Package Leaflet: Information for the patient

Doxorubicin Copharma2 mg/ml Concentrate for solution for infusion

_Doxorubicin Hydrochloride_

Read all of this leaflet carefully, before you receive this medicine.

•    Keep this leaflet. You may need to read it again.

•    If you have any further questions, please ask your doctor or your pharmacist.

•    This product has been prescribed for you personally. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.

•    If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

1.    What Doxorubicin Copharmais and what it is used for

2.    Before you receive Doxorubicin Martindale Pharma®

3.    How Doxorubicin Copharmais administered

4.    Possible side effects

5.    How to store Doxorubicin Martindale Pharma®

6.    Further information

1. What Doxorubicin Copharmais and what it is used for

Doxorubicin Copharma- the active substance of Doxorubicin hydrochloride - belongs to a group of medicines known as anthracyclines. These cytotoxic active substances are used to treat cancer, they work by killing tumour and leukaemia cells. Your doctor will be able to explain how doxorubicin might help in your particular condition.

Doxorubicin Copharmais used in the treatment of

-    leukaemias, a cancer that causes abnormal production of blood cells

-    lymphomas, a cancer affecting the immune system

-    myeloma, a cancer affecting the cells in your bone marrow known as plasma cells.

-    sarcomas, a cancer of the supporting tissues of the body (i.e.bone)

-    breast and lung cancers,

-    cancer of the bladder.

-    Advanced ovarian and endometrial cancer (a cancer of the lining of the uterus or of the uterus)

-    Malignant cancer of the kidneys tumour in children (Wilm's tumour)

-    Advanced neuroblastoma (a cancer of the nerve cells commonly found in

children)

-    Cancer develops within the stomach

-    Malignant renal tumour in children (Wilm's tumour)

-    Advanced neuroblastoma

-    Thyroid cancer

2. Before you receive Doxorubicin Copharma

You must not receive Doxorubicin Copharmain the following cases, please tell your doctor

• if you have ever had any hypersensitivity reaction to doxorubicin or any of the other ingredients of Doxorubicin Copharmaor to other anthracyclines.

•    if you have been told that your blood is thin (your bone marrow is not working well).

•    if you have or ever have had any heart problems.

•    if you have received doxorubicin or other anthracyclines, other anti-tumour drugs or immunosuppressive drugs before.

•    if you tend to bleed easily.

•    if you suffer from any kind of infections.

•    if you suffer from mouth ulcers.

•    if your liver is not working well.

•    if you suffer from cystitis (inflammation of the bladder) or if you have blood in your urine- (in case the medicine is given to you by an administration into your bladder).

Take special care with Doxorubicin Copharmaand tell your doctor

•    if you have had any radiotherapy before.

•    if you are pregnant, trying to become pregnant, likely to want to try to become pregnant in the future or if you want to father a child.

•    if you are breast-feeding.

•    if you are on a controlled sodium diet.

Doxorubicin Copharmashould be administered only under the supervision of a qualified physician experienced in therapy toxic to cells. Also, patients must be carefully and frequently monitored.

A burning sensation in the area of the infusion may be a sign of an injection error and the infusion must be stopped immediately.

Using other medicines

Please inform your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

The following medications can interact with Doxorubicin Copharma2 mg/ml concentrate for solution for infusion :

•    Other cytostatics (medication against cancer) e.g. anthracyclines. cyclophosphamide, cytarabine, cisplatin, fluorouracil, taxanes (e.g. paclitaxel), mercaptopurine,methotrexate, streptozocin

•    Ciclosporin (used in organ and tissue transplants)

•    Cardioactive drugs (medications for heart diseases), e.g. calcium channel blockers, digoxin

•    Cimetidine (used in the treatment of heartburn and stomach ulcers)

•    Live vaccines (e.g. polio(myelities), malaria)

•    Phenobarbital and other barbiturate ( used in the treatment of epilepsia )

•    Amphotericin ( medication for fungal infections )

•    Trastuzumab ( used in the treatment of breast cancer )

•    Ritonavir (used to treat HIV)

•    Clozapine (an antipsychotic)

•    Sulphonamides or other diuretics

Please note that these statements may also apply to products used some time ago or at some time in the future.

Pregnancy and breast-feeding

It is known that doxorubicin passes the placenta and harms the unborn in animal experiments. Therefore doxorubicin must not be administered if you are pregnant.

The drug also concentrates in human milk. Your doctor will decide whether nursing or the drug should be discontinued.

Women must not get pregnant during the treatment with Doxorubicin Martindale Pharma®. If you get pregnant during treatment with Doxorubicin Martindale Pharma®, please inform your doctor immediately.

During the treatment and until 6 months after the treatment was stopped you should practice effective contraception regardless of whether the male or the female partner took Doxorubicin Martindale Pharma®.

For safety reasons, men wanting a baby should preserve unexposed sperm prior to treatment with Doxorubicin hydrochloride.

Ask you doctor for advice before taking any medicine.

Driving and using machines

Due to the frequent occurrence of drowsiness, nausea and vomiting, you are not advised to drive cars and operate machinery.

Important information about some of the ingredients of Doxorubicin Martindale Pharma®

Please tell your doctor if you are on low-sodium diet. He/she will take into account that 1 ml of Doxorubicin Copharmacontains 3.5 mg sodium.

3. How Doxorubicin Copharmais administered

Dilute before use.

Method and routes of administration

Do not administer the medicine yourself. Your medicine will be given to you by intravenous infusion, into a blood vessel, under the direction of specialists. You will be monitored regularly both during and after your treatment.

If you suffer from superficial bladder cancer it is possible that you may receive your medicine into your bladder (intravesical use).

Dosage

The dosage is usually calculated on the basis of your body surface area. 60 - 75 mg per square metre of body surface area may be given every three weeks when used alone. The dosage may need to be reduced to 30 - 60 mg per square metre of body surface area and the treatment interval prolonged when given in combination with other anti-tumour drugs. If given weekly the recommended dose is 15 - 20 mg per square metre of body surface area.

Your doctor will advise you of how much you will need.

The dosage for intravescical administration is 30-50 mg in 25-50 ml of physiological saline. The solution should remain in the bladder for 1-2 hours. During this period the patient should be turned 90^o every 15 minutes. To avoid undesired dilution with urine the patient should be informed not to drink anything for a period of 12 hours before the instillation. The instillation may be repeated with an interval of 1 week to 1 month. Your doctor will advise you of how often you need it.

Patients with reduced liver and renal function

If your liver or kidney function is reduced, the dosage should be decreased. Your doctor will advise you of how much you need.

Children/Elderly or patients after radiotherapy

The dosage may need to be reduced in children and the elderly or if you have received any radiotherapy.

Your doctor will advise you of how much you need.

Patients with bone marrow suppression

The dosage may need to be reduced in patients with bone marrow suppression. Your doctor will advise you of how much you need.

Obese patients

The starting dose may be reduced in obese patients or the dose interval may be prolonged. Your doctor will advise you of how much you need and how often.

If you take more Doxorubicin Copharmathan you should

Acute overdosing worsens side effects like sores in the mouth, decreases the number of white blood cells and platelets in the blood and can lead to cardiac problems. Treatment will include administration of antibiotics, transfusions of granulocytes and thrombocytes, and treatment of mouth sores and heart effects. Cardiac disorders may occur up to six months after the overdosage.

4. Possible Side Effects

Like all medicines Doxorubicin Copharmacan cause side effects, although not everybody gets them.

Please contact your doctor or nurse immediately if you notice any of the following side effects:

•    Feeling dizzy, feverish, short of breath with a tight chest or throat or have an itchy rash. This type of allergic reaction can be very serious.

•    Anaemia (a low red blood cell count) that can leave you feeling tired and lethargic.

•    White blood cell counts (which fight infection) can also drop, increasing the chance of infections and a raised temperature (fever).

•    Platelets (these are cells that help the blood to clot) can be affected which could make you bruise or bleed more easily. It is important to seek medical advice if this happens. Your doctor should test your blood cell count during treatment.

•    Doxorubicin may cause decreased activity in your bone marrow

Doxorubicin Copharmamay cause a red colouration of the urine for one or two days after administration. This is normal and nothing to worry about.

Frequency:

Very common (more than 1 in 10 patients)

Common (more than 1 in 100 patients, but less than 1 in 10 patients)

Uncommon (more than 1 in 1,000 patients, but less than 1 in 100 patients) Rare (more than 1 in 10,000 patients, but less than 1 in 1,000 patients) Very rare (less than 1 in 10,000 patients)

Not known (cannot be estimated from the available data)

Common	•    cardiomyopathy (heart muscle disease) •    ECG (electrocardiogram) changes •    bone-marrow suppression (deficiency in blood cells causing infection and bleeding) •    nausea (feeling sick) •    vomiting (being sick) •    mucositis (inflammation of membranes in digestive tract) •    anorexia (eating disorder) •    diarrhoea - may result in dehydration •    chemical cystitis ((bladder inflammation) sometimes haemorrhagic (with blood in the urine) following administration into the bladder •    alopecia (hair loss) normally reversible •    sepsis ( bacterial infection ) •    septiciaemia ( bacterial infection of blood )
Uncommon	•    ulceration and necrosis (death of cells/tissues) of the colon (intestine) in combination with cytarabine. •    phlebitis •    gastrointestinal bleeding •    abdominal pain •    local hypersensitivity reaction of the field of radiation •    dehydration
Rare	•    secondary leukaemia ( blood cancer developed after treatment for another cancer ) when in combination with anti-neoplastic drugs which damage the DNA. •    tumor lysis syndrome ( complications of having chemotherapy ) •    conjunctivitis (inflammation of the outermost layer of the eye) •    urticaria (hives) •    exanthema (type of rash) •    erythematous reactions (rash-like symptoms) along the vein used for the injection •    hyperpigmentation (darkened areas) of skin and nails •    onycholysis (loosening of the nails) •    anaphylactic reactions (severe allergic reactions with or without shock including skin rash, pruritis (itching), fever and chills) •    shivering •    fever •    dizziness
Not known	•    thrombophlebitis ( vein inflammation under the skin ) •    thromboembolism ( clot formed in a blood vessel ) •    arrhythmia ( irregular heartbeat ) •    heart failure ( loss of cardiac function ) •    acute renal failure ( loss of renal function ) •    hyperuricaemia ( high uric acid level in blood ) •    bronchospasm ( coughing or difficulty in breathing because of narrowing sudden of airways ) •    pneumonitis ( inflammation of lung tissue )

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

5.    How to store Doxorubicin Copharma

Keep out of the reach and sight of children.

Do not use Doxorubicin Copharmaafter the expiry date which is stated on the label and carton. The expiry date refers to the last day of that month.

Store the unopened vials in a refrigerator (2-8°C). Keep the container in the outer carton in order to protect from light.

The product should be used immediately after opening the vial.

For Single Dose Use Only. Any unused solution should be discarded immediately after initial use.

Do not use Doxorubicin Copharmaif you notice that the solution is not clear, red and practically free of particles.

Medicines should not be disposed of via wastewater or household waste in order to protect the environment.

6.    Further information

What Doxorubicin hydrochloride contains

Doxorubicin Martindale Pharma 2 mg/mL is a concentrate for solution for infusion containing doxorubicin hydrochloride, which is the active substance.

The other ingredients are sodium chloride, hydrochloric acid (for pH adjustment) and water for injections.

What Doxorubicin Copharmalooks like and contents of the pack

Doxorubicin Copharma2 mg/ml Concentrate for solution for infusion is a clear, red

solution which is practically free of particles.

•    Each    5    ml    vial    of    Doxorubicin    Copharmacontains    10    mg    of    doxorubicin

hydrochloride

•    Each    10    ml    vial    of    Doxorubicin    Copharmacontains    20    mg    of    doxorubicin

hydrochloride

•    Each    25    ml    vial    of    Doxorubicin    Copharmacontains    50    mg    of    doxorubicin

hydrochloride

•    Each    75    ml    vial    of    Doxorubicin    Copharmacontains    150    mg    of    doxorubicin

hydrochloride

•    Each 100 ml vial of Doxorubicin Copharmacontains 200 mg of doxorubicin hydrochloride

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

Marketing Authorisation Holder:    Manufacturer:

COPHARMA ApS    Oncotec Pharma J^gersborg

Alle 164DK-2820 Gentofte    Am Pharmapark

DK-2820 Gentofte    D-06861 Dessau-Roplau

Germany

This leaflet was approved in .

This medicinal product is authorised in the Member States of the EEA under the following names:

Denmark	Doxorubicin ”Copharma”
Finland	Doxorubicin Copharma 2 mg/ml infuusiokonsentraatti, liuosta varten
Norway	Doxorubicin Copharma 2mg/ml Infusjonsv^ske
United Kingdom	Doxorubicin COPHARMA 2 mg/ml Concentrate for solution for infusion
Sweden	Doxorubicin Copharma, 2mg/ml koncentrat till infusionsvatska, losning

Technical Prescribing Information

Doxorubicin Copharma2 mg/ml Concentrate for solution for infusion

The following information is intended for medical or healthcare professionals only:

Doxorubicin Copharmamay be further diluted in Sodium Chloride 0.9% or Glucose 5% and administered as an intravenous infusion. The infusion solution should be prepared immediately before use.

The injection solution contains no preservative and any unused portion of the vial should be discarded immediately.

Incompatibilities

Contact with any solution of an alkaline pH should be avoided as it will result in hydrolysis of the drug. Doxorubicin should not be mixed with heparin and 5-fluorouracil since a precipitate may form, and it is not recommended that doxorubicin be mixed with other drugs until specific compatibility data are available.

In use stability

Chemical and physical in-use stability has been demonstrated in Sodium Chloride 0.9 % or Glucose 5 % for up to 48 hours at 2 - 8°C and for up to 24 hours at 25°C when prepared in PVC infusion bags and polypropylene syringes protected from light.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Guidelines for the safe handling and disposal of cytotoxic agents

For single use only.

Observe guidelines for handling cytotoxic drugs.

The following protective recommendations are given due to the toxic nature of this substance:

-    Personnel should be trained in good technique for handling.

-    Pregnant staff should be excluded from working with this drug.

-    Personnel handling doxorubicin should wear protective clothing: goggles, gowns and disposable gloves and masks.

-    All items used for administration or cleaning, including gloves, should be placed in high risk waste disposal bags for high temperature (700°C) incineration.

Accidental contact with the skin should be treated immediately by copious lavage with water or soap and water. In an accidental contact, the eyes should be rinsed copiously with water or sodium bicarbonate solution. Medical attention should be sought.

Spillage or leakage should be treated with dilute sodium hypochlorite (1 % available chlorine) solution, preferably soaking overnight and then rinse with water.

All cleaning materials should be disposed of as indicated previously.