INFORMATION FOR HEALTH PROFESSIONALS
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Injection : 15, 000 international units.
It is recommended that Blenoxane 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 fibrosis is the most severe toxicity associated with Blenoxane. The most frequent presentation is pneumonitis occasionally progressing to pulmonary fibrosis. Its occurrence is higher in elderly patients and in those receiving greater than 400, 000 international units total dose, but pulmonary toxicity has been observed in young patients and those treated with low doses.
A severe idiosyncratic reaction consisting of hypotension, mental confusion, fever, chills, and wheezing has been reported in approximately 6% of lymphoma patients treated with Blenoxane, and in approximately 1% of other patients.
Blenoxane (sterile bleomycin sulphate ) is a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus. It is freely soluble in water.
Note: A unit of bleomycin is equal to the formerly used milligram activity. The term milligram activity is a misnomer and was changed to units to be more precise.
Although the exact mechanism of action of Blenoxane is unknown, available evidence would seem to indicate that the main mode of action is the inhibition of DNA synthesis with some evidence of lesser inhibition of RNA and protein synthesis.
When administered intrapleurally for the treatment of malignant pleural effusion, Blenoxane acts as a sclerosing agent. Following intrapleural administration the resultant bleomycin plasma concentrations suggest a systemic absorption rate of approximately 45%.
In mice, high concentrations of Blenoxane are found in the skin, lungs, kidneys, peritoneum and lymphatics. Tumour cells of the skin and lungs have been found to have high concentrations of Blenoxane in contrast to the low concentrations found in haematopoietic tissue. The low concentrations of Blenoxane found in bone marrow may be related to high levels of Blenoxane degradative enzymes found in that tissue.
In patients with a creatinine clearance of > 35mL per minute, the serum or plasma terminal elimination half-life of bleomycin is approximately 115 minutes. In patients with a creatinine clearance of < 35mL per minute, the plasma or serum terminal elimination half-life increases exponentially as the creatinine clearance decreases. In humans, 60 to 70% of an administered dose is recovered in the urine as active bleomycin. Protein binding of bleomycin is less than 1%.
An association between decreased renal function and enhanced bleomycin-related toxicities has been reported. Pharmacokinetic/pharacodynamic relationships suggest that enhancement of toxicity is a consequence of reduced renal clearance of bleomycin resulting in prolonged elimination half-life and increased area-under-the-plasma-concentration-vs.-time-curve compared to patients with normal renal function. Dosage reductions of 40-75% have been recommended for patients with creatinine clearance values ≤ 40 mL/min.
Blenoxane should be considered a palliative treatment. It has been shown to be useful in the management of the following neoplasms either as a single agent or in proven combinations with other approved chemotherapeutic agents; Squamous Cell Carcinoma: Head and neck including mouth, tongue, tonsil, nasopharynx, oropharynx, sinus, palate, lip, buccal mucosa, gingiva, epiglottis, skin, larynx, penis, cervix, and vulva. The response to Blenoxane is poorer in patients with head and neck cancer previously irradiated.
Lymphomas: Hodgkin's disease and non-Hodgkin's lymphoma.
Testicular Carcinoma: Embryonal cell, choriocarcinoma, and teratocarcinoma.
Bleomycin is effective as a sclerosing agent for the treatment of malignant pleural effusion and prevention of recurrent pleural effusion. Single dose instillation is generally sufficient.
Because of the possibility of anaphylactoid reaction, lymphoma patients should be treated with 2 000 international units or less for the first 2 doses. If no acute reaction occurs, then the regular dosage schedule may be followed.
The following dose schedules are recommended:
Squamous cell carcinoma, non-Hodgkin's lymphoma, testicular carcinoma: 250 to 500 international units/kg (10,000 to 20, 000 international units/m²) given intravenously, intramuscularly, or subcutaneously weekly or twice weekly.
Hodgkin's Disease: 250 to 500 international units/kg (10,000 to 20,000 international units/m²) given intravenously, intramuscularly, or subcutaneously weekly or twice weekly.
Pulmonary toxicity of Blenoxane appears to be dose-related with a striking increase when the total dose is over 400,000 international units. Total doses over 400,000 international units should be given with great caution. Note: When Blenoxane is used in combination with other antineoplastic agents, pulmonary toxicities may occur at lower doses.
Improvements of Hodgkin's disease and testicular tumours is prompt and noted within two weeks. If no improvement is seen by this time, improvement is unlikely. Squamous cell cancers respond more slowly, sometimes requiring as long as three weeks before any improvement is noted.
Blenoxane may be given by the intramuscular, intravenous, subcutaneous or intrapleural routes.
Intramuscular or Subcutaneous: Dissolve the contents of a Blenoxane vial in 1 to 5mL of Sterile Water for Injection. Sodium Chloride for Injection, or Bacteriostatic Water for Injection.
Intravenous: Dissolve the contents of the vial in 5mL or more of a solution suitable for injection, e.g. physiologic saline, and administer slowly over a period of ten minutes.
Malignant Pleural Effusion - 60,000 international units administered as a single dose bolus intrapleural injection.
For intrapleural administration dissolve 60,000 international units in 50-100 mL sodium chloride injection 0.9%, and administer through a thoracostomy tube following drainage of excess pleural fluid and confirmation of complete lung expansion. The thoracostomy tube is then clamped. The patient should be moved from the supine to the left and right lateral position several times during the next four hours. The clamp is then removed and suction reestablished.
The intrapleural injection of topical anaesthetics or systemic narcotic analgesia is generally not required.
As bleomycin is mostly excreted unchanged and as there is a high correlation between renal bleomycin clearance and creatinine clearance, modification of dose has been suggested for impairment of renal function. Dosage reductions of 40-75% have been recommended for patients with creatinine clearance values of ≤ 40 mL/min.
Blenoxane is contraindicated in patients who have demonstrated a hypersensitive or an idiosyncratic reaction to it.
Patients receiving Blenoxane must be observed carefully and frequently during and after therapy. It should be used with extreme caution in patients with significant impairment of renal function or compromised pulmonary function.
Pulmonary toxicities occur in 10% of treated patients. In approximately 1%, the nonspecific pneumonitis induced by Blenoxane progresses to pulmonary fibrosis, and death. Although this is age and dose related, the toxicity is unpredictable. Frequent x-rays are recommended. Pulmonary toxicity may occur up to 1 month after Blenoxane is discontinued.
Idiosyncratic reactions similar to anaphylaxis have been reported in 6% of lymphoma patients treated with Blenoxane, and in approximately 1% of other patients. Since these usually occur after the first or second dose, careful monitoring is essential after these doses.
Renal or hepatic toxicity, beginning as a deterioration in renal or liver function tests, have been reported infrequently. These toxicities may occur, however, at any time after initiation of therapy.
Gonadal suppression may occur and may be irreversible.
Use of Blenoxane in pregnant women is not recommended as Blenoxane has been shown to be tetratogenic in mice.
The carcinogenic potential of Blenoxane in humans is unknown. Given its mechanism of action, it should be considered to be a possible carcinogen in man. Bleomycin has been shown to be mutagenic in both in vitro and in vivo test systems. Bleomycin is teratogenic in rats and mice given the drug during organogenesis. The effects of Blenoxane on fertility have not be established.
It is not known if Blenoxane is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Blenoxane, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pulmonary: This is potentially the most serious side effect, occurring in approximately 10% of treated patients. The most frequent presentation is pneumonitis occasionally progressing to pulmonary fibrosis. Approximately 1% of patients treated have died of pulmonary fibrosis. Pulmonary toxicity is both dose and age-related, being more common in patients over 70 years of age and in those receiving over 400,000 international units total dose. This toxicity, however, is unpredictable and has been seen occasionally in young patients receiving low doses. Pulmonary complications are more likely in smokers, following general anaesthesia or radiotherapy. Mortality may be as high as 10% in patients who have received pulmonary irradiation.
Because of lack of specificity of the clinical syndrome, the identification of patients with pulmonary toxicity due to Blenoxane has been extremely difficult. The earliest symptom associated with Blenoxane pulmonary toxicity is dyspnoea. The earliest sign is fine rales.
Radiographically, Blenoxane-induced pnuemonitis produces nonspecific patchy opacities, usually of the lower lung fields. The most common changes in pulmonary function tests are a decrease in total lung volume and a decrease in vital capacity. However, these changes are not predictive of the development of pulmonary fibrosis.
The microscopic tissue changes due to Blenoxane toxicity include bronchiolar squamous metaplasia, reactive macrophages, atypical alveolar epithelial cells, fibrinous oedema, and interstitial fibrosis. The acute stage may involve capillary changes and subsequent fibrinous exudation into alveoli producing a change similar to hyaline membrane formation and progressing to a diffuse interstitial fibrosis resembling the Hamman-Rich syndrome. These microscopic findings are nonspecific, e.g. similar changes are seen in radiation pneumonitis, pneumocystic pneumonitis,
To monitor the onset of pulmonary toxicity, x-rays of the chest should be taken every 1 to 2 weeks. If pulmonary changes are noted, treatment should be discontinued until it can be determined if they are drug related. Recent studies have suggested that sequential measurement of the pulmonary diffusion capacity for carbon monoxide (DLco) during treatment with Blenoxane may be an indicator of subclinical pulmonary toxicity. It is recommended that the DLco be monitored monthly if it is to be employed to detect pulmonary toxicities, and thus the drug should be discontinued when the DLco falls below 30 to 35% of the pretreatment value.
Because of bleomycin's sensitisation of lung tissue, patients who have received bleomycin are at greater risk of developing pulmonary toxicity when oxygen is administered in any clinical situation. While long exposure to very high oxygen concentrations is a known cause of lung damage, after bleomycin administration, lung damage can occur at lower concentrations than usually would be considered safe. Suggested preventive measures are: (1) Maintain FI O2 at concentrations approximating that of room air (25%) during surgery and the post-operative period. (2) Carefully monitor fluid replacement, focusing more on colloid administration than crystalloid administration.
Sudden onset of an acute chest pain syndrome suggestive of pleuropericarditis has been rarely reported during Blenoxane infusions. Although each patient must be individually evaluated, further courses of Blenoxane do not appear to be contraindicated.
Pulmonary adverse events which may be related to the intrapleural administration of Blenoxane have been reported only rarely.
Idiosyncratic Reactions: In approximately 6% of the lymphoma patients treated with Blenoxane and in approximately 1% of other patients, an idiosyncratic reaction, similar clinically to anaphylaxis, has been reported. The reaction may be immediate or delayed for several hours, and usually occurs after the first or second dose. It consists of hypotension, mental confusion, fever, chills, and wheezing. Treatment is symptomatic, including volume expansion, pressor agents, antihistamines, and corticosteroids.
Skin and Mucous Membranes: These are the most frequent side effects, being reported in approximately 50% of treated patients. These consist of erythema, rash striae, vesiculation, hyperpigmentation, and tenderness of the skin. Hyperkeratosis, nail changes, alopecia, pruritis, and stomalitis have also been reported. It was necessary to discontinue Blenoxane therapy in 2% of treated patients because of these toxicities.
Skin toxicity is a relatively late manifestation. It usually develops in the 2nd and 3rd week of treatment after 150,000 to 200,000 international units of Blenoxane have been administered and appears to be related to the cumulative dose.
Other: Fever, chills, and vomiting are frequently reported side effects. Anorexia and weight loss are common and may persist long after termination of this medication. Pain at tumour site, phlebitis, and other local reactions have been reported infrequently.
Vascular toxicities coincident with the use of Blenoxane in combination with other antineoplastic agents have been reported rarely. The events are clinically heterogeneous and may include myocardial infarction, cerebrovascular accident, thrombotic microangiopathy (HUS) or cerebrovascular arteritis. Various mechanisms have been proposed for these vascular complications. There are also reports of Raynaud's phenomenon occurring in patients treated with Blenoxane in combination with vinblastine with or without cisplatin or, in few cases, with Blenoxane as a single agent. It is currently unknown if the cause of Raynaud's phenomenon in these cases is the disease, underlying vascular compromise, Blenoxane, vinblastine, hypomagnesaemia, or a combination of any of these factors.
Intrapleural administration of Blenoxane has occasionally been associated with local pain. Hypotension possibly requiring symptomatic treatment has been reported infrequently. Death has been very rarely reported in association with Blenoxane pleurodesis in these very seriously ill patients.
No information is available. BLENOXANE is probably not removed by dialysis.
When stored at room temperature 2-8°C (Refrigerate. Do not freeze), BLENOXANE is stable until expiration date indicated on package. Blenoxane should not be used beyond its designated expiration date.
Blenoxane is stable for 24 hours at room temperature (25°C) in Sodium Chloride Injection.
Note: Procedures for proper handling and disposal of anti-cancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Prescription Medicine.
Injection, 15,000 international units, vial, 10s.
Bristol-Myers Squibb (NZ) Ltd
P.O. Box 12657
Penrose
Auckland
New Zealand
September 2002