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DOXORUBICIN 2 MG/ML CONCENTRATE FOR SOLUTION FOR INFUSION

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

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Doxorubicin 2 mg/ml concentrate for solution for infusion.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Doxorubicin hydrochloride
1ml contains 2 mg Doxorubicin hydrochloride.

Each 5ml vial contains 10 mg of Doxorubicin hydrochloride.
Each 10ml vial contains 20 mg of Doxorubicin hydrochloride.
Each 25ml vial contains 50 mg of Doxorubicin hydrochloride.
Each 50ml vial contains 100 mg of Doxorubicin hydrochloride.
Each 100ml vial contains 200 mg of Doxorubicin hydrochloride.

Excipients: The product contains sodium chloride (3.54 mg sodium per 1 ml).
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Concentrate for solution for infusion
Red concentrate for infusion. pH = 2.5 – 3.5

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Breast cancer, sarcoma, small-cell carcinoma of the lung, Hodgkin disease or
non-Hodgkin lymphoma, acute leukaemia, cancer of the thyroid, bladder,
ovaries, Paediatric tumours, such as neuroblastoma.
Doxorubicin is frequently used in combination chemotherapy regimens with
other cytotoxic drugs.

4.2

Posology and method of administration
Treatment with Doxorubicin 2 mg/ml concentrate for solution for infusion
should be started by or after consultation with a doctor with extensive
experience from cytostatic treatment.
The concentrate is injected via the tubing of a freely-running intravenous
infusion (Sodium chloride 0.9% intravenous infusion or Dextrose 5%
intravenous infusion) over 2-15 minutes. This technique minimizes the risk
of thrombophlebitis or perivenous extravasation which can lead to severe
cellulitis and vesication.
Intravenous administration: The dosage of doxorubicin depends on dosage
regimen, general status and previous treatment of the patient.
Several dosage regimens exist: The recommended dose is 60-75 mg/m² body
surface i.v. as a single dose or in divided doses on 2-3 consecutive days
administered with 21 day’s intervals. The lower dose should be given to
patients with bone marrow depression.
When Doxorubicin 2 mg/ml concentrate for solution for infusion is
administered in combination with other cytostatics, the dosage should be
reduced to 30-60 mg/m².
In patients, who cannot receive the full dose (eg. in case of
immunosuppression, old age), an alternative dosage is 15-20 mg/m² body
surface per week.
In order to avoid cardiomyopathy, it is recommended that the cumulative total
lifetime dose of doxorubicin (including related drugs such as daunorubicin)
2

should not exceed 450-550mg/m body surface area; 450 mg/m² should not be
exceeded in cases of previous radiation of mediastinum, previous or
concomitant treatment with potentially cardiotoxic agents.
In cases of decreased liver function, the dosage should be reduced according
to the following table:

Serum bilirubin
20-50 micro mole/L
> 50 micro mole/L

Recommended dose
50% normal dose
25% normal dose

In cases of renal insufficiency with a GFR less than 10 ml/min, 75% of the
calculated dose should be administered.
Dosage in children may need to be reduced, please refer to treatment
protocols and the specialist literature.
Intravesical administration: Doxorubicin 2 mg/ml concentrate for solution for
infusion can be given by intravesical instillation for treatment of superficial
cancer of the bladder and to prevent relapse after transurethral resection
(T.U.R). The recommended dose for intravesical treatment of superficial
cancer of the bladder is 30-50 mg in 25-50 ml of physiological saline per
instillation.. The solution should remain in the bladder for 1-2 hours.
o

During this period the patient should be turned 90 every 15 minutes. To avoid
undesired dilution with urine the patient should be informed not to drink
anything for a period of 12 hours before the instillation (this should reduce the
production of urine to about 50 ml/h). The instillation may be repeated with an
interval of 1 week to 1 month, dependent on whether the treatment is
therapeutic or prophylactic.
Treatment control
Prior to start of the treatment it is recommended to measure the liver function
by using conventional tests such as AST, ALT, ALP and bilirubin as well as
the renal function (see section 4.4).
Control of the left ventricular function Analysis of LVEF using ultrasound or
heart scintigraphy should be performed in order to optimise the heart condition
of the patient. This control should be made prior to the start of the treatment
and after each accumulated dose of approximately 100 mg/m² (see section
4.4).
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.
Intravesical instillation is contraindicated in invasive bladder tumours.

4.3

Contraindications
Hypersensitivity to doxorubicin, other anthracyclines or anthracenediones
Contraindications for intravenous administration:
-remaining myelosuppression or severe stomatitis which appeared during
previous
cytotoxic treatment

-general infection
-severe impaired liver function
-severe arrhythmia, impaired heart function, previous cardiac infarct
-previous treatment with anthracyclines with maximal cumulative doses
Contraindications for intravesical administration:
-invasive tumours that have penetrated the bladder (beyond T1)
-urinary tract infections
-inflammation of the bladder
-problems with catheterisation
Doxorubicin may not be given during pregnancy and lactation (see section
4.6).

4.4

Special warnings and precautions for use
A careful control of possible clinical complications should be performed,
particularly in elderly patients, in patients with a history of heart disease, or
with bone-marrow suppression, or patients who previously have been treated
with anthracyclines, or treated with radiation in the mediastinum.
Control of blood values: Before every treatment cycle total and differential
leukocyte count, erythrocyte and thrombocyte counts should be performed.
Bone-marrow suppression induced by Doxorubicin 2 mg/ml concentrate for
solution for infusion, primarily affecting the leukocytes, requires a thorough
haematological monitoring since severe myelosuppression may lead to
superinfections and bleedings. Severe leucopoenia may appear at doses
recommended for treatment of solid tumours (a number of leukocytes of 1
3

000/mm or lower is expected during full dose treatment with Doxorubicin 2
mg/ml concentrate for solution for infusion). The leucopoenia is most
pronounced 10 – 14 days after the treatment and leukocytes have in most
cases returned to normal at day 21.
Control of heart function: There is a known risk of development of
anthracycline induced cumulative dose-dependent cardiomyopathy. Therefore
2

a cumulative dose of (450-)550 mg/m should not be exceeded. At doses above
this, the risk of development of heart failure considerably increases. The heart
function should therefore be assessed before start of the treatment and
carefully monitored during the whole treatment. Electrocardiography before
and after each treatment cycle is recommended. Changes in ECG such as
depression or negative T-wave, decrease in the ST-segment or arrhythmias are
usually signs of an acute but transient (reversible) toxic effect and are not
considered indications for suspension of doxorubicin therapy. However, a
reduction in the amplitude of the QRS-wave and a prolongation of the systolic
interval are considered more indicative of anthracycline-induced cardiac
toxicity. The best sign to predict cardiomyopathy is a reduction in the left
ventricular ejection fraction (LVEF), determined by ultrasound or heart
scintigraphy. LVEF-investigations should be performed before treatment and

2

be repeated after each accumulated dose of about 100 mg/m , and at clinical
signs of heart failure. As a rule, an absolute decrease with >10 % or a decrease
below 50 %, in patients with normal initial LVEF-values, is a sign of an
impairment of the heart function. Continued treatment with doxorubicin must
in these cases be carefully evaluated. The risk for cardiotoxicity may increase
in patients previously on radiotherapy towards the mediastinal pericardium, in
patients previously treated with other anthracyclines and/or anthracenediones,
or in patients with a history of heart diseases. The total dose of doxorubicin
administered to the individual patient should also take into account any
previous
or concomitant therapy with other potentially cardiotoxic agents such
as high-dose i.v. cyclophosphamide, mediastinal irradiation or related
anthracycline compounds such as daunorubicin.
Control of liver function: Doxorubicin is mainly eliminated via the
hepatobiliary system. The elimination of the drug can therefore be prolonged
with subsequent general toxicity if the liver function is impaired or biliary
secretion is obstructed. Before start and during treatment, control of the liver
function with conventional tests such as AST, ALT, ALP and bilirubin is
recommended. Dose reduction may be necessary (see 4.2).
Control of serum uric acid: During therapy serum uric acid may increase. In
case of hyperuricemia antihyperuricemic therapy should be initiated.
In patients with severely impaired renal function dose reductions may
be necessary (see section 4.2).
Doxorubicin 2 mg/ml concentrate for solution for infusion may potentiate
the toxicity of other anticancer chemotherapies (see section 4.5).
Doxorubicin amplifies the radiation toxicity to heart muscle, mucous
membranes, skin and liver.
A stinging or burning sensation at the site of administration may signify a
small degree of extravasation. If extravasation is suspected or occurs, the
injection should be discontinued and restarted in a different blood vessel.
Cooling the area for 24 hours can reduce the discomfort. The patient should be
carefully monitored for several weeks. Surgical measures might be necessary.
The patient should be informed that the urine might be reddish after
administration.
This medicinal product contains 3.54 mg sodium per 1 ml of doxorubicin
hydrochloride concentrate for solution for infusion. This should be taken into
consideration by patients on a controlled sodium diet

4.5

Interaction with other medicinal products and other forms of interaction
Doxorubicin cardiotoxicity is enhanced by previous or concurrent use of other

anthracyclines, or other potentially cardiotoxic drugs (e.g. 5-fluorouracile,
cyclophosphamide or paclitaxel) or with products affecting cardiac function
(like calcium antagonists). When doxorubicin is used together with the above
mentioned agents, cardiac function must be followed carefully.
Doxorubicin hepatotoxicity may be enhanced by other hepatotoxic treatment
modalities (e.g. 6-mercaptopurine).
Doxorubicin 2 mg/ml concentrate for solution for infusion used in
combination with ciclosporin might require dose-adjustment. At concomitant
administration of ciclosporin, the clearance of doxorubicin is reduced by
approximate 50%. The doxorubicin AUC is increased by 55% and AUC of
doxorubicinol by 350%. With this combination a 40% dose reduction of
doxorubicin is suggested. Ciclosporin inhibits, similar to verapamil, both
CYP3A4 and P-glycoprotein, which might explain the interaction and
resulting in an increase in adverse effects.
Cimetidine also reduced the plasma clearance and increased the AUC of
Doxorubicin, possibly by similar mechanisms as suggested for ciclosporin,
and may thus lead to an increase in adverse effects. Conversely, phenobarbital
decreased Doxorubicin plasma levels and may thus lead to a decrease in
efficacy.
Doxorubicin potentiates the effect of radiation therapy and can, even if
administered some considerable time after discontinuation of the radiation
therapy, cause severe symptoms in the area concerned.
Doxorubicin may cause exacerbations of hemorrhagic cystitis
caused by previous cyclophosphamide therapy.
Doxorubicin therapy may lead to increased serum uric acid, therefore dose
adjustment of uric acid lowering agents may be necessary.
Doxorubicin may reduce oral bioavailability of digoxin.
During treatment with Doxorubicin 2 mg/ml concentrate for solution for
infusion patients should not be actively vaccinated and also avoid contact with
recently polio vaccinated persons.

4.6

Fertility, pregnancy and lactation
Pregnancy:
Doxorubicin should not be given during pregnancy. In general cytostatics
should only be administered during pregnancy on strict indication, and the
benefit to the mother weighed against possible hazards to the foetus.
In animal studies, doxorubicin has shown embryo-, foeto- and teratogenic
effects (see 5.3 Preclinical safety data).Men and women should use effective
contraception during and up to 6 months after treatment.

Lactation:
Doxorubicin has been reported to be excreted in human breast milk. A risk to
the suckling child cannot be excluded. Breast-feeding should be discontinued
during treatment with doxorubicin.

4.7

Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been
performed.

4.8

Undesirable effects
Treatment with doxorubicin often causes undesirable effects, and some of
these effects are serious enough to entail careful monitoring of the patient. The
frequency and kind of undesirable effects are influenced by the speed of
administration and the dosage. Bone-marrow suppression is an acute dose
limiting adverse effect, but is mostly transient. Clinical consequences of
doxorubicin bone marrow/haematological toxicity may be fever, infections,
sepsis/septicaemia, septic shock, haemorrhages, tissue hypoxia or death.
Nausea and vomiting as well as alopecia are seen in almost all patients.
Common (≥1/100 to <1/10)
Cardiac disorders: Cardiomyopathy (2%; e.g. decrease of LVEF,
dyspnoea), ECG changes (e.g. sinus tachycardia, tachyarythmia,
ventricular tachycardia, bradycardia, bundle branch block)
Blood and lymphatic system disorders: Bone-marrow suppression
Gastrointestinal disorders: Nausea, vomiting, mucositis, anorexia,
diarrhoea
Renal and urinary disorders: Local reactions (chemical cystitis) might
occur at intravesical treatment
Skin and subcutaneous tissue disorders: Alopecia

Uncommon (≥ 1/1,000 to <1/100)
Gastrointestinal disorders: In combination with cytarabine ulceration
and necrosis of the colon, in particular the caecum, have been reported.
Rare (≥1/10,000 to <1/1,000)
Eye disorders: Conjunctivitis

Skin and subcutaneous tissue disorders:
Urticaria, exanthema, local erythematous reactions along the vein
which was used for the injection, hyperpigmentation of skin and
nails, onycholysis General disorders and administration site
conditions: Anaphylactic reactions, shivering, fever, dizziness
Blood and lymphatic system disorders:
Maximal bone-marrow suppression occurs after 10-14 days, but the white and
red blood cell counts (blood values) are often normalised after 21 days. Dose
reduction or increase of the dose interval should be considered if the blood
values are not normalised. Haematological monitoring should be undertaken
regularly in both haematological and non-haematological conditions.
Secondary acute myeloid leukaemia (AML), with or without a pre-leukaemic
phase, has in rare cases been reported in patients simultaneously treated with
doxorubicin and antineoplastic drugs, which damage the DNA. These cases
might have a short latency period, 1-3 years.
Cardiac disorders: Cardiotoxicity may be manifested in tachycardia including
supraventricular tachycardia and ECG changes. Cardiomyopathy can develop
even long after discontinuation of the treatment, and is of serious nature. It is
often characterised by a decrease in LVEF, a decrease in amplitude of the
QRS wave, rapid onset of cardiac dilatation, which often does not respond to
treatment with medicinal products with inotropic effect. Acute transient ECG
changes that occur directly in connection with, or a few hours after the
administration, are in most cases reversible and are usually of no clinical
significance.
Gastrointestinal disorders: Nausea and vomiting often occur during the first
24 hours after the administration. Mucositis (stomatitis and oesophagitis) may
occur 5-10 days after administration, and is more frequent and serious when a
therapy, which involves treatment during three consecutive days, is applied.
Ulceration and necrosis of the colon, in particular the caecum, resulting in
bleeding and serious infections, sometimes fatal, have been reported in
patients with acute non lymphocytic leukaemia, who, during three days, were
treated with doxorubicin in combination with cytarabine. Hyperpigmentation
of oral mucosa also occurred.
Skin and subcutaneous tissue disorders: Alopecia is dose-dependent and in
most cases reversible. Photosensitization, “radiation recall reaction”.
Extravasation can lead to severe cellulitis, vesication and local tissue necrosis
which may require surgical measures (including skin grafts).
Other side effects:
Hyperuricaemia, bronchospasm, amenorrhoea, transient increase of liver
enzymes.

4.9

Overdose
Acute overdosage of doxorubicin may lead to myelosuppression (particularly
leucopoenia and thrombocytopenia), generally 10 – 14 days following
overdose, gastrointestinal toxic effects (particularly mucositis) and acute
cardiac alterations, which may occur within 24 hours. Treatment includes
intravenous antibiotics, transfusion of granulocytes and thrombocytes and
treatment of the gastrointestinal symptoms and heart effects. Moving the
patient to a sterile room and the use of a haemopoietic growth factor should be
considered. Single doses of 250 mg and 500 mg of doxorubicin have proved
fatal.
2

Chronic overdosage, with a cumulative dose exceeding 550 mg/m increases
the risk for cardiomyopathy and may lead to heart failure, which should be
treated along conventional lines. Delayed cardiac failure may occur up to six
months after the overdosage.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
ATC code: L01D B01 Anthracyclines and related substances
Doxorubicin belongs to the group of anthracyclines and is a cytostatic
antibiotic that has been isolated from cultures of Streptomyces peucetius var.
caesius. It is now prepared semi-synthetically from daunorubicin. Doxorubicin
is a strong tissue irritant.
The biological activity of doxorubicin is attributed to its DNA-binding
property, which results in inhibition of the enzymatic system, vital for the
DNA-replication and the DNA-transcription. The blocking of the cellular
cycle seems to be maximal during S phase and mitosis, but inhibition has also
been observed during other cell cycle phases.

5.2

Pharmacokinetic properties
After intravenous administration, doxorubicin elimination is characterised by
a tri-phasic elimination from plasma with a terminal half life of
approximately 30 hours. The distribution volume is approximately 25 L/kg.
The degree of protein binding in plasma is approximately 70%.
Highest drug concentrations are attained in the lung, liver, spleen,
kidney, heart, small intestine and bone-marrow. Doxorubicin does not
cross the blood-brain barrier.

Doxorubicin is rapidly metabolised, and the main metabolite is the less active
13dihydroderivative doxorubicinol. Within five days approximately 5% is
recovered in the urine, whilst 40-50% is excreted through the bile within 7
days. Reduced liver function results in a slower elimination of the substance.

5.3

Preclinical safety data
Animal studies from literature show that doxorubicin affects the fertility, is
embryo- and foetotoxic and teratogenic. Other data shows that doxorubicin is
mutagenic.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Hydrochloric acid
Sodium chloride
Water for injections

6.2

Incompatibilities
Doxorubicin 2 mg/ml concentrate for solution for infusion must not be mixed
with heparin, as this will result in precipitation. Until detailed compatibility
information about miscibility is available, Doxorubicin 2 mg/ml concentrate
for solution for infusion should not be mixed with any other medicinal
products.
Incompatibilities with the following products have also been reported:
Aminophyllin, cephalotin, dexamethasone, fluorouracil, hydrocortisone.

6.3

Shelf life
Unopened vial: 2 years
From a microbiological point of view, the product should be used
immediately. If not used immediately, in-use storage times and conditions
prior to use are the responsibility of the user
From a chemical and physical point of view, the product should be used
immediately after first opening. Any unused portion must be discarded after
use

6.4

Special precautions for storage
Store in a refrigerator (2ºC - 8ºC)
Keep vial in the outer carton in order to protect from light
Store in an upright position

6.5

Nature and contents of container
Colourless, borosilicate, type I glass vial with chlorobutyl based, type I rubber
stopper and aluminium cap with plastic flip-off top, containing 5ml, 10ml,
25ml, 50ml or 100ml of sterile solution of Doxorubicin hydrochloride 2 mg/ml
Pack sizes: 1 x 5ml, 1 x 10ml, 1 x 25ml, 1 x 50ml, 1 x 100ml
Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling
The injection solution contains no preservative and any unused portion of the
vial should be discarded immediately.
Doxorubicin 2 mg/ml concentrate for solution for infusion is compatible with
sodium chloride 0.9% and dextrose 5%.
Guidelines for the safe handling and disposal of antineoplastic agents:
1. Adequate protective disposable gloves, goggles, gown and mask should be
worn.
2. Precautions should be taken to avoid the medicinal product accidentally
coming into contact with the eyes. In the event of contact with the eyes,
irrigate with large amounts of water and/or 0.9% sodium chloride solution.
Then seek medical evaluation by a physician.
3. 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. Always wash hands after removing gloves.
4. Spillage or leakage should be treated with diluted sodium hypochlorite
(1% available chlorine) solution, preferably by soaking, and then water or
most simply with phosphate buffer (pH>8) until the solution is destained.
All cleaning materials should be disposed of as detailed below.
5. Pregnant staff should not handle the cytotoxic preparation.

6. Adequate care and precautions should be taken in the disposal of items
(syringes, needles etc) used to reconstitute and/or dilute cytotoxic
medicinal products. Any unused product or waste material should be
disposed of in accordance with local requirements.

7

MARKETING AUTHORISATION HOLDER
Genepharm S.A.
18 Km Marathon Avennue,
15351 Pallini,
Athens,
Greece

8

MARKETING AUTHORISATION NUMBER(S)
PL 27766/0001

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
17/09/2009

10

DATE OF REVISION OF THE TEXT
31/08/2012

Expand Transcript

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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