Bleomycin accord

Package leaflet: Information for the patient

Bleomycyna Accord, 15,000 IU, powder for solution for injection / infusion
Bleomycini sulfas
Please read all of this leaflet carefully before using this medicine, because it contains
important information for the patient.

• Keep this leaflet, so that you can read it again if necessary.
• If you have any further questions, please consult your doctor, hospital pharmacist, or nurse.
• If you experience any side effects, including any possible side effects not listed in this leaflet, please consult your doctor, hospital pharmacist, or nurse. See section 4.

Contents of the leaflet

1. What Bleomycyna Accord is and what it is used for
2. Important information before using Bleomycyna Accord
3. How to use Bleomycyna Accord
4. Possible side effects
5. How to store Bleomycyna Accord
6. Contents of the pack and other information

1. What Bleomycyna Accord is and what it is used for

The active substance in Bleomycyna Accord is bleomycin sulfate. Bleomycyna Accord belongs to a group of medicines called cytostatics, which are anticancer medicines, sometimes referred to as chemotherapeutic agents. These medicines attack cancer cells and prevent them from dividing. Bleomycyna Accord is used in the treatment of:

• certain types of tumours (squamous cell carcinoma) of the head and neck, cervix, and external genital organs,
• certain lymph node tumours (e.g. Hodgkin’s disease and intermediate- and high-grade non-Hodgkin’s lymphomas),
• testicular cancer,
• accumulation of fluid in the lungs caused by cancer.

Bleomycyna Accord may be used alone or in combination with other anticancer medicines and (or) in combination with radiotherapy.

2. Important information before using Bleomycyna Accord

Do not use Bleomycyna Accord:

• if the patient is allergic to bleomycin sulfate or any other similar anticancer drug,
• if the patient has ataxia-telangiectasia (a very rare inherited disease causing difficulties in movement coordination and increased risk of infections),
• if the patient has acute lung infection or severe lung function disorders,
• if the patient previously experienced lung damage (probably) caused by bleomycin,
• during breastfeeding (see section "Pregnancy and breastfeeding").

Warnings and precautions
Before starting treatment with Bleomycyna Accord, consult a doctor, pharmacist,
or nurse:

• if the patient is over 60 years of age,
• if the patient has kidney or liver function disorders,
• if the patient currently has or has previously had lung diseases,
• if the patient has undergone radiotherapy to the lungs before bleomycin treatment or is receiving radiotherapy during bleomycin treatment,
• if the patient has chickenpox,
• if the patient is receiving oxygen. Inform the doctor about bleomycin use. Also inform the doctor if the patient has a planned surgical procedure, as modification of bleomycin treatment may be necessary.

The above patient groups are more susceptible to harmful effects of bleomycin on the lungs. The patient
will likely be examined more frequently by a doctor and (or) undergo chest X-rays.
Regular lung function tests should be performed in patients treated with bleomycin to monitor
potential harmful effects of bleomycin on the lungs.
Immediately inform the doctor if the patient develops cough and (or) shortness of breath, as this
may indicate harmful effects of bleomycin on the lungs.
Cases of blood cancer (acute myeloid leukemia) and myelodysplastic syndrome (a condition in which
the bone marrow fails to produce sufficient healthy blood cells or platelets) have been reported in
patients treated simultaneously with bleomycin and other cytostatic agents [substances inhibiting
cell growth (division)].
Like other cytotoxic drugs, bleomycin may cause tumor lysis syndrome in patients with rapidly
growing tumors. Appropriate supportive treatment and pharmacological management may prevent
or alleviate such complications.

Bleomycyna Accord and other medicines
Inform the doctor or pharmacist about all medicines currently used, recently used, or planned
for use by the patient.
Interactions occur when medicinal products used simultaneously affect each other's efficacy and (or)
adverse effects. Interactions may occur when bleomycin is used with the following medicines:

• Carmustine, mitomycin, cyclophosphamide, gemcitabine (used in treatment of certain types of cancer) and methotrexate (used in treatment of certain types of cancer, rheumatoid arthritis and severe skin diseases): increased risk of harmful effects on the lungs.
• Cisplatin (an anticancer drug) and other drugs causing kidney damage: increased risk of bleomycin adverse effects (increased pulmonary toxicity).
• Vinca alkaloids (a group of medicinal products used in treatment of certain cancer types, e.g. vincristine, vinblastine): circulatory disturbances in limbs (fingers, toes, nose tip) may occur. In very severe cases, these body parts may undergo necrosis.
• Acetyldigoxin (a medicine used to treat heart disorders): risk of reduced efficacy of acetyldigoxin.
• Phenytoin (a medicine used to treat epilepsy): risk of reduced efficacy of phenytoin.
• Clozapine (a medicine for schizophrenia): may cause severe decrease in white blood cell count, increasing the risk of infections.
• Radiotherapy: increased risk of adverse effects affecting the lungs and (or) mucous membranes.
• Oxygen: increased risk of pulmonary toxicity when oxygen is administered during anesthesia.
• Gentamicin, amikacin and ticarcillin (medicines inhibiting bacterial growth): their efficacy may be reduced.
• Cyclosporine and tacrolimus (medicines reducing immune system activity): risk of excessive lymphocyte production.
• Granulocyte colony-stimulating factor: may lead to increased lung damage.
• Live vaccines: risk of severe or life-threatening infections caused by the vaccine. Live vaccines should not be administered to patients receiving bleomycin.

Pregnancy, breastfeeding and fertility

Pregnancy
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or plans to have a child,
she should consult a doctor or pharmacist before using this medicine.
Animal studies have shown that the drug may harm the developing embryo.
Bleomycin should be avoided during pregnancy, especially during the first three months.
If treatment with bleomycin is necessary during the first three months of pregnancy, medical
consultation regarding termination of pregnancy is required.
Both men and women must use effective contraception during treatment with bleomycin and for
6 months after completion of treatment. If pregnancy occurs during bleomycin treatment, genetic
counseling is recommended.
Men planning to have children in the future should seek advice about sperm storage before starting
bleomycin treatment, as treatment may cause irreversible infertility.

Breastfeeding
It is not known whether bleomycin or its metabolites pass into human milk, but due to the potential
harmful effects of bleomycin on the infant, breastfeeding must not be performed during treatment.

Fertility
Treatment with Bleomycyna Accord may cause irreversible infertility.

Driving and using machines
This medicine may affect reaction ability and capacity to drive vehicles.
Adverse effects of chemotherapy with bleomycin, such as nausea and vomiting, may occur.
If such effects occur, the patient should not drive or operate machinery requiring concentration.

Bleomycyna Accord, powder for solution for injection/infusion contains sodium.
The medicine contains less than 1 mmol of sodium (23 mg) per dose, meaning the medicine is considered "sodium-free".

3. How to use Bleomycyna Accord

The required dose will be determined by your doctor based on the dosing information provided later in this leaflet.
Typical dosage:
The (total) dose depends on the therapeutic indication, age, renal function, and concomitant use of other antineoplastic agents. Your doctor will determine the dose of bleomycin, duration of treatment, and number of treatment days. These may vary depending on the individual patient.
There is a risk of severe hypersensitivity reactions, especially in patients diagnosed with lymphoma, which may occur immediately after administration of the drug or somewhat later. Therefore, your doctor will administer a test dose and observe you for 4 hours before starting treatment with bleomycin for the first time.
Method of administration
Your doctor may administer bleomycin: intravenously or intra-arterially, subcutaneously, intramuscularly, directly into the tumour, or into the space surrounding the lung (intracavitary/intrapleural) by injection or infusion.
Use in children and adolescents
There is insufficient data on the use of bleomycin in children and adolescents. Until more information becomes available, bleomycin should only be used in children and adolescents under exceptional circumstances and in specialized centres.
Use of more Bleomycyna Accord than prescribed
Symptoms that may occur if a patient has received an overdose of Bleomycyna Accord include: low blood pressure, fever, rapid heartbeat, and shock. If any of these symptoms occur, inform the doctor immediately, who will initiate appropriate treatment. Administration of the drug must be stopped immediately.
Information for the doctor
Information on the management of overdose can be found at the end of this leaflet.
Missed dose of Bleomycyna Accord
If a patient misses a dose, contact the treating doctor to determine whether and when the missed dose should be made up.
Stopping Bleomycyna Accord
If the patient stops taking Bleomycyna Accord suddenly without consulting the doctor, previous symptoms may recur.
If you have any further questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everybody will experience them.
Bleomycyna Accord may cause immediate and delayed adverse reactions.
Fever on the day of injection is the earliest reaction. Loss of appetite, hair loss, chills, fatigue, lung inflammation (interstitial pneumonitis) – shortness of breath or cough, mucosal inflammation and nausea may also occur. Pain at the injection site and around the tumour site has been observed occasionally. Other rare adverse reactions include hypotension and local thrombophlebitis following intravenous administration.
Skin and mucous membrane changes are the most common adverse reactions and are observed in up to 50% of treated patients. These include: redness, rash, itching, ulceration, striae, blistering, severe pigmentation, tenderness and swelling of fingertips.

Serious adverse reactions
Inform the doctor immediately if the patient experiences any of the following symptoms:

• cough
• shortness of breath
• crackling or popping sound during breathing

Treatment may need to be discontinued.
Other adverse reactions include:

Very common (may affect more than 1 in 10 people)

• interstitial pneumonitis (inflammatory changes in the lungs)
• pulmonary fibrosis (lung tissue disease caused by increased formation of connective tissue between alveoli)
• breathing difficulties
• loss of appetite
• weight loss
• nausea and vomiting
• mucositis (inflammation of mucous membranes)
• oral mucositis (inflammation of the oral mucosa)
• inflammatory redness of the skin
• itching
• striae
• blistering
• pigmentation (increased pigment production)
• tenderness and swelling of fingertips
• hyperkeratosis (excessive thickening of the skin)
• hair loss

Common (may affect up to 1 in 10 people)

• severe hypersensitivity reactions. These reactions may occur immediately or several hours after the first or second dose. Inform the doctor immediately if sudden wheezing, difficulty breathing, swelling of eyelids, face or lips, rash or itching occur (especially if affecting the whole body). Idiosyncratic reactions (various types of hypersensitivity reactions).
• headache
• acute respiratory failure (acute respiratory distress syndrome, ARDS)
• respiratory failure
• pulmonary embolism
• rash, urticaria, erythema
• skin sclerosis
• oedema (due to fluid retention in tissues)
• inflammatory skin reaction
• fever, chills and malaise

Uncommon (may affect up to 1 in 100 people)

• bone marrow suppression (damage to bone marrow)
• leukopenia (reduced white blood cell count)
• neutropenia (reduced number of neutrophils in the blood)
• thrombocytopenia (reduced platelet count)
• haemorrhage (bleeding)
• dizziness
• disorientation
• hypotension (low blood pressure)
• angular cheilitis and diarrhoea
• nail deformity and discoloration, blister formation at pressure points
• muscle and joint pain
• oliguria (reduced urine output)
• dysuria (pain during urination)
• polyuria (increased urine volume)
• urinary retention
• tumour site pain
• phlebitis (vein inflammation)
• venous wall hypertrophy (thickening of venous walls) and venous access narrowing (with intravenous administration)
• sclerosis (tissue hardening after intramuscular or local administration)

Rare (may affect up to 1 in 1,000 people)

• febrile neutropenia (fever caused by reduced white blood cell count)
• myocardial infarction, pericarditis (inflammation of the fibrous sac surrounding the heart) and chest pain
• encephalitis, thrombotic microangiopathy (disease of capillaries and small arteries), haemolytic-uraemic syndrome (a severe blood and kidney disorder)
• cerebral arteritis (inflammation of small and medium-sized arteries in the brain)
• Raynaud's phenomenon (vascular disorder), arterial thrombosis, deep vein thrombosis
• liver function disorders
• scleroderma (hardening of connective tissue)

Very rare (may affect up to 1 in 10,000 people)

• tumour lysis syndrome (a disorder occurring after rapid breakdown of tumours)

Frequency not known (cannot be estimated from available data)

• systemic infection (sepsis)
• marked decrease in blood cells (pancytopenia)
• reduced number of red blood cells (anaemia)

Reporting of adverse reactions
If any adverse reactions occur, including any possible adverse reactions not listed in this leaflet, consult a doctor, hospital pharmacist or nurse.
Adverse reactions can also be reported directly to the Department of Monitoring Adverse Drug Reactions, Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Al. Jerozolimskie 181C
02-222 Warsaw
tel.: + 48 22 49 21 301
fax: + 48 22 49 21 309
website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorisation holder.
Reporting adverse reactions helps provide more information on the safety of this medicine.

5. How to store Bleomycyna Accord

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and vial following EXP.
The expiry date refers to the last day of the stated month.
Store in a refrigerator (2°C - 8°C).
After reconstitution and dilution, chemical and physical stability of the medicine has been demonstrated for 10 days at a temperature of 2°C to 8°C and for 48 hours at room temperature. From a microbiological standpoint, the reconstituted/diluted medicinal product should be used immediately. If the product is not used immediately, the user is responsible for the storage conditions and duration prior to use, which should not exceed the stability periods stated above.
For single use only. Discard any unused portion.
Do not use Bleomycyna Accord if visible signs of deterioration of the medicinal product or vial are observed, such as discoloration of the powder or damage to the vial or closure.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Contents of the pack and other information

What Bleomycyna Accord contains
The active substance is bleomycin (in the form of bleomycin sulfate).
One vial contains 15,000 international units (IU) of bleomycin (in the form of bleomycin sulfate).
The other ingredients are: sodium hydroxide (for pH adjustment), hydrochloric acid (for pH adjustment).

What Bleomycyna Accord looks like and contents of the pack
A white or yellowish lyophilized substance in a vial made of colourless glass (type I), closed with a bromobutyl rubber stopper and an aluminium flip-off seal.
The pack contains 1, 10 or 100 vials.
Not all pack sizes may be marketed.

Marketing Authorisation Holder
Accord Healthcare Polska Sp. z o.o.
ul. Taśmowa 7
02-677 Warszawa
Tel: + 48 22 577 28 00

Manufacturer/Importer
Accord Healthcare Polska Sp. z o.o.
ul. Lutomierska 50,
95-200, Pabianice

This medicinal product is authorised in the European Economic Area and the United Kingdom (Northern Ireland) under the following names:

The following information is intended for healthcare professionals only

Dosage and method of administration
Bleomycin is administered parenterally by intramuscular injection,
intravenous injection/infusion, intra-arterial injection/infusion, subcutaneous injection,
injection into a tumour mass, or intrapleural administration.

Dosage
Adults

1. Squamous cell carcinoma
   Intramuscular or intravenous injection: 10–15 x 10^6 IU/m² body surface area (BSA), once or twice weekly, at 3–4 week intervals, up to a cumulative lifetime dose of 360 x 10^6 IU.
   Intravenous infusion: 10–15 x 10^6 IU/m² BSA per day, administered over 6–24 hours for 4 to 7 consecutive days, repeated at 3–4 week intervals.

2. Hodgkin's disease and non-Hodgkin lymphomas
   Monotherapy: intramuscular or intravenous injection: 5–15 x 10^6 IU/m² BSA, once or twice weekly, up to a cumulative dose of 225 x 10^6 IU. Due to the risk of pseudoanaphylactic reactions, patients with lymphoma should initially receive small test doses (e.g. 2 x 10^6 IU) for the first two administrations. If no acute reactions occur within 4 hours of observation, standard dosing may be continued.

3. Testicular tumours
   Intramuscular or intravenous injection: 10–15 x 10^6 IU/m² BSA, once or twice weekly, at 3–4 week intervals, up to a total cumulative dose of 400 x 10^6 IU.
   Intravenous infusion: 10–15 x 10^6 IU/m² BSA per day, administered over 6–24 hours for 5–6 consecutive days, repeated at 3–4 week intervals.

4. Malignant pleural effusion
   60 x 10^6 IU in 100 ml of physiological saline solution, administered intrapleurally as a single dose, which may be repeated after 2–4 weeks depending on response.
   Since approximately 45% of bleomycin is absorbed systemically, this should be taken into account when determining the cumulative lifetime dose (considering body surface area, renal and pulmonary function).
   The occurrence of mucositis (stomatitis) is the most helpful indicator for assessing patient tolerance and determining maximum dose. The total cumulative dose should not exceed 400 x 10^6 IU (equivalent to 225 x 10^6 IU/m² BSA) in patients under 60 years of age due to increased risk of pulmonary toxicity across all indications. In patients with lymphoma, the total cumulative dose should not exceed 225 x 10^6 IU.

In Hodgkin's disease and testicular tumours, improvement occurs rapidly and may be evident within two weeks. If no improvement is observed by this time, it is unlikely to occur. Squamous cell carcinoma responds more slowly; in some cases, up to three weeks may pass before improvement becomes apparent.

Elderly patients (over 60 years of age)
The total dose of bleomycin in elderly patients should be reduced according to the table below:

Children and adolescents
There are insufficient data on the use of bleomycin in children and adolescents. Until more information becomes available, bleomycin should be used in this patient group only under exceptional circumstances and in specialized centers. If the drug is indicated as part of combination therapy, the dose is usually calculated based on body surface area and individually adjusted for each patient. Current specialized protocols and guidelines should be consulted to determine the appropriate treatment regimen.

Renal impairment
In patients with renal impairment, especially when creatinine clearance is <35 ml/min, bleomycin elimination is delayed. There are no specific guidelines for dose adjustment in these patients; however, it is recommended that patients with moderate renal impairment (GFR 10–50 ml/min) receive 75% of the usual dose at the usual dosing intervals, and patients with severe renal impairment (GFR below 10 ml/min) should receive 50% of the usual dose at the usual recommended intervals. Dose adjustment is not required in patients with GFR above 50 ml/min.

Combination therapy
When bleomycin is used in combination therapy, dose modification may be necessary. The dose of bleomycin should be reduced when administered concurrently with radiotherapy, as this increases the risk of mucosal damage. Dose modification may also be required when bleomycin is used in combination chemotherapy. Detailed information on treatment regimens used in specific indications can be found in current literature.

Method of administration and preparation of injection solution:
N.B.: The entire contents of the vial (15,000 IU) should be dissolved in an appropriate volume of solvent to prepare the solution. The required number of units for treatment is then withdrawn from this solution.

Pharmaceutical incompatibilities
Bleomycin must not be mixed with solutions of basic amino acids, riboflavin, ascorbic acid, dexamethasone, aminophylline, benzylpenicillin, carbenicillin, cephalothin, cefazolin, diazepam, furosemide, glutathione, hydrogen peroxide, sodium succinate hydrocortisone, methotrexate, mitomycin, nafcillin, penicillin G, substances containing sulfhydryl groups, terbutaline, and thiols.

Bleomycin forms chelating complexes with divalent and trivalent cations; therefore, it must not be mixed with solutions containing such ions (particularly copper).

Intramuscular injection
The vial contents should be dissolved in 1–5 ml of physiological saline. Since repeated intramuscular injections at the same site may cause local discomfort, the injection site should be rotated regularly. In case of significant local discomfort, a local anesthetic such as 1.5–2 ml of 1% lidocaine hydrochloride may be added to the injection solution.

Intravenous injection
The vial contents should be dissolved in 5–10 ml of physiological saline and administered slowly over 5–10 minutes. Rapid bolus injection should be avoided, as it leads to high drug concentrations in plasma within the pulmonary vessels, increasing the risk of lung damage.

Intravenous infusion
Dissolve the vial contents in 200–1000 ml of physiological saline.

Intra-arterial injection
Dissolve the bleomycin vial contents in at least 5 ml of physiological saline and administer over 5–10 minutes.

Intra-arterial infusion
Dissolve bleomycin in 200–1000 ml of physiological saline. The infusion may be administered over several hours to several days. Heparin may be added to prevent thrombosis at the injection site, particularly when the infusion is administered over a prolonged period.

Intra-arterial injection or infusion into the artery supplying the tumor usually demonstrates greater efficacy than other systemic routes of administration. Toxic effects are similar to those observed with intravenous injection or infusion.

Subcutaneous injection
Dissolve the vial contents in up to 5 ml of physiological saline. Absorption after subcutaneous injection is delayed and may resemble a slow intravenous infusion. This route of administration is rarely used. Care should be taken to avoid intradermal injection.

Intratumoral injection
Dissolve bleomycin in physiological saline to obtain a concentration of 1–3 x 10 IU/ml. The solution is injected directly into the tumor and surrounding tissue.

Intrapleural administration
After draining the pleural cavity, bleomycin is dissolved in 100 ml of physiological saline and administered through a puncture cannula or drainage catheter. The cannula or catheter is then removed. To ensure even distribution of bleomycin within the serous cavity, the patient's position should be changed every 5 minutes over a 20-minute period. Approximately 45% of bleomycin is absorbed; this should be taken into account when determining the total dose (body surface area, renal and pulmonary function).

Perivascular administration of bleomycin usually does not require any special measures. In case of doubt (e.g., highly concentrated solution, hardened tissues, etc.), perfusion with physiological saline solution may be performed.

After reconstitution/dilution, the chemical and physical stability of the drug has been demonstrated for 10 days when stored at 2°C to 8°C protected from light, and for 48 hours at room temperature. From a microbiological standpoint, the reconstituted/diluted medicinal product should be used immediately. If not used immediately, the responsibility for storage conditions and duration prior to use lies with the user and should not exceed the stability times indicated above.

For single use only. The prepared solution is clear and pale yellow. Unused solution must be discarded.

Special precautions for disposal and preparation of the medicinal product for use
General guidelines for safe handling of cytotoxic medicinal products must be observed. Appropriate precautions should be taken to avoid contact with skin, mucous membranes, and eyes. In case of contamination, contaminated areas should be thoroughly washed with water.

Protective clothing should be worn when handling urine produced within 72 hours after administration of bleomycin.

Information on overdose
There is no specific antidote. Removal of bleomycin from the body by dialysis is practically impossible. Acute overdose reaction includes hypotension, fever, tachycardia, and generalized shock. Treatment is purely symptomatic. In case of respiratory complications, the patient should be treated with corticosteroids and a broad-spectrum antibiotic. Pulmonary reaction to overdose (fibrosis) is usually irreversible unless diagnosed at an early stage.