Zavedos

/ Pfizer

For intravenous use only. Not for intrathecal use.
Dosage is calculated on the basis of body surface area.
Acute non- lymphocytic 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 lymphocytic leukaemia (ALL)
Adults:
As single agent in ALL the suggested dose in adults is 12 mg/m2 i.v. daily for 3
days.
Children:
10 mg/m² i.v. daily for 3 days, as a single agent.
All of these dosage schedules should, however, take into account the haematological status of the patient and the dosages of other cytotoxic drugs
when used in combination.
Administration of a second course should be delayed in patients who develop
severe mucositis until recovery from this toxicity has occurred and a dose reduction of 25% is recommended.
For directions on dilution of the product before administration, see prescribing information.

Antimitotic and cytotoxic agent. Acute non-lymphocytic leukemia (ANLL) in
adults for remission induction in untreated patients or for remission induction in
relapsed or refractory patients. Acute lymphocytic leukemia (ALL) as secondline treatment in adults and children.

• known hypersensitivity to the active substance or to any of the excipients, and/or to other anthracyclines or anthracenediones
• The use should be avoided in patients with heart disease and myocardial failure
• Severe renal impairment
• Severe hepatic impairment
• Uncontrolled infections
• Breast-feeding
• Attenuated live vaccines (against yellow fever, chickenpox, herpes zoster, measles, mumps, rubella, tuberculosis, rotavirus, influenza) and for the 6 months following the discontinuation of chemotherapy
• Severe heart failure
• Myocardial infarction in the previous six months
• Severe cardiomyopathy
• Severe arrhythmia
• Persistent myelosuppression
• Previous treatment with idarubicin hydrochloride and/or other anthracyclines or anthracenediones at the maximum cumulative dose

General
This medicinal product must be administered by the intravenous route only.
The administration must be monitored by a qualified doctor with experience of cytotoxic therapies.
Before starting treatment with this drug, patients must be free from the adverse effects of any previous cytotoxic therapy (such as stomatitis, neutropoenia, thrombocytopoenia and generalised infections).
Heart function
Anthracycline treatment is associated with a risk of cardiotoxicity. This may be delayed or appear immediately.
• Immediate cardiotoxicity: primarily presents as sinus tachycardia, ventricular extrasystole, ventricular tachycardia and electrocardiogram abnormalities (T-wave changes, atrioventricular conduction disturbances, branch block).
These effects are not generally predictive of the development of delayed cardiotoxicity, are rarely serious from a clinical perspective and do not generally require discontinuation of the treatment.
• Delayed cardiotoxicity: can develop later during treatment, in the two to three months following the end of treatment or, more rarely, several months or years after the end of treatment.
Delayed cardiomyopathy presents as reduced left ventricular ejection fraction (LVEF) and/or signs and symptoms of congestive heart failure, such as dyspnoea, pulmonary oedema, dependent oedema, cardiomegaly and hepatomegaly, oliguria, ascites, pleural effusion and gallop rhythm. Life-threatening congestive heart failure is the most severe form of cardiomyopathy caused by anthracyclines and represents a cumulative toxicity risk that limits the maximum dose of this medicinal product.
The maximum cumulative dose of idarubicin hydrochloride has not been defined, but at a dose of 93 mg/m2, no changes in heart function have been reported. However, cardiomyopathy linked to idarubicin hydrochloride was reported in 5% of patients who received a cumulative intravenous dose of 150 to 290 mg/m2. The available data on patients treated with oral idarubicin hydrochloride up to a dose of 400 mg/m2 suggest that there is a low probability of cardiotoxicity.
Heart function must be assessed before and throughout treatment, to reduce the risk of severe heart failure.
• Before treatment: clinical assessment, ECG with either ventricular scintigraphy or echocardiography, particularly in patients with risk factors for increased cardiac toxicity: symptomatic or asymptomatic cardiovascular disease, previous or concomitant radiotherapy of the mediastinal/pericardial region, previous treatment with other anthracyclines or anthracenediones, and concomitant use of other medicinal products that can affect cardiac contractility.
• During treatment: regular monitoring of LVEF (assessed using ventricular scintigraphy [MUGA] and/or an echocardiogram [ECHO]), with immediate discontinuation of this drug at the first signs of deterioration in function.
LVEF must be measured repeatedly by MUGA or ECHO, particularly when high and cumulative doses of anthracycline are being used. The technique used for the assessment must be reproducible throughout the entire monitoring period.
Heart function must be monitored particularly closely in patients receiving high cumulative doses and in those with risk factors. However, the cardiac toxicity associated with this drug can still occur with lower cumulative doses, whether or not risk factors are present.
• Delayed effects: infants and children seem to be more susceptible to anthracycline-induced cardiac toxicity, and their heart function must be monitored regularly over the long term.
The toxicity of this medicinal product and other anthracyclines and anthracenediones is likely to be additive.
Anthracyclines, including idarubicin, must not be administered in combination with other cardiotoxic agents (e.g. trastuzumab) without closely monitoring the patient’s heart function.
Patients receiving anthracyclines after discontinuing other cardiotoxic agents, particularly those with a long half-life, such as trastuzumab, may be exposed to an increased risk of cardiotoxicity. As the reported half-life of trastuzumab is variable. The trastuzumab may persist in circulation for up to 7 months after the discontinuation of treatment. Therefore, physicians should avoid anthracycline-based therapy for up to 7 months after the discontinuation of trastuzumab when possible. If this is not possible, the patient’s cardiac function should be monitored carefully.
Haematological toxicity
Like other cytotoxic agents, this medicinal product can cause myelosuppression. The main manifestation of the haematological toxicity of this drug is dose-dependent, reversible leukopoenia and/or neutropoenia. This myelosuppression is also the most common form of dose-limiting toxicity. Leukopoenia and neutropoenia generally reach their lowest point between the 10th and 14th days of treatment; leukocyte/neutrophil counts generally return to normal around the 21st day. Thrombocytopoenia and anaemia can also occur.
The clinical consequences of severe myelosuppression include fever, infection, sepsis/septicaemia, septic shock, haemorrhage, tissue hypoxia and death.
Haematological parameters, including white blood cell count, must be assessed before and during each treatment cycle.
In the absence of sufficient data, the oral administration of this drug is not recommended in patients who have undergone total body irradiation or haematopoietic stem cell transplantation.
Secondary leukaemia
Secondary leukaemia, with or without a pre-leukaemic phase, has been reported in patients treated with anthracyclines, including this medicinal product. Secondary leukaemia is more common when the product is administered in combination with DNA-altering antineoplastic agents, when patients have been pre-treated with a cytotoxic medicinal product, or when the anthracycline doses have been increased incrementally. This secondary leukaemia can have a latency period of one to three years. Some forms of leukaemia arising subsequent to the administration of anticancer agents can be cured if treated promptly and appropriately. Haematological monitoring is therefore required for all patients treated with this medicinal product.
Gastrointestinal toxicity
This medicinal product is an emetic. Mucositis (generally stomatitis, less commonly oesophagitis) generally appears at the start of treatment. If severe, it can develop into ulceration of the mucous membrane within a few days. The majority of patients recover at around the third week of treatment.
Severe gastrointestinal events (such as perforation and bleeding) have occasionally been observed in patients treated orally with this drug who have acute leukaemia, or who have another disease or have previously taken a different treatment known to cause gastrointestinal complications.
In patients with an active gastrointestinal disease that entails an increased risk of bleeding and/or perforation, the doctor must assess the risk-benefit ratio of oral administration.
Hepatic and/or renal function
Since hepatic and/or renal impairment can affect the metabolism of idarubicin, hepatic and renal function (serum bilirubin and serum creatinine levels) must be assessed before and during treatment. In a number of phase III clinical studies, treatment with this drug was contraindicated where serum bilirubin and/or creatinine levels exceeded 2.0 mg/dL.
In the absence of pharmacokinetic data, oral administration of idarubicin is not recommended if the patient has even moderate hepatic and/or renal impairment.
Injection site effects
Sclerosis may appear in small vessels or following repeat injections into the same vein. Compliance with the administration guidelines can reduce the risk of phlebitis and thrombophlebitis at the injection site.
Extravasation
Extravasation of idarubicin during intravenous injection can cause local pain, severe tissue damage (blistering, severe inflammation of subcutaneous tissue) and necrosis. If these signs appear during intravenous injection of this drug, discontinue the administration immediately.
In the case of extravasation, dexrazoxane may be used preventatively or to reduce tissue damage.
Tumour lysis syndrome
This medicinal product can induce hyperuricaemia due to the increased purine catabolism that occurs during the rapid lysis of neoplastic cells (tumour lysis syndrome) following treatment administration. The levels of uric acid, potassium, calcium, phosphates and creatinine in the blood must be assessed regularly during treatment. Hydration, very careful urine alkalinisation and prophylactic treatment with allopurinol or another urate lowering agent to prevent hyperuricaemia can minimise the potential complications of tumour lysis syndrome.
Immunosuppressant effects/increased susceptibility to infection
Combination with live attenuated vaccines is contraindicated, as it may lead to a potentially fatal generalised vaccine disease. Dead or inactivated viral vaccines may be administered, although their efficacy may be diminished.
Before initiating leukaemia treatment, appropriate measures must be taken to control any systemic infections.
Reproductive system
Idarubicin can cause genotoxicity. Men Male and female patients treated with idarubicin hydrochloride are advised to adopt effective contraceptive measures during therapy and for a period after treatment.
Men treated with idarubicin hydrochloride are advised, if appropriate and available, to seek advice on sperm preservation due to the possibility of irreversible infertility caused by the therapy. Patients desiring to have children after completion of therapy should be advised to discuss with an appropriate specialist first.
Other
As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism, have been reported during idarubicin hydrochloride use.
This medicine is not recommended in combination with phenytoin (and, by extrapolation, with fosphenytoin).
Patients must be warned that this medicine may cause red-coloured urine 1 to 2 days after its administration.

Very common: Infection, anaemia, leukopoenia, neutropoenia, febrile neutropoenia, pancytopoenia, thrombocytopenia, anorexia, sinus tachycardia, tachyarrhythmia, bradycardia, asymptomatic reduced left ventricular ejection fraction, nausea, vomiting and diarrhoea, mucositis/stomatitis, abdominal pain, burning sensations, alopecia, red discolouration of urine one to two days after administration, fever, headaches, chills, asymptomatic reduced left ventricular ejection fraction, ECG abnormalities (T-wave abnormality).
Common: Cardiomyopathy, phlebitis, deep vein thrombosis, haemorrhage, gastrointestinal tract bleeding, colic, rash, pruritus, reactivated skin reactions in irradiated zone, increased hepatic enzymes and bilirubin.
See prescribing information for full details.

When combined with other chemotherapies, idarubicin hydrochloride can lead to additive toxicity, particularly with regards to medullary/haematological effects and gastrointestinal effects. Heart function must be monitored throughout the treatment if this drug is used in chemotherapy that also involves other potentially cardiotoxic products, as well as if other products for cardiac disease (e.g. calcium channel blockers) are used concomitantly.
Changes in hepatic or renal function caused by concomitant treatments can affect the metabolism, pharmacokinetics, efficacy and/or toxicity of idarubicin.
Additive myelosuppression can appear when radiotherapy takes place concomitantly or two to three weeks before treatment with this drug.
INTERACTIONS COMMON TO ALL CYTOTOXIC AGENTS
Contraindicated combinations
+ Live attenuated vaccines (against yellow fever, chickenpox, herpes zoster, measles, mumps, rubella, tuberculosis, rotavirus, influenza) and for the 6 months following the discontinuation of chemotherapy Risk of potentially fatal generalised vaccine disease.
Inadvisable combinations
+ Olaparib: Risk of increased cytotoxic myelosuppressive effect.
+ Phenytoin (and, by extrapolation, fosphenytoin): Risk of occurrence of seizures due to decreased gastrointestinal absorption by the cytotoxic agent of phenytoin alone, or risk of an increase in toxicity and a loss of efficacy of the cytotoxic agent due to an increase in the hepatic metabolism by phenytoin or by fosphenytoin.
Associations requiring precautions for use
+ Antivitamin K: Increased risk of thrombosis and bleeding in the course of tumour diseases. In addition, possible interaction between the AVK and chemotherapy.
More frequent monitoring of the INR.
Associations to be taken into account
+ Flucytosine: Risk of increased haematological toxicity.
+ Immunosuppressive drugs (ciclosporin, everolimus, sirolimus, tacrolimus, temsirolimus): Excessive immunodepression with a risk of lymphoproliferative syndrome.

Pregnancy
There are limited amount data from the use of idarubicin in pregnant women. Studies in animals have shown reproductive toxicity.
Idarubicin should not be used during pregnancy unless only if the potential benefit justifies the potential risk to the foetus. The patient should be informed of the potential hazard to the foetus.
Women of childbearing potential/ Contraception in males and females
Women of child bearing potential should be advised not to become pregnant and to use effective contraception during treatment with idarubicin and for at least 6.5 months after the last dose. Men with female partners of childbearing potential should be advised to use effective contraception during treatment with idarubicin and for at least 3.5 months after the last dose.
Breast-feeding
It is not known whether idarubicin passes into breast milk. As other anthracyclines are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from idarubicin, women should be advised not to breastfeed during treatment with idarubicin and for at least 14 days after the last dose.
Fertility
Idarubicin can cause chromosome damage in human spermatozoa and/or infertility. For these reasons, men treated with idarubicin should use effective contraceptive methods for at least 3.5 months after the last dose. Both men and women should seek advice on fertility preservation before treatment.

Overdose is associated with the risk of acute and delayed myocardial toxicity and a risk of intensified myelosuppression and other adverse events.
Very high doses of idarubicin may be expected to cause acute myocardial toxicity within 24 hours and severe myelosuppression for the following week to two weeks.
Treatment consists in transferring the patient to a specialised unit and maintaining vital functions via blood transfusions and palliative nursing care.
Delayed heart failure has been observed with anthracyclines for up to several months after the overdose.
Patients must therefore be monitored closely and if signs of heart failure are observed, appropriate treatment must be started.

Incompatibilities: 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.