WARNING: CARDIOMYOPATHY, SECONDARY MALIGNANCIES, EXTRAVASATION AND TISSUE NECROSIS, and SEVERE MYELOSUPPRESSION Cardiomyopathy: Myocardial damage, including acute left ventricular failure can occur with doxorubicin. The risk of cardiomyopathy is proportional to the cumulative exposure with incidences from 1% to 20% for cumulative doses from 300 mg/m 2 to 500 mg/m 2 when doxorubicin is administered every 3 weeks. The risk of cardiomyopathy is further increased with concomitant cardiotoxic therapy. Assess LVEF before and regularly during and after treatment with doxorubicin [see Warnings and Precautions ( 5.1 )]. Secondary Malignancies: Secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) occur at a higher incidence in patients treated with anthracyclines, including doxorubicin [see Warnings and Precautions ( 5.2 )]. Extravasation and Tissue Necrosis: Extravasation of doxorubicin can result in severe local tissue injury and necrosis requiring wide excision of the affected area and skin grafting.Immediately terminate the drug, and apply ice to the affected area [see Warnings and Precautions ( 5.3 )]. Severe myelosuppression resulting in serious infection, septic shock, requirement for transfusions, hospitalization, and death may occur [see Warnings and Precautions ( 5.4 )]. WARNING: CARDIOMYOPATHY, SECONDARY MALIGNANCIES, EXTRAVASATION AND TISSUE NECROSIS, and SEVERE MYELOSUPPRESSION See full prescribing information for complete boxed warning. Cardiomyopathy: Myocardial damage can occur with doxorubicin with incidences from 1% to 20% for cumulative doses from 300 mg/m 2 to 500 mg/m 2 when doxorubicin is administered every 3 weeks. The risk of cardiomyopathy is further increased with concomitant cardiotoxic therapy. Assess left ventricular ejection fraction (LVEF) before and regularly during and after treatment with doxorubicin HCl. ( 5.1 ) Secondary Malignancies: Secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) occur at a higher incidence in patients treated with anthracyclines, including doxorubicin. ( 5.2 ) Extravasation and Tissue Necrosis: Extravasation of doxorubicin can result in severe local tissue injury and necrosis requiring wide excision and skin grafting.Immediately terminate the drug, and apply ice to the affected area. ( 5.3 ) Severe myelosuppression resulting in serious infection, septic shock, requirement for transfusions, hospitalization, and death may occur. ( 5.4 )
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warnings and cautions
5 WARNINGS AND PRECAUTIONS Radiation-induced toxicity can be increased by the administration of doxorubicin. Radiation recall can occur in patients who receive doxorubicin after prior radiation therapy ( 5.7 ). Embryofetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to the fetus ( 5.8 ). 5.1 Cardiomyopathy and Arrhythmias Cardiomyopathy Doxorubicin 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. 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). The probability of developing cardiomyopathy 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 , when doxorubicin is administered every 3 weeks. 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 treatment. Assess left ventricular cardiac function (e.g., MUGA or echocardiogram) prior to initiation of doxorubicin, 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 [see Use in Specific Populations (8.4 )] . Consider the use of dexrazoxane to reduce the incidence and severity of cardiomyopathy due to doxorubicin administration in patients who have received a cumulative doxorubicin dose of 300 mg/m 2 and who will continue to receive doxorubicin. Arrhythmias Doxorubicin can result in arrhythmias, including life-threatening arrhythmias, during or within a few hours after doxorubicin administration and at any time point during treatment. Tachyarrhythmias, including sinus tachycardia, premature ventricular contractions, and ventricular tachycardia, as well as bradycardia may 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 dose-modifications of doxorubicin. 5.2 Secondary Malignancies The risk of developing secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) is increased following treatment with doxorubicin. 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. 5.3 Extravasation and Tissue Necrosis Extravasation of doxorubicin can result in severe local tissue injury manifesting as blistering, ulceration, and necrosis requiring wide excision of the affected area and skin grafting. When given via a peripheral venous line, infuse doxorubicin over 10 minutes or less to minimize the risk of thrombosis or perivenous extravasation. If signs or symptoms of extravasation occur, immediately terminate the injection or infusion [see Dosage and Administration (2.3) ] . 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. If extravasation is suspected, apply ice to the site intermittently for 15 minutes, 4 times a day for 3 days. If appropriate, administer dexrazoxane at the site of extravasation as soon as possible and within the first 6 hours after extravasation. 5.4 Severe Myelosuppression Doxorubicin can cause myelosuppression. In Study 1, the incidence of severe myelosuppression was: grade 4 leukopenia (0.3%), grade 3 leukopenia (3%), and grade 4 thrombocytopenia (0.1%). A dose-dependent, reversible neutropenia is the predominant manifestation of hematologic toxicity from doxorubicin. When doxorubicin is administered every 21 days, the neutrophil count reaches its nadir 10 to 14 days after administration with recovery usually occurring by the 21st day. Obtain baseline assessment of blood counts and carefully monitor patients during treatment for possible clinical complications due to myelosuppression. 5.5 Use in Patients with Hepatic Impairment The clearance of doxorubicin is decreased in patients with elevated serum bilirubin with an increased risk of toxicity [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] . Reduce the dose of doxorubicin in patients with serum bilirubin levels of 1.2 to 5.0 mg/dL [see Dosage and Administration (2.2 )] . Doxorubicin is contraindicated in patients with severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin level greater than 5 mg/dL) [see Contraindications (4) ]. Obtain liver tests including SGOT, SGPT, alkaline phosphatase, and bilirubin prior to and during doxorubicin therapy. 5.6 Tumor Lysis Syndrome Doxorubicin may 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. 5.7 Radiation Sensitization and Radiation Recall Doxorubicin 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 after prior radiation therapy. 5.8 Embryofetal Toxicity Doxorubicin can cause fetal harm when administered to a pregnant woman. Doxorubicin was teratogenic and embryotoxic in rats and rabbits at doses lower than the recommended human dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus [see Use in Specific Populations (8.1) ] . Advise female patients of reproductive potential to use highly effective contraception during treatment with doxorubicin and for 6 months after treatment. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking doxorubicin [see Use in Specific Populations (8.1) and ( 8.6 )] .
6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling. Cardiomyopathy and Arrhythmias [see Warnings and Precautions (5.1) ] Secondary Malignancies [see Warnings and Precautions (5.2) ] Extravasation and Tissue Necrosis [see Warnings and Precautions (5.3) ] Severe Myelosuppression [see Warnings and Precautions (5.4) ] Tumor Lysis Syndrome [see Warnings and Precautions (5.6) ] Radiation Sensitization and Radiation Recall [see Warnings and Precautions (5.7) ] The most common (>10%) adverse drug reactions are alopecia, nausea and vomiting ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceutical Corp. at 1-877-845-0689, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience in Breast Cancer 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 clinical practice. The safety data below were collected from 1492 women who received doxorubicin at a dose of 60 mg/m 2 and cyclophosphamide at a dose of 600 mg/m 2 (AC) every 3 weeks for 4 cycles for the adjuvant treatment of axillary lymph node positive breast cancer. The median number of cycles received was 4. Selected adverse reactions reported in this study are provided in Table 1. No treatment-related deaths were reported in patients on either arm of the study. Table 1. Selected Adverse Reactions in Patients with Early Breast Cancer Involving Axillary Lymph Nodes Adverse reactions, % of patients AC* N=1492 Conventional CMF N=739 Leukopenia Grade 3 (1,000 to 1,999 /mm 3 ) Grade 4 (<1000 /mm 3 ) 3.4 0.3 9.4 0.3 Thrombocytopenia Grade 3 (25,000 to 49,999 /mm 3 ) Grade 4 (<25,000 /mm 3 ) 0 0.1 0.3 0 Shock, sepsis 2 1 Systemic infection 2 1 Vomiting Vomiting ≤12 hours Vomiting >12 hours Intractable 34 37 5 25 12 2 Alopecia 92 71 Cardiac dysfunction Asymptomatic Transient Symptomatic 0.2 0.1 0.1 0.1 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 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of doxorubicin. 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 alanine aminotransferase, increased aspartate aminotransferase 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