DOXORUBIN 0.2%

Active substance: DOXORUBICIN HYDROCHLORIDE

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93.130.570-D
Prescriber Information Leaflet

DOXORUBIN 0.2%

doxorubicin hydrochloride
Product Summary
1. Trade Name of the Medicinal Product
Doxorubin 0.2%
2. Qualitative and Quantitative Composition
Doxorubin 0.2% injection contains doxorubicin
hydrochloride 2 mg/ml.
3. Pharmaceutical Form
Solution for Injection.
4. Clinical Particulars
4.1 Therapeutic Indications
In combination with other antineoplastic drugs,
doxorubicin is intended for the treatment of acute
lymphocytic leukaemia (except acute lymphatic
leukaemia of low risk in children), acute myeloid
leukaemia, Hodgkin- and non-Hodgkin lymphomas,
osteosarcoma, Ewing sarcoma, adult soft tissue
sarcoma, metastatic breast carcinoma, gastric
carcinoma, small-cell lung cancer, neuroblastoma,
Wilms tumour and bladder carcinoma. Doxorubicin
may be used intravesically as a single agent for
treatment and prophylaxis of superficial bladder
carcinoma.
4.2 Posology and Method of Administration
Dosage depends on tumour type, hepatic function
and concurrent chemotherapy. The commonly
recommended dosage schedule as a single agent is
60-75 mg/m² by intravenous injection once every
3 weeks. An alternative dose schedule is 20 mg/m²
intravenously, on 3 consecutive days, once every
3 weeks.
In combination with other cytotoxic agents doses of
50-75 mg/m² are administered.
Myelosuppression may be more pronounced because
of the additive effects of the drugs.
The risk of development of cardiomyopathy
gradually increases with the dosage. A cumulative
dose of 550 mg/m² should not be exceeded. The
administration of doxorubicin should be monitored
by electrocardiography, echocardiography and
carotid pulse curve: where the voltage of the QRS
wave decreases by 30 % or at a fractional shortening
of 5 %, it is recommended that treatment is stopped.
If a patient has received mediastinal irradiation, has
concomitant heart disease, or is also being treated
with other cardiotoxic, non-anthracycline cytotoxic
agents, a maximal cumulative dose of 400 mg/m² is
recommended.
Doxorubicin dosage should be reduced if the
bilirubin is elevated as follows: serum bilirubin 12 to
30 mg/ml - give 1/2 of the normal dose, bilirubin >
30 mg/l - give 1/4 of the normal dose.
In general, impaired renal function does not require a
dose reduction.
Doxorubicin may be given by intravenous bolus
injection, or as a continuous infusion. Bolus injection
causes higher peak plasma concentrations and
therefore is probably more cardiotoxic.
Doxorubicin should not be administered
intramuscularly or subcutaneously. Intravenous
administration occurs preferably through a running
intravenous infusion, over 3 to 5 minutes.
Patients at increased risk of cardiotoxicity should be
considered for treatment with a 24 hours continuous
infusion, rather than a bolus injection. In this way,
cardiotoxicity may be less frequent, without a reduction
in therapeutic efficacy. In these patients, the ejection
fraction should be measured before each course.
Dosage in children:
Dosage in children may be lowered, since they have
an increased risk for late cardiotoxicity. Myelotoxicity
should be anticipated, with nadirs at 10 to 12 days
after start of treatment, but is usually followed by a
rapid recovery due to the large bone marrow reserve
of children as compared to adults.
Superficial bladder carcinoma and bladder
carcinoma in situ:
The recommended dosage is 50 mg in 50 ml normal
saline, administered via a sterile catheter.
Initially, this dose is given weekly, later on, monthly.
The optimal duration of treatment has not yet been
determined; it ranges from 6 to 12 months.
Restrictions regarding the maximal cumulative dose,
as with intravenous administration, do not apply to
intravesical administration, because systemic
absorption of doxorubicin is negligible.

4.3 Contra-indications
Myelosuppression, pre-existing heart disease,
previous treatment with complete cumulative doses
of doxorubicin or other anthracyclines.
Doxorubicin should not be used intravesically for the
treatment of bladder carcinoma in patients with
urethral stenosis who cannot be catheterised.
4.4 Special warnings and special precautions for use
Nausea, vomiting and mucositis are often severe and
should be treated appropriately. Doxorubicin should
not be administered intramuscularly or
subcutaneously. Extravasation results in a severe and
progressive tissue necrosis. If extravasation occurs,
the injection should be terminated immediately and
restarted in another vein. Flooding with normal
saline, local infiltration with corticosteroids, or
sodium hydrogen carbonate solution (8.4%), and
application of dimethylsulphoxide have been
reported with varying success. The advice of the
plastic surgery consultant should be asked for, and
wide excision of the involved area should be
considered. Exceeding the maximum cumulative
dose of 550 mg/m² increases the risk of severe,
irreversible and therapy-resistant cardiomyopathy
and resulting congestive heart failure.
Age over 70 or below 15 years should be considered
a risk factor, as well as concomitant heart disease. In
addition, ECG changes may occur including a
reduction in the voltage of the QRS wave, and a
prolongation of the systolic time interval, and the
ejection fraction may be reduced.
In patients previously treated with other
anthracyclines or cyclophosphamide, mitomycin C or
dacarbazine, and patients who received radiotherapy
to the mediastinal area, cardiotoxicity may occur at
doses lower than the recommended cumulative limit.
Acute severe arrhythmias have been reported to
occur during or within a few hours after doxorubicin
administration.
Heart function should be assessed before, during and
after doxorubicin therapy, e.g. by ECG,
echocardiography or determination of the ejection
fraction. The high incidence of bone marrow
depression requires careful haematologic monitoring.
Doxorubicin therapy should not be started or
continued when polynuclear granulocyte counts are
below 2000/mm³, except in the treatment of acute
leukaemia, where lower limits may be applied.
Careful haematologic monitoring is also required
because of the risk of secondary leukaemias after
treatment with cytotoxic agents (see section 4.8:
“Undesirable effects”). These leukaemias can be
cured when detected at an early stage. Hepatic
function should be evaluated before and during
therapy.
Doxorubicin may induce hyperuricaemia. The blood
uric acid level should be monitored; sufficient fluid
intake should be ascertained (with a daily minimum
of 3 l/m²). If necessary, a xanthine-oxidase inhibitor
(allopurinol) may be administered.
Men as well as women should take effective
contraceptive measures during and for at least
3 months after doxorubicin therapy.
Doxorubicin may impart a red colouration to the
urine.
4.5 Interaction with other medicaments and other
forms of interaction
Doxorubicin cardiotoxicity is enhanced by previous
or concurrent use of other anthracyclines, mitomycin
C, dacarbazine, dactinomycin and, possibly,
cyclophosphamide.
Doxorubicin may cause exacerbations of
haemorrhagic cystitis caused by previous
cyclophosphamide therapy.
The effects of radiation may be enhanced, and recall
of these reactions may occur with doxorubicin
therapy, even some time after termination of
radiotherapy.
Inducers of the enzyme cytochrome P-450 (e.g.
rifampicin and barbiturates) may stimulate the
metabolism of doxorubicin, with a possible decrease
in efficacy.
Inhibitors of cytochrome P-450 (e.g. cimetidine) may
decrease the metabolism of doxorubicin, with a
possible increase in toxic effects.
4.6 Pregnancy and lactation
Clinical evidence suggests a possible adverse effect
on the foetus. In animals doxorubicin has
embryotoxic and teratogenic effects. Doxorubicin is
excreted in breast milk. Usage during pregnancy and
lactation is therefore not recommended.

93.130.570-D

• are pregnant, planning to become pregnant or
breast-feeding.
PACKAGE LEAFLET: INFORMATION FOR THE USER

DOXORUBIN 0.2%

Doxorubicin Hydrochloride
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 or nurse.
• If any of the side effects get serious, or if you
notice any side effects not listed in this leaflet,
please tell your doctor or nurse.
IN THIS LEAFLET:
1. What Doxorubin is and what it is used for
2. Before you receive Doxorubin
3. How to receive Doxorubin
4. Possible side effects
5. How to store Doxorubin
6. Further information

1

WHAT DOXORUBIN IS AND WHAT IT IS
USED FOR

Doxorubicin is an anthracycline glycoside, which
belongs to a group of medicines called cytotoxics
which are used to treat cancer.
Doxorubin is used to treat:
• acute lymphocytic leukaemia (cancer of the
blood cells made by lymph glands)
• acute myeloid leukaemia (cancer of the blood
cells made by bone marrow)
• Hodgkin and non-Hodgkin lymphoma (cancer
of the lymph glands)
• osteosarcoma (bone cancer)
• Ewing sarcoma (bone cancer in teenagers)
• adult soft tissue sarcoma (cancer of the soft
tissues)
• advanced breast cancer
• stomach cancer
• small-cell lung cancer
• neuroblastoma (cancer of the nerve tissue)
• Wilms tumour (a kidney cancer)
• bladder cancer.
In all these types of cancer normal cell growth is
disturbed. The cells grow uncontrolled which
causes your cancer. The types of cancer listed
above depends on the place in your body where
these cells grow.
Leukaemia is a cancer of the cells in your body
which produce the various components of your
blood.
Doxorubicin attacks and destroys the diseased
cells. Unfortunately, the growth of normal cells is
also affected. This may result in some of the side
effects which are discussed later in this leaflet.
Before treatment, you should discuss the risks
and benefits of this medicine with your doctor.

2

BEFORE YOU RECEIVE DOXORUBIN

Do NOT receive Doxorubin if you:
• are allergic (hypersensitive) to doxorubicin
hydrochloride or any of the other ingredients
of this medicine
• have problems with your bone marrow not
working properly (a problem with blood cell
production)
• have heart problems
• have previously received treatment with
doxorubicin or similar medicines e.g.
epirubicin
• have problems urinating

Please discuss any worries you may have about
the above warnings with your doctor
immediately. Your doctor may, however, decide
that your treatment is essential.
Take special care with Doxorubin
Tell your doctor or nurse before you start to take
this medicine if you:
• have received radiation therapy to the chest
• have liver problems
• have a history of gout.
You should also talk to your doctor before you
receive Doxorubin if you are over 70 or under
15 years of age.
Your doctor will want to monitor you with heart,
blood and liver tests before and during your
treatment with Doxorubin.
Men and women should use an effective method
of contraception during therapy and for at least
3 months afterwards.
Taking other medicines
Talk to your doctor or nurse if you are taking any
of the following:
• rifampicin (an antibiotic)
• barbiturates e.g. phenobarbital
• cimetidine (used to treat certain conditions
caused by too much acid being produced in
the stomach).
Talk to your doctor or nurse if you:
• have previously been treated with
cyclophosphamide, mitomycin C,
dactinomycin or dacarbazine (used to treat
cancer).
Please tell your doctor or nurse if you are taking
or have recently taken any other medicines,
including medicines obtained without a
prescription.
Pregnancy and breast-feeding
Doxorubin is not recommended if you are
pregnant, trying to become pregnant or
breast-feeding. If you become pregnant or
suspect that you may be pregnant during
therapy, you must tell your doctor immediately.
Driving and using machines
Doxorubin may cause frequent nausea and
vomiting. If affected do not drive or operate
machinery.

3

HOW TO RECEIVE DOXORUBIN

Your medicine will be administered by a doctor or
nurse as an injection into one of your veins. The
injection should never be given under the skin or
into a muscle. The site of injection should not be
covered or bandaged. In the case of cancer of
the bladder, Doxorubin is administered through a
catheter. Doxorubin may be given alone or in
combination with other medicines.
If you experience any pain, swelling or warmth
around the vein where Doxorubin is being
injected, tell your nurse or doctor immediately.
This may be a sign that the injection has leaked
into the surrounding tissue.
If you notice that your face is red while the
injection is being given to you, tell your doctor or
nurse immediately. This may be a sign that the
injection is being given too quickly.

How much Doxorubin will you receive and how
often:
Adults
• The dosage will depend on the type of cancer
being treated, other medicines you are
receiving, your age, height, weight and your
general medical condition
• The most commonly used dosage is
60 – 75 mg/m² every 3 weeks
• If you are being treated for cancer of the
bladder the usual dose is 50 mg/50 ml every
week and later on, every month
• Your treatment schedule may be modified
depending on your body’s response or other
medication you are receiving
• While you are being given Doxorubin your
doctor may want to monitor your heart
function. Your condition will also be closely
monitored during treatment. This will involve
blood tests
• Other medicines may be given during a course
of Doxorubin to treat or prevent side effects.
Children
Children may be given lower doses than those
used in adults.
If you have any questions about your treatment
ask your doctor or nurse.
If you receive more Doxorubin than you should
As a doctor or nurse will be giving you your
medicine, it is unlikely that you will receive an
incorrect dose. If you receive too much Doxorubin
you may suffer from side effects sooner. Tell your
doctor or nurse if you have any concerns about
the amount of medicine that you receive.
If you miss a dose of Doxorubin
It is important that you do not miss an
appointment/injection. If you do miss an
injection, you should ensure that you receive
your missed dose as soon as possible.
If you have any further questions on the use of
this product, ask your doctor or nurse.

4

POSSIBLE SIDE EFFECTS

Like all medicines, Doxorubin can cause side
effects. You should discuss them with your
doctor who will explain the risks and benefits of
your treatment. Some of the side effects can be
lessened or treated by other medicines or
therapy.
Although not all of these side effects may occur,
if they do occur, they may need medical
attention.
Tell your doctor immediately if any of the
following occur:
• blood problems, characterised by fever or
chills, sore throat, ulcers in the mouth or
throat, tiredness or weakness, unusual
bleeding or unexplained bruising
• heart problems, characterised by irregular
heartbeat, problems with the heart muscle.
After you have completed your course of
treatment, you should tell your doctor or nurse
immediately if you notice difficulty in breathing,
swelling of the feet or legs, or an irregular or
rapid heart beat.
The following side effects have also been
reported:
• inflammation, ulceration or swelling of the
nose, mouth, or throat
• flushing of the face
• inflammation of a vein with a blood clot
• conjunctivitis
• pain, swelling or warmth around the vein
where Doxorubin is being injected

• allergic reactions e.g. fever, nettle rash,
increased heartbeat, breathing problems,
dizziness
• stomach problems, nausea, vomiting,
diarrhoea
• kidney and bladder problems e.g.
inflammation and bleeding of the bladder,
blood in the urine, changed pattern of
urination, pain during urination
• liver problems, e.g. yellow eyes and skin,
abnormal liver enzymes, inflamed liver.
There is a chance that Doxorubin might cause
unwanted effects that may not occur until
months or years after the medicine is used. These
delayed effects may include certain types of
cancer, such as leukaemia. Discuss these possible
effects with your doctor.
Doxorubin may cause your urine to turn red in
colour for a couple of days after each dose.
Medicines like Doxorubin often cause temporary
hair loss. After treatment your normal hair
growth should return.
If any of the side effects get serious, or if you
notice any side effects not listed in this leaflet,
please tell your doctor or nurse.

5

HOW TO STORE DOXORUBIN

Keep out of the reach and sight of children.
The vials should be stored in a fridge and be
protected from light. Diluted solutions of
Doxorubin should be stored in a fridge for 24
hours, and be protected from light. Do not use
Doxorubin after the expiry date that is stated on
the outer packaging. The expiry date refers to
the last day of that month.

6

FURTHER INFORMATION

What Doxorubin contains:
• The active ingredient is doxorubicin
hydrochloride
• The other ingredients are sodium chloride,
hydrochloric acid/sodium hydroxide and water
for injections.
What Doxorubin looks like and contents of the
pack:
• Doxorubin 0.2% comes as a red-orange
solution for injection in vials of 5 ml (10 mg
doxorubicin hydrochloride per vial), 10 ml
(20 mg doxorubicin hydrochloride per vial),
25 ml (50 mg doxorubicin hydrochloride per
vial) and 100 ml (200 mg doxorubicin
hydrochloride per vial)
• Doxorubin 0.2% is supplied in packs of 1 or
10 vials.
Marketing Authorisation Holder and
Manufacturer
Marketing Authorisation holder and company
responsible for manufacture: Pharmachemie B.V.,
Haarlem, The Netherlands.
This leaflet was last revised: September 2011
PL 04946/0016

4.7 Effects on ability to drive and use machines
Due to the frequent occurrence of nausea and
vomiting, driving and operation of machinery should
be discouraged.
4.8 Undesirable effects
Dose limiting toxicities of therapy are
myelosuppression and cardiotoxicity.
Myelosuppression includes a transient leukopenia,
anaemia and thrombocytopenia, reaching its nadir at
10 to 14 days after treatment.
Cardiotoxicity may occur as arrhythmias directly
following drug administration; ECG changes,
including T-wave flattening and S-T depression, may
last up to 2 weeks after administration.
The risk of cardiomyopathy increases at cumulative
doses higher than 550 mg/m². Age over 70 or below
15 years should be regarded as a risk factor. Also,
concomitant or previous treatment with mitomycin
C, cyclophosphamide or dacarbazine has been
reported to potentiate doxorubicin induced
cardiomyopathy.
Cardiotoxicity may be encountered several weeks or
months after discontinuation of doxorubicin therapy.
Other adverse reactions reported are: a generally
reversible alopecia; gastrointestinal disturbances,
including nausea, vomiting and diarrhoea. Mucositis
(stomatitis or oesophagitis) may occur 5 to 10 days
after administration.
Hypersensitivity reactions, such as fever, urticaria
and anaphylaxis have been occasionally reported.
Doxorubicin influences and potentiates normal tissue
reactions to radiation. Also, late (“recall”) reactions
may occur when doxorubicin is administered some
time after irradiation. Facial flushing may occur if the
injection is given too rapidly Thrombophlebitis and
conjunctivitis have been reported.
Slight transient increases of liver enzymes have been
reported. Concomitant irradiation of the liver may
cause severe hepatoxicity, sometimes progressing to
cirrhosis.
As with other cytotoxic agents, myelodysplastic
syndrome and acute myeloid leukaemia have been
observed after treatment with combination therapy
including doxorubicin. With topoisomerase II
inhibitors, secondary leukaemias have been reported
more frequently than expected in the form of acute
myeloid leukaemia classification 2, 3 and 4. These
forms of leukaemia can have a short period of
latency (1 to 3 years). They can be cured when
detected at an early stage and with an appropriate
curative treatment (see section 4.4 “Special warnings
and special precautions for use”).
Intravesical administration may cause the following
adverse reactions: haematuria, vesical and urethral
irritation, stranguria and pollakisuria. These reactions
are usually of moderate severity and of short
duration. Intravesical administration of doxorubicin
may cause a sometimes haemorrhagic cystitis; this
may cause a decrease in bladder capacity.
Doxorubicin may impart a red colouration to the
urine.
4.9 Overdosage
Acute overdosage of doxorubicin enhances the toxic
effects of mucositis, leukopenia and
thrombocytopenia.
Overdosage at intravesical administration may cause
severe cystitis. Treatment of acute overdosage
consists of treatment of the severely myelosuppressed
patient with hospitalisation, antibiotics and
transfusions after consultation with an oncologist.
Chronic overdosage with cumulative doses exceeding
550 mg/m² increases the risk of cardiomyopathy and
resultant congestive heart failure. Treatment consists
of vigorous management of congestive heart failure
with digitalis preparations and diuretics.
Administration of a very high single dose may cause
myocardial degeneration within 24 hours.
5. Pharmacological Properties
5.1 Pharmacodynamic properties
Doxorubicin is a cytotoxic anthracycline antibiotic
isolated from cultures of Streptomyces peucetius var.
caesius. Animal studies have shown a cytotoxic
action in several solid and haematologic tumours.
The mechanism of action is not completely elucidated.
A major mechanism is probably inhibition of
topoisomerase II, resulting in DNA breakage.
Intercalation and free-radical formation is probably
of minor importance. Drug resistance, due to
increased expression of the MDR-1 gene encoding
for a multidrug efflux pump, has been reported
regularly.

5.2 Pharmacokinetic properties
The intravenous administration of doxorubicin is
followed by a rapid plasma clearance (t1/2 = 10 min.)
and significant tissue binding. The terminal half-life is
approximately 30 hours. Doxorubicin is partly
metabolised, mainly to doxorubicinol and to a lesser
extent, to the aglycon, and is conjugated to the
glucuronide and sulphate. Biliary and faecal excretion
presents the major excretion route. About 5 % of
the dose is eliminated by renal excretion. Plasma
protein binding of doxorubicin ranges from 50-85 %.
The volume of distribution is 800-3500 l/m².
Doxorubicin is not absorbed after oral
administration; it does not cross the blood-brain
barrier. Impairment of liver function may decrease
the clearance of doxorubicin and its metabolites.
5.3 Preclinical safety data
None stated.
6. Pharmaceutical Particulars
6.1 List of excipients
Sodium chloride, hydrochloric acid/sodium
hydroxide, water for injections.
6.2 Incompatibilities
Doxorubicin should not be mixed with 5-fluorouracil
or heparin. Contact with aluminium should be
avoided.
6.3 Shelf-life
Following the special precautions for storage (see
section 6.4) the shelf-life of the 5 ml, and 25 ml vials
is 36 months and the shelf-life of the 100 ml vial is
24 months as printed on the label.
The injection may be diluted with 0.9% sodium
chloride solution or 5% glucose solution. Chemical
and physical in-use stability has been demonstrated
for 7 days at room temperature (15-25°C) and
protected from light.
From a biological 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 and would normally not be
longer than 24 hours at 2 to 8°C, unless
reconstitution/dilution (etc) has taken place in
controlled and validated aseptic conditions.
6.4 Special precautions for storage
Doxorubin 0.2%, injection should be stored at
2-8°C, protected from light.
6.5 Nature and contents of container
Doxorubicin 0.2%, injection is supplied as a redorange, sterile solution in injection vials containing
5 ml (10 mg), 25 ml (50 mg), or 100 ml (200 mg),
respectively, of doxorubicin hydrochloride 2 mg/ml.
6.6 Instructions for use/handling
Any contact with the solution should be avoided.
During preparation and reconstitution a strictly
aseptic working technique should be used; protective
measures should include the use of gloves, mask,
safety goggles and protective clothing.
Use of a vertical laminar airflow (LAF) hood is
recommended.
Gloves should be worn during administration.
Waste-disposal procedures should take into account
the cytotoxic nature of this substance.
If the doxorubicin solution contacts skin, mucosae or
eyes, immediately wash thoroughly with water. Soap
may be used for skin cleansing.
7. Marketing Authorisation Holder
Pharmachemie B.V.,
Swensweg 5,
Postbus 552,
2003 RN Haarlem,
The Netherlands.
8. Marketing Authorisation Number
PL 04946/0016
9. Date of First Authorisation/Renewal of
Authorisation
4 January 1996.
10. Date of (Partial) Revision of the Text
January 2001.
Distributed by TEVA UK Limited, Eastbourne,
BN22 9AG.
67918-K

93.130.570-D

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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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