Zavedos oral

Overdose

There is no known antidote to Zavedos Oral (idarubicin hydrochloride for injection, USP). Two cases of fatal overdosage in patients receiving therapy for AML have been reported. The doses were 135 mg/m² over 3 days and 45 mg/m² of idarubicin and 90 mg/m² of daunorubicin over a three day period.

It is anticipated that overdosage with idarubicin will result in severe and prolonged myelosuppression and possibly in increased severity of gastrointestinal toxicity. Adequate supportive care including platelet transfusions, antibiotics and symptomatic treatment of mucositis is required. The effect of acute overdose on cardiac function is not fully known, but severe arrhythmia occurred in 1 of the 2 patients exposed. It is anticipated that very high doses of idarubicin may cause acute cardiac toxicity and may be associated with a higher incidence of delayed cardiac failure.

Disposition studies with idarubicin in patients undergoing dialysis have not been carried out. The profound multicompartment behavior, extensive extravascular distribution and tissue binding, coupled with the low unbound fraction available in the plasma pool make it unlikely that therapeutic efficacy or toxicity would be altered by conventional peritoneal or hemodialysis.

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.

There is no known antidote to idarubicin. Two cases of fatal overdosage in patients receiving therapy for AML have been reported. The doses were 135 mg/m² over 3 days and 45 mg/m² of idarubicin and 90 mg/m² of daunorubicin over a three day period.

It is anticipated that overdosage with idarubicin will result in severe and prolonged myelosuppression and possibly in increased severity of gastrointestinal toxicity. Adequate supportive care including platelet transfusions, antibiotics and symptomatic treatment of mucositis is required. The effect of acute overdose on cardiac function is not fully known, but severe arrhythmia occurred in 1 of the 2 patients exposed. It is anticipated that very high doses of idarubicin may cause acute cardiac toxicity and may be associated with a higher incidence of delayed cardiac failure.

Disposition studies with idarubicin in patients undergoing dialysis have not been carried out. The profound multicompartment behavior, extensive extravascular distribution and tissue binding, coupled with the low unbound fraction available in the plasma pool make it unlikely that therapeutic efficacy ortoxicity would be altered by conventional peritoneal or hemodialysis.

Very high doses of Zavedos Oral 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 up to several months after the overdose.

Patients treated with oral Zavedos Oral should be observed for possible gastrointestinal haemorrhage and severe mucosal damage.

Contraindications

-

- Hypersensitivity to other anthracyclines or anthracenediones

- Severe hepatic impairment

- Severe renal impairment

- Severe cardiomyopathy

- Recent myocardial infarction

- Severe arrhythmias

- Persistent myelosuppression

- Previous treatment with maximum cumulative doses of Zavedos Oral and/ or other anthracyclines and anthracenediones

- Breastfeeding should be stopped during drug therapy

Incompatibilities

Not known.

Prolonged contact with any alkaline pH solution must be avoided, since it can give rise to drug degradation. Zavedos Oral hydrochloride must not be mixed with heparin as it may form a precipitate.

Pharmaceutical form

Undesirable effects

Approximately 550 patients with AML have received Zavedos Oral (idarubicin hydrochloride for injection, USP) in combination with cytarabine in controlled clinical trials worldwide. In addition, over 550 patients with acute leukemia have been treated in uncontrolled trials utilizing Zavedos Oral as a single agent or in combination. The table below lists the adverse experiences reported in U.S. Study 2 (see Clinical Studies) and is representative of the experiences in other studies. These adverse experiences constitute all reported or observed experiences, including those not considered to be drug related. Patients undergoing induction therapy for AML are seriously ill due to their disease, are receiving multiple transfusions, and concomitant medications including potentially toxic antibiotics and antifungal agents. The contribution of the study drug to the adverse experience profile is difficult to establish.

The duration of aplasia and incidence of mucositis were greater on the IDR arm than the DNR arm, especially during consolidation in some U.S. controlled trials (see Clinical Studies).

The following information reflects experience based on U.S. controlled clinical trials.

Severe myelosuppression is the major toxicity associated with Zavedos Oral therapy, but this effect of the drug is required in order to eradicate the leukemic clone. During the period of myelosuppression, patients are at risk of developing infection and bleeding which may be life-threatening or fatal.

Nausea and/or vomiting, mucositis, abdominal pain and diarrhea were reported frequently, but were severe (equivalent to WHO Grade 4) in less than 5% of patients. Severe enterocolitis with perforation has been reported rarely. The risk of perforation may be increased by instrumental intervention. The possibility of perforation should be considered in patients who develop severe abdominal pain and appropriate steps for diagnosis and management should be taken.

Alopecia was reported frequently and dermatologic reactions including generalized rash, urticaria and a bullous erythrodermatous rash of the palms and soles have occurred. The dermatologic reactions were usually attributed to concomitant antibiotic therapy. Local reactions including hives at the injection site have been reported. Recall of skin reaction due to prior radiotherapy has occurred with Zavedos Oral administration.

Changes in hepatic and renal function tests have been observed. These changes were usually transient and occurred in the setting of sepsis and while patients were receiving potentially hepatotoxic and nephrotoxic antibiotics and antifungal agents. Severe changes in renal function (equivalent to WHO Grade 4) occurred in no more than 1% of patients, while severe changes in hepatic function (equivalent to WHO Grade 4) occurred in less than 5% of patients.

Congestive heart failure (frequently attributed to fluid overload), serious arrhythmias including atrial fibrillation, chest pain, myocardial infarction and asymptomatic declines in LVEF have been reported in patients undergoing induction therapy for AML. Myocardial insufficiency and arrhythmias were usually reversible and occurred in the setting of sepsis, anemia and aggressive intravenous fluid administration. The events were reported more frequently in patients over age 60 years and in those with pre-existing cardiac disease.

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)

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.

Cardiotoxicity

Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and represents the cumulative dose-limiting toxicity of the drug.

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

Approximately 550 patients with AML have received idarubicin in combination with cytarabine in controlled clinical trials worldwide. In addition, over 550 patients with acute leukemia have been treated in uncontrolled trials utilizing idarubicin as a single agent or in combination. The table below lists the adverse experiences reported in U.S.

Study 2 (see Clinical Studies) and is representative of the experiences in other studies. These adverse experiences constitute all reported or observed experiences, including those not considered to be drug related. Patients undergoing induction therapy for AML are seriously ill due to their disease, are receiving multiple transfusions, and concomitant medications including potentially toxic antibiotics and antifungal agents. The contribution of the study drug to the adverse experience profile is difficult to establish.

The duration of aplasia and incidence of mucositis were greater on the IDR arm than the DNR arm, especially during consolidation in some U.S. controlled trials (see Clinical Studies). The following information reflects experience based on U.S. controlled clinical trials.

Severe myelosuppression is the major toxicity associated with idarubicin therapy, but this effect of the drug is required in order to eradicate the leukemic clone. During the period of myelosuppression, patients are at risk of developing infection and bleeding which may be life-threatening or fatal.

Nausea and/or vomiting, mucositis, abdominal pain and diarrhea were reported frequently, but were severe (equivalent to WHO Grade 4) in less than 5% of patients. Severe enterocolitis with perforation has been reported rarely. The risk of perforation may be increased by instrumental intervention. The possibility of perforation should be considered in patients who develop severe abdominal pain and appropriate steps for diagnosis and management should be taken.

Alopecia was reported frequently and dermatologic reactions including generalized rash, urticaria and a bullous erythrodermatous rash of the palms and soles have occurred. The dermatologic reactions were usually attributed to concomitant antibiotic therapy. Local reactions including hives at the injection site have been reported. Recall of skin reaction due to prior radiotherapy has occurred with idarubicin administration.

Changes in hepatic and renal function tests have been observed. These changes were usually transient and occurred in the setting of sepsis and while patients were receiving potentially hepatotoxic and nephrotoxic antibiotics and antifungal agents. Severe changes in renal function (equivalent to WHO Grade 4) occurred in no more than 1% of patients, while severe changes in hepatic function (equivalent to WHO Grade 4) occurred in less than 5% of patients.

Congestive heart failure (frequently attributed to fluid overload), serious arrhythmias including atrial fibrillation, chest pain, myocardial infarction and asymptomatic declines in LVEF have been reported in patients undergoing induction therapy for AML. Myocardial insufficiency and arrhythmias were usually reversible and occurred in the setting of sepsis, anemia and aggressive intravenous fluid administration. The events were reported more frequently in patients over age 60 years and in those with pre-existing cardiac disease.

List of adverse reactions

The frequencies of adverse events are ranked according to the following convention:

Very common (> 1/10); common (> 1/100to <1/10); uncommon (> 1/1,000to < 1/100); rare (> 1/10,000to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Infections and infestations:

Very common: Infections

Uncommon: Sepsis, septicaemia

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Uncommon: Secondary leukemias (acute myeloid leukemia 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: Anorexia

Uncommon: Dehydration

Metabolism and nutrition disorders

Uncommon: Hyperuricaemia

Not known: Tumor lysis syndrome

Nervous system disorders

Rare: Cerebral haemorrhages

Cardiac disorders

)

Uncommon: ECG abnormalities (e.g., non-specific ST segment changes), myocardial infarction

Very rare: Pericarditis, myocarditis, atrioventricular and bundle branch block

Vascular disorders

Common: Haemorrhages, local phlebitis, thrombophlebitis

Uncommon: Shock

Very rare: Thromboembolism, flush

Gastrointestinal disorders

Very common: Nausea, vomiting, mucositis/stomatitis, diarrhoea, abdominal pain or burning feeling

Common: Gastrointestinal tract bleeding, bellyache

Uncommon: Oesophagitis, colitis (including severe enterocolitis/neutropenic enterocolitis with perforation)

Very rare: Gastric erosions or ulcerations

Hepatobiliary disorders

Common: Elevation of liver enzymes and bilirubin

Skin and subcutaneous tissue disorders

Very common: Alopecia

Common: Rash, itch, hypersensitivity of irradiated skin ('radiation recall reaction')

Uncommon: Skin and nail hyperpigmentation, urticaria, cellulitis (possibly severe), tissue necrosis

Very rare: Acral erythema

Not known: Local reaction

Renal and urinary disorders

Very common: Red colour to the urine for 1-2 days after treatment

General disorders and administration site conditions

Very common: Fever, headaches, chills

Description of selected adverse reactions

Haematopoietic system

Pronounced myelosuppression is the most severe adverse effect of Zavedos Oral treatment. However, this is necessary for the eradication of leukemic cells.

Cardiotoxicity

Life-threatening congestive heart failure is the most severe form of anthracycline-induced cardiomyopathy and represents the cumulative dose-limiting toxicity of the drug.

Gastrointestinal

Stomatitis and, in severe cases ulceration of mucosa, dehydration caused by severe diarrhoea and vomiting, risk of perforation of colon, etc.

Administration site

Other adverse reactions: hyperuricaemia

Prevention of symptoms by hydration, urine alkalinisation, and prophylaxis with allopurinol may minimise potential complications of tumour lysis syndrome.

Paediatric population

Undesirable effects are similar in adults and children except a greater susceptibility to anthracycline-induced cardiac toxicity of children.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.

Preclinical safety data

No further preclinical safety data are available.

The LD50 (median values) intravenous Zavedos Oral was 4.4 mg / kg in mice, 2.9 mg / kg in rats and about 1.0 mg / kg in dogs. The main targets after a single dose were hemolymphopoietic system, especially dogs, the gastrointestinal tract. Toxic effects in rats and dogs after repeated intravenous administration of Zavedos Oral were investigated. The main target of intravenous Zavedos Oral in the above species were hemolymphopoietic system, gastrointestinal tract, kidney, liver, and male and female reproductive organs.

In relation to the heart, subacute and cardiotoxicity studies indicate that intravenous Zavedos Oral was mild to moderately cardiotoxic only lethal doses, whereas doxorubicin and daunorubicin clear even cause myocardial changes to non-lethal doses.

Zavedos Oral was genotoxic in most in vitro or in vivo performed. Intravenous Zavedos Oral was toxic to the reproductive organs, and embryotoxic and teratogenic in rats. No effects were detected worthy of mention in both mothers and in the progeny of mice which have been administered doses up to 0.2 mg/kg/day during the perinatal and postnatal periods. It is unknown whether the compound is excreted in breast milk. Intravenous Zavedos Oral, such as anthracyclines and other cytotoxic drugs, was carcinogenic in rats. A local safety study in dogs showed that the drug causes tissue necrosis from extravasation.

Therapeutic indications

Zavedos Oral (idarubicin hydrochloride for injection, USP) in combination with other approved antileukemic drugs is indicated for the treatment of acute myeloid leukemia (AML) in adults. This includes French-American-British (FAB) classifications M1 through M7.

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 Oral 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.

IDAMYCIN PFS Injection in combination with other approved antileukemic drugs is indicated for the treatment of acute myeloid leukemia (AML) in adults. This includes French-American-British (FAB) classifications M1 through M7.

Cytotoxic and antimitotic agent.

Adults

- For the treatment of acute myeloid leukaemia (AML), for remission induction in untreated patients or for remission induction in relapsed or refractory patients.

- For second line treatment of relapsed acute lymphoblastic leukaemia (ALL).

Children

- For first line treatment of acute myeloid leukaemia (AML), in combination with cytarabine, for remission induction.

- For second line treatment of relapsed acute lymphoblastic leukaemia (ALL).

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

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Anthracyclines and related substances, ATC code: L01DB06

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.

Pharmacotherapeutic group: Cytotoxic antibiotics; Anthracyclines and related substances

ATC code: L01DB06

Zavedos Oral 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. Zavedos Oral has been shown to have greater 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 Zavedos Oral compared with doxorubicin and daunorubicin. Cardiotoxicity studies in animals have indicated that Zavedos Oral has a better therapeutic index than daunorubicin and doxorubicin. The main metabolite, Zavedos Oralol, has shown, in vitro and in vivo, antitumoural activity in experimental models. In the rat, Zavedos Oralol administered at the same doses as the parent drug, is clearly less cardiotoxic than Zavedos Oral.

Pharmacokinetic properties

Pharmacokinetic studies have been performed in adult leukemia patients with normal renal and hepatic function following intravenous administration of 10 to 12 mg/m² of idarubicin daily for 3 to 4 days as a single agent or combined with cytarabine. The plasma concentrations of idarubicin are best described by a two or three compartment open model. The elimination rate of idarubicin from plasma is slow with an estimated mean terminal half-life of 22 hours (range, 4 to 48 hours) when used as a single agent and 20 hours (range, 7 to 38 hours) when used in combination with cytarabine. The elimination of the primary active metabolite, idarubicinol, is considerably slower than that of the parent drug with an estimated mean terminal half-life that exceeds 45 hours; hence, its plasma levels are sustained for a period greater than 8 days.

The disposition profile shows a rapid distributive phase with a very high volume of distribution presumably reflecting extensive tissue binding. Studies of cellular (nucleated blood and bone marrow cells) drug concentrations in leukemia patients have shown that peak cellular idarubicin concentrations are reached a few minutes after injection. Concentrations of idarubicin and idarubicinol 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. The extent of drug and metabolite accumulation predicted in leukemia patients for Days 2 and 3 of dosing, based on the mean plasma levels and half-life obtained after the first dose, is 1.7-and 2.3-fold, respectively, and suggests no change in kinetics following a daily x 3 regimen. The percentages of idarubicin and idarubicinol bound to human plasma proteins averaged 97% and 94%, respectively, at concentrations similar to maximum plasma levels obtained in the pharmacokinetic studies. The binding is concentration independent. The plasma clearance is twice the expected hepatic plasma flow indicating extensive extrahepatic metabolism.

The primary active metabolite formed is idarubicinol. As idarubicinol has cytotoxic activity, it presumably contributes to the effects of idarubicin.

The drug is eliminated predominately by biliary and to a lesser extent by renal excretion, mostly in the form of idarubicinol.

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 T½ ranging between 10-35 hours and is extensively metabolized to an active metabolite, idarubicinol, which is more slowly eliminated with a plasma T½ 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 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.

Pharmacokinetic studies have been performed in adult leukemia patients with normal renal and hepatic function following intravenous administration of 10 to 12 mg/m² of idarubicin daily for 3 to 4 days as a single agent or combined with cytarabine. The plasma concentrations of idarubicin are best described by a two or three compartment open model. The elimination rate of idarubicin from plasma is slow with an estimated mean terminal half-life of 22 hours (range, 4 to 48 hours) when used as a single agent and 20 hours (range, 7 to 38 hours) when used in combination with cytarabine. The elimination of the primary active metabolite, idarubicinol, is considerably slower than that of the parent drug with an estimated mean terminal half-life that exceeds 45 hours; hence, its plasma levels are sustained for a period greater than 8 days.

The disposition profile shows a rapid distributive phase with a very high volume of distribution presumably reflecting extensive tissue binding. Studies of cellular (nucleated blood and bone marrow cells) drug concentrations in leukemia patients have shown that peak cellular idarubicin concentrations are reached a few minutes after injection. Concentrations of idarubicin and idarubicinol 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. The extent of drug and metabolite accumulation predicted in leukemia patients for Days 2 and 3 of dosing, based on the mean plasma levels and half-life obtained after the first dose, is 1.7- and 2.3-fold, respectively, and suggests no change in kinetics following a daily × 3 regimen. The percentages of idarubicin and idarubicinol bound to human plasma proteins averaged 97% and 94%, respectively, at concentrations similar to maximum plasma levels obtained in the pharmacokinetic studies. The binding is concentration independent. The plasma clearance is twice the expected hepatic plasma flow indicating extensive extrahepatic metabolism.

The primary active metabolite formed is idarubicinol. As idarubicinol has cytotoxic activity, it presumably contributes to the effects of idarubicin.

The drug is eliminated predominately by biliary and to a lesser extent by renal excretion, mostly in the form of idarubicinol.

In adults, following oral administration of 10 to 60 mg/m2 Zavedos Oral, Zavedos Oral was rapidly absorbed with the maximum plasma concentrations of 4-12.65 ng/ml achieved in 1 to 4 hours after dosing. The terminal half-life was 12.7±6.0 hours (mean±SD). Following intravenous administration of Zavedos Oral in adults, the terminal half-life was 13.9±5.9 hours, similar to that observed after the oral administration.

After i.v. administration, Zavedos Oral is extensively metabolised to an active metabolite, Zavedos Oralol, which is slowly eliminated with a plasma T½ ranging between 41 - 69 hours. The drug is eliminated by biliary and renal excretion, mostly in the form or Zavedos Oralol.

Studies of cellular (nucleated and bone marrow blood cells) drug concentrations in leukaemic patients have shown that peak cellular Zavedos Oral concentrations are reached a few minutes after injection.

Zavedos Oral and Zavedos Oralol concentrations nucleated blood and bone marrow cells are more than a hundred times the plasma concentrations. Zavedos Oral disappearance rates in plasma and cells were almost comparable with a terminal half-life of about 15 hours. The terminal half-life of Zavedos Oralol in cells was about 72 hours.

Paediatric Population:

Pharmacokinetic measurements in 7 paediatric patients receiving intravenous Zavedos Oral in doses ranging from 15 to 40 mg/m2/3 days of treatment, showed a median Zavedos Oral half-life of 8.5 hrs (range: 3.6 - 26.4 hrs). The active metabolite, Zavedos Oralol, accumulated during the 3 days of treatment, exhibiting a median half-life of 43.7 hrs (range: 27.8 - 131 hrs).

In a separate study, pharmacokinetic measurements in 15 paediatric patients receiving oral Zavedos Oral in doses ranging from 30 to 50 mg/m2/ during the 3 days of treatment, the maximum plasma concentration of Zavedos Oral was 10.6 ng/mL (range 2.7 - 16.7 ng/mL at the 40 mg/m2 dose). The median terminal half-life of Zavedos Oral was 9.2 hrs (range: 6.4 - 25.5 hrs). Significant accumulation of Zavedos Oralol was seen over the 3 day treatment period. The observed terminal half-life value of Zavedos Oral after IV was comparable to that following oral administration in paediatric patients.

Since Cmax of Zavedos Oral is similar in children and adults following oral administrations, absorption kinetics seem not to differ between adults and children.

Following both oral and IV administrations, the elimination half-life values of Zavedos Oral in children and adults differ:

Total body clearance values of 30 - 107.9 L/h/m2 for Zavedos Oral reported for adults are higher than the values of 18 - 33 L/h/m2 reported for paediatric populations. Although Zavedos Oral has a very large volume of distribution in both adults and children, suggesting that much of the drug is bound to tissues, the shorter elimination half-life and lower total body clearance are not entirely explained by a smaller apparent volume of distribution in children compared to adults.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Zavedos Oral (idarubicin hydrochloride for injection, USP) is intended for administration under the supervision of a physician who is experienced in leukemia chemotherapy.

Zavedos Oral is a potent bone marrow suppressant. Zavedos Oral 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.

Severe myelosuppression will occur in all patients given a therapeutic dose of this agent for induction, consolidation or maintenance. Careful hematologic monitoring is required. Deaths due to infection and/or bleeding have been reported during the period of severe myelosuppression. 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 hemorrhagic condition and/or a severe infection.

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 Oral.

Myocardial toxicity as manifested by potentially fatal congestive heart failure, acute life-threatening arrhythmias or other cardiomyopathies may occur following therapy with Zavedos Oral. Appropriate therapeutic measures for the management of congestive heart failure and/or arrhythmias are indicated.

Cardiac function should be carefully monitored during treatment in order to minimize 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 in patients with anemia, bone marrow depression, infections, leukemic pericarditis and/or myocarditis, active or dormant cardiovascular disease, 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, cyclophosphamide and paclitaxel). Do not administer anthracyclines including idarubicin with other cardiotoxic agents unless the patient's cardiac function is monitored frequently. Patients receiving anthracyclines after stopping treatment with other cardiotoxic agents, especially those with long half-lives, may also be at an increased risk of developing cardiotoxicity. Avoid use of anthracycline-based therapy for at least 5 half-lives after discontinuation of the cardiotoxic agent. If anthracyclines are used before this time, carefully monitor the cardiac function. While there are no reliable means for predicting congestive heart failure, cardiomyopathy induced by anthracyclines is usually associated with a decrease of the left ventricular ejection fraction (LVEF) from pretreatment baseline values.

Since hepatic and/or renal function impairment can affect the disposition of Zavedos Oral, 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%. However, in one Phase III trial, patients with bilirubin levels between 2.6 and 5 mg% received the anthracycline with a 50% reduction in dose. Dose reduction of Zavedos Oral should be considered if the bilirubin and/or creatinine levels are above the normal range. (See DOSAGE AND ADMINISTRATION.)

Idarubicin was embryotoxic and teratogenic in the rat at a dose of 1.2 mg/m²/day or one tenth the human dose, which was nontoxic to dams. Idarubicin was embryotoxic but not teratogenic in the rabbit even at a dose of 2.4 mg/m²/day or two tenths the human dose, which was toxic to dams.

There is no conclusive information about idarubicin adversely affecting human fertility or causing teratogenesis. There has been one report of a fetal fatality after maternal exposure to idarubicin during the second trimester.

There are no adequate and well-controlled studies in pregnant women. If Zavedos Oral is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid pregnancy.

Therapy with Zavedos Oral (idarubicin hydrochloride for injection, USP) requires close observation of the patient and careful laboratory monitoring. Hyperuricemia secondary to rapid lysis of leukemic cells may be induced. Appropriate measures must be taken to prevent hyperuricemia and to control any systemic infection before beginning therapy.

Extravasation of Zavedos Oral can cause severe local tissue necrosis. Extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle. If signs or symptoms of extravasation occur the injection or infusion should be terminated immediately and restarted in another vein. (See DOSAGE AND ADMINISTRATION.)

Frequent complete blood counts and monitoring of hepatic and renal function tests are recommended.

Formal long-term carcinogenicity studies have not been conducted with idarubicin. Idarubicin and related compounds have been shown to have mutagenic and carcinogenic properties when tested in experimental models (including bacterial systems, mammalian cells in culture and female Sprague-Dawley rats).

In male dogs given 1.8 mg/m²/day 3 times/week (about one seventh the weekly human dose on a mg/m² basis) for 13 weeks, or 3 times the human dose, testicular atrophy was observed with inhibition of spermatogenesis and sperm maturation with few or no mature sperm. These effects were not readily reversed after a recovery of 8 weeks.

(See WARNINGS.)

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from idarubicin, mothers should discontinue nursing prior to taking this drug.

Safety and effectiveness in children have not been established.

Patients over 60 years of age who were undergoing induction therapy experienced congestive heart failure, serious arrhythmias, chest pain, myocardial infarction, and asymptomatic declines in LVEF more frequently than younger patients (see ADVERSE REACTIONS).

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. 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 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.

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.

Idarubicin is intended for administration under the supervision of a physician who is experienced in leukemia chemotherapy.

Idarubicin is a potent bone marrow suppressant. Idarubicin should not be given to patients with preexisting bone marrow suppression induced by previous drug therapy or radiotherapy unless the benefit warrants the risk.

Severe myelosuppression will occur in all patients given a therapeutic dose of this agent for induction, consolidation or maintenance. Careful hematologic monitoring is required. Deaths due to infection and/or bleeding have been reported during the period of severe myelosuppression. 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 hemorrhagic condition and/or a severe infection.

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 idarubicin.

Myocardial toxicity as manifested by potentially fatal congestive heart failure, acute life-threatening arrhythmias or other cardiomyopathies may occur following therapy with idarubicin. Appropriate therapeutic measures for the management of congestive heart failure and/or arrhythmias are indicated.

Cardiac function should be carefully monitored during treatment in order to minimize 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 in patients with anemia, bone marrow depression, infections, leukemic pericarditis and/or myocarditis, active or dormant cardiovascular disease, 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, cyclophosphamide and paclitaxel). Do not administer idarubicin with other cardiotoxic agents unless the patient's cardiac function is monitored frequently. Patients receiving anthracyclines after stopping treatment with other cardiotoxic agents, especially those with long half-lives, may also be at an increased risk of developing cardiotoxicity. Avoid the use of anthracycline-based therapy for at least 5 half-lives after discontinuation of the cardiotoxic agent. If anthracyclines are used before this time, carefully monitor the cardiac function. While there are no reliable means for predicting congestive heart failure, cardiomyopathy induced by anthracyclines is usually associated with a decrease of the left ventricular ejection fraction (LVEF) from pretreatment baseline values.

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%. However, in one Phase III trial, patients with bilirubin levels between 2.6 and 5 mg% received the anthracycline with a 50% reduction in dose. Dose reduction of idarubicin should be considered if the bilirubin and/or creatinine levels are above the normal range. (See DOSAGE AND ADMINISTRATION.)

Idarubicin was embryotoxic and teratogenic in the rat at a dose of 1.2 mg/m²/day or one tenth the human dose, which was nontoxic to dams. Idarubicin was embryotoxic but not teratogenic in the rabbit even at a dose of 2.4 mg/m²/day or two tenths the human dose, which was toxic to dams. There is no conclusive information about idarubicin adversely affecting human fertility or causing teratogenesis. There has been one report of a fetal fatality after maternal exposure to idarubicin during the second trimester.

There are no adequate and well-controlled studies in pregnant women. If idarubicin is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid pregnancy.

Therapy with idarubicin requires close observation of the patient and careful laboratory monitoring. Hyperuricemia secondary to rapid lysis of leukemic cells may be induced. Appropriate measures must be taken to prevent hyperuricemia and to control any systemic infection before beginning therapy.

Extravasation of idarubicin can cause severe local tissue necrosis. Extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle. If signs or symptoms of extravasation occur the injection or infusion should be terminated immediately and restarted in another vein. (See DOSAGE AND ADMINISTRATION.)

Frequent complete blood counts and monitoring of hepatic and renal function tests are recommended.

Formal long-term carcinogenicity studies have not been conducted with idarubicin. Idarubicin and related compounds have been shown to have mutagenic and carcinogenic properties when tested in experimental models (including bacterial systems, mammalian cells in culture and female Sprague- Dawley rats).

In male dogs given 1.8 mg/m²/day 3 times/week (about one seventh the weekly human dose on a mg/m² basis) for 13 weeks, or 3 times the human dose, testicular atrophy was observed with inhibition of spermatogenesis and sperm maturation with few or no mature sperm. These effects were not readily reversed after a recovery of 8 weeks.

(See WARNINGS.)

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from idarubicin, mothers should discontinue nursing prior to taking this drug.

Safety and effectiveness in children have not been established.

Patients over 60 years of age who were undergoing induction therapy experienced congestive heart failure, serious arrhythmias, chest pain, myocardial infarction, and asymptomatic declines in LVEF more frequently than younger patients (see ADVERSE REACTIONS).

General

Zavedos Oral 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, overhelming infections) may be carried out.

Patients should recover from acute toxicities due to prior cytotoxic treatment (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) before beginning treatment with Zavedos Oral.

Cardic function

Cardiotoxicity is a known risk of treatment with anthracyclines that may manifest itself as early (i.e. acute) or late (i.e. delayed) events.

Early (acute) events: Early cardiotoxicity of Zavedos Oral consists mainly of sinus tachycardia and/or electrocardiogram (ECG) abnormalities, such as non-specific ST-T wave changes. Tachyarrhythmia, including premature ventricular beats and ventricular tachycardia, bradycardia, and atrioventricular and bundle branch block have also been reported. These effects are not usually predictors of subsequent development of delayed cardiotoxicity, are rarely of clinical significance, and in general do not constitute grounds for discontinuation of treatment with Zavedos Oral.

Late (delayed) events: Delayed cardiotoxicity usually develops at a late stage during therapy or within 2 to 3 months of ending treatment, but later events, several months to years after completion of treatment, have also been reported. Delayed cardiomyopathy manifests as a reduction in left ventricular ejection fraction (LVEF) and/or signs and symptoms of congestive heart failure, 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 congestive heart failure is the most severe form of anthracycline-induced cardiomyopathy and constitutes the cumulative dose-limiting toxicity of the drug.

The cumulative dose limits for IV or oral Zavedos Oral have not been defined. However, Zavedos Oral-related cardiomyopathy was reported in 5% of patients who received cumulative IV doses of 150 to 290 mg/m2. The available data on patients treated with total cumulative doses of up to 400 mg/m2 Zavedos Oral p.o. suggest a low incidence of cardiotoxicity.

Cardiac function should be assessed before initiation of treatment with Zavedos Oral and must be monitored throughout therapy to minimise the risk of severe cardiac insufficiency. The risk may be reduced by regular monitoring of LVEF throughout the treatment, with prompt discontinuation of Zavedos Oral at the first sign of impaired function. Appropriate quantitative methods for repeated assessment of cardiac function (evaluation of LVEF) include cardiac scintigraphy or echocardiography. A baseline cardiac evaluation consisting of an electrocardiogram accompanied by cardiac or myocardial scintigraphy, or an echocardiogram, is recommended, especially in patients with elevated cardiotoxicity risk factors.

Repeated measurements of LVEF must be performed by means of cardiac scintigraphy or echocardiogram, particularly with higher cumulative doses of anthracyclines. 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 anthracenedione agents, and concomitant use of drugs capable of suppressing cardiac contractility or cardiotoxic drugs (for example trastuzumab). Anthracyclines, including Zavedos Oral, 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. Trastuzumab has a half-life of approximately 28-38 days and it can persist in the circulation for up to 27 weeks. Therefore, physicians should wherever possible avoid anthracycline-based therapy for up to 27 weeks after discontinuation of trastuzumab. If anthracyclines are used within this period, careful monitoring of cardiac function is recommended.

Cardiac function monitoring must be particularly rigorous in patients treated with high cumulative doses and in those with risk factors. However, cardiotoxicity can occur with lower cumulative doses of idaribicin, irrespective of the presence of cardiac risk factors.

A long-term assessment of cardiac function in infants and children must be carried out periodically, since they appear to be highly susceptible to anthracycline-induced cardiac toxicity.

The toxicity caused by Zavedos Oral and other anthracyclines or anthracenedione agents is likely to be additive.

Haematological toxicity

Zavedos Oral is a potent bone marrow suppressant. Severe myelosuppression will occur in all patients given a therapeutic dose of this drug.

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

A dose-dependent reversible leukopenia and/or granulocytopenia (neutropenia) is the predominant manifestation of Zavedos Oral haematologic toxicity and is the most common acute dose-limiting 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 preleukaemic phase, has been reported in patients treated with anthracyclines, including Zavedos Oral. 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 anthracyclines have been escalated. These leukaemias can have a 1- to 3-years latency period.

Gastrointestinal

Zavedos Oral 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 Zavedos Oral 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 Zavedos Oral therapy against the risk.

Hepatic and renal function

Since hepatic and/or renal function impairment can affect the disposition of Zavedos Oral, 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/dl. With other anthracyclines a 50% dose reduction is generally used if bilirubin levels are in the range 1.2 - 2.0-mg/dl.

Effects at the injection site

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 Zavedos Oral 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 Zavedos Oral, the drug infusion should be immediately stopped.

In cases of extravasation dexrazoxane can be used to prevent or reduce tissue injury.

Tumour lysis syndrome

Zavedos Oral may induce hyperuricemia as a consequence of the extensive purine catabolism that accompanies rapid drug-induced lysis of the neoplastic cells ('tumour lysis syndrome'). Blood uric acid levels, potassium, calcium, phosphate, and creatinine should be evaluated after initial treatment. Hydration, urine alkalinisation, and prophylaxis with allopurinol to prevent hyperuricemia may minimise potential complications of tumour lysis syndrome.

Immunosuppressive effects/Increased susceptibility to infections

Administration of live or live-attenuated vaccines (like yellow fever) in patients with immunocompromised by chemotherapeutic agents including Zavedos Oral, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving Zavedos Oral. Killed or inactivated vaccines can be administered; however, the response to such vaccines may be diminished.

Reproductive system

Male treated with Zavedos Oral 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 Zavedos Oral.

This product may cause a red colouration of the urine for 1 - 2 days after administration and patients should be advised of this fact.

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.

The effect of Zavedos Oral on the ability to drive and use machinery has not been systematically evaluated.

Dosage (Posology) and method of administration

(See WARNINGS)

For induction therapy in adult patients with AML the following dose schedule is recommended:

Zavedos Oral (idarubicin hydrochloride for injection, USP) 12 mg/m² daily for 3 days by slow (10 to 15 min) intravenous injection in combination with cytarabine. The cytarabine may be given as 100 mg/m² daily by continuous infusion for 7 days or as cytarabine 25 mg/m² intravenous bolus followed by cytarabine 200 mg/m² daily for 5 days continuous infusion. In patients with unequivocal evidence of leukemia after the first induction course, a second course may be administered. Administration of the second course should be delayed in patients who experience severe mucositis, until recovery from this toxicity has occurred, and a dose reduction of 25% is recommended. In patients with hepatic and/or renal impairment, a dose reduction of Zavedos Oral should be considered. Zavedos Oral should not be administered if the bilirubin level exceeds 5 mg%. (See WARNINGS.)

The benefit of consolidation in prolonging the duration of remissions and survival is not proven. There is no consensus regarding optional regimens to be used for consolidation. (See Clinical Studies for doses used in U.S. clinical studies.)

Caution in handling of the powder and preparation of the solution must be exercised as skin reactions associated with Zavedos Oral may occur. Skin accidently exposed to Zavedos Oral should be washed thoroughly with soap and water and if the eyes are involved, standard irrigation techniques should be used immediately. The use of goggles, gloves, and protective gowns is recommended during preparation and administration of the drug.

Zavedos Oral 20 mg vials should be reconstituted with 20 mL of Water for Injection, USP, to give a final concentration of 1 mg/mL of idarubicin hydrochloride. Bacteriostatic diluents are not recommended. The reconstituted solution is hypotonic, and the recommended administration procedure via a freely flowing intravenous infusion must be followed.

The vial contents are under a negative pressure to minimize aerosol formation during reconstitution; therefore, particular care should be taken when the needle is inserted. Inhalation of any aerosol produced during reconstitution must be avoided.

Reconstituted solutions are physically and chemically stable for 72 hours (3 days) under refrigeration (2° to 8°C, 36° to 46°F) and at controlled room temperature, (15° to 30°C, 59° to 86°F). Discard unused solutions in an appropriate manner (see Handling and Disposal).

Care in the administration of Zavedos Oral will reduce the chance of perivenous infiltration. It may also decrease the chance of local reactions such as urticaria and erythematous streaking. During intravenous administration of Zavedos Oral extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the injection or infusion should be immediately terminated and restarted in another vein. If it is known or suspected that subcutaneous extravasation has occurred, it is recommended that intermittent ice packs (½ hour immediately, then ½ hour 4 times per day for 3 days) be placed over the area of extravasation and that the affected extremity be elevated. Because of the progressive nature of extravasation reactions, the area of injection should be frequently examined and plastic surgery consultation obtained early if there is any sign of a local reaction such as pain, erythema, edema or vesication. If ulceration begins or there is severe persistent pain at the site of extravasation, early wide excision of the involved area should be considered.

Zavedos Oral should be administered slowly (over 10 to 15 minutes) into the tubing of a freely running intravenous infusion of Sodium Chloride Injection USP (0.9%) or 5% Dextrose Injection USP. The tubing should be attached to a Butterfly needle or other suitable device and inserted preferably into a large vein.

Unless specific compatibility data are available, Zavedos Oral should not be mixed with other drugs. Precipitation occurs with heparin. Prolonged contact with any solution of an alkaline pH will result in degradation of the drug.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and containers permit.

Procedures for handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Store at controlled room temperature, 15° to 30°C (59° to 86°F), and protect from light.

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 Oral should be considered..

The capsules should be swallowed whole with some water and should not be sucked, bitten or chewed. Zavedos Oral Capsules may also be taken with a light meal.

(See WARNINGS)

For induction therapy in adult patients with AML the following dose schedule is recommended:

IDAMYCIN PFS Injection 12 mg/m² daily for 3 days by slow (10 to 15 min) intravenous injection in combination with cytarabine. The cytarabine may be given as 100 mg/m² daily by continuous infusion for 7 days or as cytarabine 25 mg/m² intravenous bolus followed by cytarabine 200 mg/m² daily for 5 days continuous infusion. In patients with unequivocal evidence of leukemia after the first induction course, a second course may be administered. Administration of the second course should be delayed in patients who experience severe mucositis, until recovery from this toxicity has occurred, and a dose reduction of 25% is recommended. In patients with hepatic and/or renal impairment, a dose reduction of IDAMYCIN PFS should be considered. IDAMYCIN PFS should not be administered if the bilirubin level exceeds 5 mg%. (See WARNINGS.)

The benefit of consolidation in prolonging the duration of remissions and survival is not proven. There is no consensus regarding optional regimens to be used for consolidation. (See Clinical Studies for doses used in U.S. Clinical studies.)

Caution in handling the solution must be exercised as skin reactions associated with IDAMYCIN PFS may occur. Skin accidentally exposed to IDAMYCIN PFS should be washed thoroughly with soap and water and if the eyes are involved, standard irrigation techniques should be used immediately. The use of goggles, gloves, and protective gowns is recommended during preparation and administration of the drug.

Care in the administration of IDAMYCIN PFS will reduce the chance of perivenous infiltration. It may also decrease the chance of local reactions such as urticaria and erythematous streaking. During intravenous administration of IDAMYCIN PFS extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the injection or infusion should be immediately terminated and restarted in another vein. If it is known or suspected that subcutaneous extravasation has occurred, it is recommended that intermittent ice packs (½ hour immediately, then ½ hour 4 times per day for 3 days) be placed over the area of extravasation and that the affected extremity be elevated. Because of the progressive nature of extravasation reactions, the area of injection should be frequently examined and plastic surgery consultation obtained early if there is any sign of a local reaction such as pain, erythema, edema or vesication. If ulceration begins or there is severe persistent pain at the site of extravasation, early wide excision of the involved area should be considered.

IDAMYCIN PFS should be administered slowly (over 10 to 15 minutes) into the tubing of a freely running intravenous infusion of Sodium Chloride Injection, USP (0.9%) or 5% Dextrose Injection, USP. The tubing should be attached to a Butterfly needle or other suitable device and inserted preferably into a large vein.

Unless specific compatibility data are available, IDAMYCIN PFS should not be mixed with other drugs. Precipitation occurs with heparin. Prolonged contact with any solution of an alkaline pH will result in degradation of the drug.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and containers permit.

Procedures for handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Posology

Dosage is usually calculated on the basis of body surface area (mg/m2). For intravenous use.

Acute non-lymphocytic leukaemia (AML)

Adults: In acute non-lymphocytic leukaemia the recommended dose is 12 mg/m2 IV daily for 3 days in combination with cytarabine. Other dose schedule which could be used in acute non-lymphocytic leukaemia, as a single agent or in combination, is 8 mg/m2 IV daily for 5 days.

Children: the recommended dose range is 10-12 mg/m2 i.v. daily for 3 days in combination with cytarabine.

Acute lymphocytic leukaemia (ALL)

Adults: As single agent the suggested dose is 12 mg/m2 i.v. daily for 3 days.

Children: As single agent the suggested dose is 10 mg/m2 i.v. daily for 3 days

Note: These are only general guidelines. Refer to individual protocols for exact dosage.

All of the dosage schedules should take into account the haematological status of the patient, and the dosages of other cytotoxic drugs when used in combination.

Method of administration

Intravenous administration of Zavedos Oral should be performed carefully. It's recommended that Zavedos Oral is 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, vesication and tissue necrosis. Direct injection is not recommended, due to the risk of extravasation, which may occur even with the adequate blood return by aspiration through the needle.

Special precautions for disposal and other handling

None stated.

Zavedos Oral Accord solution must only be administered intravenously via an infusion line with a freely running intravenous infusion of 0.9% sodium chloride over a period of 5 to 10 minutes.

This method minimises the risks of thrombosis and perivascular extravasation which can lead to severe cellulitis and necrosis. Phlebosclerosis can result from injection into small veins or repeated injections into the same vein.

The following recommendations for protection are given, due to the toxic nature of this substance:

- Personnel must be trained in the correct handling method

- Pregnant women must be excluded from working with this drug

- Personnel handling the drug must wear protective clothing: eyewear, overalls, disposable gloves and masks

- A work area should be set up with a surface protected with absorbent paper, plasticised on one side

- All instruments used for administration or cleaning, including gloves, must be disposed of in high-risk containers for incineration at high temperatures

Spills or leaks must be treated with dilute sodium hypochlorite solution (1% chlorine) and then with water.

All cleaning materials must then be disposed of as described above.

Accidental contact with skin or eyes must be treated immediately by washing thoroughly with water, soap and water, or sodium bicarbonate solution; medical attention may be necessary. Discard any unused solution.

Any remaining medicine, as well as all the materials that were used for its reconstitution, dilution and administration, must be destroyed in accordance with the hospital procedure applicable for cytotoxic agents and in compliance with current legislation relating to the elimination of hazardous waste.