Source: Health Products Regulatory Authority (IE) Revision Year: 2011 Publisher: Teva Pharma B.V. Computerweg 10 3542 DR Utrecht Netherlands
Hypersensitivity to doxorubicin, other anthracyclines or anthracenediones or one of the excipients:
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.
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):
Doxorubicin should not be administered by the intramuscular, subcutaneous, oral or intrathecal route.
The patient should be informed that the urine might be reddish after administration.
Nausea, vomiting and mucositis after often extremely severe and should be treated appropriately.
When the maximum total cumulative dose is exceeded (adults 550 mg/m² BSA, in cases of prior thorax radiation therapy or during concomitant alkylating therapy 400 mg/m2 BSA), the rate of anthracycline-induced cardiomyopathy increases rapidly even without pre-existing risk factors. Cardiotoxicity was, however, observed at much lower total doses in isolated cases. After a total cumulative dose of 550 mg/m2 BSA, patients have, for instance, an about 5% risk of developing serious heart failure.
The cumulative dose has to be considered when the medicinal product is used in children who tolerate lower life-time total doses on the whole and in whom additional radiation therapy, young age on the beginning of therapy, and aggressive concomitant therapies result in a particularly high risk that they develop late, life-threatening cardiac organ toxicity with ventricular dysfunction, heart failure and/or arrhythmia. Girls, in comparison with boys, moreover seem to be particularly predisposed to developing delayed cardiotoxicity after a therapy with doxorubicin.
Particular caution is also indicated in children younger than 2 years and in patients with cardiologic pre-treatment (coronary heart disease, heart failure) as well as in a chronological relation with hyperthermic therapy.
Before, during and after chemotherapy with doxorubicin, the cardiac function should be monitored by means of ECG, ECHO and MUGA scan.
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 a therapy with doxorubicin is initiated.
An antiemetic prophylaxis is recommended.
Note: Doxorubicin should not be used in the presence of inflammations, ulcerations or diarrhoea.
Before every treatment cycle total and differential leukocyte count, erythrocyte and thrombocyte counts should be performed. Bone-marrow suppression induced by Doxorubicin hydrochloride, primarily affecting the leukocytes, requires a thorough haematological monitoring since severe myelosuppression may lead to superinfections and bleedings. Severe leucopenia may appear at doses recommended for treatment of solid tumours (a number of leukocytes of 1000/mm3 or lower is expected during full dose treatment with Doxorubicin hydrochloride). The leucopenia is most pronounced 10-14 days after the treatment and leukocytes have in most cases returned to normal at day 21. Treatment may not be started or continued when polynuclear granulocytes are less than 2000/mm3. With treatment of acute leukaemias this value may be adjusted lower, depending on the circumstances. Also regular hematologic examination is required because of the risk of secondary leukaemia after treatment with oncolytic agents. A remission of acute leukaemia may be realized if diagnosed in an early phase and treated with the appropriate chemotherapeutic schedules.
There is a known risk of development of anthracycline induced cumulative dose-dependent cardiomyopathy. Therefore a cumulative dose of 450-550 mg/m2 should not be exceeded. At doses above this, the risk of development of heart failure considerably increases. Doxorubicin-induced cardiotoxicity usually occurs during treatment or within two months after discontinuation of treatment, but occurrences of late complications (from months to years after treatment) have been reported. The heart function should therefore be assessed before start of the treatment and carefully monitored during the whole treatment. Electrocardiography before and after each treatment cycle is recommended. Changes in ECG such as depression or negative T-wave, decrease in the ST-segment or arrhythmias are usually signs of an acute but transient (reversible) toxic effect and are not considered indications for suspension of doxorubicin therapy. 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.
The best sign to predict cardiomyopathy is a reduction in the left ventricular ejection fraction (LVEF), determined by ultrasound or heart scintigraphy. LVEF-investigations should be performed before treatment and be repeated after each accumulated dose of about 100 mg/m2, and at clinical signs of heart failure. 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. The risk for cardiotoxicity may increase in patients previously on radiotherapy towards the mediastinal pericardium, in patients previously treated with other anthracyclines and/or anthracenediones, in patients aged over 70 or below 15 years, or in patients with a history of heart diseases. The total dose of doxorubicin administered to the individual patient should also take into account any previous or concomitant therapy with other potentially cardiotoxic agents such as high-dose i.v. cyclophosphamide, mediastinal irradiation or related anthracycline compounds such as daunorubicin. Acute severe arrhythmias have been reported to occur during or within a few hours after doxorubicin administration.
Cardiac symptoms may also manifest during pregnancy in women that have been treated with doxorubicin in the past (up to 20 years), even if they did not have signs of cardiac adverse events before. Cases of congestive heart failure and pulmonary oedema have been reported. Women that have been treated with doxorubicin in the past and who become pregnant should be monitored for cardiac adverse events. See also section 4.8.
Doxorubicin is mainly eliminated via the hepatobiliary system. The elimination of the drug can therefore be prolonged with subsequent general toxicity if the liver function is impaired or biliary secretion is obstructed. Before start and during treatment, control of the liver function with conventional tests such as AST, ALT, ALP and bilirubin is recommended as dose adjustment may be necessary (see section 4.2). In patients with severe hepatic impairment the risk-benefit of doxorubicin treatment should be evaluated before administration. In patients with previous radiotherapy to the mediastinal area severe hepatotoxicity has been reported, sometimes leading to death. Serum total bilirubin should be evaluated before and during treatment with doxorubicin.
During therapy serum uric acid may increase. In case of hyperuricemia antihyperuricemic therapy should be initiated. The blood uric acid level should be monitored; sufficient fluid intake should be ascertained (with a daily minimum of 3 1/m²). If necessary a xanthine-oxidase inhibitor (allopurinol) may be administered.
Inpatients with severely impaired renal function dose reductions may be necessary (see section 4.2).
Doxorubicin hydrochloride may potentiate the toxicity of other anticancer chemotherapies (see section 4.5).
Doxorubicin potentiates the radiation toxicity to cardiac muscle, mucosa, skin and liver.
Carcinogenesis, mutagenesis and impairment of fertility: Doxorubicin was genotoxic and mutagenic in vitro and in vivo tests.
In women, doxorubicin may cause infertility during the period of drug administration. Doxorubicin may cause amenorrhoea. Ovulation and menstruation appear to return after termination of therapy, although premature menopause can occur.
Doxorubicin is mutagenic and can induce chromosomal damage in human spermatozoa. Oligospermia or azoospermia may be permanent; however, sperm counts have been reported to return to normospermic levels in some instances. This may occur several years after the end of therapy. Men undergoing doxorubicin treatment should use effective contraceptive methods. Men being treated with doxorubicin are advised not to father a child during and up to 6 months after treatment and to seek advise on cryo-conservation (or cryo-preservation) of sperm prior to treatment because of the possibility of reversible infertility due to therapy with doxorubicin. Women should not become pregnant during and up to 6 months after treatment.
A stinging or burning sensation at the site of administration may signify a small degree of extravasation. Extravasation results in a severe and progressive tissue necrosis. If extravasation is suspected or occurs, the injection should be discontinued and restarted in a different blood vessel. Cooling the area for 24 hours can reduce the discomfort. The patient should be carefully monitored for several weeks. Surgical measures might be necessary.
Vaccines are not recommended (see section 4.5). During treatment with Doxorubicin hydrochloride patients should avoid contact with recently polio vaccinated persons.
Doxorubicin cardiotoxicity is enhanced by previous or concurrent use of other anthracyclines, or other potentially cardiotoxic drugs (e.g. 5-fluorouracil, cyclophosphamide or paclitaxel) or with products affecting cardiac function (like calcium antagonists). When doxorubicin is used together with the above mentioned agents, cardiac function must be followed carefully.
The use of trastuzumab in combination with anthracyclines (such as doxorubicin) is associated with a high cardiotoxic risk.
If possible, physicians should avoid anthracycline-based therapy for up to 24 weeks after stopping trastuzumab. If anthracyclines are used, the patient’s cardiac function should be monitored carefully. Concurrent use of anthracyclines and trastuzumab should be restricted to a well-controlled clinical trial setting with cardiac monitoring. Patients who have previously received anthracyclines are also at risk of cardiotoxicity with trastuzumab treatment, although the risk is lower than with concurrent use of trastuzumab and anthracyclines.
(Pre-)treatment with drugs affecting the function of the bone marrow (e.g. cytostatic agents, sulfonamides, chloramphenicol, phenytoin, amidopyrine derivates, antiretroviral drugs) might lead to severe hematopoetic disturbances. The dosage of doxorubicin has to be changed if necessary. The toxic effects of a doxorubicin therapy may be increased in a combination with other cytostatics (e.g. cytarabine, cisplatin, cyclophosphamide).
Doxorubicin hepatotoxicity may be enhanced by other hepatotoxic treatment modalities (e.g. 6-mercaptopurine).
Doxorubicin hydrochloride used in combination with ciclosporin might require dose-adjustment. At concomitant administration of ciclosporin, the clearance of doxorubicin is reduced by approximatley 50%. The doxorubicin AUC is increased by 55% and AUC of *doxorubicin*ol by 350%. With this combination a 40% dose reduction of doxorubicin is suggested. Ciclosporin inhibits, similar to verapamil, both CYP3A4 and P-glycoprotein, which might explain the interaction and resulting increase in adverse effects.
Cytochrome P-450 inhibitors (e.g. cimetidine) also reduce the plasma clearance and increase the AUC of doxorubicin, possibly by similar mechanisms as suggested for ciclosporin, and may thus lead to an increase in adverse effects. Conversely, cytochrome P-450 inducers (e.g. phenobarbital and rifampicin) decrease Doxorubicin plasma levels and may thus lead to a decrease in efficacy.
Doxorubicin is a potent, radiosensitizing agent (“radiosensitizer”), and recall phenomena induced by it may be life-threatening. Any preceding, concomitant or subsequent radiation therapy may increase the cardiotoxicity or hepatotoxicity of doxorubicin. This applies also to concomitant therapies with cardiotoxic or hepatotoxic drugs. If a doxorubicin therapy follows a treatment with cyclophosphamide, this may not only increase cardiotoxicity, but also aggravate haemorrhagic cystitis.
If paclitaxel is given before doxorubicin, this may result in an elevated plasma concentration of doxorubicin and/or its metabolites. There are data suggesting that this effect is lower if the anthracycline is given before paclitaxel.
Doxorubicin therapy may lead to increased serum uric acid, therefore dose adjustment of uric acid lowering agents may be necessary.
Doxorubicin may reduce oral bioavailability of digoxin.
The absorption of antiepileptic drugs (e.g. carbamazepine, phenytoin, valproate) is decreased after concomitant use of Doxorubicin hydrochloride.
During treatment with Doxorubicin hydrochloride patients should not be actively vaccinated and also avoid contact with recently polio vaccinated persons.
Doxorubicin binds to heparin and 5-fluorouracil. Precipitations and loss of action of both substances are therefore possible. See section 6.2 for more details.
Doxorubicin should not be given during pregnancy. In general cytostatics should only be administered during pregnancy on strict indication, and the benefit to the mother weighed against possible hazards to the foetus. In animal studies, doxorubicin has shown embryo-, feto- and teratogenic effects (see section 5.3).
Men and women should use effective contraception during and up to 6 months after treatment.
Doxorubicin has been reported to be excreted in human breast milk. A risk to the suckling child cannot be excluded. Since the use of doxorubicin during breast-feeding is contraindicated, breast-feeding should be discontinued during treatment with doxorubicin (see section 4.3).
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.
Treatment with doxorubicin often causes undesirable effects, and some of these effects are serious enough to entail careful monitoring of the patient. The frequency and kind of undesirable effects are influenced by the speed of administration and the dosage. Bone-marrow suppression is an acute dose limiting adverse effect, but is mostly transient. Clinical consequences of doxorubicin bone marrow/haematological toxicity may be fever, infections, sepsis/septicaemia, septic shock, haemorrhages, tissue hypoxia or death. Nausea and vomiting as well as alopecia are seen in almost all patients.
Intravesical administration may cause the following adverse reactions: hematuria, vesical and urethral irritation, stranguria and pollakisuria. These reactions are usually of moderate severity and of short duration.
Intravesical administration of doxorubicin may sometimes cause hemorrhagic cystitis; this may cause a decrease in bladder capacity.
Extravasation can lead to severe cellulitis, vesication, thrombophlebitis, lymphangitis and local tissue necrosis which may require surgical measures (including skin grafts).
Adverse reactions are listed below, by system organ class and absolute frequency (all reported events). Frequencies are defined as: very common (£ 1/10), common (£ 1/100, < 1/10); uncommon (^ 1/1,000, < 1/100); rare (^ 1/10,000, < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).
Very Common: Cardiotoxicity.
Common: Life-threatening congestive (dilatative) cardiomyopathy (after cumulative dose of 550 mg/m2).
Sinus tachycardia, ventricular tachycardia, tachyarrhythmia, supraventricular and ventricular extrasystoles, bradycardia, arrhythmia.
Asymptomatic reduction of the left ventricular ejection fraction.
Very rare: Unspecific ECG changes (ST changes, low voltage, long QT intervals).
Isolated cases of life-threatening arrhythmias, acute left ventricular failure, pericarditis, fatal pericarditis-myocarditis syndrome. Atrio ventricular block, bundle branch block.
Doxorubicin is cardiotoxic. The risk that the cardiotoxic side-effects become manifest is elevated during and after radiation therapy of the mediastinal region, after a pre-treatment with potentially cardiotoxic agents (e.g. anthracyclines, cyclophosphamide), and in elderly patients (over 60 years) and patients with manifest arterial hypertension. (See section 4.4). The cardiotoxic effect of doxorubicin can manifest in two types:
The acute-type side-effects occur mostly within the first 24 to 48 hours after initiation of therapy, are not dose-dependent and are characterized by the following symptoms: temporary arrhythmia (frequent), especially sinus tachycardia (frequent), and supraventricular and ventricular extrasystoles. They are (very rarely) characterized by unspecific ECG changes (ST changes, low voltage, and long QT intervals).
These changes are generally reversible, and their appearance is no contraindication for the repeated use of doxorubicin. However life-threatening arrhythmias may occur during, or few hours after the use of doxorubicin; in isolated cases, acute left ventricular failure, pericarditis or fatal pericarditis-myocarditis syndrome was reported.
The delayed-type side-effects are manifestations of dose-dependent cumulative organ toxicity, which is generally irreversible and often life-threatening. They often manifest as congestive (dilatative) cardiomyopathy with the signs of left ventricular failure within few months of the termination of therapy. Cardiotoxicity may, however, become manifest for the first time as late as several years after the termination of the therapy; its incidence increases with the total cumulative dose. (See section 4.4).
Very common: Myelosuppression including leukopenia, neutropenia, thrombocytopenia, anaemia.
Myelosuppression is one of the dose-limiting side-effects and may be serious. It manifests mainly in the decrease of the leukocyte count. Leucopenia was observed in almost 75% of the patients with an adequate bone marrow reserve who were treated with 60 mg/m² BSA every 21 days. Although less frequently, thrombocytopenia, neutropenia, and anaemia were also reported. Superinfections (very frequent) and haemorrhage were likewise observed in a connexion with the appearance of bone marrow suppression. Myelosuppression usually culminates 10 to 14 days after the administration of doxorubicin and subsides between the 21st and 28 day in most cases. If appearing, thrombocytopenia or anaemia occurs in the same period, but is usually less severe. (See section 4.4).
Not known: Conjunctivitis/keratitis, increased lachrymation.
Not known: Bronchospasm.
Very common: Gastrointestinal disturbance.
Diarrhoea.
Nausea and vomiting.
Mucositis, stomatitis, oesophagitis.
Common: Anorexia.
Uncommon: Gastrointestinal haemorrhage.
Abdominal pain.
Necrosis of the large intestine with massive haemorrhage and severe infections.
Very rare: Gastric erosions/ulcers.
Ulceration of the mucous membranes (mouth, pharynx, oesophagus, gastrointestinal tract).
Hyperpigmentation of the oral mucous membrane.
The emetogenic potential of doxorubicin is high; relatively severe nausea and vomiting occur in about 80% of the patients on the first day of therapy, but also later. (See section 4.4). Further, loss of appetite (frequent) and ulceration of the mucous membranes in the mouth and pharynx and in the oesophagus and gastrointestinal tract may appear. In severe forms, this can lead to infections. Diarrhoea (very frequent) can occur secondary to an inhibition of proliferation in the intestinal epithelium. Necrosis of the large intestine with massive haemorrhage and severe infections (uncommon) was reported in connection with combination therapies with cytarabine. After radiation therapy, oesophagitis (uncommon) may occur during a therapy with doxorubicin and may lead to oesophageal strictures.
Very common: Red coloration to the urine.
Common: Dysuria.
Chemical cystitis following intravesical administration (with dysuric complaints such as vesical irritation, urethral irritation, dysuria, stranguria, pollakisuria, haematuria, vesicular spasms, hemorrhagic cystitis).
Very rare: Acute renal failure (isolated cases).
Hyperuricaemia and subsequent uric acid nephropathy as a consequence of massive tumour lysis.
Very common: Alopecia (dose-dependent and in most cases reversible).
Reddening.
Photosensitization.
Common: Local hypersensitivity reactions in the field of radiation (“radiation recall reaction”).
Itching.
Rare: Urticaria.
Exanthema.
Hyperpigmentation of skin and nails.
Onycholysis.
Extravasation (may lead to severe cellulites, vesication, thrombophlebitis, lymphangitis, and local tissue necrosis).
Very rare: Acral erythemas.
Blistering.
Palmar-plantar erythrodysaesthesia.
Not known: Actinic keratosis
Not known: Arthralgia.
Endocrine disorders
Very rare: Amenorrhoea.
Hot flashes.
Oligospermia.
Azoospermia.
Very rare: Hyperuricaemia.
Uncommon: Sepsis/septicaemia.
Uncommon: Acute lymphocytic leukaemia.
Acute myelogenic leukaemia
Secondary leukaemia (sometimes) with or without a preleukaemic phase was observed in patients who were treated with anthracyclines (including doxorubicin). Secondary leukaemia occurs more frequently if the drug is given in combination with DNA-altering cytostatics (e.g. alkylating substances, platinum derivatives) or radiation therapy, if the patients had received an intense prior therapy with cytotoxic drugs, or if the dosage of anthracyclines was raised. Such leukaemias can occur after 1 to 7 years' latency.
Not known: Radiation damage (skin, lungs, oesophagus, gastrointestinal mucosa, heart) that is already healing may reappear following doxorubicin administration.
Common: Haemorrhage.
Very rare: Thromboembolism.
Very common: Fever.
Uncommon: Dehydration.
Rare: Shivering.
Dizziness.
Injection site reactions (local erythematous reactions along the vein, pain, phlebitis, phlebosclerosis).
Rare: Anaphylactic reactions.
Not known: Hepatotoxicity (sometimes progressing to cirrhosis).
Transient increase of liver enzymes.
Doxorubicin must not be mixed with heparin, as this will result in precipitation. Until detailed compatibility information about miscibility is available, Doxorubicin should not be mixed with other medicinal products than those mentioned under section 6.6.
Incompatibilities with the following products have been reported: Aminophyllin, cephalotin, dexamethasone, fluorouracil, hydrocortisone.
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