This information is intended for use by health professionals
Intravenous administration:The dosage of doxorubicin depends on dosage regimen, general status and previous treatment of the patient. Dose schedule of doxorubicin hydrochloride administration could vary according to indication (solid tumors or acute leukemia) and according to its use in the specific treatment regimen (as single agent or in combination with other cytotoxic agents or as a part of multidisciplinary procedures that include combination of chemotherapy, surgical procedure and radiotherapy and hormonal treatment).
MonotherapyDosage is usually calculated on the basis of body surface area (mg/m2). On this basis, a dose of 60 - 75 mg/m2 body surface area is recommended every three weeks when doxorubicin is used as a single agent.
Combination regimenWhen doxorubicin hydrochloride is administered in combination with other antitumour agents with overlapping toxicity, such as high-dose i.v. cyclophosphamide or related anthracycline compounds such as daunorubicin, idarubicin and/or epirubicin, the dosage of doxorubicin should be reduced to 30-60 mg/m2 every 3 4 weeks. In patients, who cannot receive the full dose (eg. in case of immunosuppression, old age), an alternative dosage is 15-20 mg/m2 body surface per week.
Intravesical administration:Doxorubicin may be used by intravesical instillation for the treatment of superficial bladder carcinoma or in prophylaxis of tumor recurrence after transurethral resection (T.U.R) in patients with high risk of recurrence. The recommended doxorubicin hydrochloride dose for local intravesical treatment of superficial bladder tumors is instillation of 30-50 mg in 25-50 ml of sodium chloride 9 mg/ml (0.9%) solution for injection. The optimal concentration is about 1 mg/ml. Generally the solution should be retained intravesically for 1 to 2 hours. During this period the patient should be turned 90° every 15 minutes. The patient should not drink fluids for 12 hours prior to the treatment to avoid undesired dilution with urine (this should reduce the production of urine to about 50 ml/h). The instillation may be repeated with an interval of 1 week to 1 month, dependent on whether the treatment is therapeutic or prophylactic.
Patients with impaired hepatic functionSince doxorubicin hydrochloride is mainly excreted via liver and bile, the elimination of the medicinal product may be decreased in patients with hepatic function impairment or bile flow obstruction and this could result in severe secondary effects. General dose adjustment recommendations in patients with hepatic function impairment are based on serum bilirubin concentration:
|Serum Bilirubin||Recommended Dose|
|20-50 micro mole/L||½ normal dose|
|> 50 micro mol/L||¼ normal dose|
Patients with impaired renal functionIn patients with renal insufficiency (GFR < 10 ml/min), only 75% of the planned dose should be given.In order to avoid cardiomyopathy, it is recommended that the cumulative total lifetime dose of Doxorubicin (including related drugs such as daunorubicin) should not exceed 450-550mg/m2 body surface area. If a patient with concomitant heart disease receives mediastinal and/or heart irradiation, prior treatment with alkylating agents, and high-risk patients (with arterial hypertension since > 5 years, with prior coronary, valvular or myocardial heart damage, age over 70 years) with a maximum total dose of 400 mg/m2 body surface area should not be exceeded and the cardiac function of these patients should be monitored (see section 4.4).
Dose in childrenDosage in children may need to be reduced, please refer to treatment protocols and the specialist literature.
Obese patientsA reduced starting dose or prolonged dose interval might need to be considered in obese patients (see section 4.4).
Contraindications for intravenous administration:• Hypersensitivity to anthracendiones or other anthracyclines• Marked persisting myelosuppression and/or severe stomatitis induced by previous treatment with other cytotoxic agents and/or radiation • Previous treatment with maximum cumulative doses of doxorubicin and/or other anthracyclines (e.g. daunorubicin, epirubicin, idarubicin) and anthracenediones (see section 4.4).• Generalized infection• Severe impaired liver function• Severe arrhythmias, heart failure, previous myocardial infarction, acute inflammatory heart disease • Increased haemorrhagic tendency• Breast-feeding (see section 4.6)
Contraindications for intravesical administration:• Invasive tumors that have penetrated the bladder (beyond T1)• Bladder inflammation• Haematuria• Difficult urinary catheter introduction (e.g. in large intravesical tumors)• Breast-feeding (see section 4.6)• Urinary tract infectionsDoxorubicin may not be given during pregnancy and lactation (see section 4.6).
Treatment controlPrior 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).
Control of the left ventricular functionAnalysis 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).
Cardiac FunctionCardiotoxicity 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.
Liver functionThe 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).
Haematologic ToxicityDoxorubicin 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 leukaemiaSecondary 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 administrationIntravesical 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.
Control of serum uric acid: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).
Gastrointestinal effectsAn antiemetic prophylaxis is recommended. Note: Doxorubicin should not be used in the presence in inflammations, ulcerations or diarrhoea.
ExtravasationPerivenous 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.
RadiotherapyRadiation-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.
InfertilityDoxorubicin 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.
Anticancer therapies: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).
Vaccines: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.
Other:The systemic clearance of doxorubicin is reduced in obese patients (i.e. >130% ideal body weight) (see section 4.2).
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) (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.
PregnancyDoxorubicin 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.
LactationDoxorubicin 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).
FertilityFor 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.
|Infections and infestations||Sepsis, septiciaemia|
|Neoplasms benign and malignant||Secondary acute myeloid leukaemia when in combination with anti-neoplastic drugs which damage the DNA. (see section 4.4), tumour lysis syndrome||Acute lymphocytic leukaemia and acute myelogenous leukaemia.|
|Blood and lymphatic system disorders:||bone-marrow suppression, leucopenia and neutropenia||Thrombocytopenia, anaemia|
|Immune System disorders||Anaphylactic reactions|
|Metabolism and Nutrition Disorders||Anorexia||dehydration||hyperuricaemia (see section 4.4)|
|Eye disorders||Conjunctivitis||keratitis and lacrimation|
|Cardiac disorders||cardiomyopathy, (2%: e.g. decrease of LVEF. dyspnoea);||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.|
|Vascular disorders||phlebitis||Thrombophlebitis; Thromboembolism; hot flushes, shock|
|Gastrointestinal disorders||nausea: vomiting; mucositis/stomatitis; diarrhoea,||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)||Oesophagitis,gastric erosions, colitis hyperpigmentation of oral mucosa|
|Respiratory, thoracic and mediastinal disorders||Bronchospasm, radiation pneumonitis|
|Skin and subcutaneous tissue disorder's:||alopecia||Itching, local hypersensitivity reaction of the field of radiation (recall phenomenon)||urticaria, exanthema, local erythematous reactions along the vein which was used for the injection, hyperpigmentation of skin and nails, onycholysis||tissue hypoxia, acral erythema and plantar-palmar dysaesthesia, photosensitivity|
|Renal and urinary disorders||local reactions (chemical cystitis) might occur at intravesical treatment (i.e. dysuria, urinary frequency, nocturia, stranguria, haematuria, necrosis of the bladder wall)||acute renal failure,|
|Reproductive system and breast disorders||Amenorrhoea, oligospermia, azoospermia (see section 4.4)|
|General disorders and administration site conditions:||anaphylactic reactions, shivering, fever, dizziness||A stinging or burning sensation at the administration site (see section 4.4) Malaise/weakness, asthenia, chills|
|Hepatobiliar disorders||Hepatotoxicity, transient increase of liver enzymes,|
|Surgical and medical procedure||Extravasation can lead to severe cellulitis, vesication and local tissue necrosis which may require surgical measures (including skin grafts) (see section 4.4)|
DistributionFollowing intravenous injection, doxorubicin is rapidly cleared from the blood and widely distributed into tissues including lungs, liver, heart, spleen, lymph nodes, bone marrow and kidneys. The volume of distribution is about 25 litres. The degree of protein binding is 60-70%.Doxorubicin does not cross the blood-brain barrier, although higher levels in liquor may be reached in the presence of brain metastases or leukemic cerebral dissemination. Doxorubicin is rapidly distributed into the ascites, where it reaches higher concentrations than in plasma. Doxorubicin is secreted into breast milk.
EliminationThe elimination of doxorubicin from the blood is triphasic with mean half-lives of 12 minutes (distribution), 3.3 hours and about 30 hours. Doxorubicin undergoes rapid metabolism in the liver. The main metabolite is the pharmacologically active doxorubicinol. Other metabolites are deoxyrubicin aglycone, glucuronide and sulphate conjugate. About 40 to 50% of a dose is excreted in bile within 7 days, of which about half is excreted as unchanged drug and the rest as metabolites. Only 5-15% of the administered dose is eliminated in urine.
Special populationsAs the elimination of doxorubicin is mainly hepatic, impairment of liver function results in slower excretion, and consequently, increased retention and accumulation in plasma and tissues. Dose reduction is generally advised.Although renal excretion is a minor elimination pathway for doxorubicin, severe renal impairment might affect total elimination and require dose reduction.In a study in obese patients (>130% of ideal bodyweight) the doxorubicin clearance was reduced and the half life increased compared with a normal-weight control group. Dose adjustments might be necessary in the obese. In cancer patients, doxorubicin is reduced to adriamycinol, which is an active cytotoxic agent. This reduction appears to be catalysed by cytoplasmic nadph-dependent aldo-keto reductases that are found in all tissues and play an important role in determining the overall pharmacokinetics of doxorubicin. Microsomal glycosidases present in most tissues split doxorubicin and adriamycinol into inactive aglycones. The aglycones may then undergo 0-demethylation, followed by conjugation to sulphate or glucuronide esters, and excretion in the bile.
Preparation1. Personnel should be trained in good technique for handling.2. Pregnant staff should be excluded from working with this drug.3. Personnel handling doxorubicin should wear protective clothing: goggles, gowns, disposable gloves and masks.4. All items used for administration or cleaning, including gloves, should be placed in high risk waste disposal bags for high temperature (700°C) incineration.5. All cleaning materials should be disposed of as indicated previously.6. Always wash hands after removing gloves.
Contamination1. In case of contact with skin or mucous membrane, thoroughly wash the affected area with soap and water or sodium bicarbonate solution. However, do not graze the skin by using a scrubbing brush. A bland cream may be used to treat transient stinging of skin.2. In case of contact with eye(s), hold back the eyelid(s) and flush the affected eyes with copious amounts of water for at least 15 minutes or normal sodium chloride 9 mg/ml (0.9%) solution for injection. Then seek medical evaluation by a physician or eye specialist.3. In the event of spillage or leakage treat with 1% sodium hypochlorite solution or most simply with phosphate buffer (pH>8) until solution is destained. Use a cloth/sponge kept in the designate area. Rinse twice with water. Put all cloths into a plastic bag and seal for incineration.
Administration:Intravenous (IV) administration of Doxorubicin must be very careful and it is advisable to give the medicinal product via the tubing of a freely running intravenous sodium chloride 9 mg/ml (0.9%) or dextrose 50 mg/ml (5%) within 2 to 15 minutes. This method minimizes the risk of thrombosis development and perivenous extravasation that result in severe cellulitis, vesication and tissue necrosis, and also provides rinse of the vein after the administration.Remnants of the medicinal product as well as all materials that have been used for dilution and administration must be destroyed according to hospital standard procedures applicable to cytotoxic agents with due regard to current laws related to the disposal of hazardous waste.
DisposalSingle use only. Any unused product or waste material should be disposed of in accordance with local requirements. Observe guidelines for handling cytotoxic drugs.