Special Warning : אזהרת שימוש

4.4       Special warnings and precautions for use


General
ZAVEDOS for injection must be administered by the intravenous route only.
ZAVEDOS administration must be monitored by a qualified doctor with experience of cytotoxic therapies.
Before starting treatment with ZAVEDOS, 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 ZAVEDOS 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 ZAVEDOS 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 ZAVEDOS 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 (see section 4.5).
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, ZAVEDOS can cause myelosuppression. The main manifestation of the haematological toxicity of ZAVEDOS 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 ZAVEDOS 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 ZAVEDOS. 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 such as ZAVEDOS (see section 4.8) can be cured if treated promptly and appropriately. Haematological monitoring is therefore required for all patients treated with ZAVEDOS.
Gastrointestinal toxicity
ZAVEDOS 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 ZAVEDOS 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 ZAVEDOS 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 ZAVEDOS 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 (see section 4.2).
Extravasation
Extravasation of ZAVEDOS 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 ZAVEDOS, discontinue the administration immediately.
In the case of extravasation, dexrazoxane may be used preventatively or to reduce tissue damage.
Tumour lysis syndrome
ZAVEDOS 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 (see sections 4.3 and 4.5). 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 (see section 4.6). 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 ZAVEDOS use.

This medicine is not recommended in combination with phenytoin (and, by extrapolation, with fosphenytoin) (see section 4.5).
Patients must be warned that this medicine may cause red-coloured urine 1 to 2 days after its administration.

Effects on Driving

4.7      Effects on ability to drive and use machines

The effects of ZAVEDOS on the ability to drive vehicles and use machines have not been systematically evaluated.