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ZAVEDOS 5MG POWDER FOR SOLUTION FOR INJECTION

Active substance(s): IDARUBICIN HYDROCHLORIDE

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Injection

idarubicin hydrochloride

Late (i.e. delayed) events
Delayed cardiotoxicity usually develops late in the course of therapy 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, 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.
Cumulative dose limits for i.v. or oral idarubicin have not been defined. However, idarubicinrelated cardiomyopathy was reported in 5% of patients who received cumulative i.v.
doses of 150 to 290 mg/m2. Available data on patients treated with oral idarubicin total
cumulative doses up to 400 mg/m2 suggest a low probability of cardiotoxicity.
Cardiac function should be assessed before patients undergo treatment with
idarubicin 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 idarubicin at
the first sign of impaired function. The appropriate quantitative method for repeated
assessment of cardiac function (evaluation of LVEF)
includes Multiple Gated Acquisition (MUGA) scan 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.
Risk factors for cardiac toxicity include active or dormant cardiovascular disease, prior
or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy
with other anthracyclines or anthracenediones, and concomitant use of drugs with
the ability to suppress cardiac contractility or cardiotoxic drugs (e.g. trastuzumab).
Anthracyclines including idarubicin should not be administered in combination with
other cardiotoxic agents unless the patient’s cardiac function is closely monitored.
(see Interactions). Patients receiving anthracyclines after stopping treatment with
other cardiotoxic agents, especially those with long half-lives such as trastuzumab,
may also be at an increased risk of developing cardiotoxicity. The reported half-life of
trastuzumab is approximately 28 - 38 days and may persist in the circulation for up to
27 weeks. Therefore, physicians should avoid anthracycline-based therapy for up to
27 weeks after stopping trastuzumab when possible. If anthracyclines are used before
this time, careful monitoring of cardiac function is recommended.
Cardiac function monitoring must be particularly strict in patients receiving high
cumulative doses and in those with risk factors. However, cardiotoxicity with idarubicin
may occur at lower cumulative doses whether or not cardiac risk factors are present.
In infants and children there appears to be a greater susceptibility to anthracycline
induced cardiac toxicity, and a long-term periodic evaluation of cardiac function has to
be performed. It is probable that the toxicity of idarubicin and other anthracyclines or
anthracenediones is additive.

Haematologic toxicity
Idarubicin is a potent bone marrow suppressant. Severe myelosuppression will occur
in all patients given a therapeutic dose of this agent.
Haematologic profiles should be assessed before and during each cycle of therapy
with idarubicin, including differential white blood cell (WBC) counts.
A dose-dependent, reversible leukopenia and/or granulocytopenia (neutropenia) is the
predominant manifestation of idarubicin hematologic toxicity and is the most common
acute doselimiting toxicity of this drug. Leukopenia and neutropenia are usually
severe; thrombocytopenia and anaemia may also occur. Neutrophil and platelet
counts usually reach their nadir 10 to 14 days after drug administration; however, cell
counts generally return to normal levels during the third week. During the phase of
severe myelosuppression, deaths due to infections and/or haemorrhages have been
reported. Clinical consequences of severe myelosuppression include fever, infections,
sepsis/septicaemia, septic shock, haemorrhage, tissue hypoxia, or death. If febrile
neutropenia occurs, treatment with an i.v. antibiotic is recommended.
Secondary leukaemia
Secondary leukaemia, with or without a preleukemic phase, has been reported
in patients treated with anthracyclines, including idarubicin. Secondary leukemia
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.
Gastrointestinal
Idarubicin is emetigenic. Mucositis (mainly stomatitis, less often oesophagitis)
generally appears early after drug administration and, if severe, may progress over
a few days to mucosal ulcerations. Most patients recover from this adverse event by
the third week of therapy.
Occasionally, episodes of serious gastrointestinal events (such as perforation or
bleeding) have been observed in patients receiving oral idarubicin who had acute
leukaemia or a history of other pathologies or had received medications known to
lead to gastrointestinal complications. In patients with active gastrointestinal disease
with increased risk of bleeding and/or perforation, the physician must balance the
benefit of oral idarubicin therapy against the risk.
Hepatic and/or renal function
Since hepatic and/or renal function impairment can affect the disposition of idarubicin,
liver and kidney function should be evaluated with conventional clinical laboratory tests
(using serum bilirubin and serum creatinine as indicators) prior to, and during, treatment.
In a number of Phase III clinical trials, treatment was contraindicated if bilirubin and/or
creatinine serum levels exceeded 2.0-mg %. With other anthracyclines a 50% dose
reduction is generally used if bilirubin levels are in the range 1.2 to 2.0-mg %.
Effects at site of injection
Phlebosclerosis may result from an injection into a small vessel or from previous
injections into the same vein. Following the recommended administration procedures
may minimize the risk of phlebitis/thrombophlebitis at the injection site .
Extravasation
Extravasation of idarubicin during intravenous injection may cause local pain, severe
tissue lesions (vesication, severe cellulitis), and necrosis. Should signs or symptoms of

N. ZAVL-GB11

Package leaflet: Information for the user
®

Zavedos

FPO

Biological activity
Idarubicin, an original anthracycline, is a DNA inter-calating agent which interacts with
topoisomerase II and has an inhibitory effect on nucleic acid synthesis.
The modification in position 4 of the anthracycline structure gives the compound a
high lipophilicity which results in an increased rate of cellular uptake compared with
doxorubicin and daunorubicin.
Idarubicin has been shown to have a higher potency with respect to daunorubicin and
to be an effective agent against murine leukaemia and lymphomas both by i.v. and
oral routes. Studies in-vitro on human and murine anthracycline-resistant cells have
shown a lower degree of cross-resistance for idarubicin compared with doxorubicin
and daunorubicin.
Cardiotoxicity studies in animals have indicated that idarubicin has a better
therapeutic index than daunorubicin and doxorubicin. The main metabolite,
idarubicinol, has shown in-vitro and in-vivo, antitumoural activity in experimental
models. In the rat, darubicinol, administered at the same doses as the parent drug, is
clearly less cardiotoxic than idarubicin.
Clinical pharmacology
In adults, following oral administration of 10 to 60 mg/m2 idarubicin, idarubicin
was rapidly absorbed with the maximum plasma concentrations of 4-12.65 ng/mL
achieved in 1 to 4 hours after dosing. The terminal half-life was 12.7±6.0 hrs
(mean±SD). Following intravenous administration of idarubicin in adults, the terminal
half-life was 13.9±5.9 hrs, similar to that observed after the oral administration.
After i.v. administration idarubicin is extensively metabolized to an active metabolite,
idarubicinol, which is more slowly eliminated with a plasma t1/2 ranging between
41 and 69 hours. The drug is eliminated by biliary and renal excretion, mostly in
the form of idarubicinol. Studies of cellular (nucleated blood and bone marrow cells)
drug concentrations in leukemic patients have shown that peak cellular idarubicin
concentrations are reached a few minutes after injection.
Idarubicin and idarubicinol concentrations in nucleated blood and bone marrow cells
are more than a hundred times the plasma concentrations.
Idarubicin disappearance rates in plasma and cells were almost comparable with a
terminal half life of about 15 hours. The terminal half life of idarubicinol in cells was
about 72 hours.
Paediatric population
Pharmacokinetic measurements in 7 paediatric patients receiving intravenous
idarubicin in doses ranging from 15 to 40 mg/m2 over the 3 days of treatment,
showed a median idarubicin half-life of 8.5 hrs (range: 3.6-26.4 hrs).
The active metabolite, idarubicinol, accumulated during the 3 days of treatment,
exhibiting a median half-life of 43.7 hrs (range: 27.8-131 hrs). In a separate study,
pharmacokinetic measurements in 15 paediatric patients receiving oral idarubicin in

Another dose-schedule which has been used in ANLL / AML as a single agent and in
combination is 8 mg/m2 i.v. daily for 5 days.
Children: The dose range suggested is 10-12 mg/m2 i.v. daily for 3 days, in combination
with cytarabine.
Acute lymphoblastic leukaemia (ALL)
Adults: As a single agent in ALL the suggested dose is 12 mg/m2 i.v. daily for 3 days.
Children: The suggested dose is 10 mg/m2 i.v. daily for 3 days, as a single agent.
NOTE: These are general guidelines. Refer to individual protocols for exact dosage.
All of these dosage schedules should, however, take into account the haematological
status of the patient and the dosages of other cytotoxic drugs
when used in combination.
Warning: this product is not for intrathecal use.
Contraindications, warnings, etc.:
Contraindications
- hypersensitivity to idarubicin or to any of the excipients listed in Presentation,
other anthracyclines or anthracenediones
- severe hepatic impairment
- severe renal impairment
- severe cardiomyopathy
- recent myocardial infarction
- severe arrhythmias
- persistent myelosuppression
- previous treatment with maximum cumulative doses of idarubicin and/or other
anthracyclines and anthracenediones (see Warnings and precautions)
- breast-feeding should be stopped during drug therapy (see Use during
pregnancy and lactation)
- uncontrolled infections
Warnings and precautions
General
Idarubicin should be administered only under the supervision of physicians
experienced in the use of cytotoxic chemotherapy.
This ensures that immediate and effective treatment of severe complications of the disease
and/or its treatment (e.g. haemorrhage, overwhelming infections) may be carried out.
Patients should recover from acute toxicities of prior cytotoxic treatment (such as
stomatitis, neutropenia, thrombocytopenia, and generalized infections) before beginning
treatment with idarubicin.
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 idarubicin consists mainly of sinus tachycardia and/or
electrocardiogram (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 effects do not usually predict subsequent development of
delayed cardiotoxicity, are rarely of clinical importance, and are generally not a reason
for the discontinuation of idarubicin treatment.

FPO

Zavedos® P owder for Solution for

doses ranging from 30 to 50 mg/m2 during the 3 days of treatment, the maximum
plasma concentration of idarubicin was 10.6 ng/mL (range 2.7-16.7 ng/mL at the
40 mg/m2 dose). The median terminal half-life of idarubicin of was 9.2 hrs (range: 6.425.5 hrs). Significant accumulation of idarubicinol was seen over the 3 day treatment
period. The observed terminal half-life value of idarubicin after i.v. was comparable to
that following oral administration in paediatric patients.
Since Cmax of idarubicin is similar in children and adults following oral administrations,
absorption kinetics seem not to differ between adults and children.
Following both oral and i.v. administrations, the elimination half-life values of idarubicin
in children and adults differ.
Total body clearance values of 30-107.9 L/h/m2 for idarubicin reported for adults
are higher than the values of 18-33 L/h/m2 reported for paediatric populations
Although idarubicin has a very large volume of distribution in both adults and children,
suggesting that much of the drug is bound to tissues, the shorter elimination half-life
and lower total body clearance are not entirely explained
by a smaller apparent volume of distribution in children compared to adults.
Presentation
Sterile, pyrogen-free, orange-red, freeze-dried powder in vials containing 5 mg and
10 mg of idarubicin hydrochloride with 50 mg and 100 mg of lactose respectively.
Uses
Antimitotic and cytotoxic agent.
Adults
For the treatment of acute non-lymphoblastic leukaemia (ANLL) also referred to
as acute myeloid leukaemia (AML) for remission induction in untreated patients or for
remission induction in relapsed or refractory patients.
For second line treatment of relapsed acute lymphoblastic leukaemia (ALL).
Children
For first line treatment of acute non-lymphoblastic leukaemia (ANLL), also referred
to as acute myeloid leukaemia (AML) in combination with cytarabine, for remission
induction.
For second line treatment of acute lymphoblastic leukaemia (ALL).
Zavedos may be used in combination chemotherapy regimens involving other cytotoxic
agents (see Dosage and administration).
Dosage and administration
For reconstitution, the contents of the 5 mg vial should be dissolved in 5 ml of Water
for Injections, the 10 mg vial in 10 ml of Water for Injections. Zavedos must be
administered only by the intravenous route and the reconstituted solution should be
given via the tubing of a freely running intravenous infusion of 0.9% Sodium Chloride
Injection taking 5 to 10 minutes over the injection.
This technique minimises the risk of thrombosis or perivenous extravasation which can
lead to severe cellulitis and necrosis. Venous sclerosis may result from injection into
small veins or repeated injections into the same vein.
Dosage is usually calculated on the basis of body surface area.
Acute non-lymphoblastic leukaemia (ANLL) also referred to as acute myeloid
leukaemia (AML)
Adults: The dose schedule suggested is 12 mg/m2 i.v. daily for 3 days in combination
with cytarabine.

5  mg and 10 mg Powder for
Solution for Injection

idarubicin hydrochloride

Read all of this leaflet carefully before you
start taking this medicine because it contains
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any questions, ask your doctor,
pharmacist or nurse.
- This medicine has been prescribed for you only.
Do not pass it on to others. It may harm them,
even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor,
pharmacist or nurse. This includes any
possible side effects not listed in this leaflet.
See section 4.
What is in this leaflet:
1. What Zavedos is and what it is used for
2. What you need to know before you take
Zavedos
3. How Zavedos will be given to you
4. Possible side effects
5. How to store Zavedos
6. Contents of the pack and other information
1. What Zavedos is and what it is used for
Zavedos contains an active ingredient called
idarubicin, which belongs to a group of medicines
called anthracyclines. Zavedos interferes with
ways in which the cells of your body grow and
increase in number and is used in the treatment
of cancers (chemotherapy).
Zavedos is used in adults and children for the
treatment of acute non lymphoblastic leukaemia

(ANLL), also referred to as acute myeloid
leukaemia (AML).
Zavedos is also used in adults and children
as a second line treatment of relapsed acute
lymphoblastic leukaemia (ALL).
2. What you need to know before you take
Zavedos
Do not take Zavedos:
- If you have ever had an allergic (hypersensitivity)
reaction to
- idarubicin or any of the other ingredients of
this medicine (listed in section 6).
- other anthracyclines or anthracenediones.
- If you have an infection which is not under control.
- If your liver or kidneys are not working properly.
- If you have had previous or current history of
bone marrow depression caused by previous
therapy.
- If you have had a previous or current history of
heart disease.
- If you have had a previous or current history of
abnormal heart rhythms.
- If you have previously been treated with high
doses of idarubicin and/ or other anthracyclines
or anthracenediones.
- If you are breast-feeding.
- If you have an intolerance to sugars. If you
have been told by your doctor that you have
an intolerance to some sugars, contact your
doctor before taking this medicinal product.
Warnings and precautions
Talk to your doctor, pharmacist or nurse before
taking Zavedos if you:
- Suffer from bone marrow depression caused
by previous therapy.

- Have suffered from heart trouble in the past or
are presently receiving treatment for this.
- You have had a previous or current history of
stomach problems (e.g. ulcer) or any problem
with your bowels.
In these cases, Zavedos might not be a suitable
treatment for you, or a reduced dose might have
to be used.
Children
Babies and children are more at risk to heart
problems that may be caused by taking Zavedos.
Regular checks of the heart for a longer time will
be needed.
Regular checks by your doctor during
Zavedos treatment
Before starting and during treatment you will need
regular checks including blood tests.
Your doctor will be making regular checks of:
- Your blood, to check for low blood cell counts
that may need treatment.
- Your heart function, as Zavedos can have
effects upon this.
- Your liver and kidneys – again using blood
tests – to check that Zavedos is not affecting
the way they functions in a harmful way.
- Blood uric acid levels – Zavedos may increase
uric acid levels in the blood, which might cause
gout. Another medicine may be given if your
uric acid levels are too high.
You will find more information on some of these
effects in section 4.

Other medicines and Zavedos
Tell your doctor or pharmacist if you are taking,
have recently taken or might take any other
medicines, including medicines obtained without
a prescription, in particular, if you:
- Are given medicines or were previously
given medicines such as anthracyclines or
anthracenediones that have a similar action
to Zavedos. They can make the effects of
Zavedos stronger.
- Are using Zavedos with medicines like calcium
channel blockers or chemotherapies that have
cardiac toxicity.
- Are receiving radiotherapy.
- Are taking oral drugs that prevent blood clots
as it will require close monitoring.
- Are taking a medicine called Cyclosporin A.
You should not take live or live-attenuated vaccines
(e.g. yellow fever) because of the risk of serious
infection after treatment with chemotherapy.
Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may
be pregnant or are planning to have a baby, ask
your doctor or pharmacist for advice before taking
this medicine. Avoid becoming pregnant while
you or your partner is being treated with Zavedos.
If you are sexually active, you are advised to use
effective birth control to prevent pregnancy during
treatment, whether you are male or female. Males
should continue to use effective contraception up
to 3 months after treatment. Zavedos may harm an
unborn child, so it is important to tell your doctor if
you think you are pregnant.
Do not breast-feed whilst receiving Zavedos,
as some of the drug may get into your milk and
possibly harm your child.

N. ZAVL-GB11

Page 2

Heart damage can occur when high doses of
Zavedos are given. This may not be detected for
several weeks, so regular tests may be required
during this period.
Intestinal bleeding can occur with high doses
of Zavedos. This may need to be observed for
patients treated with oral idarubicin.
4. Possible side effects
Like all medicines, this medicine can cause side
effects, although not everybody gets them.
Tell your doctor immediately if you experience
any of the following symptoms after taking
this medicine. Although they are very rare the
symptoms can be severe.
• You may have allergic reactions such as feel
dizzy, feverish, short of breath with a tight chest,
with or without an itchy rash.
• You have an inflammation of the pericardium
(the fibrous sac surrounding the heart),
inflammation of the heart muscle, a disease
of the electrical system of the heart.
• A condition in which a blood clot that has
formed inside a blood vessel or inside the
heart, redness of the skin, typically over the
cheeks or neck.
• Stomach ulcer (abdominal pain or burning
sensation).
• Hand foot syndrome (tingling, redness, flaking,
swelling or small sores on the palms of the
hands or soles of the feet).
• Anaemia (low red cells) that can leave you
feeling tired and lethargic.
• Leukopenia (low white cells) leading to increased
chance of infections with symptoms of raised
temperature or fever and chills (like flu).
N. ZAVL-GB11

Driving and using machines
Special care should be taken if it is essential that
you drive or operate machinery while undergoing
treatment especially if you are lacking strength or
are in a debilitated condition.
Zavedos contains lactose
If you have been told by your doctor that you
have an intolerance to some sugars, contact your
doctor before taking this medicinal product.
3. How Zavedos will be given to you
Zavedos will be given to you by injection into the
veins. It should not be given by injection into your
spine.
- Your doctor will prescribe the required amount
(the dose). The dose is decided by taking into
account your condition being treated, your
height and weight.
- From your height and weight the doctor
will work out your body surface area; this
is necessary because the dose is usually
calculated as “... milligrams per square metre”
(mg/m2), given by injection, on 3 days running.
- However, your doctor may alter the dose and
number of days treatment depending on your
condition and any other treatment you may receive.
If you use more Zavedos than you should
High doses can worsen side effects like sores
in the mouth or may decrease the number of
white blood cells and platelets (these help the
blood to clot) in the blood. Should this happen,
you may need antibiotics or blood transfusions.
Mouth ulcers can be treated to make them less
uncomfortable as they heal.

• Thrombocytopenia (low platelets, these help the
blood to clot). You may bruise more easily or
bleed more than usual if you hurt yourself.
• Tumour lysis syndrome (severe infections can
occur after treatment with idarubicin alone or in
combination with other medicines, and may be fatal).
Very common side effects (may affect more than
1 in 10 people)
• Infections.
• Decrease in number of red blood cells, reduced
numbers of white blood cells, abnormally low
amount of platelets.
• A lack or loss of appetite for food.
• Feeling sick or being sick, the painful inflammation
and ulceration of the mucous membranes lining
the digestive tract, diarrhoea, stomach ache.
• Hair loss.
• Red colouration of urine.
• Fever (rise in temperature).
• Headache.
• Chills.
Common side effects (may affect up to 1 in
10 people)
• Increase or decrease in heart rate, irregular heart
beat/pulse, heart failure, heart attack.
• Inflammation of the vein, swelling (inflammation)
of a vein caused by a blood clot.
• Bleeding from the intestines, bellyache.
• Liver enzyme elevation.
• Rash, itch.
• Haemorrhages.
• Increased sensitivity of irradiated skin ‘radiation
recall reaction’.
Uncommon side effects (may affect up to 1 in
100 people)
• Blood infection, bacteria in the blood.

• Cancers of blood such as secondary leukaemia or
unfavourable leukaemia (acute myeloid leukaemia
(AML) or myelodysplastic syndrome (MDS)).
• Painful joints due to increased uric acid levels
in your blood (gouty arthritis).
• ECG changes.
• Shock.
• Inflammation of the oesophagus, inflammation
of the colon.
• Darkening of the skin and nails.
• Excessive loss of body fluid.
• Spreading of bacterial infection below the skin
surface and tissue damage.
• Heart attack.
• Hives.
Rare side effects (may affect up to 1 in
1,000 people)
• Stroke.
Very Rare side effects (may affect up to 1 in
10,000 people)
• Serious allergic reaction.
• Inflammation of the pericardium (the fibrous
sac surrounding the heart), defect in the heart’s
electrical system.
• Minor ulceration of the gastric mucosa.
• Hand foot syndrome.
• Inflammation of covering of the heart and heart
muscle.
• Thromboembolism.
• Flush.
Additional side effects experienced, (frequency
cannot be estimated from the available data)
• Change in certain chemicals in the blood.
• Abnormally low levels of all blood cells
produced by the bone marrow.
• Local skin reaction.

Additional side effects in children
Side effects seen in children are similar to those
seen for adults. Children have a higher risk for heart
problems that could be caused by taking Zavedos.
Reporting of side effects
If you get any side effects, talk to your doctor,
pharmacist or nurse. This includes any possible
side effects not listed in this leaflet. You can also
report side effects directly (see details below).
By reporting side effects you can help provide
more information on the safety of this medicine.
United Kingdom
Yellow Card Scheme website:
www.mhra.gov.uk/yellowcard
Ireland
HPRA Pharmacovigilance,
Earlsfort Terrace, IRL - Dublin 2;
Tel: +353 1 6764971; Fax: +353 1 6762517.
Website: www.hpra.ie;
E-mail: medsafety@hpra.ie.
5. How to store Zavedos
Keep this medicine out of the sight and reach of
children.
Do not use Zavedos after the expiry date, which is
stated on the vial after EXP. The expiry date refers
to the last date of that month.
Zavedos should be given to you by injection within
24 hours of being made up from the dry powder in
the vial. It should be kept in the fridge during this time.
Do not throw away any medicines via wastewater
or household waste. Ask your pharmacist how to
throw away medicines you no longer use. These
measures will help protect the environment.

6. Contents of the pack and other information
What Zavedos contains
The active substance is idarubicin hydrochloride.
The other ingredient is lactose monohydrate
What Zavedos looks like and the contents of
the pack
Zavedos is supplied as an orange-red powder in a
vial containing either 5 mg or 10 mg of the active
substance idarubicin hydrochloride. The vials are
packed singly in cartons. Your doctor or nurse will
make up the Zavedos with water into an injection.
Marketing Authorisation Holder and
Manufacturer
PL Holder: Pfizer Limited Ramsgate Road,
Sandwich, Kent, CT13 9NJ, UK
PA Holder: Pfizer Healthcare Ireland
9 Riverwalk, National Digital Park,
Citywest Business Campus,
Dublin 24, Ireland.
Manufacturer: Actavis Italy S.p.A.
10 Viale Pasteur
20014 Nerviano (MI)
Italy
Company Contact Address:
If you have any comments on the way this leaflet
is written, please contact Medical Information at
Pfizer Limited in Walton Oaks, Tadworth, Surrey,
Tel :01304 616161.
This leaflet was last revised in
UK: 11/2014
IE: 10/2014
Ref: ZD 12_2

Page 4

extravasation occur during intravenous administration of idarubicin, the drug infusion should
be immediately stopped.
In cases of extravasation dexrazoxane can be used to prevent or reduce tissue injury.
Tumour lysis syndrome
Idarubicin may induce hyperuricaemia as a consequence of the extensive purine catabolism
that accompanies rapid drug-induced lysis of neoplastic cells (‘tumour lysis syndrome’).
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.
Immunosuppressant effects/increased susceptibility to infections
Administration of live or live-attenuated vaccines (like yellow fever) in patients
immunocompromised by chemotherapeutic agents including idarubicin, may result in
serious or fatal infections. Vaccination with a live vaccine should be avoided in patients
receiving idarubicin. Killed or inactivated vaccines may be administered; however, the
response to such vaccines may be diminished.
Reproductive system
Men treated with idarubicin hydrochloride are advised to adopt contraceptive measures during
therapy and, if appropriate and available, to seek advice on sperm preservation due to the possibility
of irreversible infertility caused by the therapy (see Use during pregnancy and lactation).
Other
As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including
pulmonary embolism have been coincidentally reported with the use of idarubicin.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency
or glucose-galactose malabsorption should not take this medicine.
The product may cause a red colouration of the urine for 1 - 2 days after administration and
patients should be advised of this fact.
Effects on ability to drive and use machines
The effect of idarubicin on the ability to drive or use machinery has not been
systematically evaluated.
Adverse reactions
The frequencies of undesirable effects are based on the following categories:
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 (frequency cannot be estimated from the available data)
Infections and infestations
Very common
Infections
Uncommon
Sepsis, septicaemia
Neoplasms benign, malignant and
unspecified (including cysts and polyps)
Uncommon
Secondary leukaemia (acute myeloid leukaemia
and myelodysplastic syndrome)
Blood and lymphatic system disorders
N. ZAVL-GB11

Very common
Not known
Immune system disorders
Very rare
Endocrine disorders
Very common
Uncommon
Metabolism and nutrition disorders
Uncommon
Not Known
Nervous system disorders
Rare
Cardiac disorders
Common

Uncommon
Very rare
Vascular disorders
Common
Uncommon
Very rare
Gastrointestinal disorders
Very common
Common
Uncommon
Very rare
Hepatobiliary disorders
Common
Skin and subcutaneous tissue disorders
Very common
Common
Uncommon
Very rare

Anaemia, severe leukopenia and neutropenia,
thrombocytopenia
Pancytopenia
Anaphylaxis
Anorexia
Dehydration
Hyperuricaemia
Tumour Lysis Syndrome
Cerebral haemorrhages
Bradycardia, sinus tachycardia,
tachyarrhythmia, asymptomatic reduction of
left ventricular ejection fraction, congestive
heart failure, Cardiomyopathies (see Warnings
and precautions for associated signs and
symptoms)
ECG abnormalities (e.g. nonspecific ST
segment changes), myocardial infarction
Pericarditis, myocarditis, atrioventricular and
bundle branch block
Local phlebitis, thrombophlebitis, haemorrhages
Shock
Thromboembolism, flush
Nausea, vomiting, mucositis/stomatitis,
diarrhoea, abdominal pain or burning sensation
Gastrointestinal tract bleeding, bellyache
Oesophagitis, colitis (including severe
enterocolitis / neutropenic enterocolitis with
perforation)
Gastric erosions or ulcerations
Elevation of the liver enzymes and bilirubin
Alopecia
Rash, itch, hypersensitivity of irradiated skin
(‘radiation recall reaction’)
Skin and nail hyperpigmentation, urticaria,
cellulitis (this event can be severe), tissue necrosis
Acral erythema

Not known
Renal and urinary disorders
Very common

Local reaction

Red coloration of the urine for 1 – 2 days after
the treatment.
General disorders and administration site
conditions
Very common
Fever, headache, chills
Description of selected adverse reactions
Haematopoietic system
Pronounced myelosuppression is the most severe adverse effect of idarubicin treatment.
However, this is necessary for the eradication of leukemic cells
(see Warnings and precautions).
Cardiotoxicity
Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and
represents the cumulative dose-limiting toxicity of the drug (see Warnings and precautions).
Gastrointestinal
Stomatitis and in severe cases ulceration of mucosa, dehydration caused by severe
vomiting and diarrhoea; risk of perforation of colon etc.
Administration site
Phlebitis/thrombophlebitis and prevention measures discussed in Dosage and
administration; unintended paravenous infiltrates may cause pain, severe cellulites
and tissue necrosis.
Other adverse reactions: hyperuricaemia
Prevention of symptoms by hydration, urine alkalinisation, and prophylaxis with allopurinol
may minimise potential complications of tumour lysis syndrome.
Paediatric population
Undesirable effects are similar in adults and children except a greater susceptibility to
anthracycline-induced cardiac toxicity of children.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product
is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
United Kingdom
Healthcare professionals are asked to report any suspected adverse reactions via the
Yellow Card Scheme at
www.mhra.gov.uk/yellowcard.
Ireland
Healthcare professionals are asked to report any suspected adverse reactions via
HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2,
Tel: +353 1 6764971, Fax: +353 1 6762517,
Website: www.hpra.ie,
Email: medsafety@hpra.ie
Use during pregnancy and lactation
Fertility: Idarubicin can induce chromosomal damage in human spermatozoa. For this
reason, males undergoing treatment with idarubicin should use effective contraceptive
methods up to 3 months after treatment (see Warnings and precautions).

Pregnancy: The embryotoxic potential of idarubicin has been demonstrated in both in vitro
and in vivo studies. However, there are no adequate and well-controlled studies in pregnant
women. Women of childbearing potential should be advised not to become pregnant during
treatment and adopt adequate contraceptive measures during therapy as suggested by a
physician. Idarubicin should be used during pregnancy only if the potential benefit justifies
the potential risk to the foetus. The patient should be informed of the potential hazard to the
foetus. Patients desiring to have children after completion of therapy should be advised to
obtain genetic counselling first if appropriate and available.
Breast-feeding: It is not known whether idarubicin or its metabolites are excreted in human
milk. Mothers should not breast-feed during treatment with idarubicin hydrochloride.
Interactions
Idarubicin is a potent myelosuppressant and combination chemotherapy regimens
including other agents with similar action may be expected to induce additive
myelosuppressant effects (see Warnings and precautions). The use of idarubicin
in combination chemotherapy with other potentially cardiotoxic drugs, as well as the
concomitant use of other cardioactive compounds (e.g. calcium channel blockers),
requires monitoring of cardiac function throughout treatment.
Changes in hepatic or renal function induced by concomitant therapies may affect idarubicin
metabolism, pharmacokinetics, and therapeutic efficacy and/or toxicity
(see Warnings and precautions).
An additive myelosuppressant effect may occur when radiotherapy is given concomitantly
or within 2-3 weeks prior to treatment with idarubicin.
Concomitant use of live attenuated vaccines (e.g. yellow fever) is not recommended, due to a risk of
possibly fatal systemic disease. The risk is increased in subjects who are already immunosuppressed
by their underlying disease. An inactivated vaccine should be used if available.
At combination of oral anticoagulants and anticancer chemotherapy, increased frequency of
the INR (International Normalised Ratio) monitoring is recommended, since the risk for an
interaction cannot be excluded.
Cyclosporin A: The co-administration of cyclosporin A as a single chemosensitizer
significantly increased idarubicin AUC (1.78-fold) and idarubicinol AUC (2.46-fold) in
patients with acute leukaemia. The clinical significance of this interaction is unknown.
A dosage adjustment may be necessary in some patients.
Overdose
Although the single-dose packaging is designed to minimise the risk of overdosage and no data
on overdosage exists, should this occur gastric lavage should be carried out as soon as possible.
Patients treated with oral idarubicin should be observed for possible gastro-intestinal
haemorrhage and severe mucosal damage. Very high doses of idarubicin may be expected
to cause acute myocardial toxicity within 24 hours and severe myelosuppression within one
or two weeks. Treatment should further aim to support the patient during this period and
should utilise such measures as blood transfusions and reverse-barrier nursing.
Delayed cardiac failure has been seen with the anthracyclines up to several months after the overdose.
Patients should be observed carefully and if signs of cardiac failure arise, should be treated
along conventional lines.
Pharmaceutical precautions
The vial contents are under a negative pressure to minimise aerosol formation during
reconstitution; particular care should be taken when the needle is inserted. Inhalation of
any aerosol produced during reconstitution must be avoided.

The following protective recommendations which are valid for all cytotoxic agents are given:
- Personnel should be trained in good technique for reconstitution and handling.
- Pregnant staff should be excluded from working with this drug.
- Personnel handling the drug should wear protective clothing; goggles, gowns and
disposable gloves and masks.
- A designated area should be defined for reconstitution (preferably under a vertical
laminar flow system). The work surface should be protected by disposable,
plasticbacked, absorbent paper.
All items used for reconstitution, administration or cleaning, including gloves, should be
placed in high-risk, waste disposal bags for high temperature incineration.
Accidental contact with the skin or eyes should be treated immediately by copious lavage
with water or sodium bicarbonate solution.
Spillage or leakage should be treated with dilute sodium hypochlorite (1% available
chlorine) solution, preferably by soaking, and then water. All cleaning materials should
subsequently be disposed of as indicated previously.
When aseptically prepared, the product may be stored for up to 24 hours at 2°C to
8°C. The product does not contain an antimicrobial preservative. Therefore if aseptic
preparation cannot be ensured, the product must be prepared immediately before use
and any unused portion discarded.
Prolonged contact with any solution of an alkaline pH should be avoided as it will result in
degradation of the drug. Zavedos should not be mixed with heparin as a precipitate may
form and it is not recommended that it be mixed with other drugs.
Package quantities
5 mg and 10 mg vials for injection.
Prescription only medicine
Zavedos 5 mg : PL00057/1061, PA 822/142/003
Zavedos 10 mg : PL 00057/1060,
Further information is available to the medical and allied professions on request
from: Medical Information Department, Pfizer Limited, Walton Oaks,
Dorking Road, Tadworth, KT20 7NS - Tel: 01304 616161
PL HOLDER:
Pfizer Limited
Ramsgate Road, Sandwich, Kent CT13 9NJ, UK.
PA HOLDER:
Pfizer Healthcare Ireland
9 Riverwalk, National Digital Park.
Citywest Business Campus,
Dublin 24, Ireland.
Ref: ZD 12_2

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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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