Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2016 Publisher: Accord Healthcare Limited, Sage House, 319, Pinner Road, North Harrow, Middlesex, HA1 4HF, United Kingdom
Hypersensitivity to the active substance doxorubicin hydrochloride or to any of the excipients.
Contraindications for intravenous administration:
Contraindications for intravesical administration:
Doxorubicin may not be given during pregnancy and lactation (see section 4.6).
Doxorubicin Injection should be administered only under the supervision of a qualified physician experienced in cytotoxic therapy for i.v. or intravesical use. Doxorubicin hydrochloride may potentiate the toxicity of other anticancer therapies. 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.
Initial treatment with doxorubicin requires close observation of the patient and extensive laboratory monitoring. It could be recommended therefore, that patients be hospitalised at least during the first phase of treatment. Doxorubicin may cause infertility during the time of drug administration.
Patients should recover from the acute toxicities of prior cytotoxic treatment (such as stomatitis, neutropenia. thrombocytopenia. and generalized infections) before beginning treatment with doxorubicin.
Before or during treatment with doxorubicin the following monitoring examinations are recommended (how often these examinations are done will depend on the general condition, the dose and the concomitant medication):
Prior to start of the treatment it is recommended to measure the liver function by using conventional tests such as AST, ALT, ALP and bilirubin as well as the renal function, (see section 4.4).
Analysis of LVEF using ultrasound or heart scintigraphy should be performed in order to optimise the heart condition of the patient. This control should be made prior to the start of the treatment and after each accumulated dose of approximately 100 mg/m² (see section 4.4).
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 symptoms generally indicate acute transient toxicity. These effects do not usually predict subsequent development of delayed cardiotoxicity, and are generally not a consideration for discontinuation of doxorubicin treatment. Flattening and widening of the QRS-complex beyond normal limits may indicate doxorubicin hydrochloride-induced cardiomyopathy. As a rule, in patients with a normal LVEF baseline value (=50%), a 10% decrease of absolute value or dropping below the 50% threshold indicates cardiac dysfunction and in such situation treatment with doxorubicin hydrochloride should be carefully considered.
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 left ventricular ejection fraction (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.
The probability of developing CHF, estimated around 1% to 2% at a cumulative dose of 300 mg/m² 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. If the patient has other potential risk factors of cardiotoxicity (history of cardiovascular disease, previous therapy with other anthracyclines or anthracenediones, prior or concomitant radiotherapy to the mediastinal/pericardial area, and concomitant use of medicinal products with the ability to suppress cardiac contractility, including cyclophosphamide and 5-fluoruracil), cardiotoxiciry with doxorubicin may occur at lower cumulative doses and cardiac function should be carefully monitored.
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.
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).
Doxorubicin may produce myelosuppression (See Section 4.8) Haetnatologic 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. Dose reduction or increase of the dose interval should be considered if the blood values are not normalised. 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 with or without a preleukaemic phase, has been reported in patients treated with anthracyclines (including doxorubicin). Secondary leukaemia is more common when such medicinal products are given in combination with other DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic medicinal products or when doses of the anthracyclines have been escalated. These leukaemias can have a 1 to 3 year latency period.
Intravesical administration of doxorubicin may cause symptoms of chemical cystitis (i.e. dysuria, urinary frequency, 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).
Tile intravesical route of administration should not be attempted in patients with, invasive tumours that have penetrated the bladder wall, urinary tract infections, and inflammatory conditions of the bladder.
During therapy serum uric acid may increase. In case of hyperuricemia antihyperuricemic therapy should be initiated.
In patients with severely impaired renal function dose reductions may be necessary (see section 4.2).
An antiemetic prophylaxis is recommended.
Note: Doxorubicin should not be used in the presence in inflammations, ulcerations or diarrhoea.
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.
Radiation-induced toxicities (myocardium, mucosa, skin and liver) have also been reported. Special caution is mandatory for patients who have had radiotherapy previously, are having radiotherapy concurrently or are planning to have radiotherapy. These patients are at special risk of local reactions in the radiation field (recall phenomenon) if doxorubicin hydrochloride is used. Severe, sometimes fatal, hepatotoxicity (liver damage) has been reported in this connection. Prior radiation to the mediastinum increases the cardiotoxicity of doxorubicin. The cumulative dose of 400 mg/m² must not be exceeded especially in this case.
Doxorubicin can have genotoxic effects. Doxorubicin may cause infertility during the time of drug administration. In women, doxorubicin may cause amenorrhea. Although ovulation and menstruation appear to return after termination of therapy, premature menopause can occur. Women should not become pregnant during and up to 6 months after treatment.
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 measures. Also are advised not to father a child during and up to 6 months after treatment and to seek advice on cryo-conservation (or cryo-preservation) of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with doxorubicin.
Doxorubicin may potentiate the toxicity of other anticancer therapies. Exacerbation of cyclophosphamide-induced haemorrhagic cystitis and enhanced hepatotoxicity of 6-mercaptopurine have 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).
This medicinal product is generally not recommended in combination with live, attenuated vaccines. Contact to persons recently vaccinated against polio should be avoided. Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including doxorubicin, may result in serious or fatal infections. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
The systemic clearance of doxorubicin is reduced in obese patients (i.e. >130% ideal body weight) (see section 4.2).
Doxorubicin may induce hyperuricaemia as a consequence of the extensive purine catabolism that accompanies drug-induced rapid lysis of neoplastic cells (tumour-lysis syndrome) (see section 4.8). 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.
A stinging or burning sensation at the site of administration may signify a small degree of extravasation. 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.
Doxorubicin hydrochloride may impart a red colour to the urine. Patients should be cautioned that this does not pose any health hazards.
Dosage should not be repeated in the presence or development of bone marrow depression or buccal ulceration. The latter may be preceded by premonitory buccal burning sensations and repetition in the presence of this symptom is not advised.
Doxorubicin cardiotoxicity is enhanced by previous or concurrent use of other anthracyclines, or other potentially cardiotoxic drugs (e.g. 5-fluorouracile, 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. Trastuzumab and anthracyclines should not be used in combination for the time being, except in well controlled clinical studies where the cardiac function is monitored. When anthracyclines are used after the end of a therapy with trastuzumab, an elevated risk of cardiotoxicity may result. The half-life of trastuzumab is approximately 28-38 days and may persist in the circulation for up to 27 weeks. If possible, there should be a sufficiently long interval (up to 27 weeks) between the end of a therapy with trastuzumab and the beginning of the anthracycline therapy. Careful monitoring of the cardiac function is imperative.
Doxorubicin hepatotoxicity may be enhanced by other hepatotoxic treatment modalities (e.g. 6-mercaptopurine).
Doxorubicin undergoes metabolism via Cytochrome P450 (CYP450) and is a substrate for the Pgp transporter, Concomitant administration of inhibitors of CYP450 and/or Pgp might lead to increased plasma concentrations of doxorubicin and thereby increased toxicity. Conversely, concomitant administration of inducers of CYP450, such as rifampicin and barbiturates, might decrease plasma concentrations of doxorubicin and reduce efficacy.
Ciclosporin, an inhibitor of CYP3A4 and Pgp, increased the AUC of doxorubicin and doxorubicinol by 55% and 350%, respectively. The combination might require dose adjustment. Cimetidine has also been shown to reduce the plasma clearance and increase the AUC of doxorubicin.
Paclitaxel administered shortly before doxorubicin may decrease clearance and increase plasma concentrations of doxorubicin. Some data indicate that this interaction is less pronounced when doxorubicin is administered before paclitaxel.
Barbiturates may lead to an accelerated plasma clearance of doxorubicin, while the concomitant administration of phenytoin may result in lower plasma phenytoin levels.
Elevated serum doxorubicin concentrations were reported after the concomitant administration of doxorubicin and ritonavir.
The toxic effects of a doxorubicin therapy may be increased in a combination with other cytostatics (e.g. cytarabine, cisplatin, and cyclophosphamide). Necroses of the large intestine with massive haemorrhage and severe infections may occur in connection with combination therapies with cytarabine.
Clozapine may increase the risk and severity of the hematologic toxicity of Doxorubicin.
Marked nephrotoxicity of Amphotericin B can occur during doxorubicin therapy.
As doxorubicin is rapidly metabolised and predominantly eliminated by the biliary system, the concomitant administration of known hepatotoxic chemotherapeutic agents (e.g. mercaptopurine, methotrexate, streptozocin) could potentially increase the toxicity of doxorubicin as a result of reduced hepatic clearance of the drug. Dosing of doxorubicin must be modified if concomitant therapy with hepatotoxic drugs is mandatory.
Doxorubicin is a potent, radio sensitizing agent (“radio sensitizer”), 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.
Doxorubicin may cause exacerbations of hemorrhagic cystitis caused by previous cyclophosphamide therapy.
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.
During treatment with Doxorubicin patients should not be actively vaccinated and also avoid contact with recently polio vaccinated persons.
In a clinical study, an increase in doxorubicin AUC of 21% was observed when given with sorafenib 400 mg twice daily. The clinical significance of this finding is unknown.
Doxorubicin has been found in foetal tissue (liver, kidney, lungs) at concentrations several times those in maternal plasma indicating that it does pass the placenta. In animals studies, doxorubicin has shown embryo-, foeto- and teratogenic effects (see section 5.3) and also proved to be highly mutagenic in the Ames test. Cytostatics should only be administered during pregnancy on strict indication, and the benefit to the mother weighed against possible hazards to the foetus.
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 hydrochloride during breast-feeding is contraindicated, breast-feeding should be discontinued during treatment with doxorubicin (see section 4.3).
For safety reasons, men wanting a baby should preserve unexposed sperm prior to treatment with doxorubicin and abstain from engendering a child during and 6 months after therapy. Women with childbearing potential have to use effective contraception during doxorubicin therapy and 6 months after treatment.
Due to the frequent occurrence of nausea and vomiting, driving cars and operation of machinery should be discouraged.
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.
The following adverse events have been reported in association with doxorubicin therapy:
Frequencies are defined using the following convention: 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).
Common: Sepsis, septiciaemia
Rare: Secondary acute myeloid leukaemia when in combination with anti-neoplastic drugs which damage the DNA. (see section 4.4), tumour lysis syndrome
Not known: Acute lymphocytic leukaemia and acute myelogenous leukaemia.
Common: Bone-marrow suppression, leucopenia and neutropenia
Not known: Thrombocytopenia, anaemia
Rare: Anaphylactic reactions
Common: Anorexia
Uncommon: dehydration
Not known: Hyperuricaemia (see section 4.4)
Rare: Conjunctivitis
Not known: Keratitis and lacrimation
Common: Cardiomyopathy, (2%: e.g. decrease of LVEF. dyspnoea);
Not known: Arrhythmia, asymptomatic reduction in left ventricular ejection fraction and congestive heart failure. Cardiotoxicity may be manifested in tachycardia including supraventricular tachycardia and ECG changes. (e.g. sinus tachycardia, tachyarrhythmia, ventricular tachycardia, bradycardia, atrio-ventricular and bundle branch block). Routine ECG monitoring is recommended and caution should be exercised in patients with impaired cardiac function.
Uncommon: Phlebitis
Not known: Thrombophlebitis; Thromboembolism; hot flushes, shock
Common: Nausea: vomiting; mucositis/stomatitis; diarrhoea,
Uncommon: Gastrointestinal haemorrhage, abdominal pain: ulceration of the mucous membranes in the mouth, pharynx, oesophagus and gastrointestinal tract may appear in combination with cytarabine, ulceration and necrosis of the colon, in particular the caecum, have been reported (see section 4.5)
Not known: Oesophagitis,gastric erosions, colitis hyperpigmentation of oral mucosa
Not known: Bronchospasm, radiation pneumonitis
Common: Alopecia
Uncommon: Itching, local hypersensitivity reaction of the field of radiation (recall phenomenon)
Rare: Urticaria, exanthema, local erythematous reactions along the vein which was used for the injection, hyperpigmentation of skin and nails, onycholysis
Not known: Tissue hypoxia, acral erythema and plantar-palmar dysaesthesia, photosensitivity
Common: Local reactions (chemical cystitis) might occur at intravesical treatment (i.e. dysuria, urinary frequency, nocturia, stranguria, haematuria, necrosis of the bladder wall)
Not known: Acute renal failure
Not known: Amenorrhoea, oligospermia, azoospermia (see section 4.4)
Rare: Anaphylactic reactions, shivering, fever, dizziness
Not known: A stinging or burning sensation at the administration site (see section 4.4) Malaise/weakness, asthenia, chills
Not known: Hepatotoxicity, transient increase of liver enzymes
Not known: Extravasation can lead to severe cellulitis, vesication and local tissue necrosis which may require surgical measures (including skin grafts) (see section 4.4)
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.
Doxorubicin should not be mixed with heparin, as a precipitate may form and it should not be mixed with 5-fluorouracil as degradation may occur. Prolonged contact with any solution of an alkaline pH should be avoided, as it will result in hydrolysis of the drug.
Until detailed compatibility information about miscibility is available, Doxorubicin should not be mixed with other medicinal products than those mentioned under section 6.6.
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