New Zealand - English - Medsafe (Medicines Safety Authority)
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NEW ZEALAND DATA SHEET
Daunorubicin 2 mg/mL solution for injection
QUALITATIVE AND QUANTITATIVE COMPOSITION
daunorubicin hydrochloride 2.14 mg/mL (equivalent to 2 mg/mL daunorubicin).
Daunorubicin hydrochloride occurs as a hygroscopic, crystalline, orange-red powder, freely
soluble in water and in methanol, slightly soluble in alcohol and practically insoluble in
For the full list of excipients, see section 6.1.
Solution for injection
4.1 Therapeutic indications
Daunorubicin Injection is indicated for the treatment of the following:
Acute lymphocytic (lymphoblastic) leukaemia: Daunorubicin is usually reserved for use
in cases shown to be resistant to other drugs. However, combined treatment with
daunorubicin, vincristine and a steroid has been used in the early stages of this disease.
Acute myeloblastic leukaemia: Daunorubicin has been used in all stages, alone or in
combination with other cytotoxic agents (e.g. cytarabine).
Disseminated solid tumours: Daunorubicin has been investigated for use in these
tumours and found to be effective in some cases of disseminated neuroblastoma and
4.2 Dose and method of administration
Daunorubicin Injection is intended for intravenous use only and should not be administered
by either the intramuscular or the subcutaneous routes, as severe tissue necrosis will result.
Daunorubicin must be given into a rapidly flowing intravenous infusion.
The dosage of each individual injection may vary from 0.5 to 3 mg/kg, with the frequency of
repetition according to the dose:
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0.5 to 1 mg/kg repeated at intervals of one or more days;
2 mg/kg repeated at intervals of four or more days;
2.5 or 3 mg/kg, if used, should only be given at seven to fourteen day intervals.
Dosage must be adjusted to meet individual requirements of each patient, on the basis of
clinical response and appearance or severity of toxicity. One injection has sometimes
10 injections in one series have been used.
When second or subsequent injections are to be given the doses and the time intervals depend
examination of the peripheral blood and under some circumstances, of the marrow.
In acute lymphocytic leukaemia, doses of 1 mg/kg may be repeated according to tolerance
and effect at one to four day intervals.
In acute myeloblastic leukaemia, each dose should be about 2 mg/kg, more or less, according
to effect, repeated at four to seven day intervals. Doses of over 2 mg/kg should be employed
with caution at intervals of one week or longer.
When daunorubicin is administered with other cytotoxic drugs, which have a tendency to
depress the marrow, the dosage should be suitably reduced. Examples of combination dosage
regimens are as follows:
Acute lymphocytic leukaemia: Prednisolone 100 mg/m
daily with vincristine 1.5 mg/m
the first and second days of each week, until remission occurs.
Acute myeloblastic leukaemia: Repeated intermittent courses of daunorubicin and cytosine
1.5 mg/kg and cytarabine 2 mg/kg on the first day, followed by daily cytarabine only for a
further four days. It has been reported that an average of two to three such courses at ten day
intervals is required to induce remission.
Due to cardiotoxicity, the total lifetime dosage should not exceed 20 mg/kg (see section 4.4,
Cardiac Toxicity). The drug is therefore not suitable for maintenance therapy.
Daunorubicin should not be administered to patients with severe hepatic impairment (Child-
Pugh Grade C [total score 10-15]) (see section 4.3).
For patients with mild and moderate hepatic impairment (Child-Pugh Grade A [total score 5-
6] and B [total score 7-9]), dose reductions are recommended based on the following serum
Bilirubin 1.2 to 3 mg/dL: one-half of recommended starting dose
Bilirubin > 3 mg/dL: one-fourth of recommended starting dose
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Daunorubicin should not be administered to patients with severe renal function impairment
(GFR <10 mL/min or serum creatinine >7.9 mg/dL) (see section 4.3).
For patients with moderate renal impairment, glomerular filtration rate (GFR) between 10-20
mL/min or serum creatinine approximately between 3.4-7.9 mg/dL, the daunorubicin dose
should be reduced by one-half.
Method of Administration
It is recommended the injection be added to a free flowing IV infusion of 0.9% sodium
chloride or 5% dextrose injection. The tubing should be connected to a butterfly needle,
inserted preferably into a large vein. The dose and the size of the vein will determine the rate
of administration, which should not be less than 3-5 minutes. Erythematous streaking and
facial flushing are indications of too rapid administration.
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.
Instructions to be Given to Patients
Patients should be advised to immediately report any stinging or burning as these indicate
possible extravasations. If this occurs the infusion should be stopped, removed and restarted
in another vein.
Daunorubicin may transiently impart a red discolouration to the urine after administration;
patients should be advised to expect this.
Complete alopecia is common but reversible on withdrawal of treatment. Patients should be
made aware of this adverse effect before commencement of treatment.
Due to the increased frequency of infection as well as haemorrhagic complications resulting
from daunorubicin therapy, the patient should be instructed to notify the doctor if fever, sore
throat, or unusual bleeding or bruising occurs.
Daunorubicin Injection is contraindicated in:
Patients with persistent myelosuppression; or marked myelosuppression induced by
previous treatment with other cytotoxic agents or radiotherapy.
Patients with impaired
cardiac function (including myocardial insufficiency, recent
myocardial infarction and severe arrhythmias).
Patients who have previously received the full cumulative dose of daunorubicin and/or
doxorubicin. and/or other anthracyclines and/or anthracenediones (see section 4.4).
Patients with known hypersensitivity to daunorubicin. or any other component of the
product, other anthracyclines, or anthracenediones.
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Patients with severe infections.
Patients with severe hepatic (Child-Pugh Grade C [total score 10-15]) or renal function
impairment (GFR <10 mL/min or serum creatinine >7.9 mg/dL).
Patients who are pregnant.
4.4 Special warnings and precautions for use
Daunorubicin should be administered only under the supervision of a physician who is
experienced in the use of cancer chemotherapeutic agents.
Initial treatment with daunorubicin requires close observation of the patient and extensive
laboratory monitoring. It is recommended, therefore, that patients be hospitalised at least
during the first phase of treatment. Blood counts and monitoring of parameters of renal and
liver function should be performed prior to each treatment with daunorubicin.
Administration of myelosuppressive drugs such as daunorubicin may lead to an increased
frequency of infections and haemorrhagic complications. These complications are potentially
fatal therefore patients should be instructed to notify the physician if fever, sore throat, or
unusual bruising or bleeding occurs.
Patients should recover from acute toxicities of prior cytotoxic treatment (such as stomatitis,
neutropenia, thrombocytopenia, and generalised infections) before beginning treatment with
Special attention must be given (by close cardiac monitoring) to the cardiac toxicity exhibited
by daunorubicin, especially in infants and children.
Daunorubicin has a cardiotoxic effect, which can be manifested under two distinct sets of
Firstly, daily administration of large doses (of ≥2 mg/kg(or ≥55 mg/m
)) will result in
transient reversible electrocardiogram ECG changes in a proportion of cases. This can be
avoided by administering the drug at longer intervals.
Secondly, exceeding the total cumulative dose of 20 mg/kg (or 550 mg/m
) may result in
irreversible cardiac failure. This can occur with very little warning and after only a short
period of tachycardia.
Cardiomyopathy usually appears within 1 to 6 months after initiation of therapy. It may
develop suddenly and may not be detected by routine ECG. It may be irreversible and fatal
but responds to treatment if detected early.
Acute and Delayed Cardiotoxicity
Cardiotoxicity may be manifested by early (i.e. acute) or late (i.e. delayed) events.
Early (i.e. acute) events: Early cardiotoxicity of daunorubicin consists mainly of sinus
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Tachyarrhythmias, including premature ventricular contractions, as well as heart 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
discontinuation of daunorubicin treatment.
Late (i.e. delayed) events: Delayed cardiotoxicity usually develops late in the course of
therapy with daunorubicin 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
effusion, and gallop rhythm. Life-threatening CHF is the most severe form of anthracycline-
induced cardiomyopathy and represents the cumulative dose-limiting toxicity of the drug.
Risk Factors for Cardiotoxicity
There is increased risk of cardiac toxicity (and lower cumulative dosage limit) in patients
previously treated with doxorubicin or in those who received prior or concomitant radiation
therapy that encompassed the heart (mediastinal/pericardial area).
Pre-existing active or dormant heart disease, concomitant use of drugs with the ability to
anthracenediones are suspected co-factors of increased risk of daunorubicin-induced cardiac
anthracenediones is additive.
Anthracyclines including daunorubicin should not be administered in combination with other
monitored. Patients receiving anthracyclines after stopping treatment with other cardiotoxic
agents, especially those with long half-lives such as trastuzumab (variable half-life; washout
period up to 7 months), may also be at an increased risk of developing cardiotoxicity. Under
these conditions, a total cumulative dose of 400 mg/m
in adults should be exceeded only
with extreme caution.
It has also been suggested, but is not clearly established, that concurrent therapy with
cyclophosphamide or some other antineoplastic agents (e.g. dacarbazine, dactinomycin,
mitomycin) may increase the risk of daunorubicin-induced cardiotoxicity.
Cardiac function must be carefully monitored in all patients receiving high cumulative doses
and in those with risk factors. However, cardiotoxicity with daunorubicin may occur at lower
cumulative doses whether or not cardiac risk factors are present.
In infants and children there appears to be a greater susceptibility to anthracycline-induced
cardiac toxicity, and a long-term periodic evaluation of cardiac function has to be performed.
Total Cumulative Dosage
The incidence of cardiotoxicity is more frequent in adults receiving a total cumulative dose
over 550 mg/m
(or over 20 mg/kg body weight) or over 400 mg/m
in patients who have
received concurrent cyclophosphamide or previous chest irradiation, in the elderly, and in
patients with a history of cardiac disease or mediastinal radiation. In adults, at total
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encountered, although rare instances of pericarditis-myocarditis, not dose related, have been
Children may be more susceptible to the development of cardiomyopathy than adults.
However the risk of developing cardiomyopathy is reduced with a total dose less than
in children over 2 years of age or at a total dosage of less than 10 mg/kg in
children younger than 2 years of age with a body surface area of less than 0.5 m
Monitoring of Cardiac Function
Cardiac function should be assessed before patients undergo treatment with daunorubicin and
must be monitored throughout therapy to minimise the risk of incurring severe cardiac
impairment. There is no absolutely reliable method of predicting the patients in whom acute
congestive heart failure will develop as a result of daunorubicin therapy. However, certain
changes in the ECG and a decrease in the left ventricular ejection fraction (LVEF) from pre-
treatment baseline may help to recognise those patients at greatest risk. On the basis of the
ECG, a decrease equal to or greater than 30% in limb lead QRS voltage has been associated
with a significant risk of drug-induced cardiomyopathy. The appropriate quantitative method
for repeated evaluation of LVEF includes multi-gated radionuclide angiography (MUGA) or
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
daunorubicin at the first sign of impaired cardiac function. Early clinical diagnosis of drug-
induced congestive heart failure appears to be essential for successful treatment with digoxin,
diuretics, sodium restriction and bed rest.
Bone Marrow Depression
Bone marrow depression and consequent marked cytopenia will occur in all patients who
receive daunorubicin and requires careful monitoring. The severity being dependent on the
dose received and the regenerative capacity of the bone marrow. Evaluation of response
based on bone marrow status cellularity is necessary to guide daunorubicin treatment.
Myelosuppression is manifested primarily by
leucopenia, which is usually severe, and
thrombocytopenia. Anaemia may also occur. Leucocyte and platelet nadirs usually occur
around days 10-14, with recovery around day 21 following therapy.
daunorubicin therapy, including differential white blood cell counts.
sepsis/septicaemia, septic shock, haemorrhage, tissue hypoxia, or death. During a course of
therapy special attention should be devoted to patients with severe neutropenia and fever
(febrile neutropenia), a condition that can be possibly followed by septicaemia and death.
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In a variable proportion of cases, a severe aplasia will develop which must be anticipated in
every case by eliminating infection before treatment, by isolating the patient from infection
administration of anti-infective agents, the administration of platelet rich plasma or fresh
whole blood transfusion and, under some circumstances, the transfusion of blood or white
cells from cases of hyperleucocytic chronic myeloid leukaemia. Therapy with daunorubicin
should not be started in patients with pre-existing drug-induced bone marrow depression
unless the benefit from such treatment warrants the risk.
Secondary leukaemia, with or without a preleukemic phase, has been reported in patients
treated with anthracyclines, including daunorubicin. Secondary leukaemia is more common
when such drugs are given in combination with DNA-damaging antineoplastic agents, in
combination with radiotherapy, when patients have been heavily pre-treated with cytotoxic
drugs, or when doses of the anthracyclines have been escalated. These leukemias can have a
1- to 3-year latency period.
Immunosuppression/Increased Susceptibility to Infections
Daunorubicin possesses immunosuppressive properties. Appropriate measures should be
taken to prevent secondary infection.
chemotherapeutic agents including daunorubicin, may result in serious or fatal infections.
Vaccination with a live vaccine should be avoided in patients receiving daunorubicin. Killed
or inactivated vaccines may be administered; however, the response to such vaccines may be
diminished (see section 4.5).
concurrently and dosage should be suitably reduced (see section 4.5).
Nausea and vomiting are usually mild and transient, occurring soon after administration and
lasting 24 to 48 hours. Severe nausea and vomiting may produce dehydration. Nausea and
vomiting may be prevented or alleviated by the administration of appropriate antiemetic
Mucositis (mainly stomatitis, less often oesophagitis) may occur in patients undergoing
daunorubicin therapy. Mucositis/stomatitis generally appear early after drug administration
(burning and erythema of the oral mucosa; sores in the mouth and/or lips occurring 3 to 7
days after administration) and if severe, may progress over a few days to mucosal ulcerations
(7 to 10 days after administration). Most patients recover from this adverse event by the third
week of therapy.
Renal impairment can enhance the toxicity of recommended doses of daunorubicin. Prior to
administration, it is recommended that renal function be evaluated using conventional clinical
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laboratory tests. Dosage should be reduced
in patients with impaired renal
(see sections 4.3 and 4.2).
Daunorubicin has been implicated as causing renal failure and should therefore be used with
caution when renal damage exists.
Hepatotoxic effects have been reported resulting from daunorubicin treatment. Care should
therefore be exercised when treating patients with impaired liver function.
The major route of elimination of daunorubicin is the hepatobiliary system. Serum total
bilirubin should be evaluated before and during treatment with daunorubicin. 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).
Patients with severe hepatic impairment must not receive daunorubicin (see section 4.3).
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).
Extravasation of daunorubicin at the site of intravenous administration can cause local pain,
severe tissue lesions (vesication, severe cellulitis) and necrosis. Should signs or symptoms of
extravasation occur during intravenous administration of daunorubicin, the drug infusion
should be immediately stopped.
Hyperuricaemia/Tumour Lysis Syndrome
catabolism that accompanies rapid drug-induced destruction of a large number of leukaemia
cells (tumour-lysis syndrome).
It is recommended to check the blood uric acid urea potassium, calcium phosphate and
creatinine levels, three or four times a week during the first week of treatment, Hydration,
urine alkalinisation and prophylaxis with allopurinol to prevent hyperuricemia may minimise
potential complications of tumor-lysis syndrome.
There is little evidence of neurotoxic effects.
Complete alopecia involving beard growth and the scalp, axillary and pubic hair occurs
almost always with full doses of daunorubicin. This side-effect may cause distress to patients
but is usually reversible, with regrowth of hair, which usually occurs within two to three
months from the termination of therapy.
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Increased radiation toxicities such as skin reactions and mucositis may result from concurrent
radiotherapy and daunorubicin therapy.
4.5 Interaction with other medicines and other forms of interaction
Daunorubicin is mainly used in combination with other cytotoxic drugs. Additive toxicity
may occur especially with regard to bone marrow/haematologic and gastrointestinal effects
potentially cardiotoxic drugs as well as the concomitant use of other cardioactive compounds
(e.g. calcium channel blockers) requires monitoring of cardiac function throughout treatment.
daunorubicin metabolism, pharmacokinetics, therapeutic efficacy and/or toxicity.
The cardiotoxic effects of daunorubicin may be enhanced by concurrent treatment with
cyclophosphamide. Daunorubicin may exacerbate cyclophosphamide induced haemorrhagic
cystitis. It is recommended that the total dose of daunorubicin not exceed 400 mg/m
surface area when administered concurrently with cyclophosphamide.
cardiotoxicity. Daunorubicin should not be administered to patients who have received the
complete cumulative dose of doxorubicin.
Allopurinol, Colchicine, Probenecid or Sulphinpyrazone
daunorubicin induced hyperuricaemia because of the risk of uric acid nephropathy with
uricosuric antigout agents.
Other Bone Marrow Depressants
Reduced dosage of daunorubicin may be required.
Concurrent administration may increase the risk of hepatotoxicity.
Live Virus Vaccines
Due to its immunosuppressive properties, concurrent use of daunorubicin with a live virus
vaccine may potentiate the replication of the vaccine, increase the adverse effects of the
vaccine virus, or decrease the patient’s antibody response to the virus.
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4.6 Fertility, pregnancy and lactation
Pregnancy - Category D
Daunorubicin has shown teratogenic, mutagenic and carcinogenic potential in animals. The
drug must be considered as a potential cause of foetal malformations when administered to a
pregnant woman. Daunorubicin should not be used during pregnancy (see section 4.3).
Daunorubicin should only be used in women of childbearing potential if the expected benefits
outweigh the risks of therapy and adequate contraception is used. If the patient becomes
pregnant whilst receiving the drug she should be advised of the potential hazard to the foetus.
Category D: Drugs that have caused, are suspected to have caused - or may be expected to
cause - an increased incidence of human foetal malformations or irreversible damage. These
drugs may also have adverse pharmacological effects.
It is not known whether daunorubicin is excreted in breast milk therefore breastfeeding is not
recommended during daunorubicin therapy in lactating women. It is recommended that
daunorubicin is not administered to mothers who are breastfeeding.
Daunorubicin, could induce chromosomal damage in human spermatozoa. Men undergoing
treatment with daunorubicin should use effective contraceptive methods.
4.7 Effects on ability to drive and use machinery
No data available.
4.8 Undesirable effects
The adverse effects are listed by system organ class and frequency category. Frequency
categories are defined as: very common (
1/10), common (
1/100 to <1/10), uncommon
1/1,000 to <1/100), rare (
1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot
be estimated from the available data) (see section 4.4).
System Organ Class
Infections and Infestations
Malignant and Unspecified
(including cysts and polyps)
Acute myeloid leukemia
Blood and Lymphatic
Bone marrow failure; leukopenia;
Immune System Disorders