Doxorubicin

Mechanism of Action

The primary mechanism of action of doxorubicin involves its ability to intercalate into DNA base pairs, resulting in DNA strand breakage and inhibition of both DNA and RNA synthesis. Doxorubicin inhibits topoisomerase II, leading to DNA damage and apoptosis.[14] When combined with iron, doxorubicin also causes free radical-mediated oxidative damage to DNA, further limiting DNA synthesis. Iron chelators, such as dexrazoxane, may prevent free radical formation by limiting doxorubicin's binding to iron.[15] Pegylated liposomal doxorubicin provides comparable efficacy with lower cardiotoxicity than conventional doxorubicin.[16] Overexpression of permeability glycoprotein (P-gp) may lead to doxorubicin resistance.[17][18][19] Conventional doxorubicin induces DNA double-strand breaks in hematopoietic stem cells, increasing the risk of secondary malignancies due to high peak plasma concentrations. In contrast, liposomal doxorubicin lacks a box warning for acute myeloid leukemia (AML) because pegylated encapsulation prevents systemic spikes in free drug and reduces the risk of bone marrow toxicity.

Pharmacokinetics

Absorption: Doxorubicin demonstrates multiphasic disposition after intravenous (IV) injection. The distribution half-life is approximately 5 minutes, whereas the terminal half-life ranges from 20 to 48 hours.

Distribution: The steady-state distribution volume ranges from 809 to 1214 L/m². The plasma protein binding is approximately 75%. Doxorubicin remains detectable in the milk for up to 72 hours. Doxorubicin does not cross the blood-brain barrier.

Metabolism: The enzymatic reduction of doxorubicin and the cleavage of the daunosamine sugar lead to the formation of aglycone metabolites. This process is closely linked to free radical generation, which contributes significantly to the dose-dependent cardiotoxicity characteristic of anthracyclines. Clinically, doxorubicinol formation represents a rate-limiting step in drug disposition. Because the terminal half-life of doxorubicinol mirrors that of the parent compound and maintains an exposure ratio of approximately 0.5, this metabolite accumulates and poses a persistent risk for myocardial damage. Interactions with cytochrome P450 enzymes and membrane transporters further increase the clinical significance of this metabolic profile. Doxorubicin is a substrate for CYP3A4 and CYP2D6. Concomitant medications that inhibit or induce these enzymes can significantly alter doxorubicin exposure, increasing the risk of severe myelosuppression or reducing antitumor efficacy. Doxorubicin is a primary substrate for the efflux transporter P-gp, encoded by the ABCB1 gene. P-gp activity at the cellular level is a major determinant of multidrug resistance in solid tumors and hematologic malignancies.[20][21][22]

Excretion: Plasma clearance ranges from 324 to 809 mL/min/m² and occurs predominantly through metabolism and biliary excretion. Approximately 40% of the dose is excreted in the bile, whereas only 5% to 12% of the drug and its metabolites appear in urine. Systemic clearance of doxorubicin decreases in patients with obesity, defined as women with an actual body weight greater than 130% of ideal body weight. In patients with obesity, clearance decreases significantly without a change in volume of distribution, compared with patients whose actual body weight is less than 115% of ideal body weight. In pediatric patients aged 2 months to 20 years, doxorubicin clearance averages 1443 ± 114 mL/min/m². In children aged 2 years or older, the clearance rate (1540 mL/min/m²) is higher than that observed in adults. In contrast, the clearance rate in infants younger than 2 years (813 mL/min/m²) is lower than that in older children and comparable to values reported in adults.

Administration

Available Dosage Forms and Strengths

The conventional formulation of doxorubicin is available in 2 mg/mL strength. The formulation is supplied as 10 mg in a 5 mL single-dose flip-top vial, 20 mg in a 10 mL single-dose vial, and 50 mg in a 25 mL single-dose vial. Doxorubicin is also available as 200 mg in a 100 mL multiple-dose vial, depending on the manufacturer. Liposomal doxorubicin is available as an IV formulation at 2 mg/mL (10 and 25 mL) and as a preservative-free intravenous suspension at 2 mg/mL (10 and 25 mL). Some products may contain soy lecithin.

Doxorubicin is administered intravenously and is commonly given every 21 days. Doxorubicin appears as a highly pigmented, reddish solution. Doxorubicin is incompatible with heparin and fluorouracil and may precipitate when mixed with these drugs. Doxorubicin may be administered rapidly (over 15 to 20 minutes); however, clinicians should administer the liposomal formulation slowly to reduce the risk of infusion reactions. Store doxorubicin in a refrigerated environment and protect it from light before administration. Doxorubicin exhibits rapid tissue distribution and has an elimination half-life of up to 48 hours. Doxorubicin undergoes enzymatic reduction and requires protection to be eliminated via biliary excretion.[15]

Adult Dosing by Indication

Axillary node–positive breast cancer (adjuvant):

• 60 mg/m² IV once on the first day of a 21-day cycle. Use with cyclophosphamide. Patients should receive 4 cycles.

Leukemia (monotherapy):

• 60 to 75 mg/m² IV once on the first day of a 21-day cycle. The maximum cumulative dose is 550 mg/m² (ALL or AML).

Leukemia (combination therapy): 

• 40 to 75 mg/m² IV once on the first day of a 21- or 29-day cycle. The maximum cumulative dose is 550 mg/m² (ALL or AML).

Lymphoma (monotherapy):

• 60 to 75 mg/m² IV once on the first day of a 21-day cycle. The maximum cumulative dose is 550 mg/m² (Hodgkin and non-Hodgkin lymphoma).

Lymphoma (combination therapy): 

• 40 to 75 mg/m² IV once on the first day of a 21- or 29-day cycle. The maximum cumulative dose is 550 mg/m² (Hodgkin and non-Hodgkin lymphoma).

Solid tumors (monotherapy):

• 60 to 75 mg/m² IV once on the first day of a 21-day cycle. The maximum cumulative dose is 550 mg/m². 

Solid tumors (combination therapy): 

• 40 to 75 mg/m² IV once on the first day of a 21- or 29-day cycle. The maximum cumulative dose is 550 mg/m².

Specific Patient Populations

Hepatic impairment: The use of doxorubicin is contraindicated in severe hepatic impairment.

Renal impairment: The impact of renal function on doxorubicin pharmacokinetics has not been evaluated; renal function is unlikely to influence doxorubicin disposition.

Pregnancy considerations: Human placental cell and tissue uptake of doxorubicin is significant. Doxorubicin crosses the placenta at low levels within 4 hours of human placental perfusion. Pegylated liposomal doxorubicin demonstrates minimal uptake by human placental cells. Thus, doxorubicin should be avoided during the first trimester.[23] If doxorubicin is used during pregnancy or if a patient becomes pregnant during therapy, clinicians should counsel the patient regarding the potential risk of fetal harm. Women of reproductive potential should be advised to avoid pregnancy during treatment.

Breastfeeding considerations: Available literature indicates that breastfeeding is generally contraindicated during maternal treatment with antineoplastic anthracyclines, including doxorubicin. Although intermittent dosing with a defined abstinence period may theoretically permit breastfeeding, high concentrations and prolonged persistence of the active metabolite doxorubicinol in human milk make establishing a safe interval difficult. Earlier recommendations suggest avoiding breastfeeding for 5 to 10 days after a dose. More recent pharmacokinetic modeling suggests that up to 13 days of breastfeeding abstinence after the colostral phase may be required to minimize systemic and gastrointestinal toxicity in the breastfed infant.[24] Clinicians should advise patients that breastfeeding is contraindicated during doxorubicin therapy and engage in shared decision-making that carefully weighs the benefits of breastfeeding against the potential risks to the infant while also considering alternative feeding options. Chemotherapy can negatively impact the neonatal microbiome.[25] 

Pediatric patients: Pediatric patients face an increased risk of delayed cardiotoxicity following doxorubicin; clinicians should perform periodic cardiac evaluation to monitor for this complication. Pediatric patients are also at risk of developing secondary AML.[26]

Older patients: No overall differences in safety and effectiveness are observed between older and younger patients. The decision to use doxorubicin in geriatric patients should be based on a consideration of comorbidities, including heart failure.[27]

Adverse Effects

Adverse reactions commonly occur after doxorubicin administration, including fatigue, alopecia, nausea and vomiting, and oral sores. Bone marrow suppression and an increased risk of secondary malignancies may occur. Doxorubicin extravasation during IV administration can result in severe tissue ulceration and necrosis, which worsens over time. Doxorubicin is also associated with significant cardiac toxicity, which limits its long-term use. Doxorubicin is the most cardiotoxic agent within the anthracycline class of chemotherapeutic agents.[28] The mechanism of action of doxorubicin-induced cardiac toxicity differs from the drug's antitumor mechanism. This process involves increased oxidative stress, downregulation of cardiac-specific genes, and doxorubicin-induced apoptosis of cardiac myocytes. Doxorubicin-associated cardiac toxicity is dose-dependent, with higher cumulative doses associated with a higher incidence of toxicity.[29] Acute cardiac toxicity occurs within days of doxorubicin administration and affects approximately 11% of patients.[30]

Acute cardiac toxicity manifests as reversible myopericarditis, left ventricular dysfunction, or arrhythmias. Doxorubicin-related arrhythmias occur in up to 26% of patients who receive the therapy and can include sinus tachycardia, premature atrial and ventricular contractions, and supraventricular tachycardia. Rarely, acute left ventricular dysfunction can occur after doxorubicin administration; this condition is typically reversible. Chronic, late cardiac toxicity may also occur after doxorubicin administration and represents the most serious and potentially lethal adverse effect associated with doxorubicin therapy. The incidence of chronic doxorubicin-related cardiac toxicity is approximately 1.7%.

Doxorubicin-induced irreversible cardiomyopathy occurs within a few months after treatment but has also been reported up to 20 years after treatment termination. Congestive heart failure (CHF) may also occur. Risk factors for doxorubicin-induced CHF include higher cumulative drug dose, extremes of age, combination chemotherapy with other cardiotoxic drugs, preexisting left ventricular dysfunction, hypertension, and prior mediastinal radiation. When CHF develops after doxorubicin administration, the 1-year mortality rate is approximately 50%.[31][32][33]

According to the American Society of Clinical Oncology guidelines, patients treated with cyclophosphamide, doxorubicin, and other moderate emetic-risk antineoplastic drugs known to cause delayed nausea and vomiting may be offered dexamethasone.[34]

Hand-foot syndrome (HFS) is a dermatologic adverse effect of chemotherapies such as capecitabine and pegylated liposomal doxorubicin. A network meta-analysis indicates that topical diclofenac may prevent HFS and is associated with fewer chemotherapy dose modifications.[35] HFS should not be confused with hand-foot-mouth disease, which is caused by the coxsackievirus or enterovirus.[36]

Drug-Drug Interactions

CYP3A4, CYP2D6, and permeability glycoprotein inhibitors: These inhibitors can increase doxorubicin plasma concentrations and the risk of adverse effects. Concomitant use should be avoided. [17]

CYP3A4, CYP2D6, and permeability glycoprotein inducers: Concomitant use with these inducers (eg, phenytoin, phenobarbital, St John's wort) can decrease doxorubicin plasma concentrations. Such combinations should be avoided.

6-Mercaptopurine: Doxorubicin hydrochloride may enhance the hepatotoxic effects of 6-mercaptopurine. 

Trastuzumab: Concurrent use increases the risk of cardiac dysfunction; simultaneous administration should be avoided. The risk of cardiotoxicity may persist for up to 7 months after discontinuation; therefore, anthracycline-based therapy should be deferred when feasible. If anthracyclines must be initiated earlier, close monitoring of cardiac function is recommended.

Paclitaxel: Paclitaxel administered before doxorubicin increases doxorubicin plasma concentrations; if used together, doxorubicin should be administered before paclitaxel.

Vaccines: Administration of live or live-attenuated vaccines to immunocompromised individuals receiving chemotherapeutic drugs, including doxorubicin, may result in serious or fatal infections; live vaccines should be avoided during treatment.

Contraindications

Doxorubicin is frequently listed as a contraindication to hyperbaric oxygen (HBO) therapy. However, animal studies evaluating the combined use of HBO and doxorubicin have yielded inconsistent results, leading to ongoing controversy regarding whether HBO is truly contraindicated in patients receiving doxorubicin. In 1985, investigators studied HBO with antioxidants as a potential nonsurgical treatment for skin necrosis caused by doxorubicin extravasation. In this study, groups of rats were fed antioxidants, including beta-carotene or butylated hydroxytoluene, a common food preservative and known free radical scavenger. Subsequently, the rats were anesthetized and injected intradermally with doxorubicin. Some rats were then exposed to HBO at 2.5 ATA after doxorubicin injection. Rats receiving butylated hydroxytoluene before doxorubicin injection exhibited improved wound healing. In contrast, rats receiving HBO after doxorubicin injection experienced an 87% mortality rate, which the authors attributed to free radical formation from both HBO and doxorubicin.

Although findings from this single study suggest that concurrent administration of HBO and doxorubicin may be associated with increased mortality, subsequent studies have not shown an increase in mortality or cardiac toxicity following combined HBO and doxorubicin treatment. The effects of HBO after remote doxorubicin administration remain unknown. HBO administration may be safe after doxorubicin clearance from the body, in other words, after 5 to 6 elimination half-lives, or 12 days. Additional studies are necessary to further clarify this topic.[37]

Box Warnings

• Tissue necrosis and extravasation: Severe local tissue necrosis may occur with extravasation during administration. Doxorubicin must not be given by the intramuscular or subcutaneous route.

• Cardiotoxicity: Myocardial toxicity, manifested in its most severe form as potentially fatal CHF, may occur either during therapy or months to years after termination of therapy. Risk factors include active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal or pericardial area, previous therapy with other anthracyclines or anthracenediones, and concomitant use of other cardiotoxic drugs, which may increase the risk of cardiac toxicity. Cardiac toxicity with doxorubicin may occur at lower cumulative doses, regardless of the presence of cardiac risk factors. Pediatric patients are at increased risk for developing delayed cardiotoxicity.

• Secondary acute myeloid leukemia or myelodysplastic syndrome: Secondary AML and myelodysplastic syndrome (MDS) have been reported in patients treated with anthracyclines, including doxorubicin. Refractory secondary AML or MDS occurs more commonly when doxorubicin is administered with radiotherapy or DNA-damaging antineoplastic agents, in heavily pretreated patients, or with escalated anthracycline doses. Patients who received regimens with higher cyclophosphamide doses, radiotherapy, or those aged 50 or older had an increased risk of secondary AML or MDS. Pediatric patients are also at risk of developing secondary AML.

• Hepatic impairment: Reduce the doxorubicin dose in patients with impaired hepatic function.

• Myelosuppression: Severe myelosuppression may occur. Complete blood count (CBC) should be monitored regularly. Doxorubicin should be administered only under the supervision of an oncologist.

Box Warnings (Liposomal Doxorubicin)

• Infusion-related reactions: Serious, life-threatening, and fatal infusion-related reactions may occur with liposomal doxorubicin administration. Acute infusion-related reactions have been reported in patients with solid tumors. Liposomal doxorubicin should be withheld in the event of an infusion-related reaction and may be resumed at a reduced infusion rate once symptoms resolve. The infusion should be discontinued in cases of serious or life-threatening reactions.

• Cardiotoxicity: Left ventricular ejection fraction (LVEF) should be monitored due to the risk of cardiotoxicity. Liposomal doxorubicin is associated with a reduced incidence of heart failure compared with other anthracycline-based therapies. Meta-analyses suggest that liposomal doxorubicin provides cardioprotective benefits compared with conventional formulations.[38][39]

Monitoring

Baseline (pretreatment) and periodic cardiac function monitoring should be performed using echocardiography or multigated radionuclide angiography (MUGA) in patients receiving doxorubicin. Doxorubicin should be discontinued in patients who exhibit a decrease in LVEF during treatment. Endomyocardial biopsy may also be used to diagnose doxorubicin-induced cardiomyopathy; findings include loss of myofibrils and cytoplasmic vacuolization. No specific treatment is available for doxorubicin-induced cardiomyopathy.

Diuretics and beta-adrenergic blockers are potential options; however, these therapies do not improve overall prognosis. Cardiac transplantation has been successful in some patients with doxorubicin-induced cardiomyopathy. Because higher cumulative doxorubicin doses increase the risk of cardiomyopathy, dose limitation is recommended to reduce cardiotoxicity. Antioxidant drugs, including amlodipine and carvedilol, have been studied as potential preventive agents to reduce the incidence of doxorubicin-induced cardiotoxicity. Dexrazoxane, an iron chelator, may be coadministered with doxorubicin to reduce the cardiotoxicity of the drug. Dexrazoxane may induce myelosuppression, which doxorubicin may potentiate; therefore, its clinical efficacy remains uncertain.[40] Periodic monitoring of CBC with differential and liver function tests is recommended.[41]

Toxicity

Signs and Symptoms of Overdose/Toxicity

Acute doxorubicin overdosage can cause severe mucositis, leukopenia, and thrombocytopenia. Doxorubicin has significant potential for cardiotoxicity, as with other anthracycline drugs.[42] Nanoparticle-based formulations of doxorubicin, including liposomal doxorubicin, are associated with fewer toxicities than conventional formulations.[43] Immune checkpoint inhibitors and other potential cardiotoxic agents may increase the risk of cancer therapy–related cardiac dysfunction. Cancer therapy–related cardiac dysfunction should be monitored in patients treated with immune checkpoint inhibitors using cardiac biomarkers and echocardiography.[44]

Management of Overdose/Toxicity

In the event of overdose, priority should be given to securing the airway, breathing, and circulation. Management of acute overdose is primarily supportive. Efbemalenograstim alfa and pegfilgrastim may be considered for chemotherapy-induced neutropenia; however, additional research is needed.[45]

Management of cardiotoxicity is outlined in the 2022 American College of Cardiology/American Heart Association heart failure guidelines. In patients who develop cancer therapy–related cardiomyopathy or heart failure, a multidisciplinary discussion regarding the risks and benefits of continuing, discontinuing, or interrupting cancer therapy is recommended. In asymptomatic patients with cancer therapy–related cardiomyopathy (ejection fraction <50%), angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and beta-blockers are considered reasonable to prevent progression to heart failure and to improve cardiac function. For patients with cardiovascular risk factors or known cardiac disease who are candidates for cardiotoxic anticancer therapies, a pretreatment assessment of cardiac function is recommended to establish a baseline and inform treatment decisions. Monitoring cardiac function during treatment is also reasonable to detect drug-induced cardiomyopathy early. The benefit of initiating beta blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for primary prevention in at-risk patients remains uncertain. Serial measurement of cardiac troponin may also be reasonable for risk stratification in patients receiving potentially cardiotoxic therapies.[46]

Enhancing Healthcare Team Outcomes

Doxorubicin is a frequently used chemotherapeutic agent for the treatment of many solid tumors and requires an interprofessional healthcare team for optimal effectiveness. Although effective, doxorubicin is associated with a serious adverse effect. The interprofessional team includes primary care clinicians who refer patients to oncologists and who perform cardiac screening for patients with risk factors for heart disease. Oncology nurses assist in all aspects of care, support regimen adherence, and address patient questions. Pharmacists contribute to dosing, medication reconciliation, and patient counseling. Doxorubicin can cause irreversible cardiomyopathy, which may occur at any time after treatment. An interprofessional approach optimizes patient outcomes while minimizing potential adverse effects.

Baseline (pretreatment) and periodic monitoring of cardiac function using echocardiography or multigated radionuclide angiography (MUGA) are recommended in patients receiving doxorubicin. A cardiologist should be consulted for severe doxorubicin-related cardiotoxicity. The prescribing clinician should include a board-certified oncology pharmacist to optimize the regimen and prevent potential drug interactions. Discontinue doxorubicin in patients who exhibit a decrease in LVEF during treatment. Oncology nurses play a key role in assessing treatment effectiveness and monitoring for adverse events. Because higher cumulative doxorubicin doses increase the risk of cardiomyopathy, dose limitation is recommended to reduce cardiotoxicity.[6][47][48] An interprofessional team approach and effective communication among clinicians, advanced practice providers, specialists, pharmacists, and nurses are essential for minimizing adverse effects and improving outcomes in patients receiving doxorubicin.