Zavedos Injection 5 mg

1. Name Of The Medicinal Product

Zavedos^® Injection 5 mg

2. Qualitative And Quantitative Composition

Each vial contains:

Idarubicin HCl 5 mg

3. Pharmaceutical Form

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.

4. Clinical Particulars

4.1 Therapeutic Indications

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.

4.2 Posology And Method Of Administration

Dosage is calculated on the basis of body surface area.

Warning: Not for intrathecal use.

For reconstitution the contents of the 5 mg vial should be dissolved in 5 ml of water for injections (Ph. Eur). 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.

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.

4.3 Contraindications

Zavedos therapy should not be started in patients with severe renal and liver impairment or patients with uncontrolled infections.

4.4 Special Warnings And Precautions For Use

Not for intrathecal use.

Zavedos is intended for use under the direction of those experienced in leukaemia chemotherapy. The drug should not be given to patients with pre existing bone-marrow suppression induced by previous drug therapy or radiotherapy unless the benefit warrants the risk. Pre-existing heart disease and previous therapy with anthracyclines at high cumulative doses or other potentially cardiotoxic agents are co-factors for increased risk of idarubicin-induced cardiac toxicity and the benefit to risk ratio of idarubicin therapy in such patients should be weighed before starting treatment with Zavedos. Like most other cytotoxic agents, idarubicin has mutagenic properties and it is carcinogenic in rats.

Zavedos is a potent bone marrow suppressant. Myelosuppression, primarily of leukocytes, will therefore occur in all patients given a therapeutic dose of this agent and careful haematological monitoring including granulocytes, red cells and platelets is required.

Facilities with laboratory and supportive resources adequate to monitor drug tolerability and protect and maintain a patient compromised by drug toxicity should be available. It must be possible to treat rapidly and completely a severe haemorrhagic condition and/or severe infection.

Myocardial toxicity as manifested by potentially fatal congestive heart failure, acute life-threatening arrhythmias or other cardiomyopathies may occur during therapy or several weeks after termination of therapy. Treatment with digitalis, diuretics, sodium restriction and bed-rest is indicated. Cardiac function should be carefully monitored during treatment in order to minimise the risk of cardiac toxicity of the type described for other anthracycline compounds. The risk of such myocardial toxicity may be higher following concomitant or previous radiation to the mediastinal-pericardial area or treatment with other potentially cardiotoxic agents or in patients with a particular clinical situation due to their disease (anaemia, bone marrow depression, infection, leukaemic pericarditis and/or myocarditis).

On the basis of the recommended dosage schedules the total cumulative dose administered over two courses can be expected to reach 60-80 mg/m². Although a cumulative dose limit cannot yet be defined, a specific cardiological evaluation in cancer patients showed no significant modifications of cardiac function in patients treated with Zavedos at a mean cumulative dose of 93 mg/m².

Whilst there is no reliable method for predicting acute congestive heart failure, cardiomyopathy induced by anthracyclines is usually associated with persistent QRS voltage reduction, increased beyond normal limits of the systolic time interval (PEP/LVET) and decrease of the left ventricular ejection fraction (LVET) from pre-treatment baseline values.

An electrocardiogram or echocardiogram and a determination of left ventricular ejection fraction should be performed prior to starting therapy and during treatment with Zavedos. Early clinical diagnosis of drug-induced myocardial damage appears to be important for pharmacological treatment to be useful.

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 not given if bilirubin and/or creatinine serum levels exceeded 2 mg%. With other anthracyclines a 50% dose reduction is generally employed if bilirubin and creatinine levels are in the range 1.2-2.0 mg%.

Therapy with Zavedos requires close observation of the patient and laboratory monitoring. Patients aged over 55 years should be given vigorous supportive treatment during the aplastic period. Hyperuricaemia secondary to rapid lysis of leukaemic cells may be induced: blood uric acid levels should be monitored and appropriate therapy initiated if hyperuricaemia develops. Appropriate measures must be taken to control any systemic infection before beginning therapy.

Extravasation of Zavedos at the site of i.v. injection can cause severe local tissue necrosis. The risk of thrombophlebitis at the injection site may be minimised by following the recommended procedure of administration. A stinging or burning sensation at the site of administration signifies a small degree of extravasation and the infusion should be stopped and restarted in another vein.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Zavedos is a potent myelosuppressant and combination chemotherapy regimens which contain other agents having a similar action may be expected to lead to additive myelosuppressive effects. 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.

4.6 Pregnancy And Lactation

There is no information as to whether idarubicin may adversely affect human fertility, or cause teratogenesis. However, in rats (but not rabbits) it is teratogenic and embryotoxic. Women of child bearing potential should be advised to avoid pregnancy. If Zavedos is to be used during pregnancy or if the patient becomes pregnant during therapy, the patient should be informed of the potential hazard to the foetus. Mothers should be advised not to breast-feed whilst undergoing chemotherapy with this drug.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

Severe myelosuppression and cardiac toxicity are the two major adverse effects. Other adverse reactions include: reversible alopecia in most patients; acute nausea and vomiting; mucositis, usually involving the oral mucosa and appearing 3-10 days after starting treatment; oesophagitis and diarrhoea; fever, chills, skin rash; elevation of liver enzymes and bilirubin in about 20-30% of cases. Severe and sometimes fatal infections have been associated with idarubicin alone or in combination with cytarabine.

Idarubicin may impart a red colour to the urine for 1-2 days after administration and patients should be advised that this is no cause for alarm.

4.9 Overdose

Very high doses of Zavedos may be expected to cause acute myocardial toxicity within 24 hours and severe myelosuppression within one to two weeks. Treatment should aim to support the patient during this period and should utilise such measures as blood transfusion 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.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

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.

5.2 Pharmacokinetic Properties

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.

5.3 Preclinical Safety Data

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.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose monohydrate Ph. Eur.

6.2 Incompatibilities

None known.

6.3 Shelf Life

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

6.4 Special Precautions For Storage

Unreconstituted solution: None

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

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.

6.5 Nature And Contents Of Container

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

6.6 Special Precautions For Disposal And Other Handling

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

• 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.

Reconstitute with 5ml of Water for Injections to produce a 1mg/ml solution for injection (i.v.). See section 6.4 also.

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.

7. Marketing Authorisation Holder

Pharmacia Limited

Davy Avenue

Milton Keynes

MK5 8PH

8. Marketing Authorisation Number(S)

PL 00032/0438

9. Date Of First Authorisation/Renewal Of The Authorisation

23 May 2002

10. Date Of Revision Of The Text

Legal Category

POM.