Zavedos 5 mg Powder for Solution for Injection

Zavedos 10 mg Powder for Solution for Injection

Each vial contains 5mg idarubicin hydrochloride

Each vial contains10mg idarubicin hydrochloride

The reconstituted solution contains 1mg/ml.

For a full list of excipients, see section 6.1:

Powder for Solution for Injection

Sterile, pyrogen-free, orange-red, freeze-dried powder in vial containing 5 mg of idarubicin hydrochloride, with 50 mg of lactose monohydrate

Sterile, pyrogen-free, orange-red, freeze-dried powder in vial containing 10 mg of idarubicin hydrochloride, with 100 mg of lactose monohydrate.

For the treatment of acute non-lymphoblastic leukaemia (ANLL) in adults, for remission induction in untreated patients or for remission induction in relapsed or refractory patients.

In the treatment of relapsed acute lymphoblastic leukaemia (ALL) as second line treatment in adults and children.

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

For intravenous use only.

Not for intrathecal use.

Dosage is calculated on the basis of body surface area.

Acute non-lymphoblastic leukaemia (ANLL)

Adults

- 12 mg/m²/day i.v. daily for 3 days in combination with cytarabine.

or

- 8 mg/m²/day i.v. daily for 5 days with/without combination.

Acute lymphoblastic leukaemia (ALL)

Adults

As single agent in ALL the suggested dose in adults is 12 mg/m² i.v. daily for 3 days.

Children

10 mg/m² i.v. daily for 3 days, as a single agent.

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.

Administration of the second course should be delayed in patients who develop severe mucositis until recovery from this toxicity has occurred and a dose reduction of 25% is recommended.

For instruction on dilution of the product before administration, see section 6.6.

• Hypersensitivity to idarubicin or to any other component of the product, other anthracyclines or anthracenediones

• Severe hepatic impairment

• Severe renal impairment

• Uncontrolled infections

• Severe myocardial insufficiency

• 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)

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. hemorrhage, 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.

Haemotological Toxicity.

Idarubicin is a potent bone marrow suppressant. Severe myelosuppression will occur in all patients given a therapeutic dose of this agent.

Haematological profiles should be assessed before and during each cycle of therapy with idarubicin, including differential white blood cell (WBC) counts.

A dose-dependant reversible luekopenia 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. Clinical consequences of severe myelosuppression include fever, infections, sepsis/septicaemia, septic shock, haemorrhage, tissue hypoxia or death.

Secondary Leukemia. Secondary leukaemia, with or without a preleukaemic 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.

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 dyspnea, pulmonary edema, dependent edema, cardiomegaly, hepatomegaly, oliguira, ascitres, 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 290mg/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 multi-gated radionuclide angiography (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.

Hepatic and 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 - 2.0 mg%.

Gastrointestinal.

Idarubicin is emetigenic. Mucositis (mainly stomatitis, less often esophagitis) 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 leukemia 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.

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 extravasation occur during intravenous administration of idarubicin, the drug infusion should be immediately stopped.

Tumor 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 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.

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.

Idarubicin is a potent myelosuppressant and combination chemotherapy regimens including other agents with similar action may be expected to induce to additive myelosuppressive effects (See section 4.4).

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).

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.

An additive myelosuppressant effect may occur when radiotherapy is given concomitantly or within 2-3 weeks prior to treatment with idarubicin.

Impairment of Fertility. Idarubicin can induce chromosomal damage in human spermatozoa. For this reason, males undergoing treatment with idarubicin should use effective contraceptive methods (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 child bearing 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 fetus. 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

The effect of idarubicin on the ability to drive or use machinery has not been systematically evaluated.

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)

Hematopoietic 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)

Leukocyte and thrombocyte counts usually reach their nadir 10 - 14 days after the administration of idarubicin hydrochloride. Cell counts generally return to normal levels during the third week. During the phase of severe myelosuppression, deaths due to infections and/or hemorrhages have been reported.

Clinical consequences of myelosuppression may be fever, infections, sepsis, septic shock, hemorrhages, and tissue hypoxia, which can lead to death. If febrile neutropenia occurs, treatment with an IV antibiotic is recommended.

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).

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 the anthracyclines for up to several months after the overdose. Patients treated with oral idarubicin should be observed for possible gastrointestinal hemorrhage and severe mucosal damage.

Pharmacotherapeutic group: Anthracyclines and related substances

ATC Code: L01DB06

Idarubicin is a DNA intercalating anthracycline which interacts with the enzyme topoisomerase II and has an inhibitory effect on nucleic acid synthesis.

The modification of 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, idarubicinol administered at the same doses as the parent drug, is clearly less cardiotoxic than idarubicin.

In vitro studies have shown plasma protein binding of at least 95% for this product. This fact should be borne in mind when considering its use in combination with other drugs.

After i.v. administration to patients with normal renal and hepatic function, idarubicin is eliminated from systemic circulation (terminal plasma T_½ ranging between 11 - 25 hours) and is extensively metabolised to an active metabolite, idarubicinol, which is slowly eliminated with a plasma T_½ ranging between 41 - 69 hours). The drug is eliminated by biliary and renal excretion, mostly in the form or idarubicinol.

Studies of cellular (nucleated blood and bone marrow cells) in leukaemic 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 comparable, with a terminal half-life of about 15 hours. The terminal half-life of idarubicinol in cells was about 72 hours.

Idarubicin has mutagenic properties and it is carcinogenic in rats.

Reproduction studies in animals have shown that idarubicin is embryotoxic and teratogenic in rats but not rabbits.

Lactose monohydrate

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.

The shelf-life expiry date for this product shall not exceed three years from the date of its manufacture.

Unreconstituted solution: No special storage conditions

Reconstituted solution: The reconstituted solution is chemically stable when stored for at least 48 hours at 2-8°C and 24 hours at room temperature (20°C - 25°C); however, it is recommended that, in line with good pharmaceutical practice, the solution should not normally be stored for longer than 24 hours at 2-8°C.

The product does not contain any antibacterial preservative. Therefore of aseptic preparation cannot be ensured, the product must be prepared immediately before use and any unused portion discarded.

Colourless glass vial, type I, with chlorobutyl rubber bung and aluminium seal with insert yellow polypropylene disk.

Zavedos 10mg Powder for Solution for Injection vials are available as single vials.

The following protective recommendations are given due to the toxic nature of this substance:

• This product should be handled only by personnel who have been trained in the safe handling of such preparations.

• Pregnant staff should be excluded from working with this drug

• Personnel handling idarubicin should wear protective clothing: goggles, gowns and disposable gloves and masks

• All items used for administration or cleaning, including gloves, should be placed in high risk, waste disposal bags for high temperature incineration.

• The reconstituted solution is hypotonic and the recommended administration procedure described below must be followed.

Reconstitute with 5ml or 10ml of Water for Injections to produce a 1mg/ml solution for injection (i.v.). The reconstituted solution is clear red-orange solution, essentially free from visible foreign matter, see section 6.4 also.

Intravenous administration: Zavedos, as the reconstituted solution, must be administered only by the intravenous route. A slow administration over 5 to 10 minutes via the tubing of a freely running intravenous infusion of 0.9% sodium chloride, must be followed. A direct push injection is not recommended due to the risk of extravasation, which may occur even in the presence of adequate blood return upon needle aspiration, see section 4.4.

Spillage or leakage should be treated with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then with water.

All cleaning materials should be disposed of as indicated previously. Accidental contact with the skin and eyes should be treated immediately by copius lavage with water, or sodium bicarbonate solution, medical attention should be sought.

Discard any unused solution

Pharmacia Limited

Ramsgate Road

Sandwich

Kent CT13 9NJ, UK

PL 00032/0349

PL 00032/03490438

10^th May 2002

February 2009

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