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Document: leaflet MAH GENERIC_PL 30306-0352 change

• leaflet MAH GENERIC_PL 20075-0109
• leaflet MAH GENERIC_PL 30306-0352

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10 mm

Doxorubicin 2mg/ml Concentrate for Solution for Infusion

Doxorubicin hydrochloride

Read all of this leaflet carefully before you

start using this medicine.

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

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

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

•    The full name of this medicine is Doxorubicin 2mg/ml Concentrate for Solution for Infusion but within the leaflet it will be referred to as Doxorubicin.

Doxorubicin is also used in combination with other anti-cancer drugs.

2) Before you receive

You must not receive Doxorubicin if you are

•    allergic (hypersensitive) to doxorubicin or any of the other ingredients of

Doxorubicin

•    allergic to drugs of the class anthracyclines or anthracendiones

•    breastfeeding.

Please talk to your doctor in case any of the above applies to you.

You must not receive Doxorubicin intravenously if you

•    have been told after previous cancer therapy that you had persistent decrease in the production of blood cells (your bone marrow was not working well)

Vaccination is not recommended. Contact to persons recently vaccinated against polio should be avoided.

Doxorubicin should be administered only under the supervision of a qualified physician experienced in cancer therapy. Also, patients must be carefully and frequently monitored e.g. blood status and function test of the heart, liver and kidney.

Ifyou feel a stinging or burning sensation in the area of the infusion tell your doctor or other health care personnel immediately. Such a pain can occur if the medicine leaks out of the vein and then you will need an appropriate therapy.

Using other medicines

Please tell your doctor ifyou are taking or have recently taken any other medicines, including medicines obtained without a prescription. This is especially important in case of:

•    other medication against cancer e.g. anthracyclines (daunorubicin, epirubicin, idarubicin, trastuzumab), cyclophosphamide, cytarabine, cisplatin, fluorouracil, taxanes (e.g. paclitaxel), mercaptopurine, methotrexate, streptozocin

•    ciclosporin (used in organ and tissue transplants)

•    medications for heart diseases (cardioactive drugs) e.g. calcium channel blockers and digoxin

•    medicines that lower uric acid level in your blood

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

•    live vaccines (e.g. polio (myelitis))

•    phenytoin, phenobarbital and other barbiturate (used in the treatment of epilepsy)

•    chloramphenicol and sulfonamides (medicines for infections)

•    amphotericin B (medication for fungal infections)

•    medicines for viral infections, such as ritonavir (used to treat HIV)

•    clozapine (an antipsychotic)

•    amidopyrine derivates (for pain and inflammation).

Pregnancy and breastfeeding

Ask your doctor or pharmacist for advice before taking any medicines.

It is known that doxorubicin passes the placenta and harms the unborn in animal experiments. Therefore you should not receive doxorubicin if you are pregnant. Tell your doctor immediately if you are pregnant or think you are pregnant.

Women should not get pregnant during the treatment with Doxorubicin or up to 6 months after treatment. Men should take adequate precautions to ensure that their partner does not become pregnant during the treatment with doxorubicin and up to 6 months after the treatment. Sexually active men and women should therefore use effective contraceptive method during and up to 6 months after treatment.

Men should also seek advice on cryo-conservation (or cryo-preservation) of sperm prior to treatment because of the possibility of irreversible infertility due

•    had after previous cancer therapy severe inflammation or ulcers in the mouth

•    have some heart problems

•    tend to bleed easily

•    suffer from any kind of general infections

•    have a liver that is not working well

•    have previously received doxorubicin or other anthracyclines up to the maximal cumulative dose.

Please talk to your doctor in case any of the above applies to you.

You must not receive Doxorubicin in the bladder if you

•    have a tumour that has grown into the bladder wall

•    have urinary tract infection

•    have inflammation of the bladder

•    have blood in the urine

•    have problems with the instillation (e.g. urethral obstructions).

Please talk to your doctor in case any of the above applies to you.

Take special care with Doxorubicin and tell your doctor before treatment if you

•    are or might be pregnant, see also section on pregnancy and breastfeeding below

•    have had any radiotherapy before

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

•    have kidney problems

•    have or ever have had any heart problems.

Doxorubicin strongly reduces blood cell production in the bone marrow. This may make you more prone to infections or bleeding. Tell your doctor in case of fever or other sign of infection or in case of bleeding.

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to therapy with doxorubicin. Ifyou are considering becoming parents after the treatment please discuss this with your doctor.

The drug passes into human breast milk. Do not breastfeed while you are treated with Doxorubicin.

Driving and using machines

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

Important information about some of the ingredients of Doxorubicin

This medicinal product contains 354mg (<1mmol) sodium per ml concentrate.

This should be taken into consideration by patients on a controlled sodium diet.

31 How Doxorubicin is administered

Doxorubicin should only be given under supervision of a doctor with experience in cancer therapy.

Method and routes of administration

Your medicine will be given to you by intravenous infusion, into a blood vessel, under the direction of a specialist. Do not administer the medicine yourself. 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.

This medicinal product should be diluted before use.

Intravenous administration

The dosage is usually calculated on the basis of the body surface area. Doxorubicin may be given e.g. once a week, every

Continued over page

Doxorubicin is a potent cytotoxic agent which should only be prescribed, prepared and administered by professionals who have been trained in the safe use of the preparation. For recommendation on posology and method of administration see section 4.2 of the SPC for this medicinal product. The following guidelines should be followed when handling, preparing and disposing of doxorubicin.

For single use only.

Preparation

1.    Cytotoxic agents should be prepared for administration only by personnel who have been trained in the safe handling of such preparations. Refer to local cytotoxic guidelines before commencing.

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

3.    Personnel handling doxorubicin should wear protective clothing; goggles, gowns, disposable gloves and masks.

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

5.    All cleaning materials should be disposed of as indicated previously.

6. Always wash hands after removing gloves.

Do not use Doxorubicin 2mg/ml

Concentrate for Solution for Infusion if the

solution is not clear, red and free of particles.

Contamination

1.    In case of contact with skin or mucous membrane, thoroughly wash the affected area with soap and water or sodium bicarbonate solution. However, do not graze the skin by using a scrubbing brush. A bland cream may be used to treat transient stinging of skin.

2.    In case ofcontact with eye(s), hold back the eyelid(s) and flush the affected eye(s) with copious amounts of water for at least 15 minutes or normal sodium chloride 9 mg/ml (0.9%) solution for injection. Seek medical evaluation by a physician or eye specialist.

3.    In the event of spillage or leakage treat with 1% sodium hypochlorite solution or phosphate buffer (pH>8) until solution

is decoloured. Use a cloth/sponge kept in the designated area. Rinse twice with water. Put all cloths into a plastic bag and seal for incineration.

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three weeks or even with longer intervals between. The dose and frequency also depends on other anti-cancer medicines used, in addition to the type of disease and your general health. Your doctor will decide about the dose you will receive.

Instillation in the bladder

The dosage is 30-50mg doxorubicin in 25-50ml of physiological saline. The solution should remain in the bladder for 1-2 hours. During this period you need to turn about 90° every 15 minutes.

You should not drink anything for 12 hours before instillation in the bladder, to avoid undesired dilution of the medicine with urine. 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.

If you use more Doxorubicin than you should

As a doctor will be giving you your medicine, it is unlikely that you will receive an overdose.

However, if you have concerns you should let your doctor or nurse know immediately. 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 heart problems.

In case of overdose you should receive appropriate treatment as your doctor will decide. Heart disorders may occur up to six months after an overdose.

If you missed a dose of Doxorubicin

Your doctor will decide on the duration of your treatment with Doxorubicin. If the treatment is stopped before the advised courses of treatment is finished, the effects of the doxorubicin therapy might be reduced. Ask your doctor for advice if you wish to stop the treatment.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4| Possible side effects

•    severe allergic reactions with or without shock, including skin rash, itching, fever and chills (anaphylactic reactions)

•    shivering

•    dizziness

•    secondary leukaemia (blood cancer developed after treatment for another cancer ), when Doxorubicin is used in combination with other anticancer drugs which damage the DNA

•    tumour lysis syndrome (complications of having chemotherapy due to breakdown products of dying cancer cells which for example can affect the blood and kidneys)

•    injection site reactions including redness, rash and pain, inflammation of the vein (phlebitis), thickening or hardening of the wall of the vein (flebosclerose)

•    a stinging or burning sensation at the administration site in relation to the medicine leaking out of the vein. This can lead to death of local tissue cells and needs appropriate treatment, in some cases surgical measures.

Very rare side effects (less than 1 in 10,000

patients)

•    flushing of the face

•    changes in the heart function (unspecified ECG changes), isolated cases of life-threatening irregular heart beat (arrhythmias), heart failure, inflammation of the pericardium / myocardium, loss of nerve impulses in the heart

•    clot formation in a blood vessel

•    discoloration (pigmentation) of the oral mucosa

•    swelling and numbness of the hands and feet (acral erythema), blistering, tissue damage especially of the hands and feet, causing redness, swelling, blisters, tingling or burning sensation where leakage of the drug in the tissues occur (palmarplantar erythrodysesthesia syndrome)

•    acute kidney failure

•    abnormally high uric acid levels in the blood

•    absence of menstrual period

•    fertility problems in men (reduction or absence of active sperm).

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

Please contact your doctor or nurse immediately in case:

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

•    you feel tired and lethargic. This may be sign of anemia (a low red blood cell count)

•    you have fever or other symptoms of

infection. This may be sign of low white blood cell counts

•    you bruise or bleed more easily. This may be sign of low platelet count in your blood.

Very common side effects (more than 1 in 10 patients)

•    feeling sick, being sick, abdominal pain, digestive disorders, diarrhoea

•    inflammation of the mucous membranes e.g. in the mouth or esophagus

•    hair loss (normally reversible), skin redness, sensitivity of skin to artificial or natural light (photosensitivity)

•    red colouration of the urine, for one or two days after administration. This is normal and nothing to worry about

•    bone-marrow suppression (deficiency in blood cells) including reduction in number ofwhite blood cells (causing infection), blood platelets (causing bleeding and bruises) and red blood cells (anaemia; so the skin can be pale and weakness may occur, or shortness of breath)

•    severe heart complications (cardiotoxicity), like damage to the heart muscle or fast, slow or irregular pulse. Effects can appear shortly after the treatment is started or be observed several years later

•    fever.

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

•    bacterial infection

•    bacterial infection in the blood

•    cardiac arrhythmias (irregular heart beat, rapid heart rate, decreased heart rate), reduced amount of blood pumped through the heart, deterioration of

the function of the heart muscle (cardiomyopathy) that can be life threatening

•    bleeding (haemorrhage)

•    eating disorder (anorexia)

•    local allergic reaction of the field of radiation

•    itching

•    difficult or painful urination, bladder inflammation following instillation in the bladder, sometimes with irritation in the bladder, blood in the urine, painful urination, more frequent urination or decreased urine.

Uncommon side effects (more than 1 in 1,000 patients, but less than 1 in 100 patients)

•    acute blood cancer (certain types of leukaemia)

•    inflammation of a vein

•    bleeding in the stomach or intestines

•    ulcers in the mucous membranes of the mouth, pharynx, esophagus, stomach and the intestines

•    ulcers and possible death of cells/tissues of the colon when Doxorubicin is given in combination with the medicinal product cytarabine

•    dehydration.

Rare side effects (more than 1 in 10,000 patients, but less than 1 in 1,000 patients)

•    inflammation of the outermost layer of the eye (conjunctivitis)

•    hives; skin rash and redness

•    darkened areas of skin and nails; loosening of the nails (onycholysis)

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Side effects where frequency is not known (cannot be estimated from the available data)

•    increased tear production

•    coughing or difficulty in breathing because of sudden narrowing of airways

•    lung inflammation

•    liver toxicity, which sometimes can progress to permanent damage of liver tissue (cirrhosis)

•    transient increase of liver enzymes

•    fat, bald or crusty patches of skin (actinin keratosis)

•    severe pain and swelling in the joints

•    weakness

•    radiation damage (on the skin, lungs, throat, esophagus, stomach and intestinal mucosa, heart) already healing, may reappear following administration of doxorubicin.

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

Keep out of the reach and sight of children. Do not use Doxorubicin after the expiry date which is stated on the vial and outer carton. The expiry date refers to the last day of that month.

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

Do not use Doxorubicin ifyou notice the solution is not clear, red and free of particles. Any unused product or waste material should be disposed of in accordance with local requirements. Observe guidelines for handling cytotoxic drugs.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

ft Further information

What Doxorubicin contains

•    The active substance is doxorubicin hydrochloride. Each vial contains 2mg/ml doxorubicin hydrochloride.

•    The other ingredients are sodium chloride, hydrochloric acid and water for injections.

What Doxorubicin looks like and contents of the pack

Doxorubicin 2mg/ml Concentrate for Solution for Infusion is a clear red solution. Doxorubicin is packed in colourless glass vial with rubber stopper and sealed with aluminium cap with polypropylene disk.

Pack sizes:

1 x 5ml vial 10 x 5ml vials 1 x 10ml vial 10 x 10ml vials 1 x 25ml vial 1 x 50ml vial

Marketing Authorisation Holder

Actavis Group PTC ehf. Reykjavikurvegur 76-78 220 Hafnarfjordur Iceland

Manufacturer

Actavis Italy S.p.A Via Pasteur 10 20014 Nerviano (Milan)

Italy

This leaflet was last revised in June 2013

v actavis

Actavis, Barnstaple, EX32 8NS, UK Actavis Ireland, Euro Hs, Little Island, Cork

In use stability

Opened vials: Chemical and physical inuse stability has been demonstrated for 28 days at 2-8°C. From a microbiological point of view, unless the method of opening precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Prepared infusion solutions: Chemical and physical stability after dilution has been demonstrated at 2°C to 8°C and 25°C, protected from light for:

•    24 hours in 5% glucose solution in PP bottle to the concentrations of 1.25mg/ ml and 0.5mg/ml

•    48 hours in 0.9% sodium chloride solution in PE bottle to the concentrations of 1.25mg/ml and 0.5mg/ ml.

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 condition.

Storage times of the opened vial and diluted infusion solution are not additive.

Disposal

Any unused product or waste material should be disposed of in accordance with local requirements. Observe guidelines for handling cytotoxic drugs.

Note:

Posology of S-liposomal doxorubicin and (conventional) doxorubicin as in Doxorubicin 2mg/ml Concentrate for Solution for Infusion are different.

The two formulations cannot be used interchangeably.

Incompatibilities

Doxorubicin should not be mixed with heparin, as a precipitate may form and it should not be mixed with 5-fluorouracil as degradation may occur. Prolonged contact with any solution of an alkaline pH should be avoided as it will result in hydrolysis of the drug.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

^actavis

Actavis, Barnstaple, EX32 8NS, UK Actavis Ireland, Euro Hs, Little Island, Cork