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DAUNOXOME INJECTION 2MG/ML CONCENTRATE FOR SOLUTION FOR INFUSION

Active substance(s): DAUNORUBICIN HYDROCHLORIDE / DAUNORUBICIN HYDROCHLORIDE / DAUNORUBICIN HYDROCHLORIDE

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GB 5649 4000 C 40

SUMMARY OF PRODUCT CHARACTERISTICS

DaunoXome®

1. NAME OF THE MEDICINAL PRODUCT
DaunoXome Injection 2mg/ml Concentrate for Solution for Infusion
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Daunorubicin hydrochloride, Ph.Eur., present as citrate salt, equivalent to daunorubicin 2.0mg/ml,(50mg)
encapsulated in liposomes. The liposomes are small unilamellar vesicles with mean diameter of about
45nm. The active ingredient is daunorubicin, an anthracycline antibiotic with antineoplastic activity
originally obtained from Streptomyces peucetius. Daunorubicin has a four ring anthracycline moiety
linked by a glycosidic bond to daunosamin, an amino sugar. Daunorubicin is currently isolated from
Streptomyces coeruleorubidus and is described by the following chemical name:
(8S,10S)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-6,8,11-trihydroxy-1methoxy-7,8,9,10-tetrahydronaphthacene-5,12-dione.
Daunorubicin has a molecular weight of 527.5 and is represented by the formula C27H29NO10.
For the full list of excipients, see Section 6.1.
3. PHARMACEUTICAL FORM
Each vial contains a sterile, pyrogen free, preservative-free liposomal emulsion. This emulsion is red and
clear to slightly opalescent in appearance. The product is an injectable intended to be administered by
intravenous infusion.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
DaunoXome is indicated for the treatment of advanced HIV-related Kaposi's Sarcoma.
4.2 Posology and method of administration
DaunoXome should be administered by intravenous infusion. The recommended initial dose of
DaunoXome in patients with AIDS-related Kaposi’s sarcoma is 40mg/m2 every two weeks. The dosage of
DaunoXome must be adjusted for each patient. Therapy should be continued as long as disease control
can be maintained.
DaunoXome should be diluted with 5% dextrose for infusion before administration. The recommended
concentration after dilution is between 0.2mg and 1mg daunorubicin/ml of solution. DaunoXome should
be administered intravenously over a minimum period of 30-60 minutes (See also Sections 6.2, 6.3 and
6.6).
DaunoXome must not be given by the intramuscular or subcutaneous route or as a bolus injection.
DaunoXome is a liposomal preparation and should not be used interchangeably with conventional
daunorubicin.
Paediatric patients: DaunoXome is not recommended for use in children below 18 years of age due to
insufficient data on safety and efficacy.
Elderly: The safety and effectiveness of DaunoXome in patients over 65 years of age have not been
established. Cardiotoxicity may be more frequent in the elderly (see Section 4.4).
Hepatic impairment: Limited clinical experience exists in treating hepatically impaired patients with
DaunoXome. Therefore, based on experience with conventional daunorubicin HCl, it is recommended
that the dosage of DaunoXome be reduced if bilirubin is elevated as follows:
- Serum bilirubin 1.2 to 3mg/dl (20.3 to 50.8µmol/l), give 75% of the normal dose
- Serum bilirubin > 3mg/dl (>50.8µmol/l), give 50% of the normal dose.
Renal impairment: Limited clinical experience exists in treating renally impaired patients with DaunoXome.
Therefore, based on experience with conventional daunorubicin HCl, it is recommended that the dosage
of DaunoXome be reduced if creatinine is elevated as follows:
Serum creatinine > 3mg/dl (>265µmol/l), give 50% of the normal dose.
4.3 Contraindications
Hypersensitivity to DaunoXome, any of its excipients or other anthracyclines/anthracenediones.
Pregnancy and breast feeding.
4.4 Special warnings and precautions for use
The decision to treat must be based on an evaluation, by the physician, of the benefits and risks for the
individual patient.
Cardiotoxicity
DaunoXome and other anthracyclines can cause cardiotoxicity, notably congestive heart failure due to
cardiomyopathy. The onset of symptoms can be sudden and may not occur until weeks or months after
discontinuation of therapy. Cardiac damage may be irreversible and there have been rare reports of
fatalities, usually in patients with risk factors.
The risk of cardiotoxicity increases with total cumulative dosage of anthracyclines. Caution must therefore
be exercised in patients previously treated with anthracyclines, or those with previous (or concomitant)
therapy with other cardiotoxic compounds such as 5-fluorouracil (5-FU).
The maximum cumulative dose of DaunoXome is not known. The pharmacokinetics of liposomal
(DaunoXome) and conventional daunorubicin are different. However, based on experience with
conventional daunorubicin, daunorubicin hydrochloride must not be used if the maximum cumulative
dose of daunorubicin hydrochloride, 500-600mg/m2 in adults, or the maximum cumulative dose of other
cardiotoxic anthracyclines (e.g idarubicin, epirubicin) or anthracenediones (e.g. mitoxantrone), has been
previously administered, as the risk of life-threatening cardiac damage markedly increases. The total
cumulative dose should be limited to 400mg/m2 in patients who have had previous radiation therapy to
the chest or previous administration (at less than the maximum cumulative dose) of other potentially
cardiotoxic drugs.
The risk of cardiotoxicity appears to be higher in those with pre-existing cardiovascular disease, a history
of mediastinal radiation and the elderly. Caution must therefore be exercised when DaunoXome is given
to these patients. DaunoXome should only be given to patients with cardiovascular disease when the
benefit outweighs the risks.
Experience in patients treated with high dose DaunoXome (above 60mg/m2) for malignancies other than
Kaposi’s sarcoma indicates that the risk of cardiotoxicity may be higher in these patients.
Cardiac monitoring
Careful monitoring of cardiac function is essential in patients treated with DaunoXome.
Cardiomyopathy induced by anthracyclines is usually associated with a decreased left ventricular ejection
fraction (LVEF) measured by echocardiography or by MUGA (Multiple Gated Acquisition). Measurement
of LVEF provides a more specific method for monitoring cardiac function than ECG.
All patients should undergo baseline ECGs, echocardiography and measurement of LVEF prior to starting
DaunoXome. These tests should be repeated regularly during treatment. Furthermore, in all patients,
LVEF must be determined when a cumulative dose of 320mg/m2 has been reached, then every 160mg/m2
thereafter, in order to identify at an early stage any changes in LVEF that may be a precursor to
cardiomyopathy if DaunoXome therapy is continued.
In patients with risk factors for cardiotoxicity with DaunoXome, or those receiving high dose DaunoXome
per cycle (e.g. 120mg/m 2 or above), decreases in cardiac function may occur at lower cumulative doses
of DaunoXome, therefore consideration should be given to determination of LVEF after each treatment
cycle and before any additional DaunoXome is administered.
Transient ECG changes such as T-wave flattening, S-T segment depression and benign arrhythmias are
not considered mandatory indications for cessation of DaunoXome. A reduction of the QRS wave is
considered more indicative of cardiac toxicity.
Whenever cardiomyopathy is suspected, and/or LVEF has decreased significantly as compared to
pre-treatment values (e.g. 20% decline) and/or if the LVEF is lower than would be expected (e.g. <45%),
the benefit of continued therapy must be carefully weighed against the risk of producing irreversible
cardiac damage.
It is recommended that DaunoXome is stopped if signs or symptoms of heart failure occur.
Several long-term studies in children also suggest that after anthracycline treatment congestive
cardiomyopathies with a latency of many years may occur.
Haematological toxicity
DaunoXome is a bone marrow suppressant. The most significant effect is usually neutropenia, which may

PACKAGE LEAFLET: INFORMATION FOR
THE USER

DaunoXome
Injection 2mg/ml concentrate for

solution for infusion
Daunorubicin

Read all of this leaflet carefully before you
start using this medicine.
Keep this leaflet. You may need to
read it again.
If you have any further questions, ask
your doctor.
This medicine has been prescribed for
you. Do not pass it on to others. It may
harm them, even if their symptoms are
the same as yours.
If any of the side effects gets serious,
or if you notice any side effects not
listed in this leaflet, please tell your
doctor. See section 4.

1. What DaunoXome is
and what it is used for
What DaunoXome is
DaunoXome is an anti-cancer
medicine (a cytotoxic agent) which
reduces tumour cell growth. The
active substance of DaunoXome is
daunorubicin. DaunoXome is a special
formulation of daunorubicin (in
liposome form), which is used to treat
a type of cancer known as Kaposi’s
sarcoma. Kaposi’s sarcoma is a form of
cancer that mainly affects the skin, but
which can also affect the lungs and
intestines.

What DaunoXome is used for
DaunoXome is used for the treatment
of a severe form of Kaposi’s sarcoma in
patients with AIDS.

In this leaflet:

1. What DaunoXome is
and what it is used for
2. Before you use
DaunoXome
3. How DaunoXome is
used
4. Possible side effects
5. How to store
DaunoXome
6. Further information

2. Before you use
DaunoXome
DaunoXome is not to be used:
if you are allergic (hypersensitive)
to daunorubicin or any of the other
ingredients of DaunoXome, or
any other medicines belonging to
the same group (these are called
anthracyclines or anthracenediones).
if you are pregnant or breastfeeding.
If any of these applies to you, you
must not be given DaunoXome.
If in doubt, ask your doctor or
pharmacist for advice.

Take special care with
DaunoXome
This medicine can cause heart
problems (cardiac failure) because
of its effects on heart muscle. Rarely,
these heart problems can be fatal.
Heart problems can develop suddenly
and may occur weeks or months
after the end of treatment. Damage
to the heart may be irreversible. As
a precaution, your doctor will carry

be severe and result in fever and infection. Anemia and thrombocytopenia may also occur, but are usually
less marked. Persistent severe myelosuppression may result in sepsis, or haemorrhage. Complete blood
counts must be performed prior to each dose and frequently during the course of DaunoXome therapy.
Patients with malignancies or with HIV infection, whose immune system is already compromised, must
be monitored carefully for evidence of intercurrent or opportunistic infections.
Anti-infective therapy should be employed in the presence of suspected or confirmed infection and
during febrile neutropenia.
Haematological toxicity may require dose reduction of DaunoXome or suspension or delay of therapy.
The colony stimulating factor GCSF has been used to manage patients with neutropenia.
Caution is warranted when combining DaunoXome with other agents which suppress bone marrow
function.
Injection site reactions
Care should be taken to ensure that there is no extravasation of DaunoXome during administration.
Paravenous administration has resulted in erythema, pain and swelling around the site of tissue infiltration.
These changes are generally transitory, resolving within 6 months. However, localised tissue necrosis must
still be regarded as a possible consequence of extravasation.
If any signs or symptoms of extravasation occur (e.g. stinging, erythema), the infusion should be stopped
immediately and re-started in another vein. The affected limb should be elevated. It may be inappropriate
to provide any measure that might cause release of the drug from the liposome (such as application of
ice or corticosteroids, instillation of local antidotes, local compression, etc.)
Acute infusion-associated reactions
Acute infusion-related reactions have been reported in patients treated with DaunoXome. Symptoms
typically include back pain, flushing, chest tightness and dyspnoea. These infusion reactions may
occur during the patient’s first exposure to DaunoXome, or during re-exposure in a patient who had
previously received DaunoXome without incident. Infusion-related reactions generally occur within
the first 10 minutes of the infusion and subside when the infusion is slowed or halted. Acute allergic/
anaphylactic reactions, sometimes associated with hypotension, have also been reported.
Caution is also required with preceding, concurrent or planned radiotherapy as these patients, during
treatment with daunorubicin hydrochloride, have an increased risk of local reactions in the radiation area
(recall phenomena).
Liver and renal function
Daunorubicin hydrochloride is metabolised predominantly in the liver and is excreted via the bile.
Monitoring of liver and renal function before starting and during treatment with DaunoXome, is
recommended. For advice on dosage adjustment in patients with liver or renal impairment, see
Section 4.2.
Immunosuppressant effects/increased susceptibility to infections
Administration of live or live-attenuated vaccines in patients immunocompromised by 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.
Reproductive system and breast disorders
Daunorubicin hydrochloride inhibits fertility. Based on experience with conventional daunorubicin,
amenorrhoea and azoospermia may occur. Irreversible disorders of fertility are possible (see Section 4.6).
Birth defects
Daunorubicin may cause serious birth defects when used during pregnancy (see Section 4.6). DaunoXome
is contra-indicated in pregnancy (see Section 4.3).
4.5 Interaction with other medicinal products and other forms of interaction
Daunorubicin hydrochloride is mainly metabolised in the liver; concomitant medication influencing liver
function may also therefore influence the metabolism or pharmacokinetics of daunorubicin hydrochloride
and, as a consequence, influence efficacy and/or toxicity.
Protease Inhibitors (PIs) and Non Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) are known inhibitors
of Cytochrome P450 IIIA (CYP-3A) and may also have a role in the inhibition of the drug transporting
protein, P-glycoprotein (P-gp). Daunorubicin and other anthracyclines may undergo some metabolism
by CYP-3A and are known substrates of P-gp. There is therefore a theoretical possibility of interaction
between DaunoXome and these two groups of antiviral therapy. To date however, a single study has
indicated that there is no effect of PIs or NNRTIs on DaunoXome’s pharmacokinetic properties. Limited
data from one small study where patients were treated with and without protease inhibitors indicate
that there were no major changes in DaunoXome associated toxicity.
Caution should be exercised when DaunoXome is used concomitantly with other myelosuppressive or
cardiotoxic agents. The risk of gastrointestinal side-effects increases with the concurrent administration
of other cytotoxics. Mucositis (oral and gastrointestinal) occurring in association with daunorubicincontaining chemotherapy may impair the absorption of oral medicinal products. Live vaccines should
be avoided. Killed or inactivated vaccines should be used with caution (see Section 4.4).
Caution should be taken when DaunoXome is administered concurrently with antiplatelet drugs such as
aspirin (acetylsalicylic acid), clopidogrel, dipyridamole, eptifibatide and other agents which inhibit
platelet/thrombocyte aggregation. Thrombocytopenic patients will be at increased risk of bleeding
disorders.
4.6 Fertility, pregnancy and lactation
Fertility and Contraceptive Measures
Daunorubicin could induce chromosomal damage in human spermatozoa. Men should receive
counselling on sperm cryopreservation before the start of daunorubicin treatment because of the
possibility of irreversible infertility. Men undergoing treatment with daunorubicin should use effective
contraceptive methods during and for 6 months after treatment.
Women of childbearing potential have to use effective contraception while they or their male partner is
receiving DaunoXome, and for 6 months following discontinuation of treatment with DaunoXome. For
women who want to become pregnant after completing DaunoXome treatment, genetic counselling is
also recommended.
Pregnancy
Studies in animals have shown reproductive toxicity (see Section 5.3 Preclinical safety data). Like most
other anticancer drugs, daunorubicin has shown embryotoxic, teratogenic, mutagenic and carcinogenic
potential in animals. There are no or limited amount of data from the use of daunorubicin in pregnant
women, although a few women who received daunorubicin during the second and third trimesters of
pregnancy have delivered apparently normal infants.
According to experimental data, 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 unless
the clinical condition of the woman requires treatment with daunorubicin and justifies the potential risk
to the foetus. Women of child-bearing potential who have to undergo daunorubicin therapy should be
informed about the potential hazard to the foetus and should be advised to avoid becoming pregnant
during treatment. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving
the drug, the woman should be informed of the potential hazard to the foetus. The possibility of genetic
counselling should also be utilised. In any case, cardiologic examination and a blood count are
recommended in foetuses and newborns born to mothers who received treatment with daunorubicin
during pregnancy.
Lactation
It is unknown whether daunorubicin/metabolites are excreted in human milk; other anthracyclines
are excreted in breast milk. DaunoXome is contraindicated during breast-feeding (see Section 4.3
Contraindications).
4.7 Effects on ability to drive and use machines
No studies have been performed on the effects of DaunoXome on the ability to drive and use machines.
However, patients should be informed that dizziness, nausea and vomiting have been reported with
DaunoXome and may affect the ability to drive and operate machinery.

out tests to monitor your heart’s
performance, before and during the
treatment.
Make sure your doctor knows
about any heart problems you have
had
Tell your doctor if you have been
treated before with any medicines
in the same class as DaunoXome
(anthracyclines or anthracenediones).
The risk of heart problems is higher in
some situations:
if you have existing heart problems
if you are over 65 years old
if you have been given high doses
of DaunoXome, or high total
doses of other anthracycline/
anthracenedione medicines as
well as DaunoXome
if you have been treated with other
medicines that may damage the
heart
if you have received radiation
therapy to the chest.
DaunoXome can suppress bone
marrow activity, which can cause
fever; infections, including infection in
the blood (sepsis); bleeding problems
and reduced red blood cells (anaemia).
Your doctor will carry out regular
blood monitoring. The risk of bone
marrow problems with DaunoXome is
higher if you already have a weakened
immune system.
Daunoxome may also cause tissue
damage such as redness, swelling
or pain at the site of infusion if the
product leaks from the vein. This
damage usually resolves within 6
months.
Tell your doctor if you notice a
stinging pain, redness or leakage of
fluid in the area of the infusion site.
Tell your doctor before treatment
with DaunoXome if you have received,
are receiving or are due to receive
radiation therapy.
If you have impaired kidney or liver
function, your doctor may reduce your
dose of DaunoXome.
DaunoXome is not usually
recommended for children or older
people. Its safety and efficacy has not
yet been studied in these two groups.

Other medicines and
DaunoXome
Tell your doctor if you are taking any
other medicines, or have recently
taken any. This includes medicines and
herbal products you bought without a
prescription.
Daunorubicin can cause inflammation
of the lining of the mouth and
gastrointestinal tract which may affect
the absorption of other medicines
taken orally (by mouth).
Other medicines that affect the
heart or bone marrow
Your doctor will be especially careful if
DaunoXome is given at the same time
as any medicine which reduces the
function of the heart or of the bone
marrow, and with medicines that
suppress the immune system. This
includes medicines in the same class
as DaunoXome (anthracyclines or
anthracenediones).
Other anti-cancer medicines
If you are being treated with other
cytotoxics (anti-cancer medicines) at
the same time as DaunoXome, you
are likely to be at an increased risk of
gastrointestinal side effects.
Anti-viral medicines for HIV
There is a possibility that DaunoXome
may interact with two groups of
anti-HIV medicines, protease inhibitors
(PIs) and non-nucleoside reverse
transcriptase inhibitors (NNRTIs).
Antiplatelet medicines to prevent
blood clots
You should tell your doctor if you are
taking an antiplatelet medicine to
prevent blood clots. Some examples
of antiplatelet medicines are aspirin
(acetylsalicylic acid), clopidogrel,
dipyridamole, eptifibatide; there are
other antiplatelet medicines also
available, so you should check with
your doctor if you are not sure.
Medicines that affect the liver
Some medicines may have an effect
on how your liver works and may,
therefore, have an effect on
DaunoXome. Please tell your doctor
about all other medicines that you are
taking or that you have taken recently.

Vaccinations
Tell your doctor or nurse that you are
taking DaunoXome if you are due to
receive any vaccination, as some
vaccines cannot be given to patients
being treated with DaunoXome.
Tell your doctor if you are taking
or have recently taken any of these.

Pregnancy, breast-feeding
and fertility
If you are pregnant or breast-feeding,
think you may be pregnant or are
planning to have a baby, ask your
doctor or pharmacist for advice
before taking this medicine.
DaunoXome can cause serious birth
defects if it is used during pregnancy.
Therefore, DaunoXome must not be
used during pregnancy, unless your
doctor considers it to be vital.
In this case, your doctor should discuss
the possible risks for your unborn child
with you. If you become pregnant
during treatment, you should seek
genetic advice.
DaunoXome should not be used in
mothers who are breast-feeding.
Treatment with DaunoXome may
affect your fertility (female and male).
You should speak to your doctor about
the possible effects on fertility before
your treatment starts.
Men who are treated with
daunorubicin should have counselling
about sperm cryopreservation
before the start of treatment. It is
recommended that men who are
treated with daunorubicin should
not father a child during treatment
or for 6 months afterwards.
Women of childbearing potential have
to use effective contraception during
treatment with daunorubicin and for 6
months after treatment. For women
who want to become pregnant after
treatment with daunorubicin, genetic
counselling is also recommended.

28/04/16

4.8 Undesirable effects
The adverse reactions considered at least possibly related to treatment with DaunoXome are listed below,
by body system organ class and absolute frequency. Frequencies are defined as follows: very common
≥ 10%; common ≥ 1% and < 10%; uncommon ≥ 0.1% and < 1%; rare ≥ 0.01% and < 0.1%, very rare < 0.01%,
not known (cannot be estimated from the available data).
System Organ
Class

Frequency of adverse reactions
Very Common
Common

Infections and
infestations

Infections

Blood and
lymphatic
system
disorders

Bone marrow
suppression,
Bone marrow
failure,
Agranulocytosis,
Neutropenia,
Febrile
neutropenia,
Leucopenia,
Pancytopenia,
Thrombocytopenia and
Anaemia*

Immune
system
disorders

Infusionassociated
reactions
(including back
pain, flushing,
chest tightness,
dyspnoea,
allergic
reactions)*

Psychiatric
disorders

Depression

Cardiac
disorders*

Haemorrhage

Respiratory,
thoracic and
mediastinal
disorders

Dyspnoea

Gastrointestinal
disorders

Stomatitis,
Mucous
ulcerations,
Nausea,
Vomiting,
Diarrhoea,
Abdominal pain

6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Liposome:
Distearoylphosphatidylcholine
Cholesterol, USNF
Citric acid, Ph.Eur.
Congestive
heart failure,
Cardiomyopathy

Atrial
fibrillation,
Myocardial
infarction
Shock

Colitis

Hepatobiliary
disorders

Skin and
subcutaneous
tissue
disorders

Transient
elevations in
serum bilirubin,
aspartate
aminotransferase (AST) and
alkaline phosphatase (ALP)
concentrations,
Hepatitis,
Hepatic failure
Alopecia

Palmar-plantar
erythrodysaesthesia
syndrome**

Renal and
urinary
disorders

Red
discolouration
of urine

Reproductive
system and
breast
disorders

Amenorrhoea,
Azoospermia

General
disorders and
administration
site conditions

Asthenia,
Fatigue,
Fever, Chills

Extravasation at
the injection site
may result in
erythema, pain
and swelling*

* See Section 4.4
** Palmar-plantar erythrodysaesthesia syndrome (hand-foot syndrome) has been reported rarely in
patients treated with high dose DaunoXome and cytarabine for leukaemia. The condition is characterised
by swelling, pain, tingling and erythema of the palms and soles, which may lead to desquamation of the
skin in some patients. Dose reduction or delayed dosing may be required to manage the condition.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at:
www.mhra.gov.uk/yellowcard
4.9 Overdose
From experience with non-liposomal anthracycline preparations, the primary anticipated toxicity from
overdose would be myelosuppression. Other side effects may occur in more pronounced form, like
cardiomyopathy. In the event of overdose, bone marrow function and cardiac function should be
carefully monitored with appropriate therapy for any severe side-effects.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
DaunoXome is a liposomal preparation of daunorubicin formulated to maximise the selectivity of
daunorubicin for solid tumours in situ. This tumour selectivity has been demonstrated for transplanted
tumours in animal models. While in the circulation, the DaunoXome formulation protects the entrapped
daunorubicin from chemical and enzymatic degradation, minimises protein binding, and generally
decreases uptake by normal tissues, as well as by the non-reticuloendothelial system. The specific
mechanism by which DaunoXome is able to deliver daunorubicin to solid tumours in situ is not known.
However, it is believed to be a function of increased permeability of the tumour neovasculature to some
particulates in the size range of DaunoXome. Thus, by a decrease in distribution and uptake of normal
tissues and binding to plasma proteins and by selective extravasation in tumour neovasculature, the
pharmacokinetics of daunorubicin are favourably shifted towards an accumulation of DaunoXome in
tumour tissue. Once within the tumour environment, DaunoXome vesicles enter the tumour cells intact.

Driving and using machines
Do not drive a car, or use any tools
or machines immediately after
treatment with DaunoXome,
because the side effects of this
medicine could stop you doing
this safely. In particular, the
medicine can cause dizziness,
nausea or sickness (see also section
4, Possible side effects).

3. How DaunoXome is
used
DaunoXome is always given to you by
a doctor or nurse. It is given as an
infusion into a vein (a drip).
DaunoXome must not be given by
any other method.
Before use, DaunoXome will first be
diluted with a solution of glucose (5%),
and it will then be administered as an
infusion into a vein (intravenously).
Normally, DaunoXome should be used
straight after it has been diluted.
However, your doctor or pharmacist
may decide to store the diluted
DaunoXome for a maximum of 24
hours before use, depending on the
solution.
The infusion will usually take 30 to 60
minutes.

Dosage for adults
The dose of DaunoXome is calculated
on the basis of your body surface area
(which is related to your height and
weight). The starting dose is 40
milligrams per m2, given every
two weeks.
During your treatment, your doctor
may also decide to raise or lower the
amount you are given. Normally, he or
she will treat you with DaunoXome for
as long as it has a positive effect.

If you are given too much
DaunoXome
As your infusion is administered by a
doctor or nurse, it is very unusual to be
given too much of this medicine.

5.2 Pharmacokinetic properties
DaunoXome has a pharmacokinetic profile significantly different from that of conventional daunorubicin.
DaunoXome was administered intravenously over approximately 30 minutes as a single dose of 10, 20,
40, 60, or 80mg/m2. Plasma pharmacokinetic profiles for most patients demonstrated monoexponential
declines, although biexponential or Michaelis-Menton (saturation) kinetics occurred in some instances.
Peak plasma levels at 40mg/m2 ranged from 14.8 to 22.0µg/ml with a mean peak plasma level of
18.0µg/ml. The mean terminal half-life at this dose was 4.0 hours and mean total body clearance was
10.5ml/minute. This resulted in a mean area under the plasma curve of 120µg.hr/ml. Metabolism of
DaunoXome appeared not to be significant at lower doses. At 60mg/m2 and above, three metabolites
were observed, although they have not yet been identified.
DaunoXome pharmacokinetic parameters were also compared to published values for conventional
daunorubicin. At 80mg/m2, peak plasma levels ranged from 33.4 to 52.3µg/ml for DaunoXome compared
to 0.40µg/ml for conventional drug. At this dose, DaunoXome plasma levels decline monoexponentially
with a terminal half-life of 5.2 hours versus an initial half-life of 0.77 hours and a final half-life of 55.4 hours
for conventional daunorubicin. Mean clearance for DaunoXome is 6.6ml/min versus 223ml/minute for
daunorubicin. When combined, these parameters indicate that DaunoXome produces a 36-fold increase
in mean area under the plasma curve compared to conventional drug (375.3 versus 10.33µg.hr/ml).
5.3 Preclinical safety data
Animal studies with tumour models in mice have demonstrated that DaunoXome can increase
daunorubicin tumour exposure ten-fold (in terms of area under the tumour concentration vs. time curve,
AUC) when compared with equivalent doses of conventional (free) drug. The rate of drug accumulation
in tumour tissues, however, appears to be slower for DaunoXome than for conventional daunorubicin.
This difference is thought to be due to a slow diffusion process by which DaunoXome extravasates
through the tumour neovasculature into the extracellular space while free drug, in contrast, is able to
rapidly equilibrate from the circulation to both normal and neoplastic tissues. Since tumour accumulation
of DaunoXome-delivered daunorubicin is a gradual process, it is important that DaunoXome remains in
the circulation at high levels for prolonged periods. This has been shown to occur in animal studies where
plasma AUC values for daunorubicin were approximately 200-fold greater for DaunoXome than for
conventional drug. In contrast to tumour tissue, however, AUC values for normal tissues were only
moderately elevated in DaunoXome-treated animals, relative to conventional daunorubicin. Exclusive of
reticuloendothelial tissues (liver and spleen, AUC values increased by 110% and 60%, respectively) and
brain tissue (AUC value increased by 3.5 fold) AUC increases ranged from 10% for heart and lungs to 30%
for kidney and small intestines.

Dizziness

Decreased left
ventricular
ejection
fraction

Vascular
disorders

Not Known

Anaphylactic
reaction

Dehydration

Headache

Rare

Sepsis
Septic shock*

Metabolism and
nutritional
disorders

Nervous
system
disorders

Uncommon

Daunorubicin is then released over time in the cytoplasm, where it is able to exert its antineoplastic activity
over a longer period.

Tell your doctor at once if you
suspect that you have been given
too much DaunoXome. In the event
of an overdose, the side effects
listed in section 4 may appear more
pronounced.
If you have any further questions on
the use of this product, ask your
doctor or pharmacist.

4. Possible side effects
Like all medicines, DaunoXome can
cause side effects, although not
everybody gets them.
Tell your doctor at once if you
notice any of these side effects, or
any others not listed in this leaflet.

Very common side effects
(may affect more than 1 in 10 people
treated):
disease of the bone marrow. Signs
include frequent infections and
bleeding, reduced levels of red blood
cells (anaemia)
infusion reactions. Signs include
back pain, flushing, a tight feeling in
the chest and shortness of breath.
These reactions generally occur
within the first 10 minutes of the
infusion and subside when the
infusion is slowed or stopped
allergic reactions. These may include
rash or wheezing
headaches
tiredness
difficulty breathing
chills, fever
nausea, vomiting, diarrhoea, tummy
ache
hair loss
inflammation of the mucous
membranes (such as the lining of
the mouth, throat, nose, rectum
and vagina).

Buffer:
Sucrose, Ph.Eur.
Glycine, B.P.
Calcium chloride, Ph.Eur.
q.s. to approximately 25ml with Water for Injection, Ph.Eur.
6.2 Incompatibilities
To date, no incompatibilities of DaunoXome with other drugs have been reported. However, it is known
that the active component daunorubicin is physically incompatible with heparin sodium and with
dexamethasone phosphate when directly admixed. A precipitate is produced with either drug.
Additionally, because of the chemical instability of the glycosidic bond of daunorubicin, admixture into
a highly alkaline media (pH > 8.0) is not recommended. DaunoXome should not be mixed with saline;
aggregation of the liposomes may result.
Admixtures containing bacteriostatic agents such as benzyl alcohol or other detergent like molecules
should be avoided because such compounds can rupture the bilayer wall of the liposomes causing
premature leakage of the active drug.
6.3 Shelf life
The shelf-life is 52 weeks when stored at 2° - 8°C.
Chemical and physical in-use stability has been demonstrated for DaunoXome diluted with 5% dextrose,
see table below for details.
From a microbial point of view, diluted DaunoXome should be used immediately. If not used immediately,
in-use storage times and conditions prior to use are the responsibility of the user and should not be longer
than 24 hours at 2-8°C for the 5% dextrose dilutions. This recommendation is made on the assumption
that dilution has taken place in controlled and validated aseptic conditions.
Diluent

Dilution Ratio
mL to mL

Final Concentration Duration of
Chemical Stability
Daunorubicin
at 25°C
mg/mL

Duration of
Chemical Stability
at 2° - 8°C

5%
Dextrose

1:2

1.0

24 hours

24 hours

1:4

0.5

24 hours

24 hours

1:8

0.25

24 hours

24 hours

1:10

0.2

24 hours

24 hours

6.4 Special precautions for storage
Store at 2° - 8°C. Do not freeze. Protect against exposure to light. Do not store partially used vials for
future patient use. Vials are for single use only.
6.5 Nature and contents of container
DaunoXome is presented in 50ml, sterile, Type I glass vials. The closure consists of a butyl rubber stopper
and aluminium ring seal fitted with a removable plastic cap. Each single dose vial is packed in a white
chipboard carton. Included in each carton are directions for use.
6.6 Instruction for Use/Handling
Use Aseptic Technique. Aseptic technique must be strictly observed in all handling, since no preservative
or bacteriostatic agent is present in DaunoXome or in the materials recommended for dilution.
Withdraw the calculated volume of DaunoXome into a sterile syringe. Instill the DaunoXome preparation into
a sterile container with the correct amount of 5% Dextrose Injection. The recommended concentration
after dilution is between 0.2mg and 1mg daunorubicin/ml of solution. Infuse over a 30-60 minute period. As
with all parenteral drug products, inspect the solution visually for particulate matter prior to administration.
Caution: The only fluid which may be mixed with DaunoXome is 5% Dextrose Injection; DaunoXome
should not be mixed with saline, bacteriostatic agents such as benzyl alcohol, or any other solution.
An in-line filter is not recommended for the intravenous infusion of DaunoXome. However, if such a filter
is used, the mean pore diameter of the filter should not be less than 5µm.
Procedures for proper handling and disposal of anticancer drugs should be followed.
7. MARKETING AUTHORISATION HOLDER
Galen Limited
Seagoe Industrial Estate
Craigavon
BT63 5UA
UK
8. MARKETING AUTHORISATION NUMBER(S)
PL 27827/0007
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
12 October 1995
10. DATE OF REVISION OF THE TEXT
20 May 2016

Common side effects
(may affect up to 1 in 10 people treated)
dehydration
depression
dizziness
decreased ability of the left chamber
of the heart to pump blood
redness of the skin, pain and swelling
around the infusion site, caused by
leakage from a vein into
surrounding tissue.

Uncommon side effects
(may affect up to 1 in every 100 people
treated)
an infection in the blood (sepsis)
which can cause fever or chills, rapid
heartbeat or rapid breathing; and/or
septic shock (a life-threatening form
of sepsis) which also causes low
blood pressure.
disease of the heart muscle and
heart failure. Your doctor may order
some special heart function tests,
both before and during your
treatment.

Rare side effects
(may affect up to 1 in every 1,000 people
treated)
anaphylactic reactions (lifethreatening type of allergic reaction).
Signs include flushing, itching,
wheezing, and swelling of the
mouth, tongue or throat that can
prevent breathing.
heart attack; abnormal rhythm of the
heart (atrial fibrillation)
hand-foot syndrome, which is also
known as Palmar-Plantar
Erythrodysaesthesia (PPE). Signs are
swelling, redness, pain, and tingling
of the hands and feet, which may
lead to peeling of the skin.

Side effects of unknown
frequency
(frequency cannot be estimated from the
available data)
shock, which may cause a sudden drop
in blood pressure, faint or collapse
transient/temporary increases in the
blood levels of some liver enzymes
and bilirubin in laboratory tests

hepatitis, or inflammation (swelling)
of the liver which can cause different
symptoms including jaundice
(yellowing of the whites of the eyes
and skin) and lead to hepatic (liver)
failure. Your doctor will be able to tell
you if you are suffering from these
conditions
red discolouration of the urine
amenorrhoea, which is the absence
of a menstrual period in females of
child-bearing potential
azoospermia, which is a reduction in
the sperm count in males
inflammatory disease of the
(large) bowel.

Reporting of side effects
If you get any side effects, talk to your
doctor, pharmacist or nurse. This
includes any possible side effects not
listed in this leaflet. You can also report
side effects directly via the Yellow Card
Scheme at:
www.mhra.gov.uk/yellowcard
By reporting side effects you can help
provide more information on the
safety of this medicine.

5. How to store
DaunoXome
Keep out of the reach and sight of
children.
Do not use DaunoXome after the
expiry date which is stated on the
label {Expiry Date}. The product
must be used within 24 hours after
dilution with 5% glucose.
Store at 2°C to 8°C (in a refrigerator).
Do not freeze. Keep the vial in the
outer carton. Vials are for single
use only.
Medicines should not be disposed of
via wastewater or household waste.
Ask your pharmacist how to dispose
of medicines no longer required.
These measures will help to protect
the environment.

6. Further information
What DaunoXome contains
The active substance is daunorubicin
(as citrate salt) equivalent to 2 mg/mL
(total 50 mg) daunorubicin base,
encapsulated in liposomes.
The other ingredients
in the liposome are
distearoylphosphatidylcholine,
cholesterol, citric acid (E330).
The other ingredients in the buffer
are sucrose, glycine (E640), calcium
chloride (E509), water for injection.

What DaunoXome looks like
and contents of the pack
DaunoXome is a red, clear or slightly
cloudy solution in a 50 ml glass vial
containing 25 ml of concentrate.
Each vial contains daunorubicin
hydrochloride, corresponding to
50 mg of daunorubicin.

Marketing Authorisation
Holder
Galen Limited
Seagoe Industrial Estate
Craigavon
BT63 5UA
UK

Manufacturer
Almac Pharma Services Limited
Almac House
20 Seagoe Industrial Estate
Craigavon
BT63 5QD
UK
DaunoXome is registered under the
number PL 27827/0007.
This leaflet was last updated
in May 2016

28/04/16

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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