erapies (see precautions , drug interactions ). cardiac function cardiotoxicity is a known risk of anthracycline treatment. anthracycline-induced cardiotoxicity may be manifested by early (or acute) or late (delayed) events. early cardiotoxicity of doxorubicin consists mainly of sinus tachycardia and/or electrocardiogram (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, are rarely of clinical importance, and are generally not considered an indication for the suspension of doxorubicin treatment. 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 a reduction in lvef and/or signs and symptoms of congestive heart failure (chf) such as tachycardia, dyspnea, pulmonary edema, dependent edema, 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. the probability of developing impaired myocardial function, based on a combined index of signs, symptoms and decline in left ventricular ejection fraction (lvef) is estimated to be 1 to 2% at a total cumulative dose of 300 mg/m 2 of doxorubicin, 3 to 5% at a dose of 400 mg/m 2 , 5 to 8% at a dose of 450 mg/m 2 and 6 to 20% at a dose of 500 mg/m 2 given in a schedule of a bolus injection once every 3 weeks. in a retrospective review, the probability of developing congestive heart failure was reported to be 5/168 (3%) at a cumulative dose of 430 mg/m 2 of doxorubicin, 8/110 (7%) at 575 mg/m 2 , and 3/14 (21%) at 728 mg/m 2 . in a prospective study of doxorubicin in combination with cyclophosphamide, fluorouracil and/or vincristine in patients with breast cancer or small cell lung cancer, the probability of chf at various cumulative doses of doxorubicin was 1.5% at 300 mg/m 2 , 4.9% at 400 mg/m 2 , 7.7% at 450 mg/m 2 and 20.5% at 500 mg/m 2 . the risk of developing chf increases rapidly with increasing total cumulative doses of doxorubicin in excess of 400 mg/m 2 . cardiotoxicity may occur at lower doses in patients with prior mediastinal/pericardial irradiation, concomitant use of other cardiotoxic drugs, doxorubicin exposure at an early age, and advanced age. data also suggest that pre-existing heart disease is a co-factor for increased risk of doxorubicin cardiotoxicity. in such cases, cardiac toxicity may occur at doses lower than the recommended cumulative dose of doxorubicin. studies have suggested that concomitant administration of doxorubicin and calcium channel entry blockers or cardiotoxic drugs, especially those with long half-lives, e.g. trastuzumab, may increase the risk of doxorubicin cardiotoxicity (see precautions, general , dosage and administration ). the total dose of doxorubicin administered to the individual patient should also take into account previous or concomitant therapy with related compounds such as daunorubicin, idarubicin and mitoxantrone. although not formally tested, it is probable that the toxicity of doxorubicin and other anthracyclines or anthracenediones is additive. cardiomyopathy and/or congestive heart failure may be encountered several months or years after discontinuation of doxorubicin therapy. the risk of acute manifestations of doxorubicin cardiotoxicity in pediatric patients may be as much or lower than in adults. pediatric patients appear to be at particular risk for developing delayed cardiac toxicity in that doxorubicin-induced cardiomyopathy impairs myocardial growth as pediatric patients mature, subsequently leading to possible development of congestive heart failure during early adulthood. as many as 40% of pediatric patients may have subclinical cardiac dysfunction and 5 to 10% of pediatric patients may develop congestive heart failure on long term follow-up. this late cardiac toxicity may be related to the dose of doxorubicin. the longer the length of follow-up, the greater the increase in the detection rate. treatment of doxorubicin-induced congestive heart failure includes the use of digitalis, diuretics, after load reducers such as angiotensin i converting enzyme (ace) inhibitors, low salt diet, and bed rest. such intervention may relieve symptoms and improve the functional status of the patient. monitoring cardiac function the risk of serious cardiac impairment 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 preferred method for assessment of cardiac function is evaluation of lvef measured by multi-gated radionuclide angiography (muga) or echocardiography (echo). an ecg may also be done. a baseline cardiac evaluation with a muga scan or an echo is recommended, especially in patients with risk factors for increased cardiac toxicity. repeated muga or echo determinations of lvef should be performed, particularly with higher, cumulative anthracycline doses. the technique used for assessment should be consistent through follow-up. in patients with risk factors, particularly prior anthracycline or anthracenedione use, the monitoring of cardiac function must be particularly strict and the risk-benefit of continuing treatment with doxorubicin in patients with impaired cardiac function must be carefully evaluated. endomyocardial biopsy is recognized as the most sensitive diagnostic tool to detect anthracycline-induced cardiomyopathy; however, this invasive examination is not practically performed on a routine basis. ecg changes such as dysrhythmias, a reduction of the qrs voltage, or a prolongation beyond normal limits of the systolic time interval may be indicative of anthracycline-induced cardiomyopathy, but ecg is not a sensitive or specific method for following anthracycline-related cardiotoxicity. pediatric patients are at increased risk for developing delayed cardiotoxicity following doxorubicin administration and therefore a follow-up cardiac evaluation is recommended periodically to monitor for this delayed cardiotoxicity. in adults, a 10% decline in lvef to below the lower limit of normal or an absolute lvef of 45%, or a 20% decline in lvef at any level is indicative of deterioration in cardiac function. in pediatric patients, deterioration in cardiac function during or after the completion of therapy with doxorubicin is indicated by a drop in fractional shortening (fs) by an absolute value of ≥ 10 percentile units or below 29%, and a decline in lvef of 10 percentile units or an lvef below 55%. in general, if test results indicate deterioration in cardiac function associated with doxorubicin, the benefit of continued therapy should be carefully evaluated against the risk of producing irreversible cardiac damage. acute life-threatening arrhythmias have been reported to occur during or within a few hours after doxorubicin administration. hematologic toxicity as with other cytotoxic agents, doxorubicin may produce myelosuppression. myelosuppression requires careful monitoring. total and differential wbc, red blood cell (rbc), and platelet counts should be assessed before and during each cycle of therapy with doxorubicin. a dose-dependent, reversible leukopenia and/or granulocytopenia (neutropenia) are the predominant manifestations of doxorubicin hematologic toxicity and is the most common acute dose-limiting toxicities of this drug. with the recommended dose schedule, leukopenia is usually transient, reaching its nadir 10 to 14 days after treatment with recovery usually occurring by the 21st day. thrombocytopenia and anemia may also occur. clinical consequences of severe myelosuppression include fever, infections, sepsis/septicemia, septic shock, hemorrhage, tissue hypoxia, or death. secondary leukemia the occurrence of secondary aml or mds has been reported most commonly in patients treated with chemotherapy regimens containing anthracyclines (including doxorubicin) and dna-damaging antineoplastic agents, in combination with radiotherapy, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated. such cases generally have a 1 to 3 year latency period. the rate of developing secondary aml or mds has been estimated in an analysis of 8,563 patients with early breast cancer treated in 6 studies conducted by the national surgical adjuvant breast and bowel project (nsabp), including nsabp b-15. patients in these studies received standard doses of doxorubicin and standard or escalated doses of cyclophosphamide (ac) adjuvant chemotherapy and were followed for 61,810 patient years. among 4,483 such patients who received conventional doses of ac, 11 cases of aml or mds were identified, for an incidence of 0.32 cases per 1,000 patient years (95% cl, 0.16 to 0.57) and a cumulative incidence at 5 years of 0.21% (95% cl, 0.11 to 0.41%). in another analysis of 1,474 patients with breast cancer who received adjuvant treatment with doxorubicin-containing regimens in clinical trials conducted at university of texas m.d. anderson cancer center, the incidence was estimated at 1.5% at 10 years. in both experiences, patients who received regimens with higher cyclophosphamide dosages, who received radiotherapy, or who were aged 50 or older had an increased risk of secondary aml or mds. pediatric patients are also at risk of developing secondary aml. effects at site of injection phlebosclerosis may result from an injection into a small vessel or from repeated injections into the same vein. following the recommended administration procedures may minimize the risk of phlebitis/thrombophlebitis at the injection site (see dosage and administration , instruction for use/handling ). extravasation on intravenous administration of doxorubicin, extravasation may occur with or without an accompanying stinging or burning sensation, even if blood returns well on aspiration of the infusion needle. if any signs or symptoms of extravasation have occurred, the injection or infusion should be immediately terminated and restarted in another vein (see dosage and administration ). hepatic impairment since metabolism and excretion of doxorubicin occurs predominantly by the hepatobiliary route, toxicity of recommended doses of doxorubicin can be enhanced by hepatic impairment; therefore, prior to individual dosing, evaluation of hepatic function is recommended using conventional laboratory tests such as sgot, sgpt, alkaline phosphatase, and bilirubin (see dosage and administration ). immunosuppressant effects/increased susceptibility to infections 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. pregnancy category d doxorubicin can cause fetal harm when administered to a pregnant woman. doxorubicin was teratogenic and embryotoxic at doses of 0.8 mg/kg/day (about 1/13 the recommended human dose on a body surface area basis) when administered during the period of organogenesis in rats. teratogenicity and embryotoxicity were also seen using discrete periods of treatment. the most susceptible was the 6- to 9-day gestation period at doses of 1.25 mg/kg/day and greater. characteristic malformations included esophageal and intestinal atresia, tracheoesophageal fistula, hypoplasia of the urinary bladder and cardiovascular anomalies. doxorubicin was embryotoxic (increase in embryofetal deaths) and abortifacient at 0.4 mg/kg/day (about 1/14 the recommended human dose on a body surface area basis) in rabbits when administered during the period of organogenesis. there are no adequate and well-controlled studies in pregnant women. if doxorubicin is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. women of childbearing age should be advised to avoid becoming pregnant.

ee precautions , drug interactions ).

ested by a reduction in lvef and/or signs and symptoms of congestive heart failure (chf) such as tachycardia, dyspnea, pulmonary edema, dependent edema, 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. the probability of developing impaired myocardial function, based on a combined index of signs, symptoms and decline in left ventricular ejection fraction (lvef) is estimated to be 1 to 2% at a total cumulative dose of 300 mg/m 2 of doxorubicin, 3 to 5% at a dose of 400 mg/m 2 , 5 to 8% at a dose of 450 mg/m 2 and 6 to 20% at a dose of 500 mg/m 2 given in a schedule of a bolus injection once every 3 weeks. in a retrospective review, the probability of developing congestive heart failure was reported to be 5/168 (3%) at a cumulative dose of 430 mg/m 2 of doxorubicin, 8/110 (7%) at 575 mg/m 2 , and 3/14 (21%) at 728 mg/m 2 . in a prospective study of doxorubicin in combination with cyclophosphamide, fluorouracil and/or vincristine in patients with breast cancer or small cell lung cancer, the probability of chf at various cumulative doses of doxorubicin was 1.5% at 300 mg/m 2 , 4.9% at 400 mg/m 2 , 7.7% at 450 mg/m 2 and 20.5% at 500 mg/m 2 . the risk of developing chf increases rapidly with increasing total cumulative doses of doxorubicin in excess of 400 mg/m 2 . cardiotoxicity may occur at lower doses in patients with prior mediastinal/pericardial irradiation, concomitant use of other cardiotoxic drugs, doxorubicin exposure at an early age, and advanced age. data also suggest that pre-existing heart disease is a co-factor for increased risk of doxorubicin cardiotoxicity. in such cases, cardiac toxicity may occur at doses lower than the recommended cumulative dose of doxorubicin. studies have suggested that concomitant administration of doxorubicin and calcium channel entry blockers or cardiotoxic drugs, especially those with long half-lives, e.g. trastuzumab, may increase the risk of doxorubicin cardiotoxicity (see precautions, general , dosage and administration ). the total dose of doxorubicin administered to the individual patient should also take into account previous or concomitant therapy with related compounds such as daunorubicin, idarubicin and mitoxantrone. although not formally tested, it is probable that the toxicity of doxorubicin and other anthracyclines or anthracenediones is additive. cardiomyopathy and/or congestive heart failure may be encountered several months or years after discontinuation of doxorubicin therapy. the risk of acute manifestations of doxorubicin cardiotoxicity in pediatric patients may be as much or lower than in adults. pediatric patients appear to be at particular risk for developing delayed cardiac toxicity in that doxorubicin-induced cardiomyopathy impairs myocardial growth as pediatric patients mature, subsequently leading to possible development of congestive heart failure during early adulthood. as many as 40% of pediatric patients may have subclinical cardiac dysfunction and 5 to 10% of pediatric patients may develop congestive heart failure on long term follow-up. this late cardiac toxicity may be related to the dose of doxorubicin. the longer the length of follow-up, the greater the increase in the detection rate. treatment of doxorubicin-induced congestive heart failure includes the use of digitalis, diuretics, after load reducers such as angiotensin i converting enzyme (ace) inhibitors, low salt diet, and bed rest. such intervention may relieve symptoms and improve the functional status of the patient.

red cardiac function must be carefully evaluated. endomyocardial biopsy is recognized as the most sensitive diagnostic tool to detect anthracycline-induced cardiomyopathy; however, this invasive examination is not practically performed on a routine basis. ecg changes such as dysrhythmias, a reduction of the qrs voltage, or a prolongation beyond normal limits of the systolic time interval may be indicative of anthracycline-induced cardiomyopathy, but ecg is not a sensitive or specific method for following anthracycline-related cardiotoxicity. pediatric patients are at increased risk for developing delayed cardiotoxicity following doxorubicin administration and therefore a follow-up cardiac evaluation is recommended periodically to monitor for this delayed cardiotoxicity. in adults, a 10% decline in lvef to below the lower limit of normal or an absolute lvef of 45%, or a 20% decline in lvef at any level is indicative of deterioration in cardiac function. in pediatric patients, deterioration in cardiac function during or after the completion of therapy with doxorubicin is indicated by a drop in fractional shortening (fs) by an absolute value of ≥ 10 percentile units or below 29%, and a decline in lvef of 10 percentile units or an lvef below 55%. in general, if test results indicate deterioration in cardiac function associated with doxorubicin, the benefit of continued therapy should be carefully evaluated against the risk of producing irreversible cardiac damage. acute life-threatening arrhythmias have been reported to occur during or within a few hours after doxorubicin administration.

per 1,000 patient years (95% cl, 0.16 to 0.57) and a cumulative incidence at 5 years of 0.21% (95% cl, 0.11 to 0.41%). in another analysis of 1,474 patients with breast cancer who received adjuvant treatment with doxorubicin-containing regimens in clinical trials conducted at university of texas m.d. anderson cancer center, the incidence was estimated at 1.5% at 10 years. in both experiences, patients who received regimens with higher cyclophosphamide dosages, who received radiotherapy, or who were aged 50 or older had an increased risk of secondary aml or mds. pediatric patients are also at risk of developing secondary aml.

tient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. women of childbearing age should be advised to avoid becoming pregnant.

he site for 15 min. q.i.d. x 3 days may be useful. the benefit of local administration of drugs has not been clearly established. because of the progressive nature of extravasation reactions, close observation and plastic surgery consultation is recommended. blistering, ulceration and/or persistent pain are indications for wide excision surgery, followed by split-thickness skin grafting. the most commonly used dose schedule when used as a single agent is 60 to 75 mg/m 2 as a single intravenous injection administered at 21-day intervals. the lower dosage should be given to patients with inadequate marrow reserves due to old age, or prior therapy, or neoplastic marrow infiltration. doxorubicin has been used concurrently with other approved chemotherapeutic agents. evidence is available that in some types of neoplastic disease, combination chemotherapy is superior to single agents. the benefits and risks of such therapy continue to be elucidated. when used in combination with other chemotherapy drugs, the most commonly used dosage of doxorubicin is 40 to 60 mg/m 2 given as a single intravenous injection every 21 to 28 days. in a large randomized study (nsabp b-15) of patients with early breast cancer involving axillary lymph nodes (see clinical pharmacology , clinical studies and adverse reactions , adverse reactions in patients with early breast cancer receiving doxorubicin-containing adjuvant therapy ), the combination dosage regimen of ac (doxorubicin 60 mg/m 2 and cyclophosphamide 600 mg/m 2 ) was administered intravenously on day 1 of each 21-day treatment cycle. four cycles of treatment were administered. dose modifications patients in the nsabp b-15 study could have dose modifications of ac to 75% of the starting doses for neutropenic fever/infection. when necessary, the next cycle of treatment cycle was delayed until the absolute neutrophil count (anc) was ≥ 1,000 cells/mm 3 and the platelet count was ≥ 100,000 cells/mm 3 and nonhematologic toxicities had resolved. doxorubicin dosage must be reduced in case of hyperbilirubinemia as follows: plasma bilirubin concentration (mg/dl) dosage reduction (%) 1.2 to 3 50 3.1 to 5 75 reconstitution directions it is recommended that doxorubicin be slowly administered into the tubing of a freely running intravenous infusion of sodium chloride injection, usp, or 5% dextrose injection, usp. the tubing should be attached to a butterfly ® needle inserted preferably into a large vein. if possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. the rate of administration is dependent on the size of the vein and the dosage. however, the dose should be administered in not less than 3 to 5 minutes. local erythematous streaking along the vein as well as facial flushing may be indicative of too rapid an administration. a burning or stinging sensation may be indicative of perivenous infiltration and, if this occurs, the infusion should be immediately terminated and restarted in another vein. perivenous infiltration may occur painlessly. doxorubicin should not be mixed with heparin or fluorouracil since it has been reported that these drugs are incompatible to the extent that a precipitate may form. contact with alkaline solutions should be avoided since this can lead to hydrolysis of doxorubicin. until specific compatibility data are available, it is not recommended that doxorubicin be mixed with other drugs. parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. handling and disposal procedures for proper handling and disposal of anti-cancer drugs should be considered. several guidelines on this subject have been published. 1-4 there is no general agreement that all the procedures recommended in the guidelines are necessary or appropriate. however, given the toxic nature of this substance, the following protective recommendations are provided: personnel should be trained in good technique for reconstitution and handling. pregnant staff should be excluded from working with this drug. personnel handling doxorubicin should wear protective clothing: goggles, gowns and disposable gloves and masks. a designated area should be defined for reconstitution (preferably under a laminar flow system). the work surface should be protected by disposable, plastic-backed, absorbent paper. all items used for reconstitution, administration or cleaning, including gloves, should be placed in high-risk waste-disposal bags for high-temperature incineration. spillage or leakage should be treated with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water. all cleaning materials should be disposed of as indicated previously. in case of skin contact, thoroughly wash the affected area with soap and water or sodium bicarbonate solution. however, do not abrade the skin by using a scrub brush. in case of contact with the eye(s), hold back the eyelid(s) and flush the affected eye(s) with copious amounts of water for at least 15 minutes. then seek medical evaluation by a physician. always wash hands after removing gloves. caregivers of pediatric patients receiving doxorubicin should be counseled to take precautions (such as wearing latex gloves) to prevent contact with the patient’s urine and other body fluids for at least 5 days after each treatment.

drugs are incompatible to the extent that a precipitate may form. contact with alkaline solutions should be avoided since this can lead to hydrolysis of doxorubicin. until specific compatibility data are available, it is not recommended that doxorubicin be mixed with other drugs. parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

or leakage should be treated with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water. all cleaning materials should be disposed of as indicated previously. in case of skin contact, thoroughly wash the affected area with soap and water or sodium bicarbonate solution. however, do not abrade the skin by using a scrub brush. in case of contact with the eye(s), hold back the eyelid(s) and flush the affected eye(s) with copious amounts of water for at least 15 minutes. then seek medical evaluation by a physician. always wash hands after removing gloves. caregivers of pediatric patients receiving doxorubicin should be counseled to take precautions (such as wearing latex gloves) to prevent contact with the patient’s urine and other body fluids for at least 5 days after each treatment.

f mucositis. ulceration and necrosis of the colon, especially the cecum, may occur leading to bleeding or severe infections which can be fatal. this reaction has been reported in patients with acute non-lymphocytic leukemia treated with a 3-day course of doxorubicin combined with cytarabine. anorexia, abdominal pain, dehydration, diarrhea, and hyperpigmentation of the oral mucosa have been occasionally reported. hematologic (see warnings ). hypersensitivity fever, chills and urticaria have been reported occasionally. anaphylaxis may occur. a case of apparent cross sensitivity to lincomycin has been reported. neurological peripheral neurotoxicity in the form of local-regional sensory and/or motor disturbances have been reported in patients treated intra-arterially with doxorubicin, mostly in combination with cisplatin. animal studies have demonstrated seizures and coma in rodents and dogs treated with intra-carotid doxorubicin. seizures and coma have been reported in patients treated with doxorubicin in combination with cisplatin or vincristine. ocular conjunctivitis, keratitis, and lacrimation occur rarely. other malaise/asthenia have been reported. adverse reactions in patients with early breast cancer receiving doxorubicin-containing adjuvant therapy safety data were collected from approximately 2,300 women who participated in a randomized, open-label trial (nsabp b-15) evaluating the use of ac versus cmf in the treatment of early breast cancer involving axillary lymph nodes. in the safety analysis, the follow-up data from all patients receiving ac were combined (n=1,492 evaluable patients) and compared with data from patients receiving conventional cmf (i.e., oral cyclophosphamide; n=739 evaluable patients). the most relevant adverse events reported in this study are provided in table 2. table 2. relevant adverse events in patients with early breast cancer involving axillary lymph nodes ac* conventional cmf n=1,492 n=739 treatment administration mean number of cycles 3.8 5.5 total cycles 5,676 4,068 adverse events, % of patients leukopenia grade 3 (1,000 to 1,999 /mm 3 ) 3.4 9.4 grade 4 (<1000/mm 3 ) 0.3 0.3 thrombocytopenia grade 3 (25,000 to 49,999 /mm 3 ) 0 0.3 grade 4 (<25,000 /mm 3 ) 0.1 0 shock, sepsis 1.5 0.9 systemic infection 2.4 1.2 nausea and vomiting nausea only 15.5 42.8 vomiting ≤ 12 hours 34.4 25.2 vomiting >12 hours 36.8 12 intractable 4.7 1.6 alopecia 92.4 71.4 partial 22.9 56.3 complete 69.5 15.1 weight loss 5 to 10% 6.2 5.7 >10% 2.4 2.8 weight gain 5 to 10% 10.6 27.9 >10% 3.8 14.3 cardiac function asymptomatic 0.2 0.1 transient 0.1 0 symptomatic 0.1 0 treatment-related death 0 0 * includes pooled data from patients who received either ac alone for 4 cycles, or who were treated with ac for 4 cycles followed by 3 cycles of cmf

ade 3 (25,000 to 49,999 /mm 3 ) 0 0.3 grade 4 (<25,000 /mm 3 ) 0.1 0 shock, sepsis 1.5 0.9 systemic infection 2.4 1.2 nausea and vomiting nausea only 15.5 42.8 vomiting ≤ 12 hours 34.4 25.2 vomiting >12 hours 36.8 12 intractable 4.7 1.6 alopecia 92.4 71.4 partial 22.9 56.3 complete 69.5 15.1 weight loss 5 to 10% 6.2 5.7 >10% 2.4 2.8 weight gain 5 to 10% 10.6 27.9 >10% 3.8 14.3 cardiac function asymptomatic 0.2 0.1 transient 0.1 0 symptomatic 0.1 0 treatment-related death 0 0 * includes pooled data from patients who received either ac alone for 4 cycles, or who were treated with ac for 4 cycles followed by 3 cycles of cmf

is or programmed cell death. doxorubicin-induced apoptosis may be an integral component of the cellular mechanism of action relating to therapeutic effects, toxicities, or both. animal studies have shown activity in a spectrum of experimental tumors, immunosuppression, carcinogenic properties in rodents, induction of a variety of toxic effects, including delayed and progressive cardiac toxicity, myelosuppression in all species and atrophy to testes in rats and dogs. pharmacokinetics pharmacokinetic studies, determined in patients with various types of tumors undergoing either single or multi-agent therapy have shown that doxorubicin follows a multiphasic disposition after intravenous injection. in four patients, doxorubicin has demonstrated dose-independent pharmacokinetics in the dose range of 30 to 70 mg/m 2 . distribution the initial distribution half-life of approximately 5 minutes suggests rapid tissue uptake of doxorubicin, while its slow elimination from tissues is reflected by a terminal half-life of 20 to 48 hours. steady-state distribution volume ranges from 809 to 1,214 l/m 2 and is indicative of extensive drug uptake into tissues. binding of doxorubicin and its major metabolite, doxorubicinol, to plasma proteins is about 74 to 76% and is independent of plasma concentration of doxorubicin up to 1.1 mcg/ml. doxorubicin was excreted in the milk of one lactating patient, with peak milk concentration at 24 hours after treatment being approximately 4.4-fold greater than the corresponding plasma concentration. doxorubicin was detectable in the milk up to 72 hours after therapy with 70 mg/m 2 of doxorubicin given as a 15-minute intravenous infusion and 100 mg/m 2 of cisplatin as a 26-hour intravenous infusion. the peak concentration of doxorubicinol in milk at 24 hours was 0.11 mcg/ml and auc up to 24 hours was 9 mcg•h/ml while the auc for doxorubicin was 5.4 mcg•h/ml. doxorubicin does not cross the blood brain barrier. metabolism enzymatic reduction at the 7 position and cleavage of the daunosamine sugar yields aglycones which are accompanied by free radical formation, the local production of which may contribute to the cardiotoxic activity of doxorubicin. disposition of doxorubicinol (dox-ol) in patients is formation rate limited, with the terminal half-life of dox-ol being similar to doxorubicin. the relative exposure of dox-ol, i.e., the ratio between the auc of dox-ol and the auc of doxorubicin, compared to doxorubicin ranges between 0.4 and 0.6. excretion plasma clearance is in the range 324 to 809 ml/min/m 2 and is predominately by metabolism and biliary excretion. approximately 40% of the dose appears in the bile in 5 days, while only 5 to 12% of the drug and its metabolites appear in the urine during the same time period. in urine, < 3% of the dose was recovered as dox-ol over 7 days. systemic clearance of doxorubicin is significantly reduced in obese women with ideal body weight greater than 130%. there was a significant reduction in clearance without any change in volume of distribution in obese patients when compared with normal patients with less than 115% ideal body weight. pharmacokinetics in special populations pediatric following administration of 10 to 75 mg/m 2 doses of doxorubicin to 60 children and adolescents ranging from 2 months to 20 years of age, doxorubicin clearance averaged 1,443 ± 114 ml/min/m 2 . further analysis demonstrated that clearance in 52 children greater than 2 years of age (1,540 ml/min/m 2 ) was increased compared with adults. however, clearance in infants younger than 2 years of age (813 ml/min/m 2 ) was decreased compared with older children and approached the range of clearance values determined in adults. geriatric while the pharmacokinetics of elderly subjects (≥65 years of age) have been evaluated, no dosage adjustment is recommended based on age (see precautions , geriatric use ). gender a published clinical study involving 6 men and 21 women with no prior anthracycline therapy reported a significantly higher median doxorubicin clearance in the men compared to the women (1,088 ml/min/m 2 versus 433 ml/min/m 2 ). however, the terminal half-life of doxorubicin was longer in men compared to the women (54 versus 35 hours). race the influence of race on the pharmacokinetics of doxorubicin has not been evaluated. hepatic impairment the clearance of doxorubicin and doxorubicinol was reduced in patients with impaired hepatic function (see dosage and administration ). renal impairment the influence of renal function on the pharmacokinetics of doxorubicin has not been evaluated.

imately 4.4-fold greater than the corresponding plasma concentration. doxorubicin was detectable in the milk up to 72 hours after therapy with 70 mg/m 2 of doxorubicin given as a 15-minute intravenous infusion and 100 mg/m 2 of cisplatin as a 26-hour intravenous infusion. the peak concentration of doxorubicinol in milk at 24 hours was 0.11 mcg/ml and auc up to 24 hours was 9 mcg•h/ml while the auc for doxorubicin was 5.4 mcg•h/ml. doxorubicin does not cross the blood brain barrier. metabolism enzymatic reduction at the 7 position and cleavage of the daunosamine sugar yields aglycones which are accompanied by free radical formation, the local production of which may contribute to the cardiotoxic activity of doxorubicin. disposition of doxorubicinol (dox-ol) in patients is formation rate limited, with the terminal half-life of dox-ol being similar to doxorubicin. the relative exposure of dox-ol, i.e., the ratio between the auc of dox-ol and the auc of doxorubicin, compared to doxorubicin ranges between 0.4 and 0.6. excretion plasma clearance is in the range 324 to 809 ml/min/m 2 and is predominately by metabolism and biliary excretion. approximately 40% of the dose appears in the bile in 5 days, while only 5 to 12% of the drug and its metabolites appear in the urine during the same time period. in urine, < 3% of the dose was recovered as dox-ol over 7 days. systemic clearance of doxorubicin is significantly reduced in obese women with ideal body weight greater than 130%. there was a significant reduction in clearance without any change in volume of distribution in obese patients when compared with normal patients with less than 115% ideal body weight.

however, the terminal half-life of doxorubicin was longer in men compared to the women (54 versus 35 hours). race the influence of race on the pharmacokinetics of doxorubicin has not been evaluated. hepatic impairment the clearance of doxorubicin and doxorubicinol was reduced in patients with impaired hepatic function (see dosage and administration ). renal impairment the influence of renal function on the pharmacokinetics of doxorubicin has not been evaluated.

erapy was 0.76 (95% cl, 0.71 to 0.82) and for os was 0.86 (95% cl, 0.8 to 0.93). based on a conservative estimate of cmf effect (lower 2-sided 95% confidence limit of hazard ratio) and 75% retention of cmf effect on dfs, it was determined that the doxorubicin-containing regimens would be considered as non-inferior to cmf if the upper 2-sided 95% confidence limit of the hazard ratio was less than 1.06, i.e., not more than 6% worse than cmf. a similar calculation for os would require a non-inferiority margin of 1.02. six randomized trials in the ebctcg meta-analysis compared doxorubicin-containing regimens to cmf. a total of 3,510 women with early breast cancer involving axillary lymph nodes were evaluated; approximately 70% were premenopausal and 30% were postmenopausal. at the time of the meta-analysis, 1,745 first recurrences and 1,348 deaths had occurred. analyses demonstrated that doxorubicin-containing regimens retained at least 75% of the historical cmf adjuvant effect on dfs and are effective. the hazard ratio for dfs (dox:cmf) was 0.91 (95% cl, 0.82 to 1.01) and for os was 0.91 (95% cl, 0.81 to 1.03). results of these analyses for both dfs and os are provided in table 1 and figures 1 and 2. table 1. summary of randomized trials comparing doxorubicin-containing regimens versus cmf in ebctcg meta-analysis study (starting year) regimens no. of cycles no. of patients doxorubicin-containing regimens vs cmf hr (95% ci) dfs os nsabp b-15 (1984) ac 4 1,562* 0.93 (0.82 to 1.06) 0.97 (0.83 to 1.12) cmf 6 776 secsg 2 (1976) fac 6 260 0.86 (0.66 to 1.13) 0.93 (0.69 to 1.26) cmf 6 268 oncofrance (1978) facv 12 138 0.71 (0.49 to 1.03) 0.65 (0.44 to 0.96) cmf 12 113 se sweden bcg a (1980) ac 6 21 0.59 (0.22 to 1.61) 0.53 (0.21 to 1.37) cmf 6 22 nsabc israel br0283 (1983) avbcmf † cmf 4 6 6 55 50 0.91 (0.53 to 1.57) 0.88 (0.47 to 1.63) austrian bcsg 3 (1984) cmfva 6 121 1.07 (0.73 to 1.55) 0.93 (0.64 to 1.35) cmf 8 124 combined studies doxorubicin-containing regimens 2,157 0.91 (0.82 to 1.01) 0.91 (0.81 to 1.03) cmf 1,353 abbreviations: dfs = disease free survival; os = overall survival; ac = doxorubicin, cyclophosphamide; avbcmf = doxorubicin, vinblastine, cyclophosphamide, methotrexate, 5-fluorouracil; cmf = cyclophosphamide, methotrexate, 5-fluorouracil; cmfva = cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, doxorubicin; fac = 5-fluorouracil, doxorubicin, cyclophosphamide; facv = 5-fluorouracil, doxorubicin, cyclophosphamide, vincristine; hr = hazard ratio; ci = confidence interval _________________________________________________________________________________________________________________________ * includes pooled data from patients who received either ac alone for 4 cycles, or who were treated with ac for 4 cycles followed by 3 cycles of cmf. † patients received alternating cycles of avb and cmf. with respect to dfs, 2 of 6 studies (nsabp b-15 and oncofrance) met the non-inferiority standard individually and with respect to os, 1 study met the non-inferiority margin individually (oncofrance). the largest of the 6 studies in the ebctcg meta-analysis, a randomized, open-label, multicenter trial (nsabp b-15) was conducted in approximately 2,300 women (80% premenopausal; 20% postmenopausal) with early breast cancer involving axillary lymph nodes. in this trial, 6 cycles of conventional cmf was compared to 4 cycles of doxorubicin and cyclophosphamide (ac) and 4 cycles of ac followed by 3 cycles of cmf. no statistically significant differences in terms of dfs or os were observed (see table 1). figure-1 figure-2