Doxorubicin Drug Information
Generic name: DOXORUBICIN HYDROCHLORIDE
Uses of Doxorubicin
Adjuvant Breast Cancer Doxorubicin Hydrochloride Injection is indicated as a component of multi-agent adjuvant chemotherapy for treatment of women with axillary lymph node involvement following resection of primary breast cancer.
Other Cancers Doxorubicin Hydrochloride Injection is indicated for the treatment of • acute lymphoblastic leukemia • acute myeloblastic leukemia • Hodgkin lymphoma • non-Hodgkin lymphoma (NHL) • metastatic breast cancer • metastatic Wilms' tumor • metastatic neuroblastoma • metastatic soft tissue sarcoma • metastatic bone sarcoma • metastatic ovarian carcinoma • metastatic transitional cell bladder carcinoma • metastatic thyroid carcinoma • metastatic gastric carcinoma • metastatic bronchogenic carcinoma
Dosage & Administration of Doxorubicin
Recommended Dosage for Adjuvant Breast Cancer
The recommended dosage of Doxorubicin Hydrochloride Injection is 60 mg/m 2 administered as an intravenous bolus on day 1 of each 21-day treatment cycle, in combination with cyclophosphamide, for a total of four cycles.
Recommended Dosage for Other Cancers •
The recommended dosage of Doxorubicin Hydrochloride Injection when used as a single agent is intravenously every 21 days. • The recommended dosage of Doxorubicin Hydrochloride Injection, when administered in combination with other chemotherapy drugs, is intravenously every 21 to 28 days. • Consider use of the lower Doxorubicin Hydrochloride Injection dose in the recommended dosage range or longer intervals between cycles for heavily pretreated patients, elderly patients, or obese patients. • Cumulative doses above 550 mg/m 2 are associated with an increased risk of cardiomyopathy.
Dosage Modifications for Adverse Reactions Cardiomyopathy Discontinue Doxorubicin Hydrochloride Injection in patients who develop signs or symptoms of cardiomyopathy.
Dosage Modifications for Hepatic Impairment Doxorubicin Hydrochloride Injection is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C or serum bilirubin greater than 5 mg/dL). Dosage modifications for Doxorubicin Hydrochloride Injection in patients with elevated serum total bilirubin concentrations are provided in Table 1. Table 1.
Recommended
Preparation and Administration Doxorubicin Hydrochloride Injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1 Preparation Dilution of Doxorubicin Hydrochloride Injection • Dilute Doxorubicin Hydrochloride Injection in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. • Protect from light following preparation until completion of infusion. • Use within 1 hour. If not used within 1 hour, discard the diluted product.
Administration • Visually inspect for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if the solution is discolored, cloudy, or contains particulate matter. Administration by Intravenous Injection • Administer diluted Doxorubicin Hydrochloride Injection as an intravenous injection through a central intravenous line or a secure and free-flowing peripheral venous line containing 0.9% Sodium Chloride Injection, USP, 0.45% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP. • Administer intravenously over 3 to 10 minutes.
Decrease the rate of infusion if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur. Administration by Continuous Intravenous Infusion • Administer diluted Doxorubicin Hydrochloride Injection solution only through a central intravenous line. Management of Suspected Extravasation Immediately discontinue Doxorubicin Hydrochloride Injection for burning or stinging sensation or other evidence indicating peri-venous infiltration or extravasation.
Manage confirmed or suspected extravasation as follows: • Do not remove the needle until attempts are made to aspirate extravasated fluid. • Do not flush the line. • Avoid applying pressure to the site. • Apply ice to the site intermittently for 15 minutes, 4 times a day for 3 days. • If the extravasation is in an extremity, elevate the extremity. • In adults, consider administration of dexrazoxane. Management of Contact with Skin or Eyes Treat accidental contact with the skin or eyes immediately by copious lavage with water, or soap and water, or sodium bicarbonate solution. Do not abrade the skin by using a scrub brush.
Seek medical attention. Incompatibility with Other Drugs Do not admix Doxorubicin Hydrochloride Injection with other drugs. If Doxorubicin Hydrochloride Injection is mixed with heparin or fluorouracil, a precipitate may form.
Avoid contact with alkaline solutions which can lead to hydrolysis of doxorubicin hydrochloride.
| Serum Total Bilirubin Concentration | Dosage Modification |
|---|---|
| 1.2–3 mg/dL | 50% |
| 3.1–5 mg/dL | 75% |
| Greater than 5 mg/dL | Do not initiate Doxorubicin Hydrochloride Injection; discontinue Doxorubicin Hydrochloride Injection |
Side Effects of Doxorubicin
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The median number of cycles received was 4. Selected adverse reactions reported in this study are provided in Table 2.
No treatment-related deaths were reported in patients on either arm of the study. Table 2. Selected Adverse Reactions in Patients with Early Breast Cancer Involving Axillary Lymph Nodes 0
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of Doxorubicin Hydrochloride Injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac – Cardiogenic shock Cutaneous – Skin and nail hyperpigmentation, oncolysis, rash, itching, photosensitivity, urticaria, acral erythema, palmar plantar erythrodysesthesia Gastrointestinal – Nausea, mucositis, stomatitis, necrotizing colitis, typhlitis, gastric erosions, gastrointestinal tract bleeding, hematochezia, esophagitis, anorexia, abdominal pain, dehydration, diarrhea, hyperpigmentation of the oral mucosa Hypersensitivity – Anaphylaxis Laboratory Abnormalities – Increased ALT, increased AST Neurological – Peripheral sensory and motor neuropathy, seizures, coma Ocular – Conjunctivitis, keratitis, lacrimation Vascular – Phlebosclerosis, phlebitis/thrombophlebitis, hot flashes, thromboembolism Other – Malaise/asthenia, fever, chills, weight gain
| Adverse Reactions | AC Includes pooled data from patients who received either AC for 4 cycles or AC for 4 cycles followed by CMF for 3 cycles N = 1492 | Conventional CMF N = 739 |
|---|---|---|
| % | % | |
| AC = doxorubicin hydrochloride, cyclophosphamide; CMF = cyclophosphamide, methotrexate, fluorouracil | ||
| Alopecia | 92 | 71 |
| Vomiting | ||
| Vomiting ≤12 hours | 34 | 25 |
| Vomiting >12 hours | 37 | 12 |
| Intractable | 5 | 2 |
| Leukopenia | ||
| Grade 3 (1,000–1,999 /mm 3 ) | 3.4 | 9.4 |
| Grade 4 (<1000 /mm 3 ) | 0.3 | 0.3 |
| Shock, sepsis | 2 | 1 |
| Systemic infection | 2 | 1 |
| Cardiac dysfunction | ||
| Asymptomatic | 0.2 | 0.1 |
| Transient | 0.1 | 0 |
| Symptomatic | 0.1 | 0 |
| Thrombocytopenia | ||
| Grade 3 (25,000–49,999 /mm 3 ) | 0 | 0.3 |
| Grade 4 (<25,000 /mm 3 ) | 0.1 | 0 |
Warnings & Cautions for Doxorubicin
Cardiomyopathy and Arrhythmias Cardiomyopathy
Doxorubicin hydrochloride can result in myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy is generally proportional to the cumulative exposure. Include prior doses of other anthracyclines or anthracenediones in calculations of total cumulative dosage for doxorubicin hydrochloride.
Cardiomyopathy may develop during treatment or up to several years after completion of treatment and can include decrease in LVEF and signs and symptoms of congestive heart failure (CHF). There is an additive or potentially synergistic increase in the risk of cardiomyopathy in patients who have received radiotherapy to the mediastinum or concomitant therapy with other known cardiotoxic agents, such as cyclophosphamide and trastuzumab. Pericarditis and myocarditis have also been reported during or following doxorubicin hydrochloride treatment.
Assess left ventricular cardiac function (e.g., MUGA or echocardiogram) prior to initiation of Doxorubicin Hydrochloride Injection, during treatment to detect acute changes, and after treatment to detect delayed cardiotoxicity. Increase the frequency of assessments as the cumulative dose exceeds 300 mg/m 2. Use the same method of assessment of LVEF at all time points.
Discontinue Doxorubicin Hydrochloride Injection in patients who develop signs or symptoms of cardiomyopathy. Consider the use of dexrazoxane to reduce the incidence and severity of cardiomyopathy due to doxorubicin hydrochloride administration in patients who have received a cumulative doxorubicin hydrochloride dose of 300 mg/m 2 and who will continue to receive doxorubicin hydrochloride. Arrhythmias Doxorubicin hydrochloride can result in arrhythmias, including life-threatening arrhythmias, during or within a few hours after doxorubicin hydrochloride administration and at any time point during treatment.
Tachyarrhythmias, including sinus tachycardia, premature ventricular contractions, and ventricular tachycardia, as well as bradycardia, can occur. Electrocardiographic changes, including non-specific ST-T wave changes, atrioventricular and bundle-branch block can also occur. These electrocardiographic changes may be transient and self-limited and may not require a dosage modification of doxorubicin hydrochloride.
Secondary Malignancies
The risk of developing secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) is increased following treatment with doxorubicin hydrochloride. Cumulative incidences ranged from 0.2% at five years to 1.5% at 10 years in two separate trials involving the adjuvant treatment of women with breast cancer. These leukemias generally occur within 1 to 3 years of treatment.
Extravasation and Tissue Necrosis Extravasation of doxorubicin hydrochloride can cause severe local tissue injury manifesting as blistering, ulceration, and necrosis requiring wide excision of the affected area and skin grafting. Extravasation should be considered if a patient experiences a burning or stinging sensation or shows other evidence indicating peri-venous infiltration or extravasation; however, extravasation may be present in patients who do not experience a stinging or burning sensation or when blood return is present on aspiration of the infusion needle. When given via a peripheral venous line, infuse Doxorubicin Hydrochloride Injection over 10 minutes or less to minimize the risk of thrombosis or perivenous extravasation.
If extravasation is suspected, immediately discontinue the intravenous injection or continuous intravenous infusion. Apply ice to the site intermittently for 15 minutes, 4 times a day for 3 days. In adults, if appropriate, administer dexrazoxane at the site of extravasation as soon as possible and within the first 6 hours after extravasation.
Severe Myelosuppression
Doxorubicin hydrochloride can cause myelosuppression. A dose-dependent, reversible neutropenia is the predominant manifestation of myelosuppression from doxorubicin hydrochloride. Obtain complete blood counts prior to each treatment and carefully monitor patients during treatment for possible clinical complications due to myelosuppression.
Delay next dose of Doxorubicin Hydrochloride Injection if severe myelosuppression has not improved. Consider dose reduction for patients with prolonged myelosuppression based on severity of reaction.
Use in Patients with Hepatic Impairment
The clearance of doxorubicin is decreased in patients with elevated serum bilirubin with an increased risk of toxicity. Doxorubicin Hydrochloride Injection is contraindicated in patients with severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin level greater than 5 mg/dL). Reduce the dose of Doxorubicin Hydrochloride Injection in patients with serum bilirubin levels of 1.2 to 5 mg/dL.
Obtain liver tests including ALT, AST, alkaline phosphatase, and bilirubin prior to and during therapy.
Tumor Lysis Syndrome
Doxorubicin hydrochloride can induce tumor lysis syndrome in patients with rapidly growing tumors. Evaluate blood uric acid levels, potassium, calcium, phosphate, and creatinine after initial treatment. Hydration, urine alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia may minimize potential complications of tumor lysis syndrome.
Potentiation of Radiation Toxicity and Radiation Recall
Doxorubicin hydrochloride can increase radiation-induced toxicity to the myocardium, mucosa, skin, and liver. Radiation recall, including but not limited to cutaneous and pulmonary toxicity, can occur in patients who receive doxorubicin hydrochloride after prior radiation therapy.
Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, Doxorubicin Hydrochloride Injection can cause fetal harm when administered to a pregnant woman; avoid the use of Doxorubicin Hydrochloride Injection during the 1 st trimester. Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 2 nd and 3 rd trimesters. Doxorubicin hydrochloride was teratogenic and embryotoxic in rats and rabbits at doses lower than the recommended human dose.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Doxorubicin Hydrochloride Injection and for 6 months after treatment. Advise males with pregnant partners to use condoms during treatment with Doxorubicin Hydrochloride Injection and for at least 10 days after the final dose.
Drug Interactions with Doxorubicin
Effect of Other Drugs on Doxorubicin Hydrochloride Injection Inhibitors of CYP3A4, CYP2D6, and P-gp Concomitant use of doxorubicin hydrochloride with inhibitors of CYP3A4, CYP2D6, or P-glycoprotein (P-gp), increased concentrations of doxorubicin, which may increase the incidence and severity of adverse reactions of doxorubicin hydrochloride. Inducers of CYP3A4, CYP2D6, or P-gp Concomitant use of doxorubicin hydrochloride with inducers of CYP3A4, CYP2D6, or P-gp may decrease the concentration of doxorubicin. Avoid concomitant use of Doxorubicin Hydrochloride Injection with inducers of CYP3A4, CYP2D6, or P-gp.
Paclitaxel Paclitaxel, when given prior to doxorubicin hydrochloride, increases the plasma-concentrations of doxorubicin and its metabolites. Administer Doxorubicin Hydrochloride Injection prior to paclitaxel if used concomitantly.
Concomitant Use of Trastuzumab
Concomitant use of trastuzumab and doxorubicin hydrochloride results in an increased risk of cardiac dysfunction. Avoid concomitant administration of Doxorubicin Hydrochloride Injection and trastuzumab. Patients receiving doxorubicin after stopping treatment with trastuzumab may also be at an increased risk of developing cardiotoxicity.
Trastuzumab may persist in the circulation for up to 7 months. Therefore, avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab when possible. If anthracyclines are used before this time, carefully monitor cardiac function.
Concomitant Use of Dexrazoxane
Do not administer dexrazoxane as a cardioprotectant at the initiation of doxorubicin hydrochloride-containing chemotherapy regimens. In a randomized trial in women with metastatic breast cancer, initiation of dexrazoxane with doxorubicin hydrochloride-based chemotherapy resulted in a significantly lower tumor response rate (48% vs. 63%; p = 0.007) and shorter time to progression compared to doxorubicin hydrochloride-based chemotherapy alone.
Concomitant Use of 6-Mercaptopurine
Doxorubicin hydrochloride may potentiate 6-mercaptopurine-induced hepatotoxicity.
Pregnancy Safety for Doxorubicin
Pregnancy Risk Summary Based on findings in animals and its mechanism of action, Doxorubicin Hydrochloride Injection can cause fetal harm when administered to a pregnant woman; avoid the use of Doxorubicin Hydrochloride Injection during the 1 st trimester. Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 2 nd and 3 rd trimesters. Doxorubicin hydrochloride was teratogenic and embryotoxic in rats and embryotoxic in rabbits when administered during organogenesis at doses approximately 0.07 times (based on body surface area) the recommended human dose of 60 mg/m 2 (see Data ).
Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Animal Data Doxorubicin hydrochloride was teratogenic and embryotoxic at doses of 0.8 mg/kg/day (about 0.07 times the recommended human dose based on body surface area) 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, tracheo-esophageal fistula, hypoplasia of the urinary bladder, and cardiovascular anomalies.
Doxorubicin hydrochloride was embryotoxic (increase in embryo-fetal deaths) and abortifacient at 0.4 mg/kg/day (about 0.07 times the recommended human dose based on body surface area) in rabbits when administered during the period of organogenesis.
Pediatric Use of Doxorubicin
Pediatric Use Based on postmarketing reports, pediatric patients treated with doxorubicin hydrochloride are at risk for developing late cardiovascular dysfunction. Risk factors include young age at treatment (especially < 5 years), high cumulative doses and receipt of combined modality therapy. Long-term periodic cardiovascular monitoring is recommended for all pediatric patients who have received doxorubicin hydrochloride.
Doxorubicin hydrochloride, as a component of intensive chemotherapy regimens administered to pediatric patients, may contribute to prepubertal growth failure and may also contribute to gonadal impairment, which is usually temporary. There are no recommended dose adjustments based on age. Doxorubicin clearance was increased in patients aged 2 years to 20 years as compared to adults, while doxorubicin clearance was similar in infants less than 2 years as compared to adults.
Contraindications for Doxorubicin
- Doxorubicin Hydrochloride Injection are contraindicated in patients with:
- Severe myocardial insufficiency
- Recent (occurring within the past 4–6 weeks) myocardial infarction
- Severe persistent drug-induced myelosuppression
- Severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin level greater than 5 mg/dL)
- Severe hypersensitivity reaction to doxorubicin hydrochloride, including anaphylaxis
- Severe myocardial insufficiency
- Recent myocardial infarction
- Severe hepatic impairment
- Severe hypersensitivity to doxorubicin hydrochloride
Overdosage Information for Doxorubicin
Few cases of overdose have been described. A 58-year-old man with acute lymphoblastic leukemia received 10-fold overdose of doxorubicin hydrochloride (300 mg/m 2 ) in one day. He was treated with charcoal filtration, hemopoietic growth factor (G-CSF), proton pump inhibitor and antimicrobial prophylaxis.
The patient suffered sinus tachycardia, grade 4 neutropenia and thrombocytopenia for 11 days, severe mucositis and sepsis. The patient recovered completely 26 days after the overdose. The patient developed severe mucositis on days 4–7 after the overdose and chills and pyrexia on day 7.
The patient was treated with antibiotics and platelets and recovered 18 days after overdose.
Clinical Studies of Doxorubicin
Adjuvant Breast Cancer
The efficacy of doxorubicin hydrochloride-containing regimens for the post-operative, adjuvant treatment of surgically resected breast cancer was evaluated in a meta-analysis conducted by the Early Breast Cancer Trialists Collaborative Group (EBCTCG). Data from the meta-analysis of trials comparing CMF to no therapy were used to establish the historical treatment effect size for CMF regimens. The major efficacy outcome measures were disease-free survival (DFS) and overall survival (OS).
At the time of the meta-analysis, 1745 first recurrences and 1348 deaths had occurred. The analyses demonstrated that doxorubicin hydrochloride-containing regimens retained at least 75% of the historical CMF adjuvant effect on DFS with a hazard ratio (HR) of and on OS with a HR of Efficacy results are provided in Table 3 and Figures 1 and 2. Table 3.
Summary of Randomized Trials Comparing Figure 1 Figure 2
| Study (starting year) | Regimens | No. of Cycles | No. of Patients | Doxorubicin Hydrochloride‑Containing Regimens vs. CMF HR Hazard ratio of less than 1 indicates that the treatment with doxorubicin hydrochloride-containing regimens is associated with lower risk of disease recurrences or death compared to the treatment with CMF. (95% CI) | |
|---|---|---|---|---|---|
| DFS | OS | ||||
| Abbreviations: DFS = disease free survival; OS = overall survival; AC = doxorubicin hydrochloride, cyclophosphamide; AVbCMF = doxorubicin hydrochloride, vinblastine, cyclophosphamide, methotrexate, fluorouracil; CMF = cyclophosphamide, methotrexate, fluorouracil; CMFVA = cyclophosphamide, methotrexate, fluorouracil, vincristine, doxorubicin hydrochloride; FAC = fluorouracil, doxorubicin hydrochloride, cyclophosphamide; FACV = fluorouracil, doxorubicin hydrochloride, cyclophosphamide, vincristine; HR = hazard ratio; CI = confidence interval | |||||
| NSABP B-15 (1984) | AC | 4 | 1562 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. | 0.93 (0.82, 1.06) | 0.97 (0.83, 1.12) |
| CMF | 6 | 776 | |||
| SECSG 2 (1976) | FAC | 6 | 260 | 0.86 (0.66, 1.13) | 0.93 (0.69, 1.26) |
| CMF | 6 | 268 | |||
| ONCOFRANCE (1978) | FACV | 12 | 138 | 0.71 (0.49, 1.03) | 0.65 (0.44, 0.96) |
| CMF | 12 | 113 | |||
| SE Sweden BCG A (1980) | AC | 6 | 21 | 0.59 (0.22, 1.61) | 0.53 (0.21, 1.37) |
| CMF | 6 | 22 | |||
| NSABC Israel Br0283 (1983) | AVbCMF Patients received alternating cycles of AVb and CMF. | 4 6 | 55 | 0.91 (0.53, 1.57) | 0.88 (0.47, 1.63) |
| CMF | 6 | 50 | |||
| Austrian BCSG 3 (1984) | CMFVA | 6 | 121 | ||
| 1.07 (0.73, 1.55) | 0.93 (0.64, 1.35) | ||||
| CMF | 8 | 124 | |||
| Combined Studies | Doxorubicin Hydrochloride-Containing Regimen | 2157 | |||
| 0.91 (0.82, 1.01) | 0.91 (0.81, 1.03) | ||||
| CMF | 1353 | ||||
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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