Package leaflet: Information for the user

DAUNORUBICIN 20MG POWDER FOR I.V. INJECTION

daunorubicin hydrochloride

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

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

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

•    If you get any side effects talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet (see section 4).

What is in this leaflet:

1.    What daunorubicin is and what it is used for    4.    Possible side effects

2.    What you need to know before you takedaunorubicin    5.    How to store daunorubicin

3.    How you will be given daunorubicin    6.    Contents of the pack and other    information

1. WHAT DAUNORUBICIN IS AND WHAT IT IS USED FOR

The name of your medicine is Daunorubicin 20mg Powder for I.V. Injection (called daunorubicin in this leaflet). It belongs to a group of medicines used to treat acute leukaemia.

Daunorubicin works by attacking and destroying the abnormal white blood cells which are present in a person with leukaemia.

Information about Leukaemia

Leukaemia is the name for a number of diseases of the white blood cells, which form part of your blood. These cells are produced in your bone marrow. In leukaemia, the white blood cells multiply in an uncontrolled and abnormal way.

The most common signs of leukaemia are:

•    Increased number of white cells in the blood. This causes easy bruising and nose bleeds

•    Feeling tired, faint, dizzy, having pale skin. These could be symptoms of anaemia

•    Extreme tiredness (exhaustion), and headaches

•    Bone and joint pain

•    Severe infection and fever

2. WHAT YOU NEED TO KNOW BEFORE YOU TAKE DAUNORUBICIN

Before treatment, you should discuss the risks and benefits of this medicine with your doctor.

Do not have daunorubicin if:

•    You are sensitive to, or allergic to, daunorubicin or other anthracyclines or any of the other ingredients of this medicine (listed in section 6)

Signs of an allergic reaction include: a rash, swallowing or breathing problems, swelling of your lips, face, throat or tongue

•    You have chicken pox or shingles, or you have been in recent contact with anyone who has chicken pox or shingles

•    You have an infection, fever or high temperature

•    You have any heart problems

•    You are pregnant or breastfeeding

•    You have a lot of mouth ulcers

Do not have daunorubicin if any of the above applies to you. If you are not sure, talk to your doctor or nurse.

Warnings and precautions

Talk to your doctor or nurse before you are given daunorubicin if:

•    You have had radiation treatment to the chest

•    You have had any other medicines to treat leukaemia (or cancer)

•    You have or have ever had gout

•    You have or have ever had kidney stones or any other kidney problems

•    You have any liver problems

•    You are sexually active, you are advised to use effective birth control to prevent pregnancy during treatment, whether you are male or female.

If you are not sure if any of the above apply to you, talk to your doctor or nurse before being given daunorubicin.

Other medicines and daunorubicin

Tell your doctor or pharmacist if you are taking, have recently taken or might take any:

•    other medicines that may affect your heart for example, medicines to treat cancer such as 5-fluorouracil, cyclophosphamide, cisplatin, taxanes, calcium channel blockers used to control high blood pressure, chest pain, and irregular heartbeats and if you are receiving chest radiotherapy.

•    other medicines that may affect the bone marrow for example, other cancer treatments, sulphonamide, chloramphenicol (used to treat infection), diphenylhydantoin (used to treat epilepsy), amidopyrine-derivative (used to relieve pain), antiretroviral agents (used to treat HIV infection) may alter the formation of blood cells

•    other medicines that may affect your liver e.g barbiturates (drugs used in epilepsy or sleep disorders) and rifampicin (a drug used to treat TB - Tuberculosis)

•    live attenuated vaccines Pregnancy, breast-feeding and fertility

Do not have daunorubicin if you are pregnant, might become pregnant or think you might be pregnant as daunorubicin can be very damaging to your unborn baby (embryo). If pregnancy occurs during treatment this should be discussed with your doctor.

Both female and male patients must take special precautions in their sexual activity if there is any possibility for pregnancy to occur:

*    For a girl or woman of childbearing age:

You must have a negative pregnancy test before treatment and each month during treatment. This should be discussed with your doctor.

*    For men:

Do not have sex with a pregnant woman unless you use a condom. This will lessen the possibility for daunorubicin to be left in the woman's body.

You and your female partner must each use an effective contraceptive during the time you are taking daunorubicin and for 6 months after stopping treatment. This should be discussed with your doctor.

Men who wish to father children in the future should seek advice about freezing sperm before treatment with daunorubicin is started.

If you are a woman who is breast-feeding, you must not take daunorubicin. Discontinue breast-feeding before starting to take daunorubicin.

Driving and using machines

You may feel and/or be sick after being given this medicine, therefore special care should be taken when driving or using machines.

There is no information available about how daunorubicin might affect your ability to drive or use machines.

■ Daunorubicin 20mg Powder for IX Injection

Da unorubicin Hydrochloride For the Medical and Pharmaceutical Professions only

STORE BELOW 25°c PROTECT FROM LIGHT. Solutions of Daunorubicin should be freshly prepared; store at 2-8°C in the dark and use within 24 hours

PRESENTATION

Daunorubicin is a microcrystalline orange-red hygroscopic sterile powder supplied i n vials containing the equivalent of 20mg daunorubicin fas hydrochloride) and mannitol as a stabilising agent.

INDICATIONS

Daunorubicin is an anthracycline glycoside antibiotic and a potent antileukaemic agent. It also has immuno suppressant effects. The exact mechanism of antineoplastic action of daunorubicin is uncertain but may involve binding to DNAby intercalation between base pairs and inhibition of DNA and RNA synthesis by template disordering and steric obstruction. Daunorubicin is most active in the S-phase of cell division but is not cycle phase-specific. Tumour cell cross resistance has been observed between daunorubicin and doxorubicin.

No controlled paediatric studies have been conducted. The literature mentions the use of daunorubicin in treatment regimens for ALL and AML, including paediatric age groups. However, due to the ongoing search for a balance in gain or maintenance of efficacy and a decrease in toxicity, the use of daunorubicin in the treatment of paediatric ALL and AML is fluctuating in clinical practice, mainly depending on risk stratification and specific subgroups. Published studies suggest no differences in safety profile between paediatric patients and adults.

PHARMACOKINETICS

Daunorubicin is rapidly taken up by the tissues, especially by the kidneys, spleen, liver and heart, it does not cross the blood-brain barrier, subsequent release of drug and its metabolites from the tissue is slow (t1/2 = 55 hours). Daunorubicin is rapidly metabolised in the liver. The major metabolite daunorubicinoi is also active. Daunorubucin is excreted slowly in the urine, mainly as metabolites with 25% excreted in the first 5 days. Biliaiy excretion also makes a significant (40%) contribution to elimination.

DOSAGE AND ADMINISTRATION

Daunorubicin is extremely irritating to tissues and may only be administered intravenously.

Do not administer by the intramuscular or subcutaneous route.

The contents of a vial should be reconstituted with 4m! water for injections giving a concentration of 5mg per ml. The calculated dose of Daunorubicin should be further diluted with normal saline to give a final concentration of 1 mg per ml. This solution should be injected over a 20 minute period into the tubing, or side-arm, of a well placed, rapidly flowing i.v. infusion of normal saline (to minimise extravasation and possible tissue necrosis). Alternatively, the Daunorubicin may be added to a minibag of sodium chloride injection 0.9%w/v and this solution infused into the side-arm of a rapidly flowing infusion of normal saline.

Adults: 40-60mg/m² on alternate days for a course of up to three injections for the induction of remissions. Acute myelogenous leukaemia:

The recommended dose is45mg/m².

Acute lymphocytic leukaemia:

The recommended dose is45mg/m² Paediatric patients: Daunorubicin dosage for children (over 2 years) is usually calculated based on the body surface area and adjusted to meet the individual requirements of each patient, on the basis of clinical response and the patients’ haematological status. Courses may be repeated after 3 to 6 weeks.

Current specialised protocols and guidelines should be consulted for appropriate treatment regimen.

For children over 2 years the maximal cumulative dose is 300 mg/m²-

For children under 2 years of age (or below 0.5m² body surface area), the maximum cumulative dose is10mg/kg.

Elderly: Daunorubicin should be used with care in patients with inadequate bone marrow reserves due to old age. A reduction of up to 50% in dosage is recommended.

The number of injections required varies widely from patient to patient and must be determined in each case according to response and tolerance. Daunorubicin should be administered through a large vein and the infusion should be kept free flowing. When second or subsequent injections a re given, the doses and the time intervals depend on the effect of the previous doses and must be the subject of careful deliberation, examination of the peripheral blood and, under some circumstances, of the bone marrow.

The effect of Daunorubicin on the disease process and on the normal blood precursors cannot be exactly predicted for any particular case. The difference between incomplete treatment, a satisfactory remission, and overdosage with possible irreversible aplasia of the bone marrow depends on the correct choice of dosage,time intervals and total number of doses. The dosage should be reduced in patients with impaired hepatic or renal function. A 25% reduction is recommended in patients with serum bilirubin concentrations of 20-50 pmol/l or creatinine or above 105-265 pmol/l. A 50% reduction is recommended in cases with serum bilirubin concentrations of above 50 pmol/l or creatinine or above 265 pmol/l. CONTRA-INDICATIONS

Do not use in patients recently exposed to, or with existing chicken pox or herpes zoster.

PRECAUTIONS AND WARNINGS

Daunorubicin should be used under direction of a clinician conversant with the management of acute leukaemia and cytotoxic chemotherapy. The haematological status of patients should be monitored regularly.

Daunorubicin which might depress the bone marrow to the point where anti-infective agents would no longer be effective. If facilities are available, patients should be treated in a germ-free environment or, where this is not possible, reverse barrier nursing and aseptic precautions should be employed.

Anti-infective therapy should be employed in the presence ot suspected or confirmed infection and during a phase of aplasia. It should be continued for some time after the marrow has regenerated. Care should also be used in patients at risk of infection.

Rapid destruction of a large number of leukaemia cells may cause a rise in the blood uric acid or urea and so it is a wise precaution to check these concentrations three or four times a week during the first week of treatment. Fluids should be administered and allopurinol used in severe cases to prevent the development of hyperuricaemia.

Patients with heart disease should not be treated with this potentially cardiotoxic drug. Cardiotoxicity, if it occurs, islikelyto be heralded by either a persistent tachycardia, shortness of breath and swelling of feet and lower limbs, or by minor changes in the electrocardiogram and for this reason an electrocardiographic examination should be made at regular intervals during treatment. Cardiotoxicity usually appears within 1 to 6 monthsafter initiation of therapy. It may develop suddenly and not be detected by routine ECG. It may be irreversible and fatal but responds to treatment if detected early.

The risk of congestive heart failure increases significantly when the total cumulative dosage exceeds 600mg/m² in adults, 300mg/m² in children over 2 years or 10mg/kg in children under 2 years. Cardiotoxicity may be more frequent in children and the elderly. The dosage should be modified if previous or concomitant cardiotoxic drug therapy is used. Daunorubicin should be used with care in patients at risk of hyperuricaemia (e.g. in the presence of gout, urate and renal calculi), tumour cell infiltration of the bone marrow and in patients with inadequate bone marrow reserves due to previous cytotoxic drug or radiation therapy. The cumulative dose of Daunorubucin should be limited to 400m g/m² when radiation therapy to the mediastinum has been previously administered. The dose of Daunorubicin should not be repeated in the presence of bone marrow depression or buccal ulceration.

Care should be taken to avoid extravasation during intravenous administration. All steps should be taken to avoid tissuing and bandages should not be used. Facial flushing or er/thematous streaking along the vein indicates too rapid injection. If tissue necrosis is suspected, the infusion should be stopped immediately and resumed in another vein. Where extravasation has occurred, an attempt should be made to aspirate the fluid back through the needle. The effected area may be injected with hydrocortisone. Sodium bicarbonate (5ml of 8.4% w.v solution) may also be injected in the hope that through pH changes the drug will hydrolyse. The opinion of a plastic surgeon should be sought as skin grafting may be required.

Application of ice packs may help to decrease local discomfort and also prevent extension. Liberal application of corticosteroid cream and dressing the area with sterile gauze should then be carried out.

USE IN PREGNANCY

Daunorubicin crosses the placenta and experiments in animals have shown it to be mutagenic, carcinogenic and teratogenic. There is also the possibility that treatment during pregnancy may produce delayed effects in the offspring.

If appropriate, the mother should be offered the opportunity of a therapeutic abortion.

Owing to potential toxic risks to infants, breastfeeding should be discontinued during treatment.

ADVERSE REACTIONS

Bone marrow depression: in ever/ patient bone marrow function will be depressed by treatment with Daunorubicin and in a variable proportion of cases, severe aplasia with develop. The consequence may include severe infection and opportunistic infection. Leucopenia is usually more significant than thrombocytopenia. The nadir for leucopenia usually occurs between 10-14 days and recover occurs gradually over the next 1-2 weeks. Bone marrow depression must be anticipated in every case by eliminating infection before the treatment, by isolating the patient from infection during the treatment and by means of supportive therapy. This includes the continuous administration of anti-infective agents, the administration of platelet-rich plasma or fresh whole blood transfusion and, under some circumstances, the transfusion of white cell concentrates.

Other less serious adverse reactions that have been reported (in order of reducing frequency) are: stomatitis, alopecia, phlebitis, fever, anaemia, nausea, vomiting, mucositis, diarrhoea, rash and inflammator/ disease of the (large) bowel. The urine maybe temporarily coloured red after treatment. OVERDOSE

Although no cases have been reported to our knowledge, overdosage may result in drastic myelosuppression and severe cardiotoxicity with or without transient reversible ECG changes leading to congestive heart failure.

Treatment should be supportive and symptomatic. PHARMACEUTICAL PRECAUTIONS Vials containing Daunorubicin should be stored below 25°C and protected from light. Solutions of Daunorubicin should be used immediately after preparation or stored at 2-8°C and used within 24 hours. The solutions should be protected from light. The reconstituted solution does not contain an antimicrobial preservative. Daunorubicin solutions are unstable above pH8, decomposition being indicated by a change from red to blue-purple colour.

Daunorubicin injection is compatible with sodium chloride injection 0.9%. However a precipitate may form immediately if the solution is mixed with heparin sodium injection or dexamethasone sodium phosphate injection.

LEGAL CATEGORY: POM PACKAGE QUANTITIES:

Box of 1 x 20mg and 10 x 20mg vials.

FURTHER INFORMATION

Spill or Leak Procedures: Daunorubicin injection may be neutralised with sodium hypochlorite prior to disposal of unused drug or if a vial is accidentally broken.

The neutralised drug can be disposed of in the sink.

SPECIAL PROTECTION INFORMATION Daunorubicin should only be handled by staff experienced with cytotoxic drugs. Further information on handling is available from the Marketing Authorisation holder.

Text issued May 2016