Active substance(s): BLEOMYCIN SULPHATE
1. NAME OF THE MEDICINAL PRODUCT
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Bleomycin Sulphate equivalent to 15,000 IU (15 x 103 IU)
3. PHARMACEUTICAL FORM
Powder for solution for injection
White to light yellowish, freeze-dried substance
4. CLINICAL PARTICULARS
4.1 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. Hodgkin’s 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
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 lifetime cumulative
dose of 360 x 103 IU. 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.
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). Lifetime cumulative dose should
not exceed 360 x 103 IU. 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.
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 lifetime cumulative dose of 360 x 103 IU (about 24 vials).
Use in the elderly or children – see below.
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.
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
Total Dose (IU)
100 x 103
150 – 200 x 103
200 – 300 x 103
Dose per week (IU)
15 x 103
30 x 103
30 – 60 x 103
Administration of bleomycin to paediatrics 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/dL, it is recommended to half the above dosages.
With serum creatinine above 4 mg/dL, 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-cavitary injection
60 x 103 IU is dissolved in 100 ml of normal saline.
For local injections bleomycin is dissolved in physiological saline to make a 1-3 x 103 IU/ml
Bleomycin is contra-indicated in patients with acute pulmonary infection or chest X-ray
findings suggesting diffuse fibrotic changes or greatly reduced lung function.
Patients with a past history of hypersensitivity or idiosyncratic reaction to an analogue of
4.4 Special warnings and precautions for use
Pulmonary toxicity of bleomycin is both dose-related and age-related. It may also occur
when lower doses are administered, especially in elderly patients, patients with reduced
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kidney function, pre-existing lung disease, previous or concurrent radiotherapy to the chest
and in patients who need administration of oxygen. It is significantly enhanced by thoracic
radiation and by hyperoxia used during surgical anaesthesia.
The earliest symptom associated with pulmonary toxicity of bleomycin is dyspnoea. Fine
rales are the earliest sign. If pulmonary changes are noted, treatment should be discontinued
until it can be determined if they are drug related. Patients should be treated with broad
spectrum antibiotics and corticosteroids.
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. If breathlessness or lung
infiltrates appear, not obviously attributable to tumour or to co-existent 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.
BLEO-KYOWA® Powder for solution for injection 15,000 IU
Read all of this leaflet carefully before you start using this medicine because
it contains important information for you.
Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor or pharmacist.
This medicine has been prescribed for you only. Do not pass it on to others.
It may harm them, even if their signs of illness are the same as yours.
If you get any side effects, talk to your doctor or nurse. This includes any
possible side effects not listed in this leaflet. See section 4.
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.
Patients should be carefully monitored under the following conditions and bleomycin dosage
should be reduced or prolong the dose interval based on clinical observation of the patient:
These clinical conditions include the following:
What is in this leaflet
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.
• Use with caution in patients with significant renal impairment as clearance may be reduced
and toxicity increased (see Section 4.2).
• Use with caution in patients with severe heart disease or hepatic dysfunction as toxicity
may be increased.
• Use with caution in patients with varicella as fatal systematic dysfunctions may occur.
Because bleomycin treatment may give rise to shock, if any abnormalities appear, withdraw
bleomycin immediately, and take appropriate measures. (Because shock is likely to develop
in patients with malignant lymphomas at the 1st – 2nd administration, you may start this drug
treatment with lower dose and after establishing that no acute reactions to the drug occur,
increase the dose to the usual level).
With long-term administration of bleomycin, peplomycin or other analogies of bleomycin,
toxicity is thought to be additive, thus administration must be performed with care.
Attention should be paid to the appearance or exacerbation of infection and any bleeding
In adults or adolescents capable of reproduction, effects on the sexual glands should be
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.
What Bleo-Kyowa is and what it is used for
What you need to know before you use Bleo-Kyowa
How to use Bleo-Kyowa
Possible side effects
How to store Bleo-Kyowa
Contents of the pack and other information
WHAT BLEO-KYOWA IS AND WHAT IT IS USED FOR
Bleo-Kyowa is an anti-cancer medicine (chemotherapy) used for treating certain
types of cancer. Bleo-Kyowa is used to treat cancer known as squamous cell
carcinoma which can affect the mouth, nose, throat, skin, cervix or external genitalia.
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.
It is also used to treat Hodgkin's disease and other types of cancer of the blood, as
well as to treat fluid producing cancers in the cavity around the lungs or in the
abdomen, and to treat testicular teratoma.
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.
Bleo-Kyowa is also of value in treating malignant melanoma (a type of skin cancer)
and thyroid, lung and bladder cancer.
4.5 Interactions with other medicinal products and other forms of
Previous or concurrent radiotherapy to the chest and/or administration of anti-tumour agents
(e.g. cisplatin) are important factors in increasing the incidence and severity of lung toxicity
such as interstitial pneumonia or pulmonary fibrosis.
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 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 Raynaud’s disease, 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
The administration of this drug to pregnant patients, or women suspected of being pregnant,
is not recommended. The use of bleomycin should be avoided whenever possible during
pregnancy, particularly during the first trimester.
Bleomycin should not be given to mothers who are breast feeding.
Bleomycin can cause congenital malformations. Women should not become pregnant during
and six months after treatment.
4.7 Effects on ability to drive and use machines
This depends on the patient’s condition and should be considered in co-operation with the
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%).
WHAT YOU NEED TO KNOW BEFORE YOU USE BLEO-KYOWA
Do not use Bleo-Kyowa:
if you are allergic to bleomycin or to any similar anti-cancer medicine
if you have a chest infection
if you have scarring of the lungs
if you have greatly reduced lung function.
If any of these apply to you, tell your doctor.
Warnings and precautions
Talk to your doctor before using Bleo-Kyowa if you have or have recently had any of
lung problems or you have been receiving oxygen
severe heart disease
liver function that is impaired
radiation to the chest.
You must also tell your doctor if you have an operation planned, as it may be
necessary to adjust your treatment with Bleo-Kyowa.
Other medicines and Bleo-Kyowa
Tell your doctor or pharmacist if you are using, have recently used or might use any
other medicines, as some medicines could interact with Bleo-Kyowa.
When Bleo-Kyowa is used with vinca alkaloids (another type of cancer drug) to treat
cancer of the testes, Raynaud’s disease (poor blood circulation which makes the
toes and fingers numb and pale) has been reported.
Use of Bleo-Kyowa together with cisplatin or radiation to the chest can cause
interstitial pneumonia (serious inflammation of the lungs) and pulmonary fibrosis
(scarring of the lungs which leads to shortness of breath).
Use of Bleo-Kyowa with clozapine should be avoided, as it may cause more severe
reduction in number of white blood cells which makes infections more likely
Use of cytotoxics (medicines that kill cancer cells) may lower the absorption of
Pregnancy, breast-feeding and fertility
If you are pregnant, breast-feeding, or think you may be pregnant do not take this
If you are planning to have a baby, ask your doctor for advice before using
Driving and using machines
A few people have reported that they feel tired or weak after the treatment. Do not
drive or use any tools or machines if you are affected.
HOW TO USE BLEO-KYOWA
Bleo-Kyowa powder from one or more vials will be dissolved in saline (a weak salt
solution that mixes well with body fluids). The solution is usually given by injection in
to muscle tissue or a blood vessel or into the chest or abdominal cavity depending on
the type of cancer. Occasionally, it is injected directly into a tumour.
The usual treatment is for 2 or 3 days in one week and may be repeated in subsequent
weeks. Sometimes the treatment is given on consecutive days for up to 5 or 10 days.
The precise dosage, frequency of dosing and duration of treatment with Bleo-Kyowa
will depend on your age, weight, medical condition and whether Bleo-Kyowa is being
given in combination with other drug treatment.
If other medicines or radiotherapy are also being used in your treatment or if you
have kidney disease or reduced kidney function, the amount of Bleo-Kyowa given to
you may be reduced.
The total dose of the medicine given in a lifetime should not go beyond
360 x 103 IU. Your doctor will keep track of your total dose.
Use in children and adolescents
The dose is calculated in relation to child body weight and such treatment will
probably take place under the supervision of a specialist treatment centre.
If during treatment you develop a dry cough, breathlessness, rapid breathing or
anything else which suggests your lungs might be affected, you may require to be
monitored by X-rays of your chest that could continue up to 4 weeks after the end of
If you are given more Bleo-Kyowa than you should
If you have been accidentally given a higher dose you may experience symptoms
such as fever, low blood pressure and rapid pulse. Your doctor may give you
supportive treatment for any symptoms that may occur.
POSSIBLE SIDE EFFECTS
Like all medicines, this medicine can cause side effects, although not everybody gets
them. These might occur at the time of treatment or might occur at some later time.
If you notice any of the following reactions tell your doctor immediately:
• inflammation of the lungs (interstitial pneumonia) – fever, chills, shortness of
breath or a cough
• severe allergic reaction – you may experience a sudden itchy rash (hives),
swelling of the hands, feet, ankles, face, lips, mouth or throat (which may
cause difficulty in swallowing or breathing), and you may feel you are going to
These are serious side effects. You may need urgent medical attention.
reduction in white blood cells
reduced blood flow to the fingers, toes and tip of the nose
a type of stroke (cerebral infarction)
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any
possible side effects not listed in this leaflet. You can also report side effects directly
via the Yellow Card Scheme, www.mhra.gov.uk/yellowcard or search for MHRA
Yellow Card in the Google Play or Apple App Store. By reporting side effects you can
help provide more information on the safety of this medicine.
HOW TO STORE BLEO-KYOWA
Keep this medicine out of the sight and reach of children.
Bleo-Kyowa should be kept in its original packaging and stored at 2-8°C.
If you experience any of the following tell your doctor or nurse as soon as
This medicine will normally be stored by the doctor providing your treatment or by
another qualified person such as a nurse or pharmacist.
Very common: (these may affect more than 1 in 10 patients)
Avoid contact of Bleo-Kyowa on the skin.
fever on the day of treatment
loss of appetite and weight loss
nausea and vomiting
sore mouth and mouth ulcers
changes in skin colour, or itchy skin
hardening, thickening, redness, tenderness or swelling of the tips of the
• hair loss
• ridging of nails, blisters on pressure points e.g. elbows
• numbness, pain or colour changes to the fingers, toes and tip of the nose, and
hardening and tightening of skin
Common: (these may affect between 1 in 10 and 1 in 100 patients)
skin rash, redness of the skin
soreness at the corners of the mouth
Uncommon: (these may affect between 1 in 100 and 1 in 1,000 patients)
changes in urinating or pain when urinating
low white blood cell count
blood vessel changes (narrowed or enlarged)
pain, swelling, redness or tenderness at the site of the injection or at the site of
Other side effects which may occur are:
• overwhelming infection (sepsis)
• severe reduction in blood cells
• reduction in blood platelets
• reduction in red blood cells
Do not use this medicine after the expiry date which is stated on the label after “Exp.”.
The expiry date refers to the last day of that month.
After being treated with Bleo-Kyowa, any remaining bleomycin solution or equipment
used for the treatment will be safely disposed of by your nurse or doctor. Do not
throw away medicines via wastewater or household waste. These measures will help
protect the environment.
The active substance is bleomycin sulphate
There are no other ingredients
What Bleo-Kyowa looks like and contents of the pack
Bleo-Kyowa is a white to yellow-ish powder which is mixed with saline before
injection. It is packaged in glass vials with a rubber stopper and aluminium seal.
Marketing Authorisation Holder
Kyowa Kirin Limited
Galabank Business Park
Aesica Queenborough Limited
Tel: 01896 664000
The following adverse reactions have been reported with bleomycin
during clinical studies and from post-marketing experience. They are
listed below by system organ class and frequency (very common ≥
1/10; common ≥ 1/100 to < 1/10; uncommon ≥1/1,000 to <1/100; not
known (cannot be estimated from available data)).
Adverse Reaction by Frequency
This medicinal product is authorised in the Member States of the EEA under
the following names:
This leaflet was last revised in 09/2017.
≥ 1/100 to
≥ 1/1,000 to
Haemorrhage Shock; vein wall Hypotension;
venous stenosis thrombosis*;
Alopecia; skin Rash; urticaria;
What Bleo-Kyowa contains
Tabulated Summary of Adverse Reactions with bleomycin:
disorders and malaise
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow
Card in the Google Play or Apple App Store.
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.
5. PHARMACOLOGICAL PROPERTIES
5.1 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 (IV)
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
intramuscular (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 mechanism for bio-transformation is 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
Animal experiences have revealed that bleomycin, like most
cytotoxics, may have teratogenic and carcinogenic potential.
Bleomycin has been reported to cause fibrosarcoma and renal
carcinoma in a laboratory animal (rat) administered subcutaneously.
Bleomycin has been reported to cause foetal malformation in
laboratory animals (mice and rats).
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
* Following intravenous administration
Like most cytotoxic agents bleomycin can give rise to both immediate
and to delayed toxic effects. The most immediate effect is fever on the
day of injection. Fever may develop with a lag time of 4-5 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.
The majority of patients who receive a full course of bleomycin
develop lesions of the skin or oral mucosa. Induration, hyperkeratosis,
reddening, tenderness and swelling of the tips of the fingers, ridging of
the nails, bulla 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 drug-related deaths have been reported rarely
following intra-cavitary instillation of bleomycin.
Reporting of suspected adverse reactions
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
the Yellow Card Scheme
Bleomycin solution should not be mixed with solutions of essential
amino acids, riboflavine, ascorbic acid, dexamethasone,
aminophylline or frusemide.
6.3 Shelf life
6.4 Special precautions for storage
Protect from light. Store at 2°C -8°C.
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 and other handling
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 affected part should be
washed with water.
7. MARKETING AUTHORISATION HOLDER
Kyowa Kirin Limited
Galabank Business Park
8. MARKETING AUTHORISATION NUMBER
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE
10. DATE OF REVISION OF THE TEXT