation and in patients over 70 years. For intrapleural administration, consider the absorption in determining the cumulative dose (45% absorbed).
|
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) |
Hold until ≤ grade 2, then 75% |
|
Grade 4 (related organ) |
Discontinue |
Management of Infusion-related reactions:
Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
| Grade | Management | Re-challenge |
| 1 or 2 |
Restart:
|
|
| 3 or 4 |
|
No adjustment required.
|
Creatinine clearance (mL/min) |
% usual dose |
|
10 – 50 |
75% |
|
< 10 |
50% |
Refer to protocols being used.
IM, SC:
- Reconstitute in 1-5mL sterile water or normal saline for injection (concentration 3 to 15 units/mL)
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 50-100mL Normal Saline (0.3 to 3 units/mL) and infuse over 10-15 minutes.
Intrapleural:
- Dissolve drug in 50 to 100 mL Normal Saline
- Instill via an indwelling thoracostomy tube after drainage. Refer to local guidelines for administration procedures.
- Store unopened vial between 2-8⁰C. Do not freeze.
Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
- 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).
Other Drug Properties:
-
Carcinogenicity:
Yes
-
Mutagenicity:
Yes
-
Teratogenicity:
Yes
Bleomycin crosses the placenta. It 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.
-
Breastfeeding:
Breastfeeding is not recommended due to the potential secretion into breast milk.
-
Fertility effects:
Yes
Bleomycin treatment may cause irreversible infertility.
| 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 |
| Drugs that may cause pulmonary toxicity (e.g. BCNU, mitomycin, cyclophosphamide, methotrexate, gemcitabine) | ↑ risk of pulmonary toxicity with concurrent bleomycin use | additive | monitor for pulmonary toxicity |
| digoxin | ↓ effect of digoxin | ↓ absorption of digoxin | monitor |
| phenytoin | ↓ efficacy of phenytoin | ↓ absorption of phenytoin | monitor phenytoin serum levels; adjust phenytoin dose if required. |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
Liver function tests (if failure suspected) |
Baseline and as clinically indicated |
Renal function tests |
Baseline and before each cycle |
Clinical assessment of mucocutaneous or respiratory effects, infusion-related reactions, thromboembolism |
At each visit; continue to monitor for pulmonary toxicity for approximately 2 months after treatment completion |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| 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 |
Baseline, regular (i.e. monthly) and as clinically indicated |
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.
Diao DY, Goodall J. Bleomycin-induced-flagellate dermatitis. CMAJ 2012;184(11):1280.
Compendium of Pharmaceuticals and Specialties. 2006. Blenoxane ®. Canadian Pharmacists Association.
Koberda M, Zieske PA, Raghavan NV, et al. Stability of bleomycin sulfate reconstituted in 5% dextrose injection or 0.9% sodium chloride injection stored in glass vials or polyvinyl chloride containers. Am J Hosp Pharm. 1990 Nov;47(11):2528-9.
Product Monograph: Bleomycin for Injection. Pfizer Canada Inc. August 8, 2017.
Product Monograph: Bleomycin for Injection. Fresenius Kabi Canada Ltd., June 1, 2016.
Sebti SM and Lazo JS. Metabolic inactivation of bleomycin analogs by bleomycin hydrolase. Pharmac Ther 1988; 38: 321-9.
Stelzer KJ , Griffin TW, Koh WJ, et al. Radiation recall skin toxicity with bleomycin in a patient with Kaposi sarcoma related to acquired immune deficiency syndrome. Cancer. 1993 Feb 15;71(4):1322-5.
Summary of Product Characteristics: Bleomycin. Accord Healthcare Limited (UK). November 2018.
April 2020 Updated pharmacokinetics, adverse effects, dosing, administration guidelines, special precautions, interactions and monitoring sections
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