Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use
General warnings
Doxorubicin should be administered only under the supervision of a qualified physician experienced in cytotoxic therapy. Also, patients must be carefully and frequently monitored during the treatment.

Patients should recover from the acute toxicities of prior cytotoxic treatment (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) before beginning treatment with doxorubicin.

A careful control of possible clinical complications should be performed, particularly in elderly patients, in patients with a history of heart disease, or with bone-marrow suppression, or patients who previously have been treated with anthracyclines, or treated with radiation in the mediastinum.

Before or during treatment with doxorubicin, the following monitoring examinations are recommended (how often these examinations are done will depend on the general condition of the patient, the dose and the concomitant medication being taken):
- radiographs of the lungs and chest and ECG
- regular monitoring of heart function (LVEF by e.g., ECG, UCG and MUGA scan) - inspection of the oral cavity and pharynx for mucosal changes
- blood tests: haematocrit, platelets, differential white cell count, SGPT, SGOT, LDH, bilirubin, uric acid.

The patient should be informed that the urine might be reddish after administration.
Nausea, vomiting and mucositis are often extremely severe and should be prevented and if necessary treated appropriately.
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 doxorubicin consists mainly of sinus tachycardia and/or 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 and are generally not a consideration for discontinuation of doxorubicin treatment. However, a reduction in the amplitude of the QRS-wave and a prolongation of the systolic time interval are considered more indicative of anthracycline-induced cardiac toxicity. As a rule, an absolute decrease with ≥10% or a decrease below 50%, in patients with normal initial LVEF-values, is a sign of an impairment of the heart function. Continued treatment with doxorubicin must in these cases be carefully evaluated.


Late (i.e. delayed) events: Delayed cardiotoxicity usually develops late in the course of therapy with doxorubicin 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 LVEF and/or signs and symptoms of congestive heart failure (CHF), such as dyspnoea, pulmonary oedema, dependent oedema, cardiomegaly and 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.

Cardiac function should be assessed before patients undergo treatment with doxorubicin 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 doxorubicin at the first sign of impaired function. The appropriate quantitative method for repeated assessment of cardiac function (evaluation of LVEF) includes multi-gated radionuclide angiography (MUGA) 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.
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The probability of developing CHF, estimated around 1% to 2% at a cumulative dose of 300 mg/m slowly increases up to the total cumulative dose of 450-550 mg/m2. Thereafter, the risk of developing CHF increases steeply and it is recommended not to exceed a maximum cumulative dose of 550 mg/m².
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 of cardiotoxic substances (e.g., trastuzumab) and age over 70 years. Anthracyclines, including doxorubicin, should not be administered in combination with other cardiotoxic agents unless the patient’s cardiac function is closely monitored (see section 4.5). 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 variable. This substance may persist in the circulation for up to 7 months. Therefore, physicians should avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab when possible. If anthracyclines are used before this time, careful monitoring of cardiac function is recommended.
Cardiac function must be carefully monitored in patients receiving high cumulative doses and in those with risk factors. However, cardiotoxicity with doxorubicin may occur at lower cumulative doses whether or not cardiac risk factors are present.

Children and adolescents are at an increased risk for developing delayed cardiotoxicity following doxorubicin administration. Females may be at greater risk than males. Follow-up cardiac evaluations are recommended periodically to monitor for this effect.
It is probable that the toxicity of doxorubicin and other anthracyclines or anthracenediones is additive.

Haematologic toxicity
Doxorubicin may produce myelosuppression (see section 4.8). If serious myelosuppression is present, doxorubicin should not be used; a dose reduction or a delay in administration is then necessary.
Care has to be taken to ensure that a serious infection and/or episode of haemorrhage can be treated fast and effectively. Existing infections should be treated before therapy with doxorubicin is initiated.

Haematologic profiles should be assessed before and during each cycle of therapy with doxorubicin, including differential white blood cell (WBC) counts. A dose-dependent, reversible leucopenia and/or 
granulocytopenia (neutropenia) is the predominant manifestation of doxorubicin haematologic toxicity and is the most common acute dose-limiting toxicity of this drug. Leucopenia and neutropenia generally reach the nadir between days 10 and 14 after drug administration; the WBC/neutrophil counts return to normal values in most cases by day 21. Thrombocytopenia and anaemia may also occur. Clinical consequences of severe myelosuppression include fever, infections, sepsis/septicaemia, septic shock, haemorrhage, tissue hypoxia or death.

Secondary leukaemia
Secondary leukaemia with or without a preleukaemic phase, has been reported in patients treated with anthracyclines. 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 disorders
Doxorubicin induces nausea and vomiting. Mucositis/stomatitis usually appears early after initiation of treatment, which, if severe, may progress within a few days to mucosal ulcerations. Most patients recover from this in the third week of therapy.
An antiemetic prophylaxis is recommended.
Note: Doxorubicin should not be used in the presence of inflammations, ulcerations or diarrhoea.

Liver function
The major route of elimination of doxorubicin is the hepatobiliary system. Serum total bilirubin should be evaluated before and during treatment with doxorubicin. Patients with elevated bilirubin may experience slower clearance of the drug with an increase in overall toxicity. Lower doses are recommended in these patients (see section 4.2). Patients with severe hepatic impairment should not receive doxorubicin (see section 4.3).

Tumour-lysis syndrome
Doxorubicin may induce hyperuricaemia as a consequence of the extensive purine catabolism that accompanies drug-induced rapid lysis of neoplastic cells (tumour-lysis syndrome) in case of high tumour burden. In these circumstances 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.

In patients with severely impaired renal function dose reductions may be necessary (see section 4.2).

Combination with other anticancer chemotherapies
Doxorubicin hydrochloride may potentiate the toxicity of other anticancer chemotherapies (see section 4.5). Exacerbation of cyclophosphamide-induced haemorrhagic cystitis and enhanced hepatotoxicity of 6-mercaptopurine have been reported. Radiation-induced toxicities ( myocardium, mucosa, skin and liver) have also been reported.
As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena including pulmonary embolism (in some cases fatal) have been coincidentally reported with the use of doxorubicin (see section 4.8).

Carcinogenesis, mutagenesis and impairment of fertility
Doxorubicin was genotoxic and mutagenic in in vitro and in vivo tests. Doxorubicin may cause infertility during the period of drug administration (see sections 4.6 and 5.3).

Injection site reaction
Injection into a small vein or repeated injections into the same vein can result in phlebosclerosis.
Following the recommended administration procedures may minimize the risk of phlebitis/thrombophlebitis at the injection site (see section 4.2).

Extravasation
Perivenous misinjection results in local necrosis and thrombophlebitis. A burning sensation in the region of the infusion needle is indicative of perivenous administration.
If extravasation occurs, the infusion or injection has to be stopped at once; the needle should be left in place for a short time and then be removed after short aspiration.
In case of extravasation start intravenous infusion of dexrazoxane, no later than 6 hours after extravasation (see the SmPC of dexrazoxane for dosing and further information). In case dexrazoxane is contraindicated, it is recommended to apply 99% dimethylsulfoxide (DMSO) locally to an area twice the size of the area concerned (4 drops to 10 cm² of skin surface area) and to repeat this three times a day for a period of no less than 14 days. If necessary, debridement should be considered. Because of the antagonistic mechanism, the area should be cooled after the application of DMSO (vasoconstriction vs.
vasodilatation), e.g., to reduce pain.
Do not use DMSO in patients who are receiving dexrazoxane to treat anthracycline-induced extravasation.
Other measures have been treated controversially in the literature and have no definite value.

Vaccines
Vaccines are not recommended (see section 4.5).
Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including doxorubicin, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving doxorubicin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished. During treatment with doxorubicin hydrochloride patients should avoid contact with recently polio vaccinated persons.

Intravesical administration
Intravesical administration of doxorubicin may cause symptoms of chemical cystitis (i.e., dysuria, frequent urinary, nocturia, stranguria, haematuria, necrosis of the bladder wall).
Special attention is needed in case of catheter problems (i.e., urethral obstruction caused by invasion of intravesical tumour). Intravesical administration is contraindicated for tumours that have penetrated the bladder (beyond T1).

Excipients
Sodium
1 vial of 5 ml of Doxorubicin Teva contains 18 mg sodium, equivalent to 0.9% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
1 vial of 10 ml of Doxorubicin Teva contains 35 mg sodium, equivalent to 1.8% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
1 vial of 25 ml of Doxorubicin Teva contains 89 mg sodium, equivalent to 4.4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
1 vial of 100 ml of Doxorubicin Teva contains 354 mg sodium, equivalent to 17.7% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Effects on Driving

4.7   Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, as nausea and vomiting are frequent, patients should be warned against driving and using machines.