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bleomycin
Drug Monograph
Drug Name | Mechanism of Action and Pharmacokinetics | Indications and Status | Adverse Effects | Dosing | Administration
Guidelines | Special Precautions | Interactions | Recommended Clinical Monitoring | Supplementary Public Funding |
References | Disclaimer A - Drug Name
bleomycin
SYNONYM(S): bLM; BLEO
COMMON TRADE NAME(S): Blenoxane® (Bristol-Myers Squibb)
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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.
Metabolism
Elimination
Cross blood brain barrier?
no
Volume of distribution
13-29 L/m2
PPB
< 10 %
Inactivated by enzymes in many tissues, including liver / GI.
Active metabolites
Bleomycin-iron complex
Inactive metabolites
yes
Excreted by kidneys; terminal half-life increases exponentially as creatinine
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clearance falls.
Urine
60-70% unchanged
Half-life
2-5 hours (IV)
Clearance
3 L/h/m2
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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
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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
Alopecia (partial)
E
Nail disorder
E D
Pruritus
E
Dermatological
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Radiation recall reaction (rare)
I
Rash
E
Skin hyperpigmentation
E D
Anorexia (common)
E
Mucositis (30%)
E
Nausea (mild, common)
I
Vomiting (mild, common)
I
Weight loss
E
Fever, chills (common)
I
Tumor pain
E
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
Gastrointestinal
General
Hematological
* "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
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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.
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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) Any use of the information is subject, at all times, to CCO’s Terms and Conditions.
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Dosage with Toxicity:
Toxicity Grade / Counts x 109/L
Pulmonary:
Pneumonitis; DLCO ≤ 35% of baseline;
Rapid ↓in FVC
Cardiac : ECG changes; pleuropericarditis
Grade 3 (related organ)
Grade 4 (related organ)
Action / % previous dose
Discontinue and investigate. If confirmed
treat with corticosteroids.
Hold and investigate; consider ↓ infusion
rate or discontinue.
75%
Discontinue
Dosage with Hepatic Impairment:
No adjustment required.
Dosage with Renal Impairment:
Creatinine clearance (mL/min)
10 – 50
< 10
% usual dose
75%
50%
Children:
Refer to protocols being used.
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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.
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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.
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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.
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H - Interactions
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AGENT
EFFECT
MECHANISM
MANAGEMENT
Cisplatin or other
nephrotoxins
↓ clearance of bleomycin in cisplatin-induced
patients treated previously
decrease in GFR
or concurrently with cisplatin
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.
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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 preexisting pulmonary dysfunction, or has had prior
pulmonary radiation, if age >70, or if total cumulative
Bleomycin dose >400 mg
routine (monthly)
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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.
August 2016 edited indications
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L - Disclaimer
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public
funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management
information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare
providers and is to be used for informational purposes only. The information is not intended to cover all possible uses,
directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate
that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is
not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All
uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information
provided in the Formulary.
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
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that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
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