Consumer medicine information

Doxorubicin Accord

Doxorubicin hydrochloride

BRAND INFORMATION

Brand name

Doxorubicin Accord

Active ingredient

Doxorubicin hydrochloride

Schedule

SUMMARY CMI

DOXORUBICIN ACCORD

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I being given Doxorubicin Accord?

Doxorubicin Accord contains the active ingredient doxorubicin hydrochloride. Doxorubicin Accord is used to treat many types of cancer. It works by stopping cancer cells from growing and multiplying.

For more information, see Section 1. Why am I using Doxorubicin Accord? in the full CMI.

2. What should I know before I am given Doxorubicin Accord?

Do not use if you have ever had an allergic reaction to doxorubicin and/or other anthracyclines or anthracenediones (e.g. daunorubicin, epirubicin, mitozantrone) or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I am given Doxorubicin Accord? in the full CMI.

3. What if I am taking other medicines?

Some medicines and Doxorubicin may interfere with each other and may affect how well each medicine works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How will I be given Doxorubicin Accord?

Doxorubicin Accord will be given to you by a doctor or a nurse by slow infusion into a vein or the bladder.

More instructions can be found in Section 4. How will I be given Doxorubicin Accord? in the full CMI.

5. What should I know while being given Doxorubicin Accord?

Things you should do	Be sure to keep all your doctor's appointments. Tell your doctor if you have any heart or liver problem. Use an effective method of birth control while you are being treated with Doxorubicin; for women for childbearing potential at least 6 months and 10 days after last dose, for men with female partners of childbearing potential for at least 3 months and 10 days after last dose. Tell your doctor immediately if you become pregnant while you are being given Doxorubicin Accord.
Things you should not do	Do not breast-feed if you are being treated with Doxorubicin Accord.
Driving or using machines	Be careful driving or operating machinery until you know how Doxorubicin Accord affects you.

For more information, see Section 5. What should I know while being given Doxorubicin Accord? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

Some serious side effects are:

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, light-headedness or back pain
swelling and redness of skin along the vein in which Doxorubicin Accord is injected
infections, fever, sweats, severe chills, bruising more easily than normal
fatigue, chest pain, palpitations, shortness of breath or swelling in the feet or legs due to fluid build-up. Doxorubicin Accord may also affect heart muscle and function. Your doctor will monitor your heart regularly before, during and after treatment.
bleeding or ulceration of the bowel
blood poisoning
kidney problems
blockage of a blood vessel caused by a clot
leukaemia

Other side effects not listed above may occur in some patients. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

DOXORUBICIN ACCORD

Active ingredient(s): Doxorubicin hydrochloride

Consumer Medicine Information (CMI)

This leaflet provides important information about using Doxorubicin Accord. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Doxorubicin Accord.

Where to find information in this leaflet:

1. Why am I being given Doxorubicin Accord?
2. What should I know before I am given Doxorubicin Accord?
3. What if I am taking other medicines?
4. How will I be given Doxorubicin Accord?
5. What should I know while being given Doxorubicin Accord?
6. Are there any side effects?
7. Product details

1. Why am I being given Doxorubicin Accord?

Doxorubicin Accord contains the active ingredient doxorubicin hydrochloride. It is used to treat many types of cancer. Doxorubicin Accord works by stopping cancer cells from growing and multiplying.

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

2. What should I know before I am given Doxorubicin Accord?

Warnings

You must not be given Doxorubicin Accord if:

you are allergic to doxorubicin and/or other anthracyclines or anthracenediones e.g. daunorubicin, epirubicin, mitozantrone, or any of the ingredients listed at the end of the CMI
you have bone marrow suppression (reduced number of red or white blood cells or platelets) caused by previous treatment with other cancer medicines or radiation therapy, symptoms include tiredness, mouth ulcers or bleeding or bruising more easily than usual
you have a generalised infection
you have an irregular heart rate, poor blood flow to the heart or had a heart attack
you have severe liver problems
you have previously received treatment with the maximum dose of doxorubicin, daunorubicin or epirubicin
you are pregnant or likely to become pregnant, as it may harm your developing baby
you are breastfeeding, as it passes into breast milk and may affect your child

You must not be given Doxorubicin Accord infusion into the bladder if you have:

a tumour of the bladder wall
a urinary infection
bladder inflammation
a catheter in the bladder
blood in your urine

Before you are given Doxorubicin Accord

Tell your doctor if you have any heart or liver problems.

You will be given a blood test and your heart will be monitored before you start treatment with Doxorubicin Accord.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

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

Men and women should use a reliable method of contraception (birth control).

Women of childbearing potential are advised to avoid becoming pregnant during treatment and to use effective contraceptive methods during treatment and for at least 6 months and 10 days after last dose.

Men with female partners of childbearing potential are advised to use effective contraception during treatment with doxorubicin and for at least 3 months and 10 days after last dose.

If you become pregnant while on treatment with Doxorubicin Accord, consult your doctor.

Nursing mothers are advised not to breastfeed while receiving Doxorubicin and for at least 10 days after last dose.

3. What if I am taking other medicines?

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

Some medicines and Doxorubicin Accord may interfere with each other. These include:

other cancer medicines, such as cyclophosphamide, paclitaxel, 6-mercaptopurine, sorafenib
some medicines used to prevent blood clots, such as heparin
propranolol and other medicines for your heart.
inactivated vaccines
verapamil used for high blood pressure, angina or irregular heart beat
phenobarbitone and phenytoin used to treat epilepsy
St. John's Wort, a herbal supplement, used for mild anxiety and low mood
cyclosporin used in transplant patients to prevent organ rejection

These medicines may be affected by Doxorubicin Accord, or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

Doxorubicin Accord given at the same time as radiation therapy may also cause unwanted effects.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Doxorubicin Accord.

Your doctor has more information on medicines to be careful with or avoid while using Doxorubicin Accord.

4. How will I be given Doxorubicin Accord?

How much will be given

Your doctor will decide what dose you will receive. This depends on your condition and other factors, such as your weight, liver function and the effect on your bone marrow of any previous treatment you may have had with x-ray or chemotherapy medicines.

Treatment is usually given once every 3 weeks, or on 3 successive days repeated every 4 weeks.

However, your doctor may give Doxorubicin Accord more or less frequently.

You will be given a blood test and your heart will be monitored before you start treatment with Doxorubicin Accord.

How it is given

Doxorubicin Accord is given by slow infusion into a vein or the bladder. If it is infused into the bladder, you will be asked not to urinate for one hour while Doxorubicin Accord is given.

If you receive too much Doxorubicin Accord

Since Doxorubicin Accord is usually given to you in hospital under the supervision of your doctor or nurse, it is very unlikely that you will be given too much of the medicine. If you think that you have been given too much Doxorubicin Accord.

You should immediately:

contact your doctor or nurse
phone the Poisons Information Centre (by calling 13 11 26)

5. What should I know while being given Doxorubicin Accord?

Things you must do

Keep all of your doctor's appointments so your progress can be checked.

It is also important to inform your doctor if you have any infection or fever before, during or after treatment with Doxorubicin Accord, as it will lower your ability to fight infection.

Tell your doctor or nurse immediately if stinging, burning or pain develops at the injection site.

Tell any other doctors, dentists, and pharmacists who treat you that you are being given Doxorubicin Accord.

Doxorubicin Accord is known to be very powerful at lowering 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.

Take the following precautions to reduce your risk of infection or bleeding:

Avoid people who have 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, toothpick or dental floss. 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
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 you may bruise or get injured.
Avoid vaccination with certain vaccines. Your doctor or pharmacist will tell you what vaccines to avoid

Your doctor will monitor the effects of Doxorubicin Accord on your blood, liver and heart regularly by giving you tests.

If you become pregnant while you are being given Doxorubicin Accord, tell your doctor immediately.

Driving or using machines

Be careful driving or operating machinery or doing jobs that require you to be alert until you know how Doxorubicin Accord affects you.

Looking after your medicine

The hospital will store Doxorubicin Accord under the correct conditions.

Getting rid of any unwanted medicine

Your doctor or pharmacist will dispose of any Doxorubicin Accord that may be left over.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

Tell your doctor or nurse as soon as possible if you do not feel well while Doxorubicin Accord is being given to you.

Common side effects

Common side effects

What to do

nausea and vomiting. This may be expected 3-6 hours after Doxorubicin Accord is given and may last for several hours
diarrhoea, dehydration, flushing of the face, abdominal pain
loss of appetite may be expected for 24 hours following each treatment with Doxorubicin Accord. This may occasionally last for several days
Doxorubicin Accord may colour your urine red for 1-2 days after treatment. This is no cause for alarm
a burning sensation in the mouth, throat, food pipe, rectum or vagina may occur usually 5 to 10 days after treatment with Doxorubicin Accord. This pain will normally subside within 10 days
hair loss is expected 1 to 2 weeks after beginning treatment with Doxorubicin Accord. You may lose all your hair, but after treatment is stopped, your hair is expected to grow back. Male patients may notice lack of beard growth during treatment
skin infections, blisters, itchy skin
bleeding or easy bruising
permanent darkening of areas on the skin, nail beds, and the inside of the mouth
discharge with itching of the eyes and crusty eyelids, dry eyes
excess tears
redness or pins and needles on the palms of your hands and soles of your feet
drowsiness, unusual tiredness, weakness, feeling unwell, hot flushes, shock
painful swelling of joints (gout)
weight gain.
infertility in both men and women
women may stop menstruating.
Regular menstruation usually returns a few months after treatment is stopped in premenopausal women, although premature menopause can occur.
men may permanently experience a low sperm count or remain infertile. Sometimes male fertility may return several years after stopping Doxorubicin Accord therapy

Speak to your doctor if you have any of these common side effects and they worry you

Serious side effects

Serious side effects

What to do

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, light-headedness or back pain
swelling and redness of skin along the vein in which Doxorubicin Accord is injected
infections, fever, sweats, severe chills, bruising more easily than normal
fatigue, chest pain, palpitations, shortness of breath or swelling in the feet or legs due to fluid build-up. Doxorubicin Accord may also affect heart muscle and function. Your doctor will monitor your heart regularly before, during and after treatment.
bleeding or ulceration of the bowel
blood poisoning
kidney problems
blockage of a blood vessel caused by a clot
leukaemia

Call your doctor straight away if you have any of these side effects

If you are given Doxorubicin Accord into the bladder, tell your doctor as soon as possible if you develop the following temporary side effects:

cystitis (pain in the bladder or back, blood in urine)
difficulty passing urine or an increased frequency of passing urine

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

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

Doxorubicin Accord is not addictive.

What Doxorubicin Accord contains

Active ingredient (main ingredient)	doxorubicin
Other ingredients (inactive ingredients)	sodium chloride water for injections

Do not take this medicine if you are allergic to any of these ingredients.

What Doxorubicin Accord looks like

Doxorubicin Accord injection is a clear red solution in a glass vial. (10 mg/5 mL: AUST R 174249, 200 mg/100 mL: AUST R 174248)

Who distributes Doxorubicin Accord

Accord Healthcare Pty Ltd
Level 24, 570 Bourke Street
Melbourne, VIC, 3000
Australia

This leaflet was prepared in November 2022.

Published by MIMS March 2023

BRAND INFORMATION

Brand name

Doxorubicin Accord

Active ingredient

Doxorubicin hydrochloride

Schedule

1 Name of Medicine

Doxorubicin hydrochloride.

2 Qualitative and Quantitative Composition

Doxorubicin hydrochloride concentrated injection is supplied as 10 mg/5 mL and 200 mg/100 mL glass vials (doxorubicin hydrochloride concentration 2 mg/mL).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Doxorubicin hydrochloride concentrated injection is a sterile, red coloured, clear solution of doxorubicin hydrochloride and sodium chloride in water for injections.

4 Clinical Particulars

4.1 Therapeutic Indications

Doxorubicin has been used successfully to produce regression in neoplastic conditions such as: acute leukaemia, Wilms' tumour, neuroblastoma, soft tissue and bone sarcomas, breast carcinoma, lymphomas of both Hodgkin's and non-Hodgkin's type, bronchogenic (lung) carcinoma, thyroid carcinoma, hepatomas, ovarian carcinoma, etc. The main antitumour activities are listed in Table 1.
Doxorubicin is also indicated by intravesical administration in the primary management of non-metastatic carcinoma of the bladder. (Tis, T1, T2).

4.2 Dose and Method of Administration

General directions.

The use of a Pharmacy Bulk Pack should be restricted to suitably qualified pharmacists operating in suitably equipped hospital pharmacies or compounding centres.
Do not administer doxorubicin by intramuscular or subcutaneous injection (see Section 4.3 Contraindications).
Care in the administration of doxorubicin will reduce the chance of perivenous infiltration. It may also decrease the chance of local effects such as urticaria and erythematous streaking.
The recommended dosage schedule is 60-75 mg/m² as a single intravenous injection administered at 21 day intervals. The lower dose should be given to patients with inadequate marrow reserves due to old age, or prior therapy, or neoplastic marrow infiltration. An alternative dose schedule is 25 to 30 mg/m² on each of three successive days repeated every 3 to 4 weeks. (The adult dosage regimens may be suitable for paediatric cases.) The recommended lifetime cumulative dose limit of doxorubicin hydrochloride is 550 mg/m² body surface area. Doxorubicin has been administered as an intra-arterial infusion for 1-3 days at doses of 45-100 mg/m².
It is recommended that doxorubicin be slowly administered into the tubing of a freely running intravenous infusion of Sodium Chloride 0.9% Injection or Glucose 5% Injection. The tubing should be attached to a butterfly needle inserted preferably into a large vein. The rate of administration is dependent on the size of the vein and the dosage. However the dose should be administered in not less than 3-5 minutes. A direct push injection is not recommended due to the risk of extravasation, which may occur even in the presence of adequate blood return upon needle aspiration.
Doxorubicin should not be mixed with heparin, dexamethasone, fluorouracil, hydrocortisone sodium succinate, aminophylline, diazepam, frusemide or cephalothin, since it has been reported that these medicines are incompatible to the extent that a precipitate may form. Doxorubicin solution may darken in colour from red to purple if mixed with fluorouracil or aminophylline. Doxorubicin is reported to be incompatible with allopurinol, cefepime and ganciclovir.
Until specific compatibility data are available, it is not recommended that doxorubicin be mixed with other medicines.
Local erythematous streaking along the vein as well as facial flushing may be indicative of too rapid administration. A burning or stinging sensation may be indicative of perivenous infiltration and the infusion should be immediately terminated and restarted in another vein.
Doxorubicin has been used in combination with other approved chemotherapeutic agents. Though evidence is available that at least in some types of neoplastic disease combination chemotherapy is superior to single agents, the benefits and risks of such therapy have not yet been fully elucidated.
The product contains no antimicrobial preservative.
The 5 mL vial size is supplied as single dose vials. The single dose vials should be used in one patient on one occasion only and any residue should be discarded within 24 hours of opening.
The 100 mL vial size is a hospital pharmacy bulk pack intended for use on one occasion for multi-dose dispensing and any residue should be discarded within 24 hours of opening. Once open, the solution may be stored for a maximum of 24 hours at 2°C to 8°C and protect from light.
Doxorubicin hydrochloride concentrated injection must be diluted prior to infusion in 5% Glucose Injection or 0.9% Sodium Chloride Injection. To reduce microbiological hazard, use as soon as practicable after dilution. If storage is necessary, store at 2°C to 8°C (Refrigerate. Do not freeze) for not more than 24 hours.
Storage of doxorubicin hydrochloride concentrated injection at refrigerated conditions can result in the formation of a gelled product. This gelled product will return to a slightly viscous to mobile solution after two to a maximum of four hours equilibration at room temperature (15-25°C).

Intravesical administration.

The following procedure is recommended:
1. The bladder should be catheterised and emptied.
2. Dilute doxorubicin hydrochloride concentrated injection to a final concentration of 80 mg in 100 mL of normal saline and instill via the catheter into the bladder.
3. The catheter should be removed and the patient instructed to be on one side. At 15 minute intervals over a one hour period, the patient should alternate to the opposite side.
4. The patient should be requested not to urinate for 1 hour, after which the bladder should be emptied of solution.
5. The procedure should be repeated at monthly intervals.

Use in children.

Adult dosage regimens may be suitable for paediatric cases.
Periodic assessment of cardiac function is recommended for children who have been treated with doxorubicin, as they may be at particular risk of developing delayed cardiotoxicity (see Section 4.4 Special Warnings and Precautions for Use).

Use in the elderly.

It is recommended that the total cumulative dose of doxorubicin for adults aged 70 years or older be restricted to 400 mg/m² body surface area.

Impaired hepatic function.

Doxorubicin is metabolised by the liver and excreted in bile. Impairment of hepatic function results in slower excretion of the medicine and consequently increased retention and accumulation in the plasma and tissues, resulting in enhanced clinical toxicity.
Doxorubicin dosage must be reduced if hepatic function is impaired according to Table 2:

Impaired renal function.

Doxorubicin and its metabolites are excreted in the urine to a minor degree and there are no clear indications that the pharmacokinetics or toxicity of doxorubicin is altered in patients with impaired renal function.

Protective measures.

Doxorubicin must be handled with care. If contact with the skin occurs, wash thoroughly with soap and water. The following protective recommendations are given due to the toxic nature of this substance:
personnel should be trained in good technique for reconstitution and handling;
pregnant staff should be excluded from working with this medicine;
personnel handling doxorubicin should wear protective clothing: goggles, gowns and disposable gloves and masks;
a designated area should be defined for reconstitution (preferably under a laminar flow system). The work surface should be protected by disposable, plastic-backed, absorbent paper;
all items used for reconstitution, administration or cleaning, including gloves, should be placed in high-risk waste-disposal bags for high-temperature incineration;
spillage or leakage should be treated with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water;
all cleaning materials should be disposed of as indicated previously;
in case of skin contact thoroughly wash the affected area with soap and water or sodium bicarbonate solution. However, do not abrade the skin by using a scrub brush;
in case of contact with the eye(s), hold back the eyelid(s) and flush the affected eye(s) with copious amounts of water for at least 15 minutes. Then seek medical evaluation by a physician;
always wash hands after removing gloves.

4.3 Contraindications

Doxorubicin is contraindicated:
1. In patients who have marked myelosuppression or severe stomatitis induced by previous treatment with other antitumour agents or by radiotherapy.
2. In patients with impaired cardiac function. Intravenous doxorubicin should not be administered to patients with severe arrhythmias, myocardial insufficiency or myocardial infarction (see Section 4.4 Special Warnings and Precautions for Use, Cardiac function).
3. In patients who have previously received the full cumulative dose of doxorubicin, daunorubicin or epirubicin.
4. In pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation).
5. In lactation (see Section 4.6 Fertility, Pregnancy and Lactation).
6. In patients with marked hepatic impairment.
7. In the presence of generalised infection.
8. In patients who are hypersensitive to doxorubicin and/or other anthracyclines or anthracenediones, or to other ingredients in the preparation.
Intravesical use of doxorubicin is contraindicated in the following cases:
1. invasive tumours which have penetrated the bladder wall;
2. urinary infections;
3. inflammation of the bladder;
4. catheterisation of the bladder (e.g. due to massive intravesical tumours);
5. haematuria.
Doxorubicin should not be administered by intramuscular or subcutaneous injection, as administration by these routes will result in severe tissue necrosis.

4.4 Special Warnings and Precautions for Use

General.

Doxorubicin should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents.
Doxorubicin is not an antimicrobial agent.
Patients should recover from acute toxicities of prior cytotoxic treatment (such as stomatitis, neutropenia, thrombocytopenia and generalised infections) before beginning treatment with doxorubicin.
Initial treatment with doxorubicin requires close observation of the patient and extensive laboratory monitoring.
It is strongly recommended therefore, that patients be hospitalised at least during the first phase of treatment. Blood count and liver function tests should be carried out prior to each doxorubicin treatment.
Doxorubicin solution should be handled with care. If either of the preparations comes in contact with the skin or mucosae, the appropriate areas should be washed thoroughly with soap and water.

Warnings.

1. For intravenous or intravesical use only. Severe local tissue necrosis will occur if there is extravasation during administration. Doxorubicin must not be given by the intramuscular or subcutaneous route.
2. Serious irreversible myocardial toxicity with delayed congestive failure often unresponsive to any cardiac supportive therapy may be encountered as total dosage approaches 550 mg/m².
3. This toxicity may occur at lower cumulative doses in patients with prior mediastinal irradiation or on concurrent cyclophosphamide therapy.
4. Dosage should be reduced in patients with impaired hepatic function.
5. Severe myelosuppression may occur.

Cardiac function.

Special attention must be given to the cardiac toxicity exhibited by doxorubicin. Cardiotoxicity is a risk of anthracycline treatment that may be manifested by early (i.e. acute) or late (i.e. delayed) events. The cardiac abnormalities caused by treatment can be separated into 2 categories:
1. ECG alterations; and
2. congestive heart failure (CHF).

Early (i.e. acute) events.

Early cardiotoxicity of doxorubicin consists mainly of sinus tachycardia and/or electrocardiogram (ECG) abnormalities such as non-specific ST-T wave changes. Tachyarrhythmias, including premature ventricular contractions, ventricular tachycardia and bradycardia, as well as atrioventricular and bundle-branch block have also been reported. These effects do not usually predict subsequent development of delayed cardiotoxicity, are rarely of clinical importance and are generally not a consideration for the discontinuation of doxorubicin treatment. ECG changes following doxorubicin treatment occur in about 10% of patients at all dose levels of doxorubicin, are usually reversible and do not appear to be related to the subsequent development of congestive cardiac failure.

Late (i.e. delayed) events.

Delayed cardiotoxicity usually develops late in the course of therapy with doxorubicin or within 2 to 3 months after treatment termination, but later events several months to years after completion of treatment have also been reported. Delayed cardiomyopathy is manifested by reduced left ventricular ejection fraction (LVEF) and/or signs and symptoms of congestive heart failure (CHF) such as dyspnoea, pulmonary oedema, dependent oedema, cardiomegaly and hepatomegaly, oliguria, ascites, pleural effusion and gallop rhythm. Subacute effects such as pericarditis/myocarditis have also been reported. Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and represents the cumulative dose-limiting toxicity of the drug.
The following measures may identify patients with early cardiomyopathy: progressive flattening or inversion of the T-waves (mainly in the left precordial leads), low QRS voltage, prolonged systolic time interval, reduced ejection fraction (echocardiography or by cardiac pool scanning) or cardiac biopsy showing characteristic electromicroscopic changes. Cardiomyopathy induced by doxorubicin is frequently fatal. Cardiac failure is often not favourably affected by presently known medical or physical therapy for cardiac support. Early clinical diagnosis of drug induced heart failure appears to be essential for successful treatment with digitalis, diuretics, low salt diet and bed rest.
Although uncommon, acute left ventricular failure has occurred, particularly in patients who have received total dosage of the drug exceeding the currently recommended limit of 550 mg/m². For this reason, cardiac function should be assessed before patients undergo treatment with doxorubicin and must be carefully monitored throughout therapy to minimise the risk of incurring severe cardiac impairment. The risk may be decreased through regular monitoring of LVEF during the course of treatment with prompt discontinuation of doxorubicin at the first sign of impaired function. The appropriate quantitative method for repeated assessment of cardiac function (evaluation of LVEF) includes multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and either a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiotoxicity. Repeated MUGA or ECHO determinations of LVEF should be performed, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent throughout follow-up. Severe cardiac toxicity may occur precipitously without antecedent ECG changes.
Baseline ECG and periodic follow-up ECG during, and immediately after drug therapy is an advisable precaution. Transient ECG changes, such as T-wave flattening, S-T depression and arrhythmias are not considered indications for suspension of doxorubicin therapy. A persistent reduction in the voltage of the QRS wave is presently considered more specifically predictive for cardiac toxicity. If this occurs, the benefit of continued therapy must be carefully evaluated against the risk of producing irreversible cardiac damage.
A decrease of the LVEF is the most predictive event related to chronic, cumulative dose-dependent cardiomyopathy. When a pre-treatment (baseline) assessment of LVEF is available, this parameter can be used as an indicator of cardiac function throughout therapy.
Children and adolescents are at an increased risk for developing delayed cardiotoxicity following doxorubicin administration. Females may be at greater risk than males. Follow-up cardiac evaluations are recommended periodically to monitor for this effect.
As a general rule, in patients with normal baseline LVEF (≥ 50%), an absolute decrease of ≥ 10% or a decline below the 50% threshold level are indicative of a deterioration of cardiac function and the continuation of doxorubicin treatment under such conditions has to be carefully evaluated.
The probability of developing impaired myocardial function based on a combined index of signs, symptoms and a decline in LVEF can be estimated to be around 1-2% at a cumulative dose of 300 mg/m²; this probability slowly increases up to the total cumulative dose of 450-550 mg/m². Thereafter, the risk of developing CHF increases more steeply, and it is recommended not to exceed the total cumulative dose of 550 mg/m².
Cardiac function must be carefully monitored in patients receiving high cumulative doses and in those with risk factors. However, cardiac toxicity with doxorubicin may occur at lower cumulative doses whether or not cardiac risk factors are present.
Risk factors for cardiac toxicity include active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with anthracyclines or anthracenediones, concomitant use of drugs with the ability to suppress cardiac contractility or other cardioactive compounds (e.g. calcium channel blocking drugs) or concomitant use of other potentially cardiotoxic drugs (e.g. cyclophosphamide, fluorouracil or trastuzumab). Anthracyclines including doxorubicin should not be administered in combination with other cardiotoxic agents unless the patient's cardiac function is closely monitored (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Patients receiving anthracyclines after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as e.g. trastuzumab (variable half-life; washout period up to 7 months), may also be at an increased risk of developing cardiotoxicity.

Note.

Trastuzumab emtansine has a shorter half-life of approximately 4 days. The half-life of trastuzumab is variable. Trastuzumab may persist in the circulation for up to 7 months. Therefore, physicians should avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab when possible. If anthracyclines are used before this time, careful monitoring of cardiac function is recommended.
For patients who have had mediastinal irradiation, concurrent high dose cyclophosphamide or hypertensive cardiomegaly it is recommended that the cumulative total lifetime dose of doxorubicin (including related drugs such as daunorubicin) be less than 450 mg/m² body surface area. Congestive heart failure and/or cardiomyopathy may be encountered several weeks after discontinuation of doxorubicin therapy.
The total (cumulative) dose levels of doxorubicin correlate with the incidence of drug induced congestive cardiac failure (cardiomyopathy). Limitation of the total dose of doxorubicin to 500 mg/m² reduces the risk of drug induced cardiomyopathy. At the cellular level, cardiotoxicity induced by doxorubicin is due to myocyte damage. Furthermore, as a consequence of the inhibition of cellular proliferation not only of neoplastic cells but also normal cells, cardiac muscle cells are unable to regenerate.
Microscopical examination of endocardial biopsies shows two major types of myocyte damage:
1. Cells totally or partially devoid of myofibrillar content, even though the nucleus and mitochondria are intact.
2. Vacuolar degeneration.
Damage to the myocardial muscle occurs with very little inflammatory reaction, muscle fibres appear to fade away. The clinical spectrum of doxorubicin toxicity ranges from subtle changes in ventricular function that can be detected only by sophisticated studies to gross congestive cardiomyopathy with symptoms and signs of advanced congestive heart failure.
It is probable that the toxicity of doxorubicin and other anthracyclines or anthracenediones is additive.
Animal studies have indicated a possible relationship between the inhibition by doxorubicin of the mitochondrial biosynthesis of Coenzyme Q10 and cardiotoxicity induced by doxorubicin. Other studies have suggested that vitamin E and other free radical acceptors may prevent doxorubicin toxicity.

Haematologic toxicity.

As with other cytotoxic agents, doxorubicin may produce myelosuppression. Haematologic profiles should be assessed before and during each cycle of therapy with doxorubicin, including differential white blood cell (WBC) counts. A dose-dependent, reversible leucopenia and/or granulocytopenia (neutropenia) is the predominant manifestation of doxorubicin haematologic toxicity and is the most common acute dose-limiting toxicity of this drug. Leucopenia and neutropenia are generally more severe with high-dose schedules, reaching the nadir in most cases between days 10-14 after drug administration; this is usually transient with the WBC/neutrophil counts returning to normal values in most cases by day 21. White blood cell counts as low as 1000/mm³ are to be expected during treatment with appropriate doses of doxorubicin.
Myelosuppression accompanies effective doxorubicin treatment in almost 100% of patients. Leucopenia is the predominant effect with thrombocytopenia and anaemia occurring less frequently. Red blood cell and platelet levels should also be monitored.
Myelosuppression is more common in patients who have had extensive radiotherapy, bone infiltration by tumour, impaired liver function when appropriate dosage reduction has not been adopted (see Section 4.2 Dose and Method of Administration) and simultaneous treatment with other myelosuppressive agents. Haematologic toxicity may require dose reduction, suspension or delay of doxorubicin therapy.
When using doxorubicin as part of chemotherapy regimens which combine drugs of similar pharmacological effects (i.e. cytotoxicity) additive toxicity is likely to occur. Such additive toxicity has to be taken into consideration especially with regard to bone marrow function.
Doxorubicin is a powerful but temporary immunosuppressant agent. Appropriate measures should be taken to prevent secondary infection. Clinical consequences of severe myelosuppression include fever, infection, sepsis/septicaemia, septic shock, haemorrhage, tissue hypoxia or death.

Secondary leukaemia.

Secondary leukaemia, with or without a pre-leukaemic phase, has been reported in patients treated with anthracyclines including doxorubicin. Secondary leukaemia is more common when such drugs are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pre-treated with cytotoxic drugs, or when doses of the anthracyclines have been escalated. This has been noted in the adjuvant and neoadjuvant setting. These leukaemias can have a 1 to 3-year latency period.

Gastrointestinal.

Doxorubicin is emetogenic. Mucositis is a frequent and painful complication of doxorubicin treatment but is less common than myelosuppression. Mucositis/stomatitis generally appears early after drug administration, most commonly developing 5 to 10 days after treatment. It typically begins as a burning sensation in the mouth and pharynx. The mucositis may involve the vagina, rectum and oesophagus, and, if severe, may progress over a few days to mucosal ulcerations with risk of secondary infection. Most patients recover from this adverse event by the third week of therapy. Retrospective comparison of the incidence of mucositis suggests that it is less frequent as the intervals between doses increase. Mucositis may be severe in patients who have had previous irradiation to the mucosae.

Obesity.

Systemic doxorubicin clearance tends to be decreased in obese patients; such patients must be carefully monitored if they are being treated with the maximum recommended doses of doxorubicin.

Effects at site of injection.

Phlebosclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Following the recommended administration procedures may minimise the risk of phlebitis/thrombophlebitis at the injection site (see Section 4.2 Dose and Method of Administration).

Immunosuppressant effects/ increased susceptibility to infections.

Administration of live or live attenuated vaccines in patients immunocompromised by chemotherapeutic agents including doxorubicin, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving doxorubicin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Doxorubicin is a powerful but temporary immunosuppressive agent. Appropriate measures should be taken to prevent secondary infection.
The risks and benefits should be considered before treating patients with an infection with doxorubicin, due to its immunosuppressive effects. Doxorubicin should only be administered with caution to patients with herpes zoster or with existing or recent chicken pox (including recent exposure), as there is a risk that severe generalised disease will develop.
Immunisation of patients being treated with doxorubicin should only be undertaken with extreme caution, after a careful review of the patient's haematological status, as doxorubicin may suppress normal defence mechanisms. Concurrent use of doxorubicin with live virus vaccines may potentiate the replication of the vaccine virus, increase adverse effects of the vaccine, and/or may decrease the patient's antibody response to the vaccine. Doxorubicin may also decrease the patient's antibody response to killed virus vaccines. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on many factors; estimates vary from three months to one year.
Patients with leukemia which are in remission should not receive live virus vaccines until at least three months after their last chemotherapy treatment.
People in close contact with a patient who is being treated with doxorubicin, especially family members, should postpone immunisation with oral polio vaccines.

Dental.

The bone marrow depressant effects of doxorubicin may cause an increased incidence of microbial infection, delayed healing and gingival bleeding. Patients should be instructed in proper oral hygiene during treatment, including caution in the use of toothbrushes, dental floss and toothpicks. Dental work, whenever possible, should be completed prior to initiation of therapy, or deferred until blood counts have returned to normal.

Enhanced toxicity.

It has been reported that doxorubicin may enhance the severity of the toxicity of anticancer therapies, e.g. cyclophosphamide induced haemorrhagic cystitis, mucositis, cardiotoxicity and bone marrow depressant effects induced by radiotherapy and hepatotoxicity of 6-mercaptopurine. Radiation-induced toxicities (myocardium, mucosae, skin and liver) have also been reported.

Extravasation.

Extravasation of doxorubicin during intravenous injection may produce local pain (a burning or stinging sensation), severe tissue lesions (vesication, severe cellulitis) and necrosis. Should signs or symptoms of extravasation occur during intravenous administration of doxorubicin, the drug infusion should be immediately stopped.
To minimise perivenous infiltration, see Section 4.2 Dose and Method of Administration.

Tumour-lysis syndrome.

Like other cytotoxic medicines, doxorubicin may induce hyperuricaemia secondary to rapid lysis of neoplastic cells (tumour-lysis syndrome). The clinician should monitor the patient's blood uric acid level, potassium, calcium phosphate and creatinine, and be prepared to use such supportive and pharmacologic measures as might be necessary to control this problem. Hydration, urine alkalinisation, and prophylaxis with allopurinol to prevent hyperuricaemia may minimise potential complications of tumour-lysis syndrome.

Other.

As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases fatal), have been coincidentally reported with the use of doxorubicin.
Doxorubicin imparts a red colouration to the urine for 1-2 days after administration and patients should be advised to expect this during active therapy.

Intravesical administration.

Administration of doxorubicin by the intravesical route may produce symptoms of chemical cystitis (such as dysuria, polyuria, nocturia, stranguria, haematuria, bladder discomfort, necrosis of the bladder wall) and bladder constriction. Special attention is required for catheterisation problems (e.g. urethral obstruction due to massive intravesical tumours). Urine cytologies and blood counts should be monitored monthly and cytoscopic examinations should be performed at regular intervals.

Instructions to be given to patients.

1. Patients should inform their physicians immediately if pain develops at the injection site.
2. Nausea and vomiting may be expected 3-6 hours after drug treatment, and may last for several hours.
3. Patients should be advised to expect a red colouration to the urine (not indicative of haematuria) for 1 to 2 days after each administration of doxorubicin.
4. Alopecia (hair loss) should be expected 1 to 2 weeks after the initiation of doxorubicin treatment. Hair loss may be complete but hair always returns after termination of treatment.
5. NB. Scalp tourniquets inflated to above systolic blood pressure and left in situ for 30 minutes over the time of doxorubicin treatment reduces the probability of alopecia.
6. Anorexia may be expected for 24 hours following each treatment and occasionally may persist for several days.
7. Hyperpigmentation, usually in the hands, nails and buccal mucosa may develop in patients receiving doxorubicin. Patients should be advised that this condition does not usually improve after termination of treatment.
8. Infertility in both sexes is usual in patients receiving doxorubicin. Amenorrhoea is frequent and in premenopausal women, regular menstruation usually returns a few months after termination of doxorubicin therapy. This is often accompanied by normal fertility.
9. Male patients should be advised that oligospermia or azoospermia may be permanent. There is a possibility that fertility may return several years after ceasing therapy. Men undergoing doxorubicin therapy should be advised to use effective contraceptive measures.
10. Patients should be instructed to inform their physicians of any prior abnormal heart or liver conditions, as this information is vital to the formulation of appropriate dosage regimes.

Use in hepatic impairment.

The major route of elimination of doxorubicin is the hepatobiliary system. Toxicity to recommended doses of doxorubicin is enhanced by hepatic impairment. Therefore, prior to the individual dosing, evaluation of hepatic function is recommended using conventional clinical laboratory tests such as AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubin and BSP (see Section 4.2 Dose and Method of Administration). Serum total bilirubin levels should also be evaluated during treatment with doxorubicin. Patients with elevated bilirubin may experience slower clearance of drug with an increase in overall toxicity. Lower doses are recommended in these patients (see Section 4.2 Dose and Method of Administration). Patients with severe hepatic impairment should not receive doxorubicin (see Section 4.3 Contraindications).
Changes in hepatic function induced by concomitant therapies, either given to achieve optimal antitumour efficacy or given for the pharmacological management of concomitant diseases, may affect doxorubicin metabolism, pharmacokinetics, therapeutic efficacy or toxicity.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration, Impaired renal function.

Use in the elderly.

Although appropriate studies with doxorubicin have not been performed in this population, cardiac toxicity may be more frequent in patients greater than or equal to 70 years of age. Caution should also be used in patients who have inadequate bone marrow reserves due to old age.

Paediatric use.

Doxorubicin induced cardiomyopathy impairs myocardial growth as children mature, so that paediatric patients may be at particular risk of developing delayed cardiotoxicity and, possibly, subsequent congestive heart failure during early adulthood. Periodic follow-up is therefore recommended for children who have been treated with doxorubicin.

Embryo-fetal toxicity.

Doxorubicin can cause genotoxicity. An effective method of contraception is required for both male and female patients during and for a period after treatment with doxorubicin. Patients desiring to have children after completion of therapy should be advised to obtain genetic counselling if appropriate and available (see Section 4.6 Fertility, Pregnancy and Lactation; Section 5.3 Preclinical Safety Data).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Doxorubicin is a major substrate of cytochrome P450 CYP3A4 and CYP2D6 and P-glycoprotein (P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4, CYP2D6 and/or P-gp (e.g. verapamil) resulting in increased concentration and clinical effect of doxorubicin. Inducers of CYP3A4 (e.g. phenobarbital, phenytoin, St. John's wort) and P-gp inducers may decrease the concentration of doxorubicin.
Doxorubicin is mainly used in combination with other cytotoxic agents. Additive toxicity may occur, especially with regard to bone marrow/haematologic and gastrointestinal effects (see Section 4.4 Special Warnings and Precautions for Use).

Adjuvant chemotherapy involving doxorubicin.

It is not recommended that doxorubicin be used routinely as adjuvant chemotherapy in any tumour category. The activity of doxorubicin in combination with other drugs is affected not only by the nature of the drug itself, but also by the schedule of administration. It is strongly recommended that in situations where doxorubicin is intended for use as adjuvant chemotherapy, higher authorities as well as the Hospital Ethical Committee be consulted.
Doxorubicin may exacerbate cyclophosphamide induced haemorrhagic cystitis and enhance the hepatotoxicity of 6-mercaptopurine (see Section 4.4 Special Warnings and Precautions for Use, Enhanced toxicity).
Concurrent treatment with cyclophosphamide, dactinomycin or mitomycin may sensitise the heart to the cardiotoxic effects of doxorubicin. The cumulative dose of doxorubicin should be reduced in patients who have received other cardiotoxic medicines, including cyclophosphamide, mitoxantrone, idarubicin, daunorubicin or epirubicin.
Doxorubicin should not be mixed with heparin since it has been reported that these drugs are incompatible to the extent that a precipitate may form.
Concurrent mediastinal radiotherapy and doxorubicin may be associated with enhanced myocardial toxicity of doxorubicin (see Section 4.4 Special Warnings and Precautions for Use).
Concurrent radiotherapy and doxorubicin treatment may be associated with increased radiation toxicity, i.e. skin reactions and mucositis.
A high incidence of congestive heart failure has been reported in patients who have received doxorubicin in association with paclitaxel.
Propranolol may increase the cardiotoxicity of doxorubicin as both medicines have been shown to inhibit cardiac mitochondrial coenzyme Q10.
Concurrent administration of calcium channel blockers with doxorubicin may increase the risk of cardiotoxicity.
Doxorubicin may raise the concentration of blood uric acid, secondary to rapid lysis of neoplastic cells; dosage adjustment of antigout agents (e.g. allopurinol, colchicine, probenecid, sulfinpyrazone) may be necessary to control hyperuricaemia. Serum uric acid concentrations should be monitored. Adequate oral hydration may prevent development of uric acid nephropathy. Alkalinisation of the urine may be necessary in some cases where serum uric acid concentrations are elevated.
The leucopenic, thrombocytopenic and bone marrow depressant effects of doxorubicin may be increased with concurrent or recent therapy with other medicines causing these effects. Symptoms may include severe dermatitis and/or mucositis. Dosage reduction may be required if doxorubicin is used concurrently or consecutively with other bone marrow depressants, including radiation therapy.
Doxorubicin may decrease the patient's antibody response to vaccines and/or may increase adverse effects of a live virus vaccine due to immunosuppression. This effect may persist from three months to one year (see Section 4.4 Special Warnings and Precautions for Use).
Hepatotoxic medications (e.g. high dose methotrexate, streptozocin) may impair hepatic function and therefore increase the toxicity of subsequently administered doxorubicin.
Phenobarbitone induces liver enzymes; therefore, concurrent administration may increase the elimination of doxorubicin. Doxorubicin may decrease serum phenytoin concentrations.
Hypersensitivity reactions to doxorubicin have been reported following recent exposure to clindamycin. The possibility of cross sensitivity between anthracyclines and clindamycin should be considered. Apparent cross sensitivity to lincomycin has also been reported.
The addition of cyclosporin to doxorubicin may result in increases in area under the concentration-time curve (AUC) for both doxorubicin and doxorubicinol, possibly due to a decrease in clearance of the parent drug and a decrease in metabolism of doxorubicinol. Literature reports suggest that adding cyclosporin to doxorubicin results in more profound and prolonged hematologic toxicity than that observed with doxorubicin alone. Severe neurotoxicity presenting as coma and seizures have also been described with concomitant administration of cyclosporin and doxorubicin.
Concurrent administration of doxorubicin and cytarabine may result in colitis and necrosis (see Section 4.8 Adverse Effects (Undesirable Effects)).
Sorafenib: Both increases (21% - 47%) and no change in the AUC of doxorubicin were observed with concomitant treatment with sorafenib 400 mg twice daily. The clinical significance of these findings is unknown.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Doxorubicin may cause infertility during the time of medicine administration. In women, doxorubicin may cause amenorrhea. Although ovulation and menstruation appear to return a few months after termination of therapy, premature menopause can occur.
Doxorubicin was toxic to male reproductive organs in animal studies, producing testicular atrophy, diffuse degeneration of the seminiferous tubules, and hypospermia.
Doxorubicin is mutagenic and can induce chromosomal damage in human spermatozoa. Oligospermia or azoospermia may be permanent; however, sperm counts have been reported to return to normospermic levels in some instances. This may occur several years after the end of therapy. Men undergoing treatment with doxorubicin should use effective contraceptive measures. Both men and women should seek advice on fertility preservation before treatment.
(Category D)
Category D: Medicines which have caused, are suspected to have cause or may be expected to cause, an increased incidence of human foetal malformations or irreversible damage. These medicines may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
Doxorubicin has been reported to be embryotoxic and teratogenic in rats, and embryotoxic and abortifacient in rabbits. Studies with rabbits and rats have revealed a decreased weight gain, and a higher incidence of resorbed fetuses. Doxorubicin has been found in fetal tissue (liver, kidney and lungs) at concentrations several times that in maternal plasma, indicating that doxorubicin crosses the placenta. Dose related mutagenic effects of doxorubicin have been reported to produce severe chromosomal aberrations in in vitro studies. In view of this activity, the use of this drug in pregnant women is not recommended.
There is no information on the drug's use in pregnancy; therefore, the drug should not be used in pregnant women or those likely to become pregnant unless the expected benefit outweighs any potential risk. If a woman receives doxorubicin during pregnancy or becomes pregnant while taking the drug, she should be apprised of the potential hazard to the fetus.

Women of childbearing potential/contraception in males and females.

Women of childbearing potential should be advised to avoid becoming pregnant during treatment and to use effective contraceptive methods during treatment and for at least 6 months and 10 days after last dose. Men with female partners of childbearing potential should be advised to use effective contraception during treatment with doxorubicin and for at least 3 months and 10 days after last dose.
Doxorubicin is distributed into milk, but limited data suggest that the amount of active medicine estimated to be ingested by a breastfed infant would be small. However, because of the potential for serious adverse effects to doxorubicin in breastfed infants, women should be instructed not to breastfeed while undergoing treatment with doxorubicin and for at least 10 days after last dose.

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.

4.8 Adverse Effects (Undesirable Effects)

Adverse reactions table.

See Table 3.

Intravesical use.

Systemic toxicity is not a common problem, however adverse effects have been noted at doses exceeding that recommended (see Section 4.2 Dose and Method of Administration).
Local adverse effects observed include chemical cystitis, contraction of the bladder, haematuria, painful micturition, frequency and urgency. These disturbances are transient. Special attention is required for catheterisation problems (e.g. ureteral obstruction due to massive intravesical tumours).

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Clinical features.

The symptoms of overdosage are likely to be an extension of doxorubicin's pharmacological action. Possible symptoms of toxicity are those listed under adverse effects. Some toxicity may be delayed (e.g. mucositis) or life threatening (e.g. myelosuppression and cardiotoxicity).

Management.

Symptomatic supportive measures should be instituted. Particular attention should be given to prevention and treatment of possible severe haemorrhages or infections secondary to severe, persistent bone marrow depression.

Acute animal toxicity.

The acute toxicity of doxorubicin in Swiss mice varies greatly according to the route of administration. The LD50 corresponds to 8.5 mg/kg by the intraperitoneal route, 21.1 mg/kg by the intravenous route, and is greater than 750 mg/kg by the oral route.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Though not completely elucidated, the mechanism of action of doxorubicin is related to its ability to bind to DNA and inhibit nucleic acid synthesis. Cell culture studies have demonstrated rapid cell penetration and perinucleolar chromatin binding, rapid inhibition of mitotic activity and nucleic acid synthesis, mutagenesis and chromosomal aberrations.
Doxorubicin has immunosuppressive effects. It inhibits the titre of haemolytic and haemagglutinating antibodies in mice immunised with sheep red blood cells. Similar evidence in man indicates that doxorubicin is a powerful but temporary immunosuppressant agent. Doxorubicin is a cell cycle, phase nonspecific cytotoxic medicine.
The toxic effects of doxorubicin on the bone marrow appear to be related to its action on proliferating myeloid cells. The cardiotoxicity of doxorubicin is probably mediated by different mechanisms. Although, in animal systems, doxorubicin does inhibit DNA synthesis in cardiac muscle, it is probable that cardiotoxicity is not directly related to inhibition of cardiac muscle replication. There are some data which suggest that it is due to the generation of free radicals which damage cardiac muscle in some uncertain way. These data also suggest that concurrent administration of Vitamin E and other free radical acceptors may prevent cardiotoxicity in experimental animal systems without impairing its antitumour efficacy. These studies need confirmation but they do suggest that it may be possible to divorce the antitumour effects of the medicine from its cumulative cardiotoxic effects.
The specificity of doxorubicin toxicity appears to be related primarily to proliferative activity of normal tissue. Thus, bone marrow, gastro-intestinal tract and gonads are the main normal tissues damaged.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Doxorubicin is not suitable for oral administration as less than 5% of the medicine is absorbed.

Distribution.

Pharmacokinetic studies show the intravenous administration of normal or radiolabelled doxorubicin is followed by rapid plasma clearance and significant tissue binding. No information on plasma-protein binding of doxorubicin is available.

Metabolism.

The metabolism and disposition of doxorubicin is still to be defined. The medicine is metabolised predominantly by the liver to doxorubicinol and several aglycone metabolites. It should be noted that several of the metabolites are cytotoxic. However, it is not certain whether any of them are more cytotoxic than the parent compound. High levels of metabolites appear rapidly in plasma and undergo a distribution phase with a measurable short initial half-life. Metabolism may be impaired in patients with abnormal hepatic function.

Excretion.

The disappearance of doxorubicin and its metabolites from the plasma follows a triphasic pharmacokinetic pattern with a mean half-life of the first phase of 12 minutes, of the second phase of 3.3 hours and of the prolonged third phase of 29.6 hours.
Urinary excretion of doxorubicin hydrochloride and its metabolites is prolonged and accounts for only 5% of the medicine excreted during the first 5 days. Approximately 50% of an administered dose is excreted in bile, and an additional 30% is excreted in bile as conjugates.
Impairment of hepatic function results in slower excretion, and consequently, increased retention and accumulation in plasma and tissues. Doxorubicin does not cross the blood brain barrier.

5.3 Preclinical Safety Data

Genotoxicity.

Doxorubicin and related compounds have been shown to have mutagenic properties when tested in experimental models.
Doxorubicin was genotoxic in a battery of in vitro or in vivo tests. An increase in the incidence of mammary tumours was reported in rats, and a trend for delay or arrest of follicular maturation was seen in female dogs.
Doxorubicin is mutagenic and can induce chromosomal damage in human spermatozoa. Oligospermia or azoospermia may be permanent; however, sperm counts have been reported to return to normospermic levels in some instances. This may occur several years after the end of therapy. Men undergoing doxorubicin treatment should use effective contraceptive measures (see Section 4.6 Fertility, Pregnancy and Lactation).
Secondary malignancies are potential delayed effects of many antineoplastic agents, although it is not clear whether the effect is related to their mutagenic or immunosuppressive action.

Carcinogenicity.

Doxorubicin and related compounds have been shown to have carcinogenic properties when tested in experimental models.
Doxorubicin is carcinogenic in animals and is potentially carcinogenic in humans.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium chloride in water for injections. Hydrochloric acid is added as necessary to adjust the pH.

6.2 Incompatibilities

Doxorubicin should not be mixed with heparin, dexamethasone, fluorouracil, hydrocortisone sodium succinate, aminophylline, diazepam, frusemide or cephalothin, since it has been reported that these medicines are incompatible to the extent that a precipitate may form. Doxorubicin solution may darken in colour from red to purple if mixed with fluorouracil or aminophylline. Doxorubicin is reported to be incompatible with allopurinol, cefepime and ganciclovir.
Until specific compatibility data are available, it is not recommended that doxorubicin be mixed with other medicines.

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 at 2°C to 8°C. (Refrigerate. Do not freeze.) Protect from light.

6.5 Nature and Contents of Container

The 5 mL vial size is supplied as single dose vials.
The 100 mL vial size is a hospital pharmacy bulk pack intended for use on one occasion for multi-dose dispensing.

Pack sizes.

1 x 5 mL glass vial; 1 x 100 mL glass vial.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Doxorubicin hydrochloride is a cytotoxic anthracycline antibiotic isolated from cultures of Streptomyces peucetius var. caesius. The chemical structure of doxorubicin consists of a tetracyclic ring, with the sugar daunosamine attached by a glycosidic linkage.
Structurally, doxorubicin is related to daunomycin (daunorubicin) and differs only in hydroxyl group substitution (instead of hydrogen) at the alkyl side chain.
Doxorubicin hydrochloride is soluble in water; slightly soluble in methanol; practically insoluble in acetone and in ethanol.
Chemical Name: (8S,10S)-10-[(3-Amino-2, 3, 6-trideoxy-alpha-L-lyxo-hexopyranosyl)-oxy]-8-glycoloyl-7,8,9,10-tetrahydro- 6,8,11-trihydroxy-1-methoxy-5, 12-naphthacenedione hydrochloride.
Molecular Formula: C₂₇H₂₉NO₁₁HCl.
Molecular Weight: 579.99.

Chemical structure.

CAS number.

25316-40-9.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

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