BLEO-KYOWA

SUMMARY OF PRODUCT CHARACTERISTICS

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NAME OF THE MEDICINAL PRODUCT
Bleo-Kyowa

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QUALITATIVE AND QUANTITATIVE COMPOSITION
Bleomycin Sulphate equivalent to 15,000 IU (15 x 103 IU)

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PHARMACEUTICAL FORM
Powder for solution for injection White to light yellowish, freeze-dried substance

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4.1

CLINICAL PARTICULARS
Therapeutic indications a. Squamous cell carcinoma affecting the mouth, nasopharynx and paranasal sinuses, larynx, oesophagus, external genitalia, cervix or skin. Well differentiated tumours usually respond better than anaplastic ones. b. Hodgkins disease and other malignant lymphomas, including mycosis fungoides. c. Testicular teratoma d. Malignant effusions of serous cavities. e. Secondary indications in which Bleomycin has been shown to be of some value (alone or in combination with other drugs) include metastatic malignant melanoma, carcinoma of the thyroid, lung and bladder.

4.2

Posology and method of administration Adults Routes of administration

Bleomycin is usually administered intramuscularly but may be given intravenously (bolus or drip), intra-arterially, intrapleurally or intraperitoneally as a solution in physiological saline. Local injection directly into the tumour may occasionally be indicated. Recommended dose and dosage schedules Squamous cell carcinoma and testicular teratoma: Used alone the normal dosage is 15 x 103 IU (1 vial) three times a week or 30 x 103 IU (2 vials) twice a week, either intramuscularly or intravenously. Treatment may continue on consecutive weeks, or more usually at intervals of 3-4 weeks, up to a total cumulative dose of 500 x 103 IU although young men with testicular tumours have frequently tolerated twice this amount. Continuous intravenous infusion at a rate of 15 x 103 IU (1 vial) per 24 hours for up to 10 days, or 30 x 103 IU (2 vials) per 24 hours for up to 5 days may produce a therapeutic effect more rapidly. The development of stomatitis is the most useful guide to the determination of individual tolerance of maximum therapeutic response. The dose may need to be adjusted when bleomycin is used in combination chemotherapy. Use in elderly or children see below. Malignant lymphomas. Used alone the recommended dosage regime is 15 x 103 IU (1 vial) once or twice a week, intramuscularly, to a total dose of 225 x 103 IU (15 vials). Dosage should be reduced in the elderly. The dose may need to be adjusted when bleomycin is used in combination chemotherapy. Use in elderly or children - see below. Malignant effusions: After drainage of the affected serous cavity 60 x 103 IU (4 vials) bleomycin dissolved in 100 ml physiological saline is introduced via the drainage needle or cannula. After instillation, the drainage needle or cannula may be withdrawn. Administration may be repeated if necessary subject to a total cumulative dose of 500 x 103 IU (about 33 vials), Use in the elderly or children - see below. Combination therapy: Bleomycin is commonly used in conjunction with radiotherapy, particularly in treatment of cancer of the head and neck region. Such a combination may enhance mucosal reactions if full doses of both forms of treatment are used and bleomycin dosage may require reduction, e.g. to 5 x 103 IU at the time of each radiotherapy fraction five days a week. Bleomycin is frequently used as one of the drugs in multiple chemotherapy regimes (e.g. squamous cell carcinoma, testicular teratoma, lymphoma). The mucosal toxicity of bleomycin should be borne in mind in the selection and dosage of drugs with similar toxic potential used in such combinations. Elderly Patients: The total dose of bleomycin used in the treatment of squamous cell carcinoma, testicular teratoma or malignant effusions should be reduced as indicated below

Age in years 80 and over 70 - 79 60 69 Under 60

Total Dose (IU) 100 x 103 150 - 200 x 103 200 - 300 x 103 500 x 103

Dose per week (IU) 15 x 103 30 x 103 30 60 x 103 30 60 x 103

Children Until further data are available, administration of bleomycin to children should take place only under exceptional circumstances and in special centres. The dosage should be based on that recommended for adults and adjusted to body surface area or body weight. Reduced kidney function With serum creatinine values of 2-4 mg%, it is recommended to half the above dosages. With serum creatinine above 4 mg%, a further reduction in dose is indicated. Preparation of solution For intramuscular injections the required dose is dissolved in up to 5 ml of suitable solvents such as physiological saline. If pain occurs at the site of injection a 1% solution of lignocaine may be used as a solvent. For intravenous injections the dose required is dissolved in 5-200 ml of physiological saline and injected slowly or added to the reservoir of a running intravenous infusion. For intra-arterial administration a slow infusion in physiological saline is used. For intra-cavity injection 60 x 103 IU is dissolved in 100ml of normal saline. For local injections bleomycin is dissolved in physiological saline to make a 13 x 103 IU/ml solution

4.3

Contraindications Bleomycin is contra-indicated in patients with acute pulmonary infection or greatly reduced lung function Patients who have previously had a hypersensitivity or idiosyncratic reaction to bleomycin.

4.4

Special warnings and precautions for use 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. If breathlessness or infiltrates appear, not obviously attributable to tumour or to coexistent lung disease, administration of the drug must be

stopped immediately and patients should be treated with a corticosteroid and a broad spectrum antibiotic. High oxygen concentrations should be used with caution in these cases. Lung function tests which use 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. When Bleomycin has been administered pre-operatively, reduced oxygen concentrations should be used during operation and post operatively. Patients treated previously or concurrently with radiation to the chest may develop more frequent or severe toxicity. Bleomycin should be used with caution in patients with significant renal impairment as clearance may be reduced and toxicity increased (see Section 4.2 Posology and Method of Administration) Bleomycin should be used with caution in patients with severe heart disease.

4.5

Interaction with other medicinal products and other forms of interaction When bleomycin is used as one of the drugs in multiple chemotherapy regimes the toxicity of bleomycin should be borne in mind in the selection and dosage of drugs with similar toxic potential. The addition of other cytotoxic drugs can necessitate changes and dose alterations. Increased pulmonary toxicity has been noted when bleomycin is given with cisplatin. Previous or concurrent radiotherapy to the chest is an important factor in increasing the incidence and severity of lung toxicity. Because of bleomycin's sensitisation of lung tissue, patients who have received bleomycin pre-operatively are at greater risk of developing pulmonary toxicity when oxygen is administered at surgery and a reduction in inspired oxygen concentration during operation and post-operatively is recommended (See Section 4.4). In patients treated for testicular cancer with a combination of bleomycin and vinca alkaloids a syndrome has been reported corresponding to morbus Raynaud, ischaemia which can lead to necrosis of peripheral parts of the body (fingers, toes, nose tip). The following clinical incompatibilities have been noted:-Cytotoxics possibly reduce the absorption of phenytoin. Concomitant use of bleomycin with clozapine should be avoided due to an increased risk of agranulocytosis

4.6

Fertility, Pregnancy and lactation Bleomycin should not normally be administered to patients who are pregnant or to mothers who are breast-feeding. Animal experiences have revealed that bleomycin, like most cytotoxics, may have teratogenic and carcinogenic potential.

4.7

Effects on ability to drive and use machines This depends on the patients condition and should be considered in cooperation with the doctor.

4.8

Undesirable effects 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%). Haematological: Common Uncommon Nervous: Common Uncommon Respiratory: Very common Gastrointestinal: Very common Common Uncommon Hepatic: Uncommon Skin: Very common Common

Haemorrhage Leukopenia Headache Dizziness Interstitial pneumonia and pulmonary fibrosis

Anorexia, weight decrease, nausea and vomiting and stomatitis Angular stomatitis Diarrhoea

Hepatic disturbances Hypertrophy of the skin, pigmentation, alopecia and deformation and discolouration of the nail Rash, urticaria and erythroderma associated with fever

Renal and Urinary: Uncommon Oliguria, micturition pain, polyuria and feeling of residual urine General Disorders and Administration Site Conditions: Very Fever, rigors and malaise common Uncommon Pain at the tumour site Hypertrophy of the venous wall and narrowing of the venous lumen when given by intravenous injection Induration when given by intramuscular or local injection

Like most cytotoxic agents bleomycin can give rise to both to immediate and to delayed toxic effects. The most immediate effect is fever on the day of injection. Anorexia, tiredness or nausea also may occur. Pain at the injection site or in the region of the tumour has occasionally been reported, and other rare adverse effects are hypotension and local thrombophlebitis after intravenous administration. The majority of patients who receive a full course of bleomycin develop lesions of the skin or oral mucosa. Induration, hyperkeratotis, reddening, tenderness and swelling of the tips of the fingers, ridging of the nails, bulk formation over pressure points such as elbows, loss of hair and stomatitis are rarely serious and usually disappear soon after completion of the course. The most serious delayed effect is interstitial pneumonia, which may develop during, or occasionally after, a course of treatment. This condition may sometimes develop into fatal pulmonary fibrosis, although such an occurrence is rare at recommended doses. Previous or concurrent radiotherapy to the chest is an important factor in increasing the incidence and severity of lung toxicity. A few cases of acute fulminant reactions with hyperpyrexia and cardiorespiratory collapse have been observed after intravenous injections of doses higher than those recommended. Hypotension, hyperpyrexia and drugrelated deaths have been reported rarely following intra-cavitary instillation of bleomycin. During post-marketing surveillance the following events have been reported: sepsis, pancytopenia, thrombocytopenia, anaemia, neutropenia, chest pain, myocardial infarction, Raynauds syndrome, embolism, thrombosis and digital ischaemia.

4.9

Overdose The acute reaction to an overdosage of bleomycin would probably include hypotension, fever, rapid pulse and general symptoms of shock. Treatment is

purely symptomatic. In the event of respiratory complications the patient should be treated with a corticosteroid and a broad-spectrum antibiotic. There is no specific antidote to bleomycin.

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5.1

PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties ATC code: LO1D C01, other cytotoxic antibiotics Bleomycin is a basic, water-soluble glycopeptide with cytotoxic activity. The mechanism of action of bleomycin is believed to involve single-strand scission of DNA, leading to inhibition of cell division, of growth and of DNA synthesis in tumour cells. Apart from its antibacterial and antitumour properties, bleomycin is relatively free from biological activity. When injected intravenously it may have a histamine-like effect on blood pressure and may cause a rise in body temperature.

5.2

Pharmacokinetic properties Bleomycin is administered parenterally. After intravenous (LV) administration of a bolus dose of 15 x 103 IU/m2 body surface, peak concentrations of 1 to 10 IU are achieved in plasma. Following the intramuseular (IM) injection of 15 x 103 IU peak plasma concentrations of about 1 IU/ml have been reported. The peak plasma concentration is reached 30 minutes after an IM injection. Continuous infusion of bleomycin 30 x 103 IU daily, for 4 to 5 days, resulted in an average steady state plasma concentration of 100-300 milli IU/ml. After IV injections of bleomycin in a dose of 15 x 103 IU/m2 body surface, the area under the serum concentration curve is, on average, 300 milli IU x min x ml-1. Bleomycin is only bound to plasma proteins to a slight extent. Bleomycin is rapidly distributed in body tissues, with the highest concentrations in skin, lungs, peritoneum and lymph. Low concentrations are seen in the bone marrow. Bleomycin could not be detected in cerebrospinal fluid after intravenous injection. Bleomycin appears to cross the placental barrier. The mecnanism for Bio-transformation in not yet fully known. Inactivation takes place during enzymatic breakdown by bleomycin hydrolase, primarily in plasma, liver and other organs and, to a much lesser degree, in skin and lungs. When bleomycin was administered as an IV bolus injection in a dose of 15 x 103 IU/m2 body surface, initial and terminal half-lives were 0.5 and 4 hours respectively. Given as a continuous intravenous infusion in a dose of 30 x 103 IU daily for 4 to 5 days bleomycin disappears from plasma with initial and terminal half-lives of about 1.3 hours and 9 hours, respectively. About two

thirds of the administered drug is excreted unchanged in the urine, probably by glomerular filtration. Approximately 50% is recovered in the urine in the 24 hours following an IV or IM injection. The rate of excretion, therefore, is highly influenced by renal function; concentrations in plasma are greatly elevated if usual doses are given to patients with renal impairment with only up to 20% excreted in 24 hours. Observations indicate that it is difficult to eliminate bleomycin from the body by dialysis.

5.3

Preclinical safety data There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the Summary of Product Characteristics.

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6.1

PHARMACEUTICAL PARTICULARS
List of excipients None.

6.2

Incompatibilities Bleomycin solution should not be mixed with solutions of essential amino acids, riboflavine, ascorbic acid, dexamethasone, aminophylline or frusemide.

6.3

Shelf life 3 years.

6.4

Special precautions for storage Protect from light. Store at 2C -8C.

6.5

Nature and contents of container 5 ml colourless glass vials with rubber closure and aluminium cap containing freeze dried bleomycin sulphate equivalent to 15,000 IU. Ten vials per carton.

6.6

Special precautions for disposal Bleomycin should be handled with care. Precautions should be taken to avoid bleomycin coming into contact with skin, mucous membranes or eyes, but in the event of contamination the effected part should be washed with water.

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MARKETING AUTHORISATION HOLDER
ProStrakan Limited 3 Galabank Business Park Galashiels TD1 1QH.

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MARKETING AUTHORISATION NUMBER(S)
PL 16508/0046

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DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
03/07/2006

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DATE OF REVISION OF THE TEXT
05/06/2012