INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
ZAVEDOS®

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

ZAVEDOS®

ZAVEDOS® 5 mg (Intravenous Injection)
ZAVEDOS® 10 mg (Intravenous Injection)
ZAVEDOS® 5 (Capsules)
ZAVEDOS® 10 (Capsules)
ZAVEDOS® 25 (Capsules)

COMPOSITION:
Vials containing 5 mg and 10 mg Idarubicin hydrochloride
Capsules containing 5 mg, 10 mg and 25 mg Idarubicin hydrochloride

PHARMACOLOGICAL CLASSIFICATION:
A 26 Cytostatic agents

PHARMACOLOGICAL ACTION:
Idarubicin, an anthracycline, is a DNA intercalating agent, which interacts with topoisomerase II and has an inhibitory effect on nucleic acid synthesis.
Idarubicin has a high potency and is an effective agent against murine leukaemia and lymphomas both by intravenous and oral route.
The modification in position 4 of the anthracycline structure gives the compound a high lipophilicity which results in an increased rate of cellular uptake.
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 half-life (t½) ranging between 10 - 35 hours and is extensively metabolised to an active metabolite, idarubicinol, which is more slowly eliminated with a plasma t½ ranging between 33 and 60 hours. Idarubicin is mostly eliminated by biliary excretion, mainly in the form of idarubicinol; urinary excretion accounting for 1 –2% of the dose as unchanged medicine 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%).

INDICATIONS:
Acute non-lymphocytic leukaemia (ANLL), including acute myeloblastic leukaemia (AML) in adults, for remission induction as front-line therapy, or for remission induction in relapsed or refractory patients.
The capsules are to be used when the intravenous route is not considered suitable.

CONTRA-INDICATIONS:
Severe renal and liver impairment.
Patients with uncontrolled infections.
Pre-existing bone marrow suppression induced by previous drug therapy or radiotherapy.
Hypersensitivity to idarubicin and/or other anthracyclines.
The use of ZAVEDOS during pregnancy or lactation should be avoided. There is no information as to whether idarubicin may adversely affect human fertility or cause teratogenesis. However, in rats (but not in rabbits) it is teratogenic and embryotoxic and women of childbearing potential should be advised to avoid pregnancy while undergoing treatment.

WARNINGS:
ZAVEDOS IS INTENDED FOR USE ONLY BY THOSE EXPERIENCED IN THE USE OF CYTOSTATICS.
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 haematologic monitoring including granulocytes, red cells and platelets is required. Facilities with laboratory and supportive resources adequate to monitor tolerability to the medicine, and to protect and maintain the patient compromised by toxicity should be available.
Myocardial toxicity, as manifested by potentially fatal congestive heart failure (CHF), acute life threatening arrhythmias or other cardiomyopathies, may occur during, or several weeks after termination of therapy. Should CHF occur, treatment with digitalis, diuretics, sodium restriction and bed rest is indicated.
ZAVEDOS should be used with caution in the treatment of patients with impaired cardiac function.
Cardiac function should be carefully monitored during treatment in order to minimize the risk of cardiac toxicity of the type described for anthracycline compounds. An electrocardiogram (ECG) or echocardiogram and a determination of left ventricular ejection fraction (LVEF) should be performed prior to starting, and during, treatment. 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, infections, leukaemic pericarditis and/or myocarditis).
While there is no reliable method for predicting acute congestive heart failure (CHF), cardiomyopathy induced by anthracyclines is usually associated with persistent QRS voltage reduction, increases beyond normal limits of the systolic time interval (PEP/LVEF) and significant decrease of the left ventricular ejection fraction (LVEF) from pretreatment baseline values. Early clinical diagnosis of drug-induced myocardial damage appears to be important for pharmacological treatment to be useful.
In renal and liver impairment kidney and liver functions should be evaluated prior to and during treatment. Treatment should be withheld if bilirubin levels exceed 0,034 mmol/L (2 mg/100 mL) and/or creatinine serum levels exceed 0,177 mmol/L (2 mg/100 mL).

DOSAGE AND DIRECTIONS FOR USE:
Acute non-lymphocytic leukaemia (ANLL) or acute myeloblastic leukaemia (AML):
ZAVEDOS Injection: In adults the suggested dose schedule is 12 mg/m² body surface area IV daily for 3 days in combination with cytarabine. Alternatively, a dose of 8 mg/m² IV may be given daily for 5 days.
ZAVEDOS Capsules: In adults the suggested dose schedule is 15 - 30 mg/m²/day for 3 days when in combination treatment and a dose of 30 mg/m²/day for 3 days in monotherapy.
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.
All dose schedules should, however, take into account the haematological status of the patient and the dosage of other cytotoxic medicine when used in combination.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Major side-effects:
Severe myelosuppression, prolonged bone marrow depression and cardiac toxicity.
Other side-effects:
Reversible alopecia, nausea and vomiting, mucositis, oesophagitis, diarrhoea, fever, chills and skin rash. Anorexia, stomatitis, phlebitis, fatigue, hyperglycaemia, headache, dysphagia, neurotoxicity and haemorrhage. Elevation of liver enzymes and bilirubin. Severe and sometimes fatal sepsis/infections have been associated with ZAVEDOS as single agent or in combination. The urine may be coloured red. Severe enterocolitis with perforation has been reported very rarely.
Precautions:
Therapy with ZAVEDOS requires close observation of the patient and laboratory monitoring. Hyperuricaemia may be induced. Appropriate measures must be taken to control any systemic infection before starting therapy.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
If overdosage with the capsules should occur, gastric lavage should be carried out as soon as possible. The patient 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 be symptomatic and supportive.
Delayed cardiac failure has been seen with the anthracyclines up to several months after an overdose. Patients should be observed carefully and if signs of cardiac failure arise, should be treated along conventional lines.

IDENTIFICATION:
ZAVEDOS INJECTION: Porous red-orange, freeze-dried cake or mass in a clear glass vial.
ZAVEDOS 5 Capsules: A hard gelatin capsule with an opaque red cap and red body containing an orange powder. “Idarubicin 5”is imprinted in black on the cap.
ZAVEDOS 10 Capsules: A hard gelatin capsule with an opaque red cap and white body containing an orange powder. “Idarubicin 10”is imprinted in black on the cap.
ZAVEDOS 25 Capsules: A hard gelatin capsule with an opaque white cap and white body containing an orange powder. “Idarubicin 25”is imprinted in black on the cap.

PRESENTATION:
Vials containing 5 mg and 10 mg idarubicin hydrochloride.
Individual capsules of 5, 10 or 25 mg idarubicin hydrochloride in amber glass bottles.

STORAGE INSTRUCTIONS:
Capsules and Freeze-dried powder for injection:
Store below 25°C and protect from light.
Reconstituted solution for injection:
Should not be stored for longer than 24 hours at room temperature below 25°C, or 48 hours in a refrigerator at 2 - 8°C.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER:

ZAVEDOS® 5 mg Injection	: Y/26/16
ZAVEDOS® 10 mg Injection	: Y/26/17
ZAVEDOS® 5 Capsules	: 30/26/0089
ZAVEDOS®10 Capsules	: 30/26/0090
ZAVEDOS®25 Capsules	: 30/26/0091

NAME AND BUSINESS ADDRESS OF APPLICANT:
Pharmacia South Africa (Pty) Limited
Alphen West G
George Street
Midrand 1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
April 1997 [Reviewed 25 Oct 2001]

New addition to this site: February 2005
Source: Pharmaceutical Industry
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