Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Accord Healthcare Limited, Sage House, 319, Pinner Road, North Harrow, Middlesex HA1 4HF, United Kingdom
Patients receiving Bleomycin chemotherapy must be carefully monitored by experienced oncologists.
A highly rigorous risk/benefit assessment should be performed following lung or mediastinal radiotherapy. Bleomycin should only be used with caution and at a reduced dose in the event of impaired renal function. Because of the possible mutagenic effects of bleomycin on male and female germ cells, reliable contraception must be ensured during therapy and for up to 6 months after the end thereof.
Patients should be carefully monitored for any signs of pulmonary dysfunction during treatment with bleomycin.
Pulmonary reactions are the most serious side effects, occurring in roughly 10% of patients treated, during or after the end of a course of treatment. The most common form is interstitial pneumonitis. If this condition is not recognised and treated promptly, it can develop into pulmonary fibrosis. Approximately 1% of patients treated have died from the consequences of pulmonary fibrosis.
Patients undergoing treatment with bleomycin should have chest X-rays weekly. These should continue to be taken for up to 4 weeks after completion of the course and patients should be kept under clinical review for approximately 2 months. With concomitant radiation therapy of the thorax, a study or an X-ray of the thorax should possibly be done more frequently.
Lung function tests with 100% oxygen should not be used in patients who have been treated with bleomycin. Lung function tests using less than 21% oxygen are recommended as an alternative. Monthly analysis of pulmonary diffusion capacity for carbon monoxide could be planned. A study of lung function, in particular the measuring of the carbon monoxide diffusion and vital capacity, often makes an early diagnosis of lung toxicity possible.
Pulmonary toxicity is both dose-related and age-related, occurring more frequently in those over the age of 70 and in patients who have received a total dose of more than 400 units. It is significantly increased by thoracic irradiation and by hyperoxia during surgical anaesthesia.
Pulmonary toxicity has also been observed on occasion in young patients receiving low doses.
Vascular changes occur in the lungs, leading to partial destruction of the elasticity of the vessel wall. The earliest symptom of pulmonary damage caused by bleomycin is dyspnoea. Fine rales are the earliest sign. If pulmonary changes are noticed, bleomycin treatment should be discontinued until it is determined whether they are caused by the medication. The patients should be treated with broad spectrum antibiotics and corticosteroids.
In the event of dyspnoea, cough, basal crepitations or lung infiltrates not clearly attributable to the neoplasm or a concomitant pulmonary disease, administration of bleomycin must be discontinued immediately and the patient should be treated with a corticosteroid and broad-spectrum antibiotics. High oxygen concentrations should be used with caution. In case of lung damage as a result of bleomycin, bleomycin should not be administered any more (see section 4.3).
Although the pulmonary toxicity of bleomycin appears to be dose-related upon exceeding a total dose of 400 units (corresponding to approx. 225 units/m² BSA), it can also be observed at lower doses, in particular in elderly patients, patients with impaired renal function, patients with pre-existing lung disease, patients with a history of or receiving concomitant thoracic radiotherapy, and patients requiring oxygen administration. These patients should be carefully monitored and the bleomycin dosage reduced or the dose interval prolonged based on clinical observation of the patient. Bleomycin should be used with extreme caution in patients with lung cancer as these patients show an increased incidence of pulmonary toxicity.
As ⅔ of the administered dose of bleomycin is excreted unchanged in the urine, renal function has a major effect on the rate of excretion. Plasma concentrations are significantly elevated when usual doses are administered to patients with renal function disorders.
Other clinical conditions requiring caution include patients with severe heart disease or hepatic dysfunction as toxicity may be increased and patients with varicella as fatal systematic dysfunctions may occur.
Idiosyncratic reactions, clinically similar to anaphylaxis, have been reported in approximately 1% of lymphoma patients treated with bleomycin. The reaction may be immediate or after a few hours delay, and usually occurs after the first or second dose. It consists of hypotension, confusion, fever, chills, wheezing and stridor. Treatment is symptomatic and comprises volume expansion, vasopressors, antihistamines and corticosteroids.
Because of the possibility of an anaphylactoid reaction (in 1% of lymphoma patients, according to the literature), patients should initially receive a test dose of 1-2 units. If there is no acute reaction, the full dose can be administered.
There have been reports of vascular toxicity following use of bleomycin, in particular in combination with other antineoplastic agents. The events are clinically heterogeneous and include myocardial infarction, cerebrovascular insults, thrombotic microangiopathies, e.g. haemolytic uraemic syndrome and cerebral arteritis.
In adults or adolescents capable of reproduction, effects on the sexual glands should be considered.
Like other cytotoxic active substances, bleomycin can trigger tumour lysis syndrome in patients with rapidly growing tumours. Appropriate supportive treatment and pharmacological measures might prevent or alleviate such complications.
Patients with creatinine clearance values of less than 50 mL/min should be treated with caution and their renal function should be carefully monitored during the administration of bleomycin. Lower doses of bleomycin may be required in these patients than those with normal renal function (see section 4.2).
Vascular pain may occur, therefore, it is important to pay due attention to concentration of the injection and administration rate. Give intravenously as slowly as possible.
Avoid repeated injections at the same site and innervated sites, particularly if administering to paediatrics. If insertion of the injection needle evokes intense pain or if blood flows back into the syringe, withdraw the needle immediately and inject at a different site.
This medicine contains less than 1 mmol sodium (23 mg) per dose, i.e essentially “sodium free”.
If bleomycin is used as part of combination chemotherapy, its toxicity should be taken into account for the selection and dosage of other agents with a similar toxicity spectrum.
An increased risk of pulmonary toxicity has been reported with concomitant administration of other agents with pulmonary toxicity, e.g. BCNU, mitomycin, cyclophosphamide, methotrexate and gemcitabine. The pulmonary toxicity of bleomycin is potentiated by combined treatment with cisplatin in particular. Special care should therefore be taken with this combination. Data from the literature indicates that cisplatin should only be administered after bleomycin.
In patients with testicular tumours treated with a combination of bleomycin and vinca alkaloids, Raynaud- like phenomena have been reported with acral ischemia, leading to necrosis of peripheral parts of the body (fingers, toes, tip of the nose).
In patients who received a combination therapy of cisplatin, vinblastine and bleomycin, a positive correlation was observed between GFR (glomerular filtration rate) and lung function. Bleomycin should therefore be used with caution in severe renal impairment patients. It was revealed in another study that increasing cisplatin doses were associated with a decrease in creatinine clearance and therefore in the elimination of bleomycin.
Previous or concurrent thoracic radiotherapy contributes significantly to increased frequency and severity of pulmonary toxicity.
Previous or concurrent radiotherapy to the head or neck is a factor increasing stomatitis and angular stomatitis may deteriorate. It may cause inflammation of pharyngolaryngeal mucosa infrequently resulting in hoarseness.
Because of bleomycin’s potential to sensitise the lung tissue, pulmonary toxicity increases if bleomycin is administered during surgical procedures involving increased oxygen supply. The inspiratory O2 concentration should therefore be reduced intraoperatively and postoperatively.
An increase in the number of neutrophil granulocytes and stimulation of the ability to generate free oxygen radicals following administration of GCSF may potentiate lung injury.
These are case reports of a reduced effect of digoxin as a result of a reduced oral bioavailability when combined with bleomycin.
There are case reports of reduced levels of phenytoin when combined with bleomycin. Risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic medicinal products or risk of toxicity enhancement or loss of efficacy of the cytotoxic medicinal product due to increased hepatic metabolism by phenytoin. Concomitant use is not recommended.
Concomitant use of bleomycin with clozapine should be avoided due to an increased risk of agranulocytosis.
The bacteriostatic efficacy of gentamicin, amikacin and ticarcillin may be reduced.
Excessive immunosuppression with risk of lymphoproliferation exists.
The administration of live vaccines may lead to serious or life-threatening infections in patients whose immune system is weakened by chemotherapy agents, including bleomycin. Vaccinations with live vaccine should be avoided in patients receiving bleomycin. Use an inactivated vaccine where this exists (poliomyelitis). Vaccination with the yellow fever vaccine has resulted in severe and fatal infections when used in combination with immunosuppressive chemo therapeutics. This risk is increased in subjects who are already immunosuppressed by their underlying disease. This combination must not be used.
There are insufficient data on the use of bleomycin in pregnant women. Studies in animals have shown reproduction toxicity (see section 5.3). On the basis of the results of animal studies and the pharmacological efficacy of the product, there is a potential risk of embryonic and foetal abnormalities. Bleomycin will pass the placenta.
Bleomycin should therefore not be used during the pregnancy, unless it is strictly necessary, particularly during the first trimester.
If pregnancy occurs during treatment, the patient should be informed about the risks for the unborn child and be monitored carefully. The possibility of genetic counselling should be considered.
Both male and female patients should take adequate contraceptive measures up to six months after the discontinuation of the therapy.
Genetic counselling is also recommended for patients wishing to have children after therapy.
Advice on conservation of sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with bleomycin.
It is unknown if Bleomycin or the metabolites are excreted in the mother’s milk. Due to possible very harmful effects on the infant, breast-feeding during treatment with bleomycin is contraindicated.
Bleomycin therapy may cause irreversible infertility.
Possible side effects of chemotherapy with bleomycin, e.g. nausea and vomiting, may indirectly affect the patient’s ability to drive or use machines.
Like most cytotoxic agents, bleomycin can cause immediate and delayed toxic effects. Fever on the day of injection is the earliest reaction. The most frequently observed adverse reactions in 1613 patients receiving bleomycin were pulmonary manifestations such as interstitial pneumonia or pulmonary fibrosis (10.2%), sclerosis of skin, pigmentation (40.6%), fever and rigors (39.8%), alopecia (29.5%), anorexia and weight decrease (28.7%), general malaise (16.0%), nausea and vomiting (14.6%), stomatitis (13.3%) and nail changes (11.2%). Pain at the injection site and in the tumour area has also been observed on occasion. Other sporadic side effects include hypotension and local thrombophlebitis following intravenous injection.
There have also been reports of Raynaud’s phenomena, both when using bleomycin as monotherapy and in combination therapy.
The following undesirable effects can occur during treatment with bleomycin:
Frequencies are defined as follows: Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), Not known (frequency cannot be estimated from the available data).
Not known: Sepsis
Uncommon: Tumour pain
Uncommon: Myelosuppression, Leukopaenia, Neutropaenia, Thrombocytopaenia, Haemorrhage
Rare: Febrile neutropaenia
Not known: Pancytopenia, Anaemia
Common: Anaphylaxis, Hypersensitivity, Idiosyncratic drug reactions
Common: Headache
Uncommon: Dizziness, Confusion
Rare: Myocardial infarction, Pericarditis, Chest pain
Uncommon: Hypotension
Rare: Cerebral infarction, Thrombotic microangiopathies, Haemolytic uraemic syndrome, Cerebral arteritis, Raynaud’s phenomena, Arterial thrombosis, Deep vein thrombosis
Not known: Peripheral ischaemia
Very common: Interstitial pneumonitis, Pulmonary fibrosis, Dyspnoea
Common: Acute respiratory distress syndrome (ARDS), Lung failure, Pulmonary embolism
Very common: Decreased appetite, Weight loss, Nausea, Vomiting, Mucositis, Stomatitis
Uncommon: Angular cheilitis, Diarrhoea
Rare: Hepatic impairment
Very common: Erythema, Pruritus, Striae, Blistering, Hyperpigmentation, Tenderness and swelling of the fingertips, Hyperkeratosis, Hair loss
Common: Exanthema, Urticaria, Skin reddening, Induration, Oedema, Flagellate dermatitis
Uncommon: Deformation and discolouration of the nails, Bulla formation at pressure points
Rare: Scleroderma
Uncommon: Muscle and joint pain
Uncommon: Oliguria, Dysuria, Polyuria, Urinary retention
Common: Pyrexia, Chills, Malaise
Uncommon: Pain in the tumour area, Phlebitis, Hypertrophy of the vein wall and venous access constriction (with i.v. administration), Induration (with i.m. or local administration)
Very rare: Tumour lysis syndrome
Fever and chills may develop with a lag time of 45 hours or more after the administration of this drug. Because a dose response relation exists between the fever and dose at a given time, if the fever is severe, appropriate measures should be taken such as administering a reduced dose at shorter intervals, or antihistaminic and antipyretic agents before and/or after administration of this drug.
If cutaneous side effects occur in AIDS patients, the treatment should be discontinued and not resumed. Skin and mucosal lesions are the most common undesirable effects and are observed in up to 50% of the patients treated. They comprise induration, oedema, erythema, pruritus, rashes, striae, ulceration, blistering, hyperpigmentation, tenderness, swelling of the fingertips, hyperkeratosis, nail changes, bulla formation at pressure points such as the elbows, hair loss and stomatitis.
Mucosal ulcers appear to be aggravated by the combination of bleomycin with radiotherapy or other medication toxic to mucous membranes. Skin toxicity occurs at a relatively late stage and is correlated with the total dose; it usually develops in the second and third week after administration of 150 to 200 units of bleomycin.
Gastrointestinal side effects such as nausea and vomiting are possible, but are observed more frequently in high-dose regimens. Antiemetics may be helpful. Loss of appetite and weight loss are common and may continue for a long time after the end of the treatment.
Bleomycin does not appear to have any significant bone marrow depressant properties. Thrombocytopaenia occurring in connection with bleomycin treatment has not been attributed to decreased production of platelets, but rather to increased destruction of platelets.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Bleomycin should not be mixed with solutions of essential amino acids, riboflavin, ascorbic acid, dexamethasone, aminophylline, benzylpenicillin, carbenicillin, cefalotine, cefazoline, diazepam, furosemide, glutathione, hydrogen peroxide, hydrocortisone Na succinate, methotrexate, mitomycin, nafcillin, penicillin G, substances containing sulphydryl groups, terbutaline, or thiols. As bleomycin forms chelating agents with bi- and tervalent cations it should not be mixed with solutions that contain such ions (in particular copper)
With the exception of the medicinal products specified under section 6.6 (“Special precautions for disposal and other handling”), this medicinal product must not be mixed with other medicinal products.
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