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PHYSICIANS LEAFLET_

Zavedos® 5 mg and 10 mg Capsules

idarubicin hydrochloride

Pharmacology

Idarubicin 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 iv. 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.

Pharmacokinetics

After oral administration to patients with normal renal and hepatic function, idarubicin is rapidly absorbed, with a peak time of 2-4 hours, is eliminated from systemic circulation with a terminal plasma t¹/2 ranging between 10-35 hours and is extensively metabolized to an active metabolite, idarubicinol, which is more slowly eliminated with a plasma t/ ranging between 33 and 60 hours. 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 idarubicinol.

Average values of absolute bioavailability have been shown to range between 18 and 39% (individual values observed in the studies ranged 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 on cellular (nucleated blood and bone marrow cells) drug concentrations in leukemic 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.

Indications

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 capsules may be used in combination chemotherapy regimens involving other cytotoxic agents.

Zavedos capsules are indicated as a single agent in the treatment of advanced breast cancer after failure of front line chemotherapy not including anthracyclines.

Dosage and administration

Dosage is usually calculated on the basis of body surface area.

In adult ANLL the recommended dose schedule 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 antileukemic agents.

In advanced breast cancer the recommended dose schedule as a single agent is 45 mg/m2 orally given either on a single day or divided over 3 consecutive days (15 mg/m2/day, to be repeated every 3 or 4 weeks based on 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 warnings). Before administration it should be ensured that the capsules are intact. They 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. Contraindications

-    hypersensitivity to idarubicin or to any of the excipients, other anthracyclines or anthracenediones

-    severe hepatic impairment

-    severe renal impairment

-    uncontrolled infections

-    severe cardiomyopathy

-    recent myocardial infarction

-    severe arrhythmias

-    persistent myelosuppression

-    previous treatment with maximum cumulative doses of idarubicin and/or other anthracyclines and anthracenediones (See warning section)

-    breast-feeding should be stopped during drug therapy (See section “use for pregnancy & lactation”)

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.

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 (see section 4.5). 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 leukopaenia 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.

Package leaflet: Information for the patient

Zavedos®5 mg and 10 mg Capsules

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 or pharmacist

•    This medicine has been prescribed for you only. Do not pass it 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 or pharmacist. 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 to take Zavedos

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 for the treatment of acute non-lymphoblastic leukaemia (ANLL) also referred to as acute myelogenous leukaemia (AML), or advanced breast cancer.

You must talk to a doctor if you do not feel better

or if you feel worse.

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) or other anthracyclines.

•    You have an infection which is not under control.

•    Your liver or kidneys are not working properly.

•    You have had previous or current history of bone marrow depression caused by previous therapy.

•    You have had a previous or current history of heart disease.

•    You have had a previous or current history of abnormal heart rhythms.

•    You have previously been treated with high doses of idarubicin and/ or other anthracyclines or anthracenediones.

•    You are breast-feeding.

Warnings and precautions

Talk to your doctor or pharmacist before taking

Zavedos:

•    If you suffer from bone marrow depression caused by previous therapy.

•    If you have suffered from heart trouble in the past or are presently receiving treatment for this.

•    If you have had a previous or current history of stomach problems (e.g. ulcer) or any problem with your bowels.

Your doctor will assess your health and discuss the risk and benefits of your treatment carefully before prescribing Zavedos capsules to you. Zavedos might not be a suitable treatment for you, or a reduced dose might have to be used. Zavedos might not be a suitable treatment for infants or children as they are more at risk of heart trouble.

Other medicines and Zavedos

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines:

•    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.

•    If you are using Zavedos with medicines like calcium channel blockers or chemotherapies that have cardiac toxicity.

•    If you are receiving radiotherapy.

•    If you are taking oral drugs that prevent blood clots as it will require close monitoring.

•    If you 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.

Zavedos with food and drink

Zavedos capsules may be taken with a light meal. Pregnancy

If you are pregnant, 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. Breast-feeding

You should not breast-feed whilst receiving Zavedos, as some of the medicine may get into your milk and possibly harm your child.

Ask your doctor or pharmacist for advice before taking any medicine.

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.

3. How to take Zavedos Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Zavedos capsules are taken by mouth.

•    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 (in square metres); this is necessary because the dose is usually calculated as .milligrams per square metre' (mg/m²).

•    The dose will be given daily for three days (or on one day only for breast cancer).

•    However, your doctor may alter the dose and number of days depending on your condition and any other treatment you may receive.

•    The capsules should be swallowed whole with some water and should not be sucked, bitten or chewed.

Regular checks by your doctor during

Zavedos treatment

During treatment 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 - again using blood tests - to check that Zavedos is not affecting the way it 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.