COMPOSITION Each vial contains bleomycin sulphate equivalent to 15 units of bleomycin.
PHARMACOLOGICAL CLASSIFICATION A 26 - Cytostatic agents.
PHARMACOLOGICAL ACTION BLENOXANE (bleomycin sulphate) is a water soluble glycopeptide antitumour antibiotic.
BLENOXANE has a strong affinity for squamous cell carcinomas. BLENOXANE has not been shown to have an immunosuppressive effect in vitro and no significant inhibition of immune response has been observed to date in patients treated with BLENOXANE. When given parenterally, BLENOXANE reaches high concentrations in the skin, lungs, kidneys, peritoneum, lymphatics and tumour tissue, if present. Tissue concentrations are particularly high in the skin and lungs. BLENOXANE is not readily metabolized or inactivated following parenteral administration.
BLENOXANE possesses antitumour activity although the mechanisms of antitumour action are not completely understood. It is known that BLENOXANE inhibits the synthesis of DNA (deoxyribonucleic acid) in tumour cells.
The major route of excretion of bleomycin is the kidney with 60 to 70 percent of an administered dose recovered in the urine as active bleomycin. Renal dysfunction can significantly prolong excretion.
In patients with creatinine clearance of <35 mL per minute, the plasma or serum terminal elimination half-life increases exponentially as the creatinine clearance decreases.
An association between the decreased renal function and enhanced bleomycin-related toxicities has been reported. Pharmacokinetic/pharmacodynamic relationships suggest that enhancement of toxicity is the 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. In the treatment of malignant pleural effusion, bleomycin acts as a sclerosing agent. Following intrapleural administration, resultant bleomycin plasma concentrations suggest a systemic absorption rate of approximately 45%.
INDICATIONS: BLENOXANE is primarily indicated for the treatment of squamous cell carcinomas of the skin, head and neck including the oesophagus. Additionally, favourable results have been obtained in a number of patients with squamous cell carcinoma of the penis, uterine cervix and in cases of choriocarcinoma and embryonal carcinoma of the testes.
Additionally, BLENOXANE has produced remissions in some cases of malignant lymphoma, Hodgkin's disease, and non-Hodgkin's lymphoma. BLENOXANE is generally not effective against tumours of the haematopoietic system. NOTE: Treatment of patients with BLENOXANE after radiation therapy is less successful than treatment prior to radiation therapy.
CONTRA-INDICATIONS Pregnancy and lactation.
BLENOXANE is contra-indicated in patients who have demonstrated a hypersensitive or an idiosyncratic reaction to it.
WARNINGS BLENOXANE should be administered under supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Patients receiving BLENOXANE must be observed carefully and frequently during and after therapy. Adequate diagnostic and treatment facilities should be available to allow appropriate management of therapy and possible complications. BLENOXANE should be used with extreme caution in patients with significant impairment of renal function or compromised pulmonary function. A repeat course of therapy is contra-indicated in any patient who has shown signs of pneumonitis or decreased pulmonary function. Pulmonary toxicities may occur. In some treated patients non-specific pneumonitis induced by BLENOXANE progresses to pulmonary fibrosis, and death. Pulmonary toxicity is more frequent in patients over 70 years of age and in those receiving total doses greater than 400 units. Although pulmonary toxicity is age- and dose-related, the toxicity is unpredictable. Renal impairment is a risk factor for the development of pulmonary toxicity. Frequent monitoring is essential (see SIDE-EFFECTS AND SPECIAL PRECAUTIONS).
DOSAGE AND DIRECTIONS FOR USE Because of the possibility of an anaphylactoid reaction, patients with lymphoma should be treated with 2 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-Hodgkins lymphoma, testicular carcinoma: 0,25 to 0,5 units/kg (10 to 20 units/m²) given intramuscularly, subcutaneously or intravenously, weekly or twice weekly. Hodgkin's disease: 0,25 to 0,5 units/kg (10 to 20 units/m²) given intramuscularly, subcutaneously or intravenously weekly or twice weekly.
After a 50 percent response, a maintenance dose of 1 unit daily or 5 units weekly intravenously or intramuscularly should be given.
NOTE: PULMONARY TOXICITY FROM BLENOXANE APPEARS TO BE DOSE RELATED WITH A STRIKING INCREASE WHEN THE TOTAL DOSE IS OVER 400 UNITS. TOTAL DOSES OVER 400 UNITS SHOULD BE GIVEN WITH GREAT CAUTION. FREQUENT CHEST X-RAYS AND CLOSE MONITORING OF PULMONARY FUNCTION DURING THERAPY ARE ADVISABLE. WHEN BLENOXANE IS USED IN COMBINATION WITH OTHER ANTI-NEOPLASTIC AGENTS, PULMONARY TOXICITIES MAY OCCUR AT LOWER DOSES.
ADMINISTRATION BLENOXANE may be given by intramuscular, subcutaneous or intravenous routes. Note: Bleomycin should not be reconstituted with dextrose-containing solutions. Any unused portion must be discarded.
Intramuscular: BLENOXANE vial should be reconstituted with 1 to 5 mL of Sterile Water for Injection or Sodium Chloride Injection 0,9% w/v. Subcutaneous: Prepare as for intramuscular injection. Intravenous: Dissolve the contents of the vial in 5 mL Sodium Chloride Injection 0,9% and administer slowly over a period of 10 minutes.
BLENOXANE may be administered in the commonly employed intravenous solutions ie Water for Injection or Sodium Chloride 0,9%, and is stable in solution at room temperature. Note: Procedures for proper handling and disposal of anti-cancer medicines should be considered.
SIDE-EFFECTS AND SPECIAL PRECAUTIONS BLENOXANE has not produced significant toxic effects in the haematopoietic system; no definite bone marrow depression or inhibition of the immune response have been observed to date in patients treated with BLENOXANE. Pulmonary Pulmonary toxicity is potentially the most serious side-effect of BLENOXANE (see WARNINGS). A unique pneumonitis which can rapidly progress to pulmonary fibrosis and even death in some patients occasionally develops as a result of therapy with BLENOXANE. It is difficult to predict which patients will develop fibrosis. However, frequent chest X-rays and measurements of pulmonary function should be obtained during therapy, particularly in older patients. Should a patient develop signs of pneumonitis, BLENOXANE should be discontinued immediately and the patient treated with corticosteroids and antibiotics.
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 dyspnea. The earliest sign is fine rales.
Radiographically, BLENOXANE-induced pneumonitis produces non-specific patchy opacities, usually of the lower lung fields. The most changes in pulmonary function tests are a decrease in total lung volume and a decrease in vital capacity. 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 non-specific. Similar changes are seen in radiation pneumonitis and 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. 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 percent of the pre-treatment value.
Patients who have received BLENOXANE are at greater risk of developing pulmonary toxicity when oxygen is administered at surgery. While long exposure to very high oxygen concentrations is a known cause of lung damage, after BLENOXANE administration, lung damage can occur at lower concentrations than usually would be considered safe. Suggested preventive measures are:
Maintain FI O2 at concentrations approximately that of room air (25 percent) during surgery and the post-operative period.
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 have been reported following the intrapleural administration of BLENOXANE. Skin and Mucous Membranes Cutaneous effects are the most frequent side-effects, occurring in most treated patients. Cutaneous toxicity is a relatively late manifestation. It usually develops in the second and third week of treatment after 150 to 200 units of BLENOXANE have been administered. Cutaneous toxicity appears to be related to cumulative dose. Cutaneous reactions include erythema, pruritus, reddening and painful ulceration, particularly at pressure points such as finger tips and elbows, rash, striae, vesiculation, thickening, hyperpigmentation and tenderness of the skin. Change in the nails and nail beds, alopecia, and stomatitis are also common. It was necessary to discontinue BLENOXANE therapy in some patients because of these toxicities. Local reactions and thrombophlebitis may occur at the site of parenteral administration. However, the toxic effects of BLENOXANE on the skin are slowly reversible following completion of therapy. Contact dermatitis has also been observed following the application of BLENOXANE to the skin of sensitive patients. Idiosyncratic Reactions A few acute reactions (pulmonary oedema, shock-like syndromes, urticaria rash), thought to be allergic in nature, have also been observed. In approximately 1 % of the patients with lymphoma who were treated with BLENOXANE an idiosyncratic reaction, similar to anaphylaxis clinically, 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. Other 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.
Fever, chills, nausea and vomiting are frequently reported side-effects. Patients may frequently develop transient fevers, 3 to 5 hours after the intravenous injection of BLENOXANE; however fever can generally be minimised by reducing the dosage.
Anorexia and weight loss are common and may persist long after termination of BLENOXANE. Pain at the tumour site, muscle pain, phlebitis and other local reactions have been reported. Combination Therapy: Vascular toxicities coincident with the use of BLENOXANE in combination with other antineoplastic agents have been reported. The events are clinically heterogeneous and may include myocardial infarction, cerebrovascular accident, thrombotic microangiopathy haemolytic-uraemic syndrome or cerebrovascular arteritis. 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, hypomagnesemia, or a combination of any of these factors. BLENOXANE occasionally has been associated with local pain following intrapleural administration. Hypotension requiring symptomatic treatment has been reported infrequently. Very rarely death has been reported in association with BLENOXANE pleurodesis in very seriously ill patients.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT: SEE SIDE-EFFECTS AND SPECIAL PRECAUTIONS. Treatment is symptomatic and supportive.
IDENTIFICATION: Dry product: A white to cream coloured powder or soft, fluffy lumps.
Reconstituted solution: Clear, colourless, free from undissolved foreign particles.
PRESENTATION: BLENOXANE is available in single vial packs. Each 5 mL vial yields 15 units of bleomycin when reconstituted.
STORAGE INSTRUCTIONS: Bleomycin vials are intended for single-dose use. Any unused solution must be discarded.
Refrigerate (2-8°C). Protect from light. Store vials in carton until required for use. Reconstituted Product: BLENOXANE is stable for 24 hours at room temperature (25°C) in Sodium Chloride Injection 0,9% or Sterile Water for Injection. Any unused portion must be discarded.
KEEP OUT OF REACH OF CHILDREN.
REGISTRATION NUMBER: 15 units: D/26/174
NAME AND BUSINESS ADDRESS OF APPLICANT: Bristol-Myers Squibb (Pty) Ltd
47 Van Buuren road
DATE OF PUBLICATION OF THIS PACKAGE INSERT: February 2003
Updated on this site: June 2005
Source: Pharmaceutical Industry