Consumer medicine information

DBL Bleomycin sulfate for injection

Bleomycin sulfate

BRAND INFORMATION

Brand name

DBL Bleomycin Sulfate for Injection

Active ingredient

Bleomycin sulfate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using DBL Bleomycin sulfate for injection.

What is in this leaflet

This leaflet answers some common questions about DBL™ Bleomycin Sulfate for Injection (DBL™ Bleomycin).

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given DBL™ Bleomycin against the benefits they expect it will have for you.

If you have any concerns about this medicine, ask your doctor or pharmacist.

Keep this leaflet in a safe place. You may need to read it again.

What DBL™ Bleomycin is used for

DBL™ Bleomycin belongs to a group of medicines known as antineoplastic or cytotoxic agents. You may hear it referred to as chemotherapy medicine.

DBL™ Bleomycin is classified as an anti-tumour antibiotic. It interferes with the growth of cancer cells, which are eventually destroyed.

Your doctor may have prescribed bleomycin for another reason.

Ask your doctor if you have any questions about why bleomycin has been prescribed for you.

This medicine is available only with a doctor’s prescription.

DBL™ Bleomycin is not recommended for use in children, as there have not been enough studies of its effects in children.

Before you are given DBL™ Bleomycin

When you must not be given it

You must not be given DBL™ Bleomycin if you have an allergy to bleomycin or any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction to DBL™ Bleomycin may include:

  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

You should not be given DBL ™ Bleomycin if you have any of the following conditions:

  • problems with blood clotting
  • severe lung problems, a lung infection or reduced lung function.

Tell your doctor if you have an infection or high temperature. Your doctor may decide to delay your treatment until the infection has gone. A mild illness, such as a cold, is not usually a reason to delay treatment.

If you are not sure whether you should start treatment with DBL™ Bleomycin, talk to your doctor.

Before you are given it

Tell your doctor or pharmacist if you have allergies to:

  • any other medicines
  • any other substances, such as foods, preservatives or dyes.

Tell your doctor or pharmacist if you are pregnant or intend to become pregnant.

Your doctor or pharmacist will discuss the possible risks and benefits of treatment with bleomycin during pregnancy.

DBL™ Bleomycin may cause birth defects if either the male or the female is receiving it at the time of conception or if it is used during pregnancy. You should use some form of birth control while you are receiving bleomycin and for at least 12 weeks after stopping. Your doctor will discuss this with you.

Tell your doctor if you are breast-feeding or plan to breast-feed. Like most antineoplastic medicines, bleomycin is not recommended while you are breast-feeding.

Tell your doctor or pharmacist if you have or have had any medical conditions, especially the following:

  • kidney disease
  • liver disease
  • lung disease.

Tell your doctor if you smoke. There is a greater chance of DBL™ Bleomycin affecting your lungs if you smoke.

Tell your doctor if you have had radiation therapy for cancer. There is a greater chance of DBL™ Bleomycin affecting your lungs if you have had radiation therapy, especially to the chest.

If you have not told your doctor or pharmacist about any of the above, tell them before you start treatment with DBL™ Bleomycin.

Taking other medicines

Tell your doctor or pharmacist if you are taking or using any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and DBL™ Bleomycin may interfere with each other.. These include:

  • digoxin, a medicine used to treat heart failure
  • phenytoin, a medicine used to treat epilepsy, fits or seizures
  • cisplatin, a medicine used to treat some types of cancer
  • oxygen therapy, which may be given to you during surgery
  • other medicines used to treat cancer, radiation therapy or any other treatment which lowers your immune system
  • general anaesthetics
  • granulocyte colony stimulating factor (such as filgrastim and lenograstim).

These medicines may be affected by DBL™ Bleomycin, or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines. Some of these medicines and DBL™ Bleomycin may interfere with each other even if they are not given at the same time. Your doctor or pharmacist will advise you.

Your doctor and pharmacist may have more information on medicines to be careful with or avoid while you are being given DBL™ Bleomycin.

How DBL™ Bleomycin is given

How much is given

Your doctor will decide what dose of DBL™ Bleomycin you will receive. This depends on your condition and other factors, such as your weight and height, kidney function and other chemotherapy medicines you are being given.

DBL™ Bleomycin may be given alone or in combination with other drugs.

Several courses of DBL™ Bleomycin therapy may be needed, depending on your response to treatment.

Additional treatment may not be repeated until your blood cell numbers return to acceptable levels and any unwanted side effects have been controlled.

Ask your doctor if you want to know more about the dose of bleomycin you receive.

How it is given

DBL™ Bleomycin should only be given by a doctor or nurse.

DBL™ Bleomycin can be given in a number of different ways:-

  • an injection under the skin
  • an injection into a muscle
  • an injection into a vein
  • an injection into an artery.

The first time you are given DBL™ Bleomycin, you will normally receive a small test dose to check that you are not allergic to bleomycin. If no reaction occurs, the full dose will be given.

How long it is given

A course of DBL™ Bleomycin may consist of a dose once or twice weekly, or it may be given as a daily dose for 7 consecutive days. This is called one cycle of chemotherapy. Your doctor will decide how many of these cycles you will need.

Overdose

As DBL™ Bleomycin will be given to you under the supervision of your doctor, it is very unlikely that you will receive too much. Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26 in Australia, or call 0800 764 766 in New Zealand) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much DBL™ Bleomycin. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of a DBL™ Bleomycin overdose include the side effects listed below in the ‘Side Effects’ section, but are usually of a more severe nature.

While you are being given DBL™ Bleomycin

Tell your doctor, nurse or pharmacist if you have any concerns before, during or after administration of bleomycin.

Things you must do

Be sure to keep all your doctor’s appointments so your progress can be checked. Your doctor may want to do some blood and other tests from time to time to check on your progress and detect any unwanted side effects.

Keep follow up appointments with your doctor. It is important to have your follow-up doses of DBL™ Bleomycin at the appropriate times to get the best effects from your treatments.

Tell any other doctors, dentists, and pharmacists who are treating you that you are being given DBL™ Bleomycin.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are being given DBL™ Bleomycin.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are being given DBL™ Bleomycin. If you become pregnant while you are being treated with DBL™ Bleomycin, tell your doctor immediately.

DBL™ Bleomycin can lower the number of white blood cells and platelets in your blood. This means that you have an increased chance of getting an infection or bleeding. The following precautions should be taken to reduce your risk of infection or bleeding:

  • Avoid people with infections. Check with your doctor immediately if you think you may be getting an infection, or if you get a fever, chills, cough, hoarse throat, lower back or side pain, or find it painful or difficult to urinate;
  • Be careful when using a toothbrush, dental floss or toothpick. Your doctor, dentist, nurse or pharmacist may recommend other ways to clean your teeth and gums. Check with your doctor before having any dental work done;
  • Be careful not to cut yourself when you are using sharp objects such as a razor or nail cutters;
  • Avoid contact sports or other situations where bruising or injury may occur.

While you are being given DBL™ Bleomycin, your doctor should order regular tests to check the number of blood cells in your blood. The results of these tests will be used to determine the amount of DBL™ Bleomycin you will be given for your next dose.

While you are being given DBL™ Bleomycin your doctor should order regular tests to check how well your kidneys are working.

Your doctor should also order periodic tests to estimate how well your liver is working during treatment with DBL™ Bleomycin.

DBL™ Bleomycin is known to affect the way the lungs work in some patients. This may be serious, therefore your doctor should arrange frequent tests to check how well your lungs are working. Your doctor may also arrange weekly chest X-rays while you are being treated with DBL™ Bleomycin. These should continue for up to 4 weeks after completion of treatment with DBL™ Bleomycin.

Things to be careful of

Be careful driving or operating machinery until you know how DBL™ Bleomycin affects you.

As with some other medicines, DBL™ Bleomycin may cause dizziness, light-headedness and tiredness in some people. Make sure you know how you react to bleomycin before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed. If this occurs do not drive. If you drink alcohol, dizziness or light-headedness may be worse.

Side effects

Tell your doctor, pharmacist or nurse as soon as possible if you do not feel well while you are being given bleomycin.

Like other medicines that treat cancer, DBL™ Bleomycin may have unwanted side effects, some of which may be serious. You may need medical treatment if you get some of these side effects.

If you are over 65 years of age you may have an increased chance of getting side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or nurse if you notice any of the following and they worry you:

  • nausea, vomiting or loss of appetite
  • tiredness or weakness
  • headaches
  • pain and inflammation at the injection site
  • rash and other skin conditions such as itchiness, tenderness, altered pain sensation and altered skin colour
  • conjunctivitis (infection/ inflammation of the eye)
  • soreness or ulceration of the mouth.

These are the more common side effects of DBL™ Bleomycin.

Tell your doctor or nurse immediately, or go to the Accident and Emergency department of your nearest hospital if you notice any of the following:

  • cough and shortness of breath
  • fever and chills
  • signs of an allergic reaction such as those listed at the start of this leaflet
  • disorientation or personality changes
  • severe nausea and vomiting
  • severe abdominal pain
  • chest pain
  • severe headache
  • severe mouth ulceration and/or anal ulceration
  • unusual bleeding or bruising (including blood in your stools or urine)
  • painful or difficult urination
  • blurred vision or eye pain
  • yellowing of the skin or eyes
  • fits (seizures).

These are very serious side effects. You may need urgent medical attention or hospitalisation.

Temporary loss of hair, particularly that on the scalp is a less common side effect of bleomycin and occurs in a small number of patients. The severity of hair loss will depend on the dose of DBL™ Bleomycin given. It is more common when other anti-cancer medicines are used together with bleomycin.

Other side effects not listed above may occur in some patients. Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

The effects of bleomycin may take some time to occur and therefore the side effects may be delayed. It is possible that the unwanted side effects may not occur until months after DBL™ Bleomycin is given. Therefore, even after you have finished receiving your DBL™ Bleomycin treatment you should tell your doctor immediately if you notice any of the side effects listed above.

After you have been given DBL™ Bleomycin

Storage

DBL™ Bleomycin will be stored in the pharmacy or on the ward. The injection is kept in a cool dry place, protected from light, where the temperature stays below 25°C.

Product description

What it looks like

DBL™ Bleomycin is a white to cream coloured powder. It must be dissolved in Water for Injections or 0.9% Sodium Chloride solution before use.

Ingredients

Active ingredient:

  • Bleomycin Sulfate 15,000 IU (15 units USP) per vial

There are no other ingredients.

DBL™ Bleomycin does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier/Sponsor

Australian Sponsor:

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizer.com.au

Date of leaflet update:
April 2019

Aust R 42569

Published by MIMS July 2019

BRAND INFORMATION

Brand name

DBL Bleomycin Sulfate for Injection

Active ingredient

Bleomycin sulfate

Schedule

S4

 

1 Name of Medicine

Bleomycin sulfate.

6.7 Physicochemical Properties

Chemical structure.

The structure of bleomycin sulfate is shown:

CAS number.

9041-93-4.

2 Qualitative and Quantitative Composition

Each vial contains bleomycin sulfate as a lyophilised powder which is equivalent to 15,000 IU bleomycin activity. Each vial contains 55-70% of bleomycin A2 and 25-32% of bleomycin B2.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Bleomycin sulfate is an antineoplastic antibiotic which is a purified mixture of glycopeptides produced by a fermentation process employing the actinomycetes Streptoverticillium species. The bleomycin mixture contains predominantly the A2 and B2 peptides.
Bleomycin sulfate is a white or yellowish white or cream coloured amorphous hygroscopic powder. It is very soluble in water, slightly soluble in dehydrated alcohol, and practically insoluble in acetone and ether.
DBL Bleomycin Sulfate for Injection is a white to cream coloured lyophilised powder or plug. When reconstituted in Water for Injection, the pH of the solution is approximately 5.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Although the precise mechanism of action of bleomycin is not fully known, it is thought that the primary action is to produce single and double strand breaks in DNA, leading to inhibition of cell division and growth, and inhibition of DNA synthesis in the cells.
Bleomycin is probably most effective against cells in the M and G2 (premitotic) phase of the cell cycle. Bleomycin has not been shown to have an immunosuppressive effect in vitro and shows no significant inhibition of immune response in patients treated with the drug.
Bleomycin inactivating enzyme has been detected in both normal and malignant cells and is particularly prominent in liver. The enzyme is not found in lung or skin, two normal tissues sensitive to bleomycin action.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Bleomycin is well absorbed in animals upon parenteral administration. Intramuscular injection of 15 units in man resulted in a maximum serum concentration of 1 milliunit/mL thirty minutes after administration. Intravenous injection of 15 units in man resulted in a maximum serum concentration of 3.3 milliunits/mL.

Distribution.

In mice, bleomycin diffusing from the blood produces high concentrations in the skin, lungs, kidneys, peritoneum, lymphatic system and susceptible tumour tissue if present. Bleomycin crosses the placenta, but does not cross the blood brain barrier. Equilibrium dialysis and gel permeation experiments suggest that less than 1.0% of the drug is protein bound after incubation with normal human serum in vitro.

Metabolism.

The majority of a bleomycin dose is not readily metabolised. The highest rate of metabolism occurs in the liver and gastrointestinal tract. A lower rate of metabolism also occurs in skin, lungs, kidneys, muscle and serum. The products of bleomycin metabolism are not known.

Excretion.

Bleomycin is primarily excreted in the urine. After intravenous injection an average of 40% of the administered dose is recovered unchanged in the urine within 24 hours. After IM injection 20% is recovered in the urine after 6 hours. The plasma half-lives have varied from 15-60 minutes in patients with normal renal function following intravenous administration. The serum half-life is prolonged in patients with renal dysfunction. In one patient with severe renal dysfunction the biological half-life was 21 hours when the creatinine clearance was 10.7 mL/min, and 13 hours when the creatinine clearance was 15.2 mL/min. There were undetectable serum levels of bleomycin 72 hours after the intravenous dose.

5.3 Preclinical Safety Data

Genotoxicity.

Bleomycin is mutagenic in both in vitro and in vivo test systems.

Carcinogenicity.

It is not known whether bleomycin is carcinogenic in humans. However, an increased incidence of nodular hyperplasia was noted in F344/N male rats with lung cancer induced by nitrosamines, after bleomycin treatment. In another study where bleomycin was administered subcutaneously to rats at a dose of 0.35 mg/kg weekly (or about 30% the recommended human dose), necropsy findings included dose related injection site fibrosarcomas and various renal tumours.

4 Clinical Particulars

4.1 Therapeutic Indications

Bleomycin is indicated for palliation and treatment adjuvant to surgery and radiation therapy of the following neoplasms.
Squamous cell carcinoma of the skin, head and neck, and oesophagus (primary indication).
Squamous cell carcinoma of the larynx, penis and uterine cervix.
Squamous cell carcinoma of the bronchus (response infrequent).
Choriocarcinoma and embryonal cell carcinoma of the testis.
Advanced Hodgkin's disease and other lymphomas.
Mycosis fungoides.

Note.

Use of bleomycin after radiation therapy is less successful than use before radiation therapy.
Bleomycin is bone marrow sparing and may be used when other cytotoxic agents are contraindicated.

4.3 Contraindications

Bleomycin is contraindicated in patients with known allergy or idiosyncrasy to the drug. Bleomycin is also contraindicated in patients with acute pulmonary infection or greatly reduced lung function.
A repeat course of therapy is contraindicated in any patient who has shown any signs of pneumonitis or decreased pulmonary function (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

It is recommended that bleomycin 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. Patients receiving bleomycin must be observed carefully and frequently during and after therapy.
After injection, bleomycin is readily absorbed and distributed in the body, particularly in the skin, lungs and any susceptible tumour tissue, leading to possible skin and pulmonary toxicity, as well as antitumour activity.

Pulmonary toxicity.

No single predictive monitoring test for bleomycin induced pulmonary toxicity has been identified. Frequent physical examinations should be undertaken. Cough, basal rales and pleuritic chest pain are frequent first signs of toxicity. Dyspnoea is usually the first symptom. If pulmonary changes are noted, treatment should be discontinued until it can be determined whether the cause is drug related. Pulmonary function tests (especially total lung volume (TLV) and forced vital capacity (FVC) may be of value in detecting early lung changes, although these are not always predictive of subsequent toxicity. It has been suggested that bleomycin should be discontinued if FVC decreases rapidly. Baseline and subsequent monthly evaluation of carbon monoxide diffusion capacity (DLCO) are also recommended, and bleomycin should be discontinued when the DLCO is less than 30-35% of the pretreatment value.
The most commonly recommended method of monitoring the onset of pulmonary toxicity is weekly chest x-rays, which should be continued up to 4 weeks after completion of treatment. However, high resolution computer tomography is a more sensitive method of detection.
Other proposed methods of monitoring pulmonary toxicity include 99mTechnetium scans and measurement of ESR, which has been found to increase prior to the development of symptomatic toxicity. However, the usefulness of these methods as predictors of development of toxicity have not been proven in clinical practice.

Anaesthesia.

Because of bleomycin's effects on lung tissue, patients who have received the drug are at increased risk of developing pulmonary toxicity when oxygen is administered during surgery. Long exposure to very high concentrations of oxygen is a known cause of lung damage, but after administration of bleomycin, lung damage can occur at oxygen concentrations lower than those usually considered safe. Therefore, to minimize the risk in patients undergoing surgery who have received bleomycin, the following is recommended:
(i) FI O2 concentration should be maintained at approximately that of room air (25%) during surgery and the post-operative period;
(ii) Fluid replacement should be carefully monitored, with emphasis on administration of colloid rather than crystalloid.

Pneumonitis.

Pneumonitis due to bleomycin has been treated with corticosteroids in an effort to prevent progression to pulmonary fibrosis. Infectious pneumonitis should receive appropriate antibiotic therapy.

Lung cancer.

Bleomycin should be used with extreme caution in patients with lung cancer as these patients show an increased incidence of pulmonary toxicity.

Compromised pulmonary function due to disease other than malignancy.

Bleomycin should be used with extreme caution in patients with compromised pulmonary function as pulmonary toxicity may be particularly dangerous in these patients (see Section 4.3 Contraindications).

Previous cytotoxic or radiation therapy (especially chest irradiation); smokers.

Bleomycin should be used with caution in patients who have had previous cytotoxic drug therapy or radiation therapy (especially chest irradiation), and in patients who smoke, since the risk of pulmonary toxicity may be increased in these patients.

Cisplatin.

Cisplatin induced renal function impairment may result in delayed clearance and bleomycin toxicity even at low doses. An increased incidence of bleomycin induced pulmonary toxicity has been observed when these two agents are administered as part of an antineoplastic treatment regimen. Dosage reduction may be required (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Granulocyte colony stimulating factor (G-CSF).

It has been suggested that concomitant administration of G-CSF and bleomycin may increase the risk of bleomycin induced pulmonary toxicity, especially at higher doses, although this has not been confirmed in clinical trials. If G-CSF is added to bleomycin containing treatment regimens, patients should be closely observed for signs of pulmonary toxicity (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Combination therapy.

Pulmonary toxicity may be observed at lower doses of bleomycin when bleomycin is administered as part of a multi-drug treatment regimen. Patients should be closely monitored for signs of pulmonary toxicity (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Cumulative dose.

Pulmonary toxicity is more common in patients receiving a total dose of more than 400,000 IU.

Idiosyncratic reactions.

Idiosyncratic reactions similar to anaphylaxis have been reported in 1% of patients treated with bleomycin (5% of lymphoma patients). Since these usually occur after the first or second dose, careful monitoring is essential after these doses.

Lymphoma patients.

All lymphoma patients should receive test doses of bleomycin before initiating full dose therapy (see Section 4.8 Adverse Effects (Undesirable Effects)).

Renal or hepatic toxicity.

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.

Use in renal impairment.

Bleomycin should be used with extreme caution in patients with severely impaired renal function (see Section 4.2 Dose and Method of Administration, Dosage adjustments).

Use in the elderly.

Patients over 70 years of age should be closely observed for signs of pulmonary toxicity due to bleomycin therapy (see Section 4.8 Adverse Effects (Undesirable Effects)).

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pharmacodynamic interactions.

Anaesthetics, general and oxygen.

Use in patients previously treated with bleomycin may result in rapid pulmonary deterioration, since bleomycin causes sensitisation of lung tissue to oxygen.

Radiation therapy.

Radiation therapy, especially to the chest area, either prior to, during or after bleomycin therapy may result in increased bleomycin toxicity. Dosage adjustment may be necessary.

Antineoplastic agents.

Concurrent use may result in increased bleomycin toxicity, or in occurrence of pulmonary toxicity at lower doses of bleomycin (see Section 4.4 Special Warnings and Precautions for Use).

Combination therapy.

Pulmonary toxicity may be observed at lower doses of bleomycin when bleomycin is administered as part of a multidrug treatment regimen. Patients should be closely monitored for signs of pulmonary toxicity (see Section 4.4 Special Warnings and Precautions for Use).

Granulocyte colony stimulating factor (G-CSF).

It has been suggested that concomitant administration of G-CSF and bleomycin may increase the risk of bleomycin induced pulmonary toxicity, especially at higher doses, although this has not been confirmed in clinical trials. If G-CSF is added to bleomycin containing treatment regimens, patients should be closely observed for signs of pulmonary toxicity (see Section 4.4 Special Warnings and Precautions for Use).

Pharmacokinetic interactions.

Cisplatin.

Cisplatin induced renal function impairment may result in delayed clearance and bleomycin toxicity even at low doses. An increased incidence of bleomycin induced pulmonary toxicity has been observed when these two agents are administered as part of an antineoplastic treatment regimen. Dosage reduction may be required (see Section 4.4 Special Warnings and Precautions for Use).

Digoxin.

Serum levels of digoxin may be reduced and its actions may be decreased. It is thought that drug induced alterations of the intestinal mucosa may be involved in the reduced GI absorption.

Phenytoin.

Serum concentrations of phenytoin may be decreased due to decreased absorption or increased metabolism of phenytoin.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of bleomycin on fertility are not known.
(Category D)
Bleomycin has caused, is suspected to have caused or may be expected to cause an increase incidence of human fetal malformations or irreversible damage. It may also have adverse pharmacological effects.
It is not known whether bleomycin is excreted in breast milk. Due to the potential for serious adverse effects in infants, it is recommended that breastfeeding is discontinued prior to administration of bleomycin sulfate to the mother.

4.8 Adverse Effects (Undesirable Effects)

Serious or life threatening effects.

Pulmonary toxicity.

The most serious toxicity of bleomycin is a subacute or chronic pneumonitis that progresses to interstitial fibrosis and may be fatal. This occurs in approximately 10% of treated patients, about 1% of whom have died of pulmonary fibrosis. Pulmonary toxicity is both age and dose related, being more common in patients over 70 years of age and in those receiving over 400,000 IU total dose. This toxicity, however, is unpredictable and has been seen occasionally in young patients receiving low doses. Also, when used in combination with other antineoplastic agents, pulmonary toxicities may occur at lower doses.
This toxicity is frequently seen in those with underlying lung disease such as emphysema and in those previously treated with pulmonary or mediastinal irradiation.
The identification of patients with pulmonary toxicity due to bleomycin has been extremely difficult. The clinical symptoms and x-ray findings of bleomycin pulmonary toxicity are not easily distinguished from other syndromes commonly observed in cancer patients, including progressive metastatic tumor (especially lymphangitic tumour), infectious processes such as Pneumocystis carinii or cytomegalovirus, or radiation injury.
The first symptoms to appear are dyspnoea, with cough and low grade fever, commonly occurring 4-10 weeks after initiation of therapy, although the time of onset of pulmonary toxicity may vary from during therapy to up to six months after the cessation of therapy.
The microscopic tissue changes due to bleomycin toxicity are frequently present as bronchiolar squamous metaplasia, reactive macrophages, atypical alveolar epithelial cells, fibrinous edema 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 and are similar to the changes produced in radiation pneumonitis, pneumocystic pneumonitis, and at times reaction to long standing malignant pulmonary disease.
Pulmonary function tests have revealed some alteration in the pulmonary status such as decreased total lung volume and decreased vital capacity, but these tests have proved to be of limited value in predicting pulmonary fibrosis. It has been suggested that bleomycin should be discontinued if forced vital capacity decreases rapidly.
Pulmonary toxicity is seen more commonly in smokers.

Idiosyncratic effects.

Hypersensitivity reactions consisting of hypotension, fever, chills, mental confusion and wheezing have occurred in approximately 1% of patients receiving bleomycin.
This idiosyncratic reaction occurs mainly in lymphoma patients (5%), may be immediate or delayed for several hours, and usually occurs after the first or second dose. The reaction has resulted in death. Treatment of anaphylactoid reactions is supportive and symptomatic and may include volume expansion, vasopressor therapy, antihistamines and corticosteroids.

Cardiovascular.

Vascular toxicities coincident with the use of bleomycin in combination with other antineoplastic agents have been reported rarely. The events are clinically heterogeneous and may include myocardial infarction, cerebrovascular accident, thrombotic microangiopathy (haemolytic uremic syndrome) or cerebrovascular arteritis. Acute chest pain syndrome, acute pericarditis, fulminant fatal hyperpyrexia and fulminant, fatal angioedema have been reported.

More common effects.

Body as a whole.

Fever, chills and headache frequently follow parenteral administration of bleomycin (20-50%). These reactions have been reported to occur most frequently with large single doses and occur within a few hours of administration lasting 4-12 hours. Usually, febrile reactions become less frequent with continued use of the drug but may occur sporadically and reoccur later in the treatment course.

Gastrointestinal.

Anorexia, nausea and vomiting (20-50%) (anorexia and weight loss may persist after discontinuing therapy), tiredness.

Mucocutaneous (50%).

Hypoesthesia which may progress to hyperesthesia, urticaria, erythematous swelling, tenderness, pruritus, hyperpigmentation (particularly in those areas subject to friction or pressure and in skin folds, nail cuticles, scars, and I.M. injection sites), patchy hyperkeratosis, alopecia, ichthyosis, rash, striae, vesiculation, peeling, and bleeding, stomatitis, ulcerations of the tongue and lips. This toxicity is usually evident within 1-3 weeks following initiation of therapy and appears to be reversible and dose related, usually after 150,000 to 200,000 IU of bleomycin has been administered and, in general, is related to total cumulative dose. In 0.2% of patients it was necessary to discontinue treatment because of this toxicity.
When bleomycin is administered intra-arterially, dermal lesions are most common in the region supplied by the artery used. The incidence of mucocutaneous adverse events is increased when bleomycin sulfate is given in combination with radiotherapy to head and neck.

Less common effects.

Body as a whole.

Idiosyncratic reactions occurring in 1% of patients (5% of lymphoma patients) (see Serious or life threatening effects).

Cardiovascular.

Diverse vascular toxicities (see Serious or life threatening effects), hypotension (more common after intrapleural administration), sudden onset of an acute chest pain syndrome, suggestive of pleuropericarditis (although each patient must be individually evaluated, further courses of bleomycin do not appear to be contraindicated), ocular haemorrhage.
There are isolated reports of Raynaud's phenomenon occurring in patients treated with a combination of bleomycin and vinblastine with or without cisplatin or, in a few cases, with bleomycin as a single agent. It is currently unknown if the cause of the Raynaud's phenomenon in these cases is the disease, underlying vascular compromise, bleomycin, vinblastine, cisplatin induced hypomagnesaemia or a combination of any or all of these.

Central nervous system.

CNS toxicity is rare, but monitoring is advised. Disorientation and aggressive behaviour have been reported.

Haematologic.

Thrombocytopenia, leukopenia, slight depression of haemoglobin levels. Bleomycin does not frequently produce serious bone marrow toxicity.

Hepatic.

Liver toxicity beginning as deterioration in liver function tests has been reported infrequently.

Injection site.

Pain at injection site, phlebitis, other local reactions.

Renal.

Renal toxicity beginning as deterioration in renal function tests has been reported infrequently.
Haematuria and cystitis have been reported.

Respiratory.

Pulmonary toxicity (10%) (see Serious or life threatening effects).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Dosage.

Initial treatment (intramuscular, intravenous or subcutaneous administration).

Total doses of over 300,000 IU should be given with great caution.
10,000 to 20,000 IU/m2 of body surface area given weekly or twice weekly.
Alternatively, give 15,000 IU daily for 7 days followed by three weeks off-treatment and repeat twice so that a total dose of approximately 300,000 IU is administered.
Improvement of lymphomas and testicular tumours is prompt i.e. within two weeks while response by squamous cell cancers may take as long as three weeks.
A therapeutic response should be observed as the total dose approaches 150,000 IU, if this is not seen, consideration should be given to other therapy.

Note.

When bleomycin is used in combination with other antineoplastic agents, pulmonary toxicities may occur at lower doses (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Method of administration.

Bleomycin may be given by the intramuscular, intravenous, subcutaneous or intra-arterial routes.

Note.

Because of the possibility of an anaphylactoid reaction, lymphoma patients should receive test doses of between 1-5 units, for the first two treatments. If no acute allergic reaction occurs within 4-6 hours, the balance of the dose may be given. Thereafter the regular dosage schedule may be followed, if no reaction occurs.

Directions for reconstitution.

For intramuscular or subcutaneous injection: dissolve the contents of the vial in 1-5 mL of Sterile Water for Injection or Sodium Chloride Intravenous Infusion 0.9%.
For intravenous or intra-arterial injection: dissolve the contents of the vial in 5-10 mL of diluent and administer slowly over a period of 10 minutes.
Suitable diluents are Water for Injections, Bacteriostatic Water for Injection and Sodium Chloride Intravenous Infusion 0.9%. Although Glucose Intravenous Infusion 5% has been used in the past, recent data suggests that it is not the diluent of choice, as over the concentration range of 300 to 15,000 IU/mL the content of Bleomycin A2 + B2 was consistently lower when Glucose Intravenous Infusion 5% was used.
Reconstituted solutions containing 150 to 15,000 IU/mL bleomycin prepared using the recommended diluents remain stable for periods of at least 24 hours when stored in the dark, at temperatures of 2-8°C or 25°C. Solutions of bleomycin sulfate in Sodium Chloride Intravenous 0.9% stored in the dark at 2-8°C for 10 days were chemically stable. However, in order to reduce the possibility of microbiological contamination, reconstituted injections should be used as soon as practicable after preparation. If storage of the reconstituted solution is necessary, store at 2-8° C for no more than 24 hours. Any unused portions must be discarded in compliance with acceptable procedures for the disposal of anticancer medicines.

Dosage adjustments.

Intra-arterial administration.

Intra-arterial infusion/perfusion is employed when increased drug concentrations at the cancer site are desired. The suggested dosage schedule is 30,000 to 60,000 IU once or twice a week until the total recommended dose of 300,000 IU is reached.

Repeat treatment.

In patients for whom a course of bleomycin treatment provides an initial but incomplete response, a repeat course is suggested. Patients who show superficial improvement after one course e.g. in cases of squamous cell carcinoma, may benefit from a second course of treatment to prevent recurrence.
A repeat course may be commenced after a minimum of 3-4 weeks following completion of the first course, providing no sign of pulmonary toxicity have been observed (see Section 4.3 Contraindications). A total dose of 150,000 IU for repeat treatment is recommended.

In impaired renal function.

As bleomycin is mostly excreted unchanged and as there is a high correlation between renal bleomycin clearance and creatinine clearance, impairment of function may require reduction in dosage and careful monitoring for toxicity. Dosage reductions of 40-75% have been recommended for patients with creatinine clearance values of ≤ 40 mL/min.

In impaired liver function.

Use adult dose with caution.

Paediatric dose.

No data available.

Geriatric dose.

Adult dose should be used with caution, particularly in patients over 70 years (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.9 Overdose

Symptoms.

There has been no reported case of overdosage. The acute reaction would probably include hypotension, fever, rapid pulse and general symptoms of shock.

Treatment.

There is no specific antidote for bleomycin overdosage. Treatment should be symptomatic and supportive. In the event of respiratory complications treatment with a corticosteroid may be beneficial and the administration of a broad spectrum antibiotic is advisable. Bleomycin is probably not dialysable.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia). In New Zealand call 0800 764 766.

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Bleomycin sulfate.

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

DBL Bleomycin Sulfate for Injection is available in vials containing 15,000 IU of bleomycin.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes