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ZAVEDOS CAPSULES 25MG

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Zavedos Capsules 25 mg.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION
Idarubicin Hydrochloride 25.0 mg HSE.

3.

PHARMACEUTICAL FORM
Opaque white cap and body, self-locking, hard gelatin capsule, size no. 2,
containing an orange powder.

4.

CLINICAL PARTICULARS

4.1.

Therapeutic indications
Acute non-lymphocytic leukaemia (ANLL).
Whenever intravenous idarubicin cannot be employed e.g. for medical,
psychological or social reasons, oral idarubicin can be used for remission
induction in patients with previously untreated, relapsed or refractory acute
non-lymphocytic leukaemia.
Zavedos may be used in combination chemotherapy regimens involving other
cytotoxic agents.
As a single agent in the treatment of advanced breast cancer after failure of
front line chemotherapy not including anthracyclines.

4.2

Posology and method of administration

Route of Administration: Oral
Dosage is usually calculated on the basis of body surface area.

In adult acute non-lymphocytic leukaemia (ANLL) also referred to as acute
myelogenous leukaemia (AML), the recommended dose schedule suggested is 30
mg/m2 orally given daily for 3 days as a single agent, or between 15 and 30 mg/m2
orally daily for 3 days in combination with other anti-leukemic agents.
In advanced breast cancer the recommended dose schedule as single agent is 45
mg/m2 orally given either on a single day or divided over 3 consecutive days, to be
repeated every 3 or 4 weeks based on the haematological recovery.
A maximum cumulative dose of 400 mg/m2 is recommended.
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.
In patients with hepatic impairment a dose reduction of Zavedos should be
considered. (See special warnings).
The capsules should be swallowed whole with some water and should not be sucked,
bitten or chewed. Zavedos Capsules may also be taken with a light meal.
4.3

Contraindications

- hypersensitivity to idarubicin or any other component of the product, other
anthracyclines or anthracenediones
- severe hepatic impairment
- severe renal impairment
- severe cardiomyopathy
- uncontrolled infections
- recent myocardial infarction
- severe arrhythmias
- persistent myelosuppression
- previous treatment with maximum cumulative doses of idarubicin and/or other
anthracyclines and anthracenediones (See section 4.4)
- breast-feeding should be stopped during drug therapy (See section 4.6)

4.4

Special warnings and precautions for use

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 bemanifested 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.
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 IV or oral idarubicin have not been defined. However,
idarubicin-related cardiomyopathy was reported in 5% of patients who received
cumulative IV 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.
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 half-life of trastuzumab is
approximately 28.5 days and may persist in the circulation for up to 24 weeks.
Therefore, physicians should avoid anthracycline-based therapy for up to 24 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 IV antibiotic is recommended.
Secondary Leukaemia
Secondary leukaemia, with or without a preleukemic phase, has been reported in
patients treated with anthracyclines, including idarubicin. 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.
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 %.

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
section 4.6).
Other
As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena,
including pulmonary embolism have been coincidentally reported with the
use of idarubicin.
The product may cause a red colouration of the urine for 1 - 2 days after
administration and patients should be advised of this fact.
4.5

Interaction with other medicinal products and other forms of interaction

Idarubicin is a potent myelosuppressant and combination chemotherapy regimens
including other agents with similar action may be expected to induce additive

myelosuppressant effects (See Section 4.4). 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 section 4.4).
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 coadminstration 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.
4.6
Fertility, pregnancy and lactation
Impairment of 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 section 4.4).
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.
Lactation
It is not known whether idarubicin or its metabolites are excreted in human milk.
Mothers should not breast-feed during treatment with idarubicin hydrochloride.
4.7

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.

4.8

Undesirable effects

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 (cannot be estimated from the available data)
Infections and infestations
Very common
Uncommon
Neoplasms benign, malignant and
unspecified (including cysts and
polyps)
Uncommon

Infections
Sepsis, septicaemia

Secondary leukaemia (acute myeloid
leukaemia and myelodysplastic
syndrome)

Blood and lymphatic system disorders
Very common
Anaemia, severe leukopenia and
neutropenia, thrombocytopenia
Not known
Pancytopenia
Immune system disorders
Very rare

Anaphylaxis

Endocrine disorders
Very common
Uncommon

Anorexia
Dehydration

Metabolism and nutrition disorders
Uncommon
Not Known

Hyperuricaemia
Tumour Lysis Syndrome

Nervous system disorders
Rare

Cerebral haemorrhages

Cardiac disorders
Common

Bradycardia, sinus tachycardia,
tachyarrhythmia, asymptomatic
reduction of left ventricular ejection
fraction, congestive heart failure,

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
Renal and urinary disorders
Very common

General disorders and administration
site conditions
Very common

cardiomyopathies (See section 4.4 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

Red coloration of the urine for 1 – 2
days after the treatment.

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
section 4.4).
Cardiotoxicity
Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy
and represents the cumulative dose-limiting toxicity of the drug (See section 4.4).
Gastrointestinal
Stomatitis and in severe cases ulceration of mucosa, dehydration caused by severe
vomiting and diarrhoea; risk of perforation of colon etc.
Other adverse reactions: hyperuricaemia
Prevention of symptoms by hydration, urine alkalinisation, and prophylaxis with
allopurinol may minimise potential complications of tumour lysis syndrome.
4.9

Overdose

Very high doses of idarubicin may be expected to cause acute myocardial toxicity
within 24 hours and severe myelosuppression within one to two weeks.
Delayed cardiac failure has been seen with anthracyclines for up to several months
after the overdose.
Patients treated with oral idarubicin should be observed for possible gastrointestinal
haemorrhage and severe mucosal damage.
5.

PHARMACOLOGICAL PROPERTIES

5.1.

Pharmacodynamic properties
Idarubicin is an antimitotic and cytotoxic agent which intercalates with DNA
and interacts with topoisomerase II and has an inhibitory effect on nucleic acid
synthesis. The compound has 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 antitumoral activity in experimental models. In the
rat, idarubicinol, administered at the same doses as the parent drug, is clearly
less cardiotoxic than idarubicin.

5.2.

Pharmacokinetic properties
After oral administration to patients with normal renal and hepatic function,
idarubicin is rapidly absorbed, with a peak time of 2-4 H., is eliminated from
systemic circulation with a terminal plasma T½ ranging between 10-35 H and
is extensively metabolized to an active metabolite, idarubicinol, which is more
slowly eliminated with a plasma T½ ranging between 33 and 60 H. The drug
is mostly eliminated by biliary excretion, mainly in the form of idarubicinol,
urinary excretion accounting for 1-2% of the dose as unchanged drug and for
up to 4.6% as idarabicinol.
Average values of absolute bioavailability have been shown to range between
18 and 39% (individual values observed in the studies ranging between 3 and
77%), whereas the average values calculated on the data from the active
metabolite, idarubicinol, are somewhat higher (29 - 58%; extremes 12 153%).
Studies of cellular (nucleated blood and bone marrow cells) drug
concentrations in leukaemic patients have shown that uptake is rapid and
almost parallels the appearance of the drug in plasma. Idarubicin and
idarubicinol concentrations in nucleated blood and bone marrow cells are
more than two hundred times the plasma concentrations. Idarubicin and
idarubicinol disappearance rates in plasma and cells were almost comparable.

5.3.

Preclinical safety data
No further preclinical safety data are available.

6.

PHARMACEUTICAL PARTICULARS

6.1.

List of excipients
Microcrystalline cellulose
Glyceryl palmito-stearate

Ph. Eur.
HSE

Capsule shell:
Titanium dioxide (E171)
Gelatin
Sodium dodecyl sulphate

Ph. Eur.
Ph. Eur.
Ph. Eur.

6.2.

Incompatibilities
Not known.

6.3.

Shelf life
36 months.

6.4.

Special precautions for storage
Store in a dry place.

6.5

Nature and contents of container
Type III amber glass bottles closed with an aluminium screw cap with a
polyethylene gasket and a polyethylene cover cap. Aluminium/aluminium
strips. Pack size: 1.

6.6

Special precautions for disposal
None stated.

7

MARKETING AUTHORISATION HOLDER
Pharmacia Limited
Ramsgate Road
Sandwich
Kent CT13 9NJ
United Kingdom

8.

MARKETING AUTHORISATION NUMBER(S)
PL: 00032/0440.

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION

30/09/2004

10

DATE OF REVISION OF THE TEXT
23/10/2012

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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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