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AGIDOX 2 MG/ML POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Agidox 2 mg/ml powder for concentrate for solution for infusion

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
One ml of reconstituted solution contains 2 mg doxorubicin hydrochloride.
10 mg vial:
Each vial contains 10 mg doxorubicin hydrochloride for reconstitution in 5 ml sodium
chloride (0.9%) solution for injection.
50 mg vial:
Each vial contains 50 mg doxorubicin hydrochloride for reconstitution in 25 ml
sodium chloride (0.9%) solution for injection.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Powder for concentrate for solution for infusion.
Red orange lyophilized powder or plug.
pH (of reconstituted solution) = 4.5 – 6.5
The osmolality of the reconstituted solution is between 240 and 370 mOsmol/kg.
The appearance of the reconstituted solution is a clear, red coloured solution.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
-

Small-cell lung cancer (SCLC)

-

Breast cancer

-

Recurrent ovarian carcinoma

-

Intravesical prophylaxis of recurrences of superficial bladder carcinoma
following transurethral resection (TUR)

-

Systemic treatment of local advanced or metastasized bladder carcinoma

-

Neoadjuvant and adjuvant therapy of osteosarcoma

-

Advanced soft-tissue sarcoma in adults

-

Ewing’s sarcoma

-

Hodgkin’s lymphoma

-

Highly malignant non-Hodgkin’s lymphoma

-

Induction and consolidation therapy in acute lymphatic leukaemia

-

Acute myeloblastic leukaemia

-

Advanced multiple myeloma

-

Advanced or recurrent endometrial carcinoma

-

Wilms’ tumour (in stage II in highly malignant variants, all advanced stages
[III – IV])

-

Advanced papillary/follicular thyroid cancer

-

Anaplastic thyroid cancer

-

Advanced neuroblastoma

Doxorubicin is frequently used in combination chemotherapy regimens with
other cytotoxic drugs.

4.2

Posology and method of administration
Agidox should be administered only under the supervision of a qualified physician
with extensive experience in cytotoxic therapy. Also, patients must be carefully and
frequently monitored during the treatment (see section 4.4).
Due to the risk of a lethal cardiomyopathy, the risks and benefits to the individual
patient should be weighted before each application.
Doxorubicin is intended for intravenous or intravesical administration only.

Intravenous administration:
Doxorubicin can be administered intravenously as bolus within minutes or as short
infusion for up to an hour or as continous infusion for up to 24 hours (see also section
6.3). In monotherapy, the dose may also be divided and administered over 2-3
consecutive days. The solution is given via the tubing of a freely running intravenous
infusion of sodium chloride 9 mg/ml (0.9%) solution for injection or dextrose 50
mg/ml (5%) solution for injection within 2 to 15 minutes. This technique minimises
the risk of thrombophlebitis or perivenous extravasations, which can lead to severe

local cellulites, vesication and tissue necrosis. A direct intravenous injection is not
recommended due to the risk of extravasation, which may occur even in the presence
of adequate blood return upon needle aspiration (see also section 6.6).
The dosage of doxorubicin depends on dosage regimen, general status and previous
treatment of the patient. Dose schedule of doxorubicin administration could vary
according to indication (solid tumours or acute leukaemia) and according to its use in
the specific treatment regimen (as single agent or in combination with other cytotoxic
agents or as a part a multidisciplinary procedures that include combination of
chemotherapy, surgical procedure and radiotherapy and hormonal treatment).
Monotherapy: dosage is usually calculated on the basis of body surface area (mg/m2).
On this basis, a dose of 60-75 mg/m2 body surface area is recommended every three
weeks when doxorubicin is used as a single agent.
Combination regimen: When doxorubicin hydrochloride is administered in
combination with other antitumor agents with overlapping toxicity such as high-dose
i.v. cyclophosphamide or related anthracycline compounds such as daunorubicin,
idarubicin and/or epirubicin, the dosage of doxorubicin should be reduced to 30-60
mg/m2 every 3-4 weeks.
In patients, who cannot receive the full dose (e. g. 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) should
not exceed 450-550mg/m2 body surface area. If patients with concomitant heart
disease receive mediastinal and/or heart irradiation, prior treatment with alkylating
agents or concomitant treatment with potentially cardiotoxic agents, and high-risk
patients (with arterial hypertension since > 5 years, with prior coronary, valvular or
myocardial heart damage, age over 70 years) a maximum total dose of 400 mg/m2
body surface area should not be exceeded and the cardiac function of these patients
should be monitored (see section 4.4).
Hepatic impairment
In cases of decreased liver function, the dosage should be reduced according to the
following table:

Serum bilirubin

Recommended dose

20-50 micro mole/l

½ normal dose

> 50-85 micro mole/l

¼ normal dose

Doxorubicin is contraindicated in patients with severe liver function disorder (>85
micromole/l) (see section 4.3).
Renal impairment

In cases of renal insufficiency with a GFR less than 10 ml/min, 75% of the calculated
dose should be administered.
Paediatric population
In view of the substantial risk of doxorubicin induced cardiotoxicity during childhood
certain maximum cumulative dosages that depend on the youth of patients should be
applied. In children (under 12 years of age) the maximal cumulative dose is usually
considered 300 mg/m2, whereas in adolescents (over 12 years of age) the maximal
cumulative dose is set to 450 mg/m2. For infants the maximal cumulative dosages are
still indecisive, but even lower tolerability is assumed.
Dosage for children should be reduced, since they have an increased risk for cardiac
toxicity especially late toxicity. Myelotoxicity should be anticipated, with nadirs at 10
to 14 days after start of treatment.
Obese patients
A reduced starting dose or prolonged dose interval might need to be considered in
obese patients (see section 4.4).

Intravesical administration:
Agidox 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 optimal
concentration is about 1 mg/ml. The solution should remain in the bladder for 1-2
hours. 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.
Note:
Posology of S-liposomal doxorubicin and (conventional) doxorubicin as in Agidox
are different. The two formulations cannot be used interchangeably.

4.3

Contraindications
Hypersensitivity to doxorubicin or to any of the excipients listed in section 6.1.
Hypersensitivity to other anthracyclines or to anthracenediones.
Contraindications for intravenous administration:
-

persistent myelosuppression or severe stomatitis which appeared during previous
cytotoxic treatment and/or radiation

-

general infection

-

severe impaired liver function

-

severe arrhythmia, impaired cardiac function, previous cardiac infarct, acute
inflammatory heart disease

-

previous treatment with anthracyclines with maximum cumulative doses

-

increased haemorrhagic tendency

-

breastfeeding.

Contraindications of intravesical administration:
-

urinary tract infections

-

inflammation of the bladder

-

problems with catheterization e.g. urethral stenosis.

-

haematuria

-

4.4

invasive tumours that have penetrated the bladder (beyond T1)

breastfeeding.

Special warnings and precautions for use
Doxorubicin should be administered only under the supervision of a physician who is
experienced in the use of cancer chemotherapeutic agents.
Patients should recover from the acute toxicities of prior cytotoxic treatment (such as
stomatitis, neutropenia, thrombocytopenia, and generalized infections) before
beginning treatment with doxorubicin.
Before or during treatment with doxorubicin the following monitoring examinations
are recommended (how often these examinations are done will depend on the general
condition of the patient, the dose and the concomitant medication):
-

radiographs of the lungs and chest and ECG

-

regular monitoring of heart function (LVEF by e.g. ECG, UCG and MUGA scan)

-

daily inspection of the oral cavity and pharynx for mucosal changes

-

blood tests: haematocrit, platelets, differential white cell count, SGPT, SGOT,
LDH,bilirubin, uric acid.

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.

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.

Cardiac function
Cardiotoxicity is a risk of anthracycline treatment that may be manifested by early
(i.e. acute) or late (i.e. delayed) events.
Early (i.e. acute) events: Early cardiotoxicity of doxorubicin consists mainly of sinus
tachycardia and/or ECG abnormalities such as non-specific ST-T wave changes.
Tachyarrhythmias, including premature ventricular contractions and ventricular
tachycardia, bradycardia, as well as atrioventricular and bundle-branch block have
also been reported. These symptoms generally indicate acute transient toxicity.
Flattening and widening of the QRS-complex beyond normal limits may indicate
doxorubicin hydrochloride-induced cardiomyopathy. As a rule, in patients with a
normal LVEF baseline value (=50%), a 10% decrease of absolute value or dropping
below the 50% threshold indicates cardiac dysfunction and in such situation treatment
with doxorubicin hydrochloride should be carefully considered.
Late (i.e. delayed) events: Delayed cardiotoxicity usually develops late in the course
of therapy with doxorubicin or within 2 to 3 months after treatment termination, but
later events, several months to years after completion of treatment, have also been
reported. Delayed cardiomyopathy is manifested by reduced left ventricular ejection
fraction (LVEF) and/or signs and symptoms of congestive heart failure (CHF) such as
dyspnoea, pulmonary oedema, dependent oedema, cardiomegaly and hepatomegaly,
oliguria, ascites, pleural effusion and gallop rhythm. Subacute effects such as
pericarditis/myocarditis have also been reported. Life-threatening CHF is the most
severe form of anthracycline-induced cardiomyopathy and represents the cumulative
dose-limiting toxicity of the drug.
Cardiac function should be assessed before patients undergo treatment with
doxorubicin and must be monitored throughout therapy to minimize the risk of
incurring severe cardiac impairment. The risk may be decreased through regular
monitoring of LVEF during the course of treatment with prompt discontinuation of
doxorubicin at the first sign of impaired function. The appropriate quantitative
method for repeated assessment of cardiac function (evaluation of LVEF) includes
multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). A
baseline cardiac evaluation with an ECG and either a MUGA scan or an ECHO is
recommended, especially in patients with risk factors for increased cardiotoxicity.
Repeated MUGA or ECHO determinations of LVEF should be performed,
particularly with higher, cumulative anthracycline doses. The technique used for
assessment should be consistent throughout follow-up.
The probability of developing CHF, estimated around 1% to 2% at a cumulative dose
of 300 mg/m2 slowly increases up to the total cumulative dose of 450-550 mg/m2.
Thereafter, the risk of developing CHF increases steeply and it is recommended not to
exceed a maximum cumulative dose of 550 mg/m2. If the patient has other potential
risk factors of cardiotoxicity (history of cardiovascular disease, previous therapy with
other anthracyclines or anthracenediones, prior or concomitant radiotherapy to the
mediastinal/pericardial area, and concomitant use of medicinal products with the

ability to suppress cardiac contractility, including cyclophosphamide and 5fluoruracil), cardiotoxicity with doxorubicin may occur at lower cumulative doses
and cardiac function should be carefully monitored.
It is probable that the toxicity of doxorubicin and other anthracyclines or
anthracenediones is additive.

Liver function
The major route of elimination of doxorubicin is the hepatobiliary system. Serum
total bilirubin should be evaluated before and during treatment with doxorubicin.
Patients with elevated bilirubin may experience slower clearance of the drug with an
increase in overall toxicity. Lower doses are recommended in these patients (see
section 4.2). Patients with severe hepatic impairment should not receive doxorubicin
(see section 4.3).

Gastrointestinal disorders
An antiemetic prophylaxis is recommended.
Doxorubicin should not be used in the presence of inflammation, ulceration or
diarrhoea.

Haematologic toxicity
Doxorubicin may produce myelosuppression (see section 4.8). If serious
myelosuppression is present, doxorubicin should not be used; a dose reduction or a
delay in administration is then necessary.
Care has to be taken to ensure that a serious infection and/or episode of haemorrhage
can be treated fast and effectively. Existing infections should be treated before a
therapy with doxorubicin is initiated.
Haematologic profiles should be assessed before and during each cycle of therapy
with doxorubicin, including differential white blood cell (WBC) counts. A dosedependent, reversible leucopenia and/or granulocytopenia (neutropenia) is the
predominant manifestation of doxorubicin haematologic toxicity and is the most
common acute dose-limiting toxicity of this drug. Leucopenia and neutropenia
generally reach the nadir between days 10 and 14 after drug administration; the
WBC/neutrophil counts return to normal values in most cases by day 21. Dose
reduction or increase of the dose interval should be considered if the blood values are
not normalised. Thrombocytopenia and anaemia may also occur. Clinical
consequences of severe myelosuppression include fever, infections,
sepsis/septicaemia, septic shock, haemorrhage, tissue hypoxia or death.

Secondary leukaemia
Secondary leukaemia, with or without a preleukaemic phase, has been reported in
patients treated with anthracyclines. Secondary leukaemia is more common when
such drugs are given in combination with DNA-damaging antineoplastic agents,
when patients have been heavily pretreated with cytotoxic drugs or when doses of the
anthracyclines have been escalated. These leukaemias can have a 1 to 3 year latency
period.

Tumour lysis syndrome
Doxorubicin may induce hyperuricaemia as a consequence of the extensive purine
catabolism that accompanies drug-induced rapid lysis of neoplastic cells (tumourlysis syndrome) (see section 4.8). Blood uric acid levels, potassium, calcium
phosphate and creatinine should be evaluated after initial treatment. Hydration, urine
alkalinization, and prophylaxis with allopurinol to prevent hyperuricaemia may
minimize potential complications of tumour lysis syndrome.

Carcinogenesis, mutagenesis and impairment of fertility
Doxorubicin was genotoxic and mutagenic in vitro and in vivo tests and may cause
infertility (see section 4.6 and section 5.3).

Intravesical administration
Intravesical administration of doxorubicin may cause symptoms of chemical cystitis
(i.e. dysuria, urinary frequency, nocturia, stranguria, haematuria, necrosis of the
bladder wall).
Special attention is needed in case of catheter problems (i.e. urethral obstruction
caused by invasion of intravesical tumour).
Intravesical administration is contraindicated for tumours that have penetrated the
bladder (beyond T1).
The intravesical route of administration should not be attempted in patients with,
invasive tumours that have penetrated the bladder wall, urinary tract infections,
inflammatory conditions of the bladder.

Radiotherapy
Special caution is mandatory for patients who have had radiotherapy previously, are
having radiotherapy concurrently or are planning to have radiotherapy. These patients
are at special risk of local reactions in the radiation field (recall phenomenon) if
Agidox is used. Severe, sometimes fatal, hepatotoxicity (liver damage) has been
reported in this connection. Prior radiation to the mediastinum increases the
cardiotoxicity of doxorubicin. The cumulative dose of 400 mg/m² must not be
exceeded especially in this case.

Anticancer therapies
Doxorubicin may potentiate the toxicity of other anticancer therapies. Exacerbation of
cyclophosphamide-induced haemorrhagic cystitis and enhanced hepatotoxicity of 6mercaptopurine have been reported.
As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena
including pulmonary embolism (in some cases fatal) have been coincidentally
reported with the use of doxorubicin (see section 4.8).

Vaccines
Vaccines are not recommended (see section 4.5). During treatment with doxorubicin
hydrochloride patients should avoid contact with recently polio vaccinated persons.

Other
The systemic clearance of doxorubicin is reduced in obese patients (i.e. >130% ideal
body weight) (see section 4.2).
The patient should be informed that the urine might be reddish, particularly in the
first specimen after administration, but that this is no cause for alarm.
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 (see section 4.8).

4.5

Interaction with other medicinal products and other forms of interaction
Doxorubicin is a major substrate of cytochrome P450 CYP3A4 and CYP2D6, and P
glycoprotein (P-gp). Clinically significant interactions have been reported with
inhibitors of CYP3A4, CYP2D6, and/or P-gp (e.g., verapamil), resulting in increased
concentration and clinical effect of doxorubicin. Inducers of CYP3A4 (e.g.,
phenobarbital, phenytoin, St. John’s Wort) and P-gp inducers may decrease the
concentration of doxorubicin.
Doxorubicin cardiotoxicity is enhanced by previous or concurrent use of other
anthracyclines, or other potentially cardiotoxic drugs (e.g. 5-fluorouracil,
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.
The use of trastuzumab in combination with anthracyclines (such as doxorubicin) is
associated with a high cardiotoxic risk. Trastuzumab and anthracyclines should not be
used in combination for the time being, except in well controlled clinical studies
where the cardiac function is monitored. When anthracyclines are used after the end
of a therapy with trastuzumab, an elevated risk of cardiotoxicity may result. If
possible, there should be a sufficiently long interval (up to 22 weeks) between the end
of a therapy with trastuzumab and the beginning of the anthracycline therapy. Careful
monitoring of the cardiac function is imperative.
(Pre-)treatment with drugs affecting the function of the bone marrow (e.g. cytostatic
agents, sulfonamides, chloramphenicol, phenytoin, amidopyrine derivates,
antiretroviral drugs) might lead to severe hematopoetic disturbances. The dosage of
doxorubicin has to be changed if necessary. The toxic effects of a doxorubicin
therapy may be increased in a combination with other cytostatics (e.g. cytarabine,
cisplatin, cyclophosphamide).
Doxorubicin hepatotoxicity may be enhanced by other hepatotoxic treatment
modalities (e.g. 6-mercaptopurine).

Ciclosporin, an inhibitor of CYP3A4 and Pgp, increased the AUC of doxorubicin and
doxorubicinol by 55% and 350%, respectively. A 40% dose reducton of doxorubicin
is proposed for this combination.
Cimetidine has also been shown to reduce the plasma clearance and increase the AUC
of doxorubicin.
Paclitaxel administered shortly before doxorubicin may decrease clearance and
increase plasma concentrations of doxorubicin. Some data indicate that this
interaction is less pronounced when doxorubicin is administered before paclitaxel.
The absorption of anticonvulsants (e.g. carbamazepine, phenytoin, valproate) is
decreased when administered in combination with doxorubicin.
Elevated serum doxorubicin concentrations were reported after the concomitant
administration of doxorubicin and ritonavir.
The toxic effects of a doxorubicin therapy may be increased in a combination with
other cytostatics (e.g.cytarabine, cisplatin, cyclophosphamide). Necroses of the large
intestine with massive haemorrhage and severe infections in connection with
combination therapies with cytarabine.
Clozapine may increase the risk and severity of the hematologic toxicity of
doxorubicin.
Marked nephrotoxicity of Amphotericin B can occur during doxorubicin therapy.
As doxorubicin is rapidly metabolised and predominantly eliminated by the biliary
system, the concomitant administration of known hepatotoxic chemotherapeutic
agents (e.g. mercaptopurine, methotrexate, streptozocin) could potentially increase
the toxicity of doxorubicin as a result of reduced hepatic clearance of the drug.
Dosing of doxorubicin must be modified if concomitant therapy with hepatotoxic
drugs is mandatory.
Doxorubicin is a potent, radiosensitizing agent (“radiosensitizer”), and recall
phenomena induced by it may be life-threatening. Any preceding, concomitant or
subsequent radiation therapy may increase the cardiotoxicity or hepatotoxicity of
doxorubicin. This applies also to concomitant therapies with cardiotoxic or
hepatotoxic drugs.
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, patients should not be actively vaccinated and
also avoid contact with recently polio vaccinated persons.
Doxorubicin binds to heparin and 5-FU. Precipitations and loss of action of both
substances are therefore possible. See 6.2 for more details.

4.6

Fertility, pregnancy and lactation
Women of childbearing potential
Doxorubicin was genotoxic and mutagenic in vitro and in vivo tests (see section 5.3).

Contraception in males and females
Men and woman who are sexually active and undergoing doxorubicin treatment
should use effective contraceptive methods. Men and women should also use
effective contraception up to 6 months after treatment.

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 section 5.3).

Breastfeeding:
Doxorubicin has been reported to be excreted in human breast milk. A risk to the
suckling child cannot be excluded. Breastfeeding should be discontinued during
treatment with doxorubicin (see section 4.3).

Fertility
In women, doxorubicin may cause infertility during the time of drug administration.
Doxorubicin may cause amenorrhoea (see section 4.8). Ovulation and menstruation
appear to return after termination of therapy, although premature menopause can
occur.
Doxorubicin is mutagenic and can induce chromosomal damage in human
spermatozoa. Oligospermia or azoospermia may be permanent; however, sperm
counts have been reported to return to normospermic levels in some instances. This
may occur several years after the end of therapy.

4.7

Effects on ability to drive and use machines
Due to the frequent occurrence of nausea and vomiting, driving cars and operation of
machinery should be discouraged.

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. Bonemarrow 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.
Intravesical administration may cause the following adverse reactions: hematuria,
vesical and urethral irritation, stranguria and pollakisuria. These reactions are usually
of moderate severity and of short duration.
Intravesical administration of doxorubicin may sometimes cause hemorrhagic cystitis;
this may cause a decrease in bladder capacity.
Extravasation can lead to severe cellulitis, vesication, thrombophlebitis, lymphangitis
and local tissue necrosis which may require surgical measures (including skin grafts).
The estimation of frequency: 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).



Immune system
disorders
Endocrine disorders



Blood and lymphatic
system disorders



Infections and
infestations
Neoplasms benign,
malignant and
unspecified (incl cysts
and polyps)



4.8

Common: sepsis, septicaemia
Uncommon:
acute lymphocytic leukaemia, acute myelogenic
leukaemia
Rare:
secondary leukaemia when in combination with
anti-neoplastic drugs which damage the DNA
(see section 4.4), tumour lysis syndrome
Very common:
myelo-suppression including leukopenia,
neutropenia, thrombocytopenia, anaemia(*)
Rare:
anaphylactic reactions
Very rare:

Eye disorders

Cardiac disorders

Vascular disorders

Respiratory, thoracic
and mediastinal
disorders
Gastrointestinal
disorders

Hepatobiliar disorders

hot flashes
Rare:
conjunctivitis
Not known:
increased lachrymation
Very common:
Cardio-toxicity(**)
Common:
life-threatening congestive (dilatative) cardiomyopathy (after cumulative dose of 550 mg/m²);
sinus tachycardia, ventricular tachycardia, tachyarrhythmia, supra-ventricular and ventricular
extrasystoles, bradycardia, arrhythmia;
asymptomatic reduction of the left ventricular
ejection fraction
Very rare:
unspecific ECG changes (ST changes, low
voltage, long QT intervals); isolated cases of lifethreatening arrhyth-mias; acute left ventricular
failure, pericarditis, fatal pericarditis-myocarditis
syndrome; atrio ventricular block, bundle branch
block
Common:
haemorrhage
Uncommon:
phlebitis
Very rare:
thrombo-embolism
Not known:
bronchospasm, radiation pneumonitis
Very common:
Gastro-intestinal disturbance(***) diarrhoea,
nausea and vomiting; mucositis, stomatitis,
oesophagitis
Common:
anorexia
Uncommon:
Gastro-intestinal haemorrhageulceration of the
mucous membranes in the mouth, pharynx ,
oesophagus and gastro-intestinal tract may
appear; in combination with cytarabine,
ulceration and necrosis of the colon, in particular
the caecum, have been reported (see section 4.5)
Very rare:
hyperpigmentation of the oral mucous membrane
Not known:

hepato-toxicity (sometimes progressing to
cirrhosis), transient increase of liver enzymes
Skin and subcutaneous
tissue disorders

Musculoskeletal and
connective tissue
disorders
Renal and urinary
disorders

Reproductive system
and breast disorders
General disorders and
administration site
conditions

Very common:
alopecia (dose-dependent and in most cases
reversible); reddening; photo-sensitization
Common:
local hypersensitivity reactions in the field of
radiation (“radiation recall reaction”); itching
Rare:
urticaria, exanthema, hyperpigmentation of skin
and nails, onycholysis; extravasation (may lead to
severe cellulites, vesication, thrombophlebitis,
lymphangitis, and local tissue necrosis)
Very rare:
acral erythemas; blistering; palmar-plantar
erythrodysaesthesia
Not known:
actinic keratosis
Not known:
Arthralgia
Very common:
red coloration to the urine
Common:
dysuria chemical cystitis following intravesical
administration (with dysuric complaints such as
vesical irritation, urethral irritation, dysuria,
stranguria, pollakisuria, haematuria, vesicular
spasms, hemorrhagic cystitis)
Very rare:
acute renal failure (isolated cases); hyperuricaemia and subsequent uric acid nephropathy
as a consequence of massive tumour lysis
Very rare:
Amenorrhoea; oligo-spermia; azoo-spermia
Very common:
Fever
Uncommon:
dehydration
Rare:
shivering,
dizziness;
injection site reactions (local erythematous
reactions along the vein, pain, phlebitis,
phlebosclerosis)
Not known:
malaise/weakness

Surgical and medical
procedure

Not known:
radiation damage (skin, lungs, oesophagus,
gastro-intestinal mucosa, heart) that is already
healing may reappear following doxorubicin
administration

(*)

Myelosuppression is one of the dose-limiting side-effects and may be serious. It
manifests mainly in the decrease of the leukocyte count. Leucopenia was observed in
almost 75% of the patients with an adequate bone marrow reserve who were treated
with 60 mg/m² BSA every 21 days. Although less frequently, thrombocytopenia,
neutropenia, and anaemia were also reported. Superinfections (very frequent) and
haemorrhage were likewise observed in a connexion with the appearance of bone
marrow suppression. Myelosuppression usually culminates 10 to 14 days after the
administration of doxorubicin and subsides between the 21st and 28th day in most
cases. If appearing, thrombocytopenia or anaemia occurs in the same period, but is
usually less severe. (See section 4.4).
(**)

Doxorubicin is cardiotoxic. The risk that the cardiotoxic side-effects become
manifest is elevated during and after radiation therapy of the mediastinal region, after
a pre-treatment with potentially cardiotoxic agents (e.g. anthracyclines,
cyclophosphamide), and in elderly patients (over 60 years) and patients with manifest
arterial hypertension. (See section 4.4).
The cardiotoxic effect of doxorubicin can manifest in two types:
Acute type
The acute-type side-effects occur mostly within the first 24 to 48 hours after initiation
of therapy, are not dosedependent and are characterized by the following symptoms:
temporary arrhythmia (frequent), especially sinus tachycardia (frequent), and
supraventricular and ventricular extrasystoles. They are (very rarely) characterized by
unspecific ECG changes (ST changes, low voltage, and long QT intervals).
These changes are generally reversible, and their appearance is no contraindication
for the repeated use of doxorubicin. However life-threatening arrhythmias may occur
during, or few hours after the use of doxorubicin; in isolated cases, acute left
ventricular failure, pericarditis or fatal pericarditis-myocarditis syndrome was
reported.
Delayed type
The delayed-type side-effects are manifestations of dose-dependent cumulative organ
toxicity, which is generally irreversible and often life-threatening. They often
manifest as congestive (dilatative) cardiomyopathy with the signs of left ventricular
failure within few months of the termination of therapy. Cardiotoxicity may,
however, become manifest for the first time as late as several years after the
termination of the therapy; its incidence increases with the total cumulative dose. (See
section 4.4).
(***)

The emetogenic potential of doxorubicin is high; relatively severe nausea and
vomiting occur in about 80% of the patients on the first day of therapy, but also later.
(See section 4.4).

Reporting of suspected adverse reactions
If you get any side effects, talk to your doctor or pharmacist. 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.

4.9

Overdose
Acute overdosage of doxorubicin may lead to myelosuppression (particularly
leucopenia 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.
Chronic overdosage, with a cumulative dose exceeding 550 mg/m2 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.
A haemodialytic therapy is probably useless in intoxications with doxorubicin
because doxorubicin has a very large volume of distribution and only 5% of a dose is
eliminated by the kidneys.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents and anthracyclines and related
substances
ATC code: L01D B01
Doxorubicin is an anthracycline antibiotic. The mechanism of action is not
completely elucidated. It is postulated that Agidox exerts its antineoplastic effect via
cytotoxic mechanisms of action, especially intercalation into DNA, inhibition of the
enzyme topoisomerase II, and formation of reactive oxygen species (ROS). All of
these have a deleterious effect on DNA synthesis: Intercalation of the doxorubicin
molecule leads to an inhibition of RNA and DNA polymerases by way of
disturbances in base recognition and sequence specificity. The inhibition of
topoisomerase II produces single and double strand breaks of the DNA helix. Scission
of DNA also originates from the chemical reaction with highly reactive oxygen

h

species like the hydroxyl radical OH . Mutagenesis and chromosomal aberrations are
the consequences.
The specificity of doxorubicin toxicity appears to be related primarily to proliferative
activity of normal tissue. Thus, bone marrow, gastro-intestinal tract and gonads are
the main normal tissues damaged.
An important cause of treatment failure with doxorubicin and other anthracyclines is
the development of resistance. In an attempt to overcome cellular resistance to
doxorubicin, the use of calcium antagonists such as verapamil has been considered
since the primary target is the cell membrane. Verapamil inhibits the slow channel of
calcium transport and can enhance cellular uptake of doxorubicin. A combination of
doxorubicin and verapamil is associated with severe cardiotoxic effects.

5.2

Pharmacokinetic properties
Distribution
Following intravenous injection, doxorubicin is rapidly cleared from the blood, and
widely distributed into tissues including lungs, liver, heart, spleen, lymph nodes, bone
marrow and kidneys. The volume of distribution is about 25 l/kg. The degree of
protein binding is 60-70%.
Doxorubicin does not cross the blood-brain barrier, although higher levels in liquor
may be reached in the presence of brain metastases or leukemic cerebral
dissemination. Doxorubicin is rapidly distributed into the ascites, where it reaches
higher concentrations than in plasma. Doxorubicin is secreted into breast milk.
Elimination
The elimination of doxorubicin from the blood is triphasic with mean half-lives of 12
minutes (distribution), 3.3 hours and about 30 hours. Doxorubicin undergoes rapid
metabolism in the liver. The main metabolite is the pharmacologically active
doxorubicinol. Other metabolites are deoxyrubicin aglycone, glucuronide and
sulphate conjugate. About 40 to 50% of a dose is excreted in bile within 7 days, of
which about half is excreted as unchanged drug and the rest as metabolites. Only 5-15
% of the administered dose is eliminated in urine.
Special populations
As the elimination of doxorubicin is mainly hepatic, impairment of liver function
results in slower excretion, and consequently, increased retention and accumulation in
plasma and tissues.
Although renal excretion is a minor elimination pathway for doxorubicin, severe renal
impairment might affect total elimination.

In a study in obese patients (>130% of ideal bodyweight) the doxorubicin clearance
was reduced and the half life increased compared with a normal-weight control
group.

5.3

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

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Lactose monohydrate

6.2

Incompatibilities
Doxorubicin should not be mixed with heparin, as a precipitate may form and it
should not be mixed with 5-fluorouracil as degradation may occur. Prolonged contact
with any solution of an alkaline pH should be avoided as it will result in hydrolysis of
the drug.
In the absence of compatibility studies, this medicinal product must not be mixed
with other medicinal products.

6.3

Shelf life
Vial before opening:
2 years.
Reconstituted solution
Chemical and physical in-use stability following reconstitution in 0.9 % sodium
chloride solution has been demonstrated for 7 days at 25°C and 15 days at 2-8°C.
From a microbiological point of view, unless the method of dilution precludes the risk
of microbiological contamination, 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 and would normally not be longer than 24 hours at 2-8°C,
unless reconstitution/dilution has taken place under controlled and validated aseptic
conditions.

Reconstituted solution further diluted in 0.9% sodium chloride solution
The chemical and physical in-use stability after dilution to a concentration of
0.1mg/ml to 1.0mg/ml has been demonstrated for 24 hours when stored protected
from light at 2-8°C.
From a microbiological point of view, unless the method of dilution precludes the risk
of microbiological contamination, 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 and would normally not be longer than 24 hours at 2-8°C,
unless reconstitution/dilution has taken place under controlled and validated aseptic
conditions.
Reconstituted solution further diluted in 5% Glucose solution
The chemical and physical in-use stability after dilution to a concentration of
0.1mg/ml to 1.0mg/ml has been demonstrated for 24 hours when stored protected
from light at 2-8°C.
From a microbiological point of view, unless the method of dilution precludes the risk
of microbiological contamination, 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 and would normally not be longer than 24 hours at 2-8°C,
unless reconstitution/dilution has taken place under controlled and validated aseptic
conditions.

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.
For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5

Nature and contents of container
Type I flint tubular glass vials, stoppered with a dark grey bromobutyl rubber stopper
and sealed with an electric blue flip off aluminium seal.
Trade package quantities: Boxes with one vial of 10 mg or 50 mg doxorubicin
hydrochloride.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
For storage conditions of the reconstituted medicinal product, see section 6.3.

Doxorubicin is a potent cytotoxic agent which should only be prescribed, prepared
and administered by professionals who have been trained in the safe use of the
preparation.
The reconstituted solution is a clear, red coloured solution.
Further dilution of the appropriate volume of the reconstituted solution with either of
0.9 % sodium chloride solution or 5 % glucose solution is required to a final
concentration of between 0.1 mg/ml and 1 mg/ml.
For recommendation on posology and method of administration see section 4.2.
For single use only.
The following guidelines should be followed when handling, preparing and disposing
of doxorubicin.
Preparation
1.

Cytotoxic agents should be prepared for administration only by personnel
who have been trained in the safe handling of such preparations. Refer to
local cytotoxic guidelines before commencing.

2.

Pregnant staff should be excluded from working with this drug.

3.

Personnel handling doxorubicin should wear protective clothing; goggles,
gowns, disposable gloves and masks.

4.

All items used for administration or cleaning, including gloves, should be
placed in high risk waste disposal bags for high temperature (700°C)
incineration.

5.

All cleaning materials should be disposed of as indicated previously.

6.

Always wash hands after removing gloves.

Contamination
1.

In case of contact with skin or mucous membrane, thoroughly wash the
affected area with soap and water or sodium bicarbonate solution. However,
do not graze the skin by using a scrubbing brush. A bland cream may be used
to treat transient stinging of skin.

2.

In case of contact with eye(s), hold back the eyelid(s) and flush the affected
eye(s) with copious amounts of water for at least 15 minutes or normal
sodium chloride 9 mg/ml (0.9%) solution for injection. Seek medical
evaluation by a physician or eye specialist.

3.

In the event of spillage or leakage treat with 1% sodium hypochlorite solution
or phosphate buffer (pH>8) until solution is decoloured. Use a cloth/sponge
kept in the designated area. Rinse twice with water. Put all cloths into a
plastic bag and seal for incineration.

Disposal
Single use only. Any unused product or waste material should be disposed of in
accordance with local requirements. Observe guidelines for handling cytotoxic drugs.

7

MARKETING AUTHORISATION HOLDER
Strides Arcolab International Ltd.
Unit 4, Metro Centre, Tolpits Lane,
Watford, Hertfordshire WD 18 9SS,
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 28176/0144

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
23/10/2014

10

DATE OF REVISION OF THE TEXT
23/10/2014

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