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WARNING: CARDIOMYOPATHY, SECONDARY MALIGNANCIES, EXTRAVASATION AND TISSUE NECROSIS, and SEVERE MYELOSUPPRESSION • Cardiomyopathy: Myocardial damage, including acute left ventricular failure, can occur with doxorubicin hydrochloride. The risk of cardiomyopathy is proportional to the cumulative exposure with incidence rates from 1%–20% for cumulative doses ranging from 300 mg/m 2 to 500 mg/m 2 when doxorubicin hydrochloride 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 hydrochloride [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 hydrochloride [see Warnings and Precautions (5.2) ] . • Extravasation and Tissue Necrosis: Extravasation of doxorubicin hydrochloride 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 hydrochloride with incidences from 1%–20% for cumulative doses from 300 mg/m 2 to 500 mg/m 2 when doxorubicin hydrochloride 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 hydrochloride. ( 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 hydrochloride. ( 5.2 ) • Extravasation and Tissue Necrosis: Extravasation of doxorubicin hydrochloride 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 )

1 INDICATIONS AND USAGE Doxorubicin Hydrochloride Injection is an anthracycline topoisomerase inhibitor indicated: • as a component of multi‑agent adjuvant chemotherapy for treatment of women with axillary lymph node involvement following resection of primary breast cancer ( 1.1 ) • for the treatment of: acute lymphoblastic leukemia, acute myeloblastic leukemia, Hodgkin lymphoma, Non-Hodgkin lymphoma, metastatic breast cancer, metastatic Wilms' tumor, metastatic neuroblastoma, metastatic soft tissue sarcoma, metastatic bone sarcomas, metastatic ovarian carcinoma, metastatic transitional cell bladder carcinoma, metastatic thyroid carcinoma, metastatic gastric carcinoma, metastatic bronchogenic carcinoma ( 1.2 ) 1.1 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 . 1.2 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

2 DOSAGE AND ADMINISTRATION • Single agent : 60 to 75 mg/m 2 given intravenously every 21 days ( 2.2 ) • In combination : 40 to 75 mg/m 2 given intravenously every 21 to 28 days ( 2.2 ) • Discontinue Doxorubicin Hydrochloride Injection in patients who develop signs or symptoms of cardiomyopathy ( 2.3 ) • Reduce dose in patients with hepatic impairment ( 2.4 ) 2.1 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 . 2.2 Recommended Dosage for Other Cancers • The recommended dosage of Doxorubicin Hydrochloride Injection when used as a single agent is 60 mg/m 2 to 75 mg/m 2 intravenously every 21 days. • The recommended dosage of Doxorubicin Hydrochloride Injection, when administered in combination with other chemotherapy drugs, is 40 mg/m 2 to 75 mg/m 2 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 [see Warnings and Precautions (5.1) ]. 2.3 Dosage Modifications for Adverse Reactions Cardiomyopathy Discontinue Doxorubicin Hydrochloride Injection in patients who develop signs or symptoms of cardiomyopathy [see Warnings and Precautions (5.1) ] . 2.4 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) [see Contraindications (4) ]. Dosage modifications for Doxorubicin Hydrochloride Injection in patients with elevated serum total bilirubin concentrations [see Warnings and Precautions (5.5) , Use in Specific Populations (8.6) ] are provided in Table 1. Table 1. Recommended Dosage Modification for Elevated Serum Total Bilirubin 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 2.5 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.

ted 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. Decrease the rate of infusion if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur. • Protect from light from preparation for infusion until completion of infusion. 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 [see Warnings and Precautions (5.3) ] . 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.

3 DOSAGE FORMS AND STRENGTHS Doxorubicin Hydrochloride Injection: o 10 mg/5 mL, 20 mg/10 mL and 50 mg/25 mL (2 mg/mL) clear red solution in a single-dose vial o 150 mg/75 mL and 200 mg/100 mL (2 mg/mL) clear red solution in a multiple-dose vial Injection: o 10 mg/5 mL, 20 mg/10 mL, 50 mg/25 mL in single-dose vial ( 3 ) o 150 mg/75 mL, and 200 mg/100 mL in multiple-dose vial ( 3 )

4 CONTRAINDICATIONS Doxorubicin Hydrochloride Injection are contraindicated in patients with: • Severe myocardial insufficiency [see Warnings and Precautions (5.1) ] • Recent (occurring within the past 4-6 weeks) myocardial infarction [see Warnings and Precautions (5.1) ] • Severe persistent drug-induced myelosuppression [see Warnings and Precautions (5.4) ] • Severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin level greater than 5 mg/dL) [see Warnings and Precautions (5.5) ] • Severe hypersensitivity reaction to doxorubicin hydrochloride, including anaphylaxis [see Adverse Reactions (6.2) ] • Severe myocardial insufficiency ( 4 ) • Recent myocardial infarction ( 4 ) • Severe persistent drug-induced myelosuppression ( 4 ) • Severe hepatic impairment ( 4 ) • Severe hypersensitivity to doxorubicin hydrochloride ( 4 )

5 WARNINGS AND PRECAUTIONS • Radiation-Induced Toxicity: Can be increased by the administration of Doxorubicin Hydrochloride Injection. Radiation recall can occur in patients who receive Doxorubicin Hydrochloride Injection after prior radiation therapy. ( 5.7) • Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and on the use of effective contraception. Advise males with female partners of reproductive potential to use effective contraception. Advise males with pregnant partners to use condoms. ( 5.8 , 8.1 , 8.3 ) 5.1 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). The probability of developing cardiomyopathy is estimated to be 1 to 2% at a total cumulative dose of 300 mg/m 2 of doxorubicin hydrochloride, 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 hydrochloride 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 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 [see Use in Specific Populations (8.4) ] . Discontinue Doxorubicin Hydrochloride Injection in patients who develop signs or symptoms of cardiomyopathy [see Dosage and Administration (2.3) ] . 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. 5.2 Secondary Malignancies The risk of developing secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) is increased following treatment with doxorubicin hydrochloride.

cardiographic changes may be transient and self-limited and may not require a dosage modification of doxorubicin hydrochloride. 5.2 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. 5.3 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 [see Dosage and Administration (2.5) ] . 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. 5.4 Severe Myelosuppression Doxorubicin hydrochloride 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 myelosuppression from doxorubicin hydrochloride. When doxorubicin hydrochloride is administered every 21 days, the neutrophil count reaches its nadir 10 to 14 days after administration with recovery usually occurring by day 21. 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. 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 (8.6) , Clinical Pharmacology (12.3) ] . 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) [see Contraindications (4) ]. Reduce the dose of Doxorubicin Hydrochloride Injection in patients with serum bilirubin levels of 1.2 to 5 mg/dL [see Dosage and Administration (2.4) ] . Obtain liver tests including ALT, AST, alkaline phosphatase, and bilirubin prior to and during therapy. 5.6 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.

e 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 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. 5.8 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 female partners of reproductive potential to use effective contraception during treatment with Doxorubicin Hydrochloride Injection and for 3 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 [see Use in Specific Populations (8.1 , 8.3) , Nonclinical Toxicology (13.1) ].

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in 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 reactions are alopecia, nausea and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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. Breast Cancer The safety data below were collected from 1492 women who received doxorubicin hydrochloride 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 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 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 6.2 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

<table ID="_RefID0E5QAG" width="90%"><caption>Table 2. Selected Adverse Reactions in Patients with Early Breast Cancer Involving Axillary Lymph Nodes</caption><col width="40%"/><col width="38%"/><col width="22%"/><thead><tr><th align="left" rowspan="2" styleCode="Rrule Lrule Toprule " valign="middle"><content styleCode="bold">Adverse Reactions</content></th><th align="center" styleCode="Rrule Botrule Toprule " valign="middle"><content styleCode="bold">AC</content><footnote ID="_RefID0EVRAG">Includes pooled data from patients who received either AC for 4 cycles or AC for 4 cycles followed by CMF for 3 cycles</footnote> <content styleCode="bold">N = 1492</content></th><th align="center" styleCode="Rrule Botrule Toprule " valign="middle"><content styleCode="bold">Conventional CMF</content> <content styleCode="bold">N = 739</content></th></tr><tr><th align="center" styleCode="Rrule Botrule " valign="middle">%</th><th align="center" styleCode="Rrule Botrule " valign="middle">%</th></tr></thead><tfoot><tr><td align="left" colspan="3" valign="top">AC = doxorubicin hydrochloride, cyclophosphamide; CMF = cyclophosphamide, methotrexate, fluorouracil</td></tr></tfoot><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Alopecia</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>92</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>71</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="middle"><paragraph>Vomiting</paragraph></td><td styleCode="Rrule " valign="middle"/><td styleCode="Rrule " valign="middle"/></tr><tr><td styleCode="Rrule Lrule " valign="middle"><paragraph> Vomiting &#x2264;12 hours</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>34</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>25</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="middle"><paragraph> Vomiting &gt;12 hours</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>37</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>12</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph> Intractable</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="middle"><paragraph>Leukopenia</paragraph></td><td styleCode="Rrule " valign="middle"/><td styleCode="Rrule " valign="middle"/></tr><tr><td styleCode="Rrule Lrule " valign="middle"><paragraph> Grade 3 (1,000&#x2013;1,999 /mm³)</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>3.4</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>9.4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph> Grade 4 (&lt;1000 /mm³)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0.3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Shock, sepsis</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1</paragraph></td></tr>

paragraph>0.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Shock, sepsis</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1</paragraph></td></tr> <tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Systemic infection</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="middle"><paragraph>Cardiac dysfunction</paragraph></td><td styleCode="Rrule " valign="middle"/><td styleCode="Rrule " valign="middle"/></tr><tr><td styleCode="Rrule Lrule " valign="middle"><paragraph> Asymptomatic</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>0.2</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>0.1</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="middle"><paragraph> Transient</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>0.1</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph> Symptomatic</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0.1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="middle"><paragraph>Thrombocytopenia</paragraph></td><td styleCode="Rrule " valign="middle"/><td styleCode="Rrule " valign="middle"/></tr><tr><td styleCode="Rrule Lrule " valign="middle"><paragraph> Grade 3 (25,000&#x2013;49,999 /mm³)</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>0.3</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph> Grade 4 (&lt;25,000 /mm³)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0.1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr></tbody></table>

7 DRUG INTERACTIONS • Avoid concomitant use of doxorubicin hydrochloride with inhibitors and inducers of CYP3A4, CYP2D6, and/or P-gp ( 7.1 ) • Do not administer doxorubicin hydrochloride in combination with trastuzumab due to increased risk of cardiac dysfunction ( 5.1 , 7.2 ) 7.1 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. Avoid concomitant use of Doxorubicin Hydrochloride Injection with inhibitors of CYP3A4, CYP2D6, or P-gp. 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. 7.2 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 [see Warnings and Precautions (5.1) ]. 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. 7.3 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. 7.4 Concomitant Use of 6-Mercaptopurine Doxorubicin hydrochloride may potentiate 6-mercaptopurine-induced hepatotoxicity. In 11 patients with refractory leukemia treated with 6-mercaptopurine (500 mg/m 2 intravenously daily for 5 days per cycle every 2–3 weeks) and doxorubicin hydrochloride (50 mg/m 2 intravenous once per cycle every 2–3 weeks) alone or with vincristine and prednisone, all developed hepatic dysfunction manifested by increased total serum bilirubin, alkaline phosphatase and aspartate aminotransferase.

8 USE IN SPECIFIC POPULATIONS • Lactation : Advise not to breastfeed ( 8.2) • Females and Males of Reproductive Potential : May impair fertility ( 8.3 ) 8.1 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 2 to 4% and 15 to 20%, 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. 8.2 Lactation Risk Summary Doxorubicin was measured in the milk of one lactating patient after therapy with 70 mg/m 2 of doxorubicin hydrochloride given as a 15-minute intravenous infusion. The peak milk concentration at 24 hours after treatment was 4.4-fold greater than the corresponding plasma concentration. Doxorubicin was detectable in the milk up to 72 hours. There are no data on the effects of doxorubicin hydrochloride on the breastfed child or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with Doxorubicin Hydrochloride Injection and for 10 days after the final dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating Doxorubicin Hydrochloride Injection. Contraception Females Doxorubicin Hydrochloride Injection can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1) ] . Advise female patients of reproductive potential to use highly effective contraception during treatment with Doxorubicin Hydrochloride Injection and for 6 months after treatment. [see Use in Specific Populations (8.1) ] . Males Doxorubicin hydrochloride may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities.

oductive potential to use highly effective contraception during treatment with Doxorubicin Hydrochloride Injection and for 6 months after treatment. [see Use in Specific Populations (8.1) ] . Males Doxorubicin hydrochloride may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities. Due to the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with Doxorubicin Hydrochloride Injection and for 3 months after treatment [see Nonclinical Toxicology (13.1) ] . Males with pregnant partners should use condoms during treatment and for at least 10 days after the final dose [see Nonclinical Toxicology (13.1) , Use in Specific Populations (8.1) ] . Infertility Females In females of reproductive potential, Doxorubicin hydrochloride may cause infertility and result in amenorrhea. Premature menopause can occur. Recovery of menses and ovulation is related to age at treatment [see Nonclinical Toxicology (13.1) ] . Males Doxorubicin hydrochloride may result in oligospermia, azoospermia, and permanent loss of fertility. Sperm counts have been reported to return to normal levels in some men. This may occur several years after the end of therapy [see Nonclinical Toxicology (13.1) ] . 8.4 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 [see Clinical Pharmacology (12.3) ] . 8.5 Geriatric Use Clinical experience in patients who were 65 years of age and older who received doxorubicin hydrochloride-based chemotherapy regimens for metastatic breast cancer showed no overall differences in safety and effectiveness compared with younger patients. 8.6 Hepatic Impairment The clearance of doxorubicin was reduced in patients with elevated serum total bilirubin levels. Doxorubicin Hydrochloride Injection is contraindicated in patients with severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin levels greater than 5 mg/dL) [see Contraindications (4) ] . Reduce the dose of Doxorubicin Hydrochloride Injection in patients with serum total bilirubin levels greater than 1.2 mg/dL [See Dosage and Administration (2.4) , Warnings and Precautions (5.5) ] .

8.1 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 2 to 4% and 15 to 20%, 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.

8.4 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 [see Clinical Pharmacology (12.3) ] .

8.5 Geriatric Use Clinical experience in patients who were 65 years of age and older who received doxorubicin hydrochloride-based chemotherapy regimens for metastatic breast cancer showed no overall differences in safety and effectiveness compared with younger patients.

10 OVERDOSAGE 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. A 17-year-old girl with osteogenic sarcoma received 150 mg of doxorubicin hydrochloride daily for 2 days (intended dose was 50 mg per day for 3 days). 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.

11 DESCRIPTION Doxorubicin hydrochloride is an anthracycline topoisomerase inhibitor isolated from cultures of Streptomyces peucetius var. caesius. The chemical name of doxorubicin hydrochloride is 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-α-L- lyxo -hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxylacetyl)-1-methoxy-, hydrochloride (8S- cis )-. The chemical structure of doxorubicin hydrochloride is: Doxorubicin Hydrochloride Injection, for intravenous use is a clear red, sterile, isotonic aqueous solution provided in vials containing 10 mg/5 mL doxorubicin hydrochloride (equivalent to 9.37 mg of doxorubicin free base), 20 mg/10 mL doxorubicin hydrochloride (equivalent to 18.74 mg of doxorubicin free base), 50 mg/25 mL doxorubicin hydrochloride (equivalent to 46.86 mg of doxorubicin free base), 150 mg/75 mL doxorubicin hydrochloride (140.58 mg of doxorubicin free base), or 200 mg/100 mL doxorubicin hydrochloride (equivalent to 187.4 mg of doxorubicin free base). The drug product has demonstrated inherent antimicrobial activity suitable for a multiple dose presentation. Each milliliter of solution contains 2 mg of doxorubicin hydrochloride and 9 mg of sodium chloride. The pH of the solution is adjusted to 3.0 with hydrochloric acid, USP. Chemical Structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The cytotoxic effect of doxorubicin hydrochloride on malignant cells and its toxic effects on various organs are thought to be related to nucleotide base intercalation and cell membrane lipid binding activities of doxorubicin. Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases. The interaction of doxorubicin with topoisomerase II to form DNA-cleavable complexes appears to be an important mechanism of doxorubicin hydrochloride cytocidal activity. 12.3 Pharmacokinetics Pharmacokinetic studies conducted in patients with various types of tumors have shown that doxorubicin follows multiphasic disposition after intravenous injection. In four patients, doxorubicin demonstrated dose-independent pharmacokinetics across a dose range of 30 mg/m 2 to 70 mg/m 2 . Distribution The distribution half-life is approximately 5 minutes. Steady-state distribution volume ranges from 809 L/m 2 to 1214 L/m 2 . Binding of doxorubicin and its major metabolite, doxorubicinol, to plasma proteins is 75% and is independent of plasma concentration of doxorubicin up to 1.1 µg/mL. Doxorubicin does not cross the blood brain barrier. Elimination Plasma clearance is ranges from 324 mL/min/m 2 to 809 mL/min/m 2 . The terminal half-life is 20 hours to 48 hours. Metabolism Doxorubicin is a substrate of CYP3A4, CYP2D6, and P-gp. 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 hydrochloride. Disposition of doxorubicinol in patients is formation rate limited, with the terminal half-life of doxorubicinol being similar to doxorubicin. The relative exposure of doxorubicinol, i.e., the ratio between the AUC of doxorubicinol and the AUC of doxorubicin is approximately 0.5. Excretion Plasma clearance 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 doxorubicinol over 7 days. Specific Populations Weight 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. Pediatric Patients Following administration of doses ranging from 10 mg/m 2 to 75 mg/m 2 of doxorubicin hydrochloride to 60 patients ranging from 2 months to 20 years, doxorubicin clearance averaged 1443 ± 114 mL/min/m 2 . Further analysis demonstrated that clearance in 52 patients ranging from 2 to 20 years (1540 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 patients (ranging from 2 to 20 years) and approached the range of clearance values determined in adults [see Use in Specific Populations (8.4) ] . Sex A published clinical study involving 6 men and 21 women with no prior anthracycline therapy reported a significantly higher median doxorubicin clearance in men compared to women (1088 mL/min/m 2 versus 433 mL/min/m 2 ).

ed the range of clearance values determined in adults [see Use in Specific Populations (8.4) ] . Sex A published clinical study involving 6 men and 21 women with no prior anthracycline therapy reported a significantly higher median doxorubicin clearance in men compared to women (1088 mL/min/m 2 versus 433 mL/min/m 2 ). However, the terminal half-life of doxorubicin was longer in men compared to women (54 versus 35 hours). Patients with Hepatic Impairment The clearance of doxorubicin and doxorubicinol was reduced in patients with elevated serum total bilirubin concentrations [see Dosage and Administration (2.4) , Warnings and Precautions (5.5)] .

12.1 Mechanism of Action The cytotoxic effect of doxorubicin hydrochloride on malignant cells and its toxic effects on various organs are thought to be related to nucleotide base intercalation and cell membrane lipid binding activities of doxorubicin. Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases. The interaction of doxorubicin with topoisomerase II to form DNA-cleavable complexes appears to be an important mechanism of doxorubicin hydrochloride cytocidal activity.

12.3 Pharmacokinetics Pharmacokinetic studies conducted in patients with various types of tumors have shown that doxorubicin follows multiphasic disposition after intravenous injection. In four patients, doxorubicin demonstrated dose-independent pharmacokinetics across a dose range of 30 mg/m 2 to 70 mg/m 2 . Distribution The distribution half-life is approximately 5 minutes. Steady-state distribution volume ranges from 809 L/m 2 to 1214 L/m 2 . Binding of doxorubicin and its major metabolite, doxorubicinol, to plasma proteins is 75% and is independent of plasma concentration of doxorubicin up to 1.1 µg/mL. Doxorubicin does not cross the blood brain barrier. Elimination Plasma clearance is ranges from 324 mL/min/m 2 to 809 mL/min/m 2 . The terminal half-life is 20 hours to 48 hours. Metabolism Doxorubicin is a substrate of CYP3A4, CYP2D6, and P-gp. 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 hydrochloride. Disposition of doxorubicinol in patients is formation rate limited, with the terminal half-life of doxorubicinol being similar to doxorubicin. The relative exposure of doxorubicinol, i.e., the ratio between the AUC of doxorubicinol and the AUC of doxorubicin is approximately 0.5. Excretion Plasma clearance 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 doxorubicinol over 7 days. Specific Populations Weight 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. Pediatric Patients Following administration of doses ranging from 10 mg/m 2 to 75 mg/m 2 of doxorubicin hydrochloride to 60 patients ranging from 2 months to 20 years, doxorubicin clearance averaged 1443 ± 114 mL/min/m 2 . Further analysis demonstrated that clearance in 52 patients ranging from 2 to 20 years (1540 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 patients (ranging from 2 to 20 years) and approached the range of clearance values determined in adults [see Use in Specific Populations (8.4) ] . Sex A published clinical study involving 6 men and 21 women with no prior anthracycline therapy reported a significantly higher median doxorubicin clearance in men compared to women (1088 mL/min/m 2 versus 433 mL/min/m 2 ). However, the terminal half-life of doxorubicin was longer in men compared to women (54 versus 35 hours). Patients with Hepatic Impairment The clearance of doxorubicin and doxorubicinol was reduced in patients with elevated serum total bilirubin concentrations [see Dosage and Administration (2.4) , Warnings and Precautions (5.5)] .

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Doxorubicin hydrochloride treatment can increase the risk of secondary malignancies based on postmarketing reports [see Warnings and Precautions (5.2) ] . Doxorubicin hydrochloride was mutagenic in the in vitro Ames assay, and clastogenic in multiple in vitro assays (CHO cell, V79 hamster cell, human lymphoblast, and SCE assays) and the in vivo mouse micronucleus assay. Doxorubicin hydrochloride decreased fertility in female rats at the doses of 0.05 and 0.2 mg/kg/day (approximately 0.005 and 0.02 times the recommended human dose, based on body surface area). A single intravenous dose of 0.1 mg/kg doxorubicin hydrochloride (approximately 0.01 times the recommended human dose based on body surface area) was toxic to male reproductive organs in animal studies, producing testicular atrophy, diffuse degeneration of the seminiferous tubules, and oligospermia/hypospermia in rats. Doxorubicin hydrochloride induces DNA damage in rabbit spermatozoa and dominant lethal mutations in mice.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Doxorubicin hydrochloride treatment can increase the risk of secondary malignancies based on postmarketing reports [see Warnings and Precautions (5.2) ] . Doxorubicin hydrochloride was mutagenic in the in vitro Ames assay, and clastogenic in multiple in vitro assays (CHO cell, V79 hamster cell, human lymphoblast, and SCE assays) and the in vivo mouse micronucleus assay. Doxorubicin hydrochloride decreased fertility in female rats at the doses of 0.05 and 0.2 mg/kg/day (approximately 0.005 and 0.02 times the recommended human dose, based on body surface area). A single intravenous dose of 0.1 mg/kg doxorubicin hydrochloride (approximately 0.01 times the recommended human dose based on body surface area) was toxic to male reproductive organs in animal studies, producing testicular atrophy, diffuse degeneration of the seminiferous tubules, and oligospermia/hypospermia in rats. Doxorubicin hydrochloride induces DNA damage in rabbit spermatozoa and dominant lethal mutations in mice.

14 CLINICAL STUDIES 14.1 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). The EBCTCG meta-analyses compared cyclophosphamide, methotrexate, and fluorouracil (CMF) to no chemotherapy (19 trials including 7523 patients) and doxorubicin hydrochloride-containing regimens with CMF as an active control (6 trials including 3510 patients). 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). Of the 3510 women (2157 received doxorubicin hydrochloride-containing regimens and 1353 received CMF treatment) with early breast cancer involving axillary lymph nodes included in the six trials from the meta-analyses, approximately 70% were premenopausal and 30% were postmenopausal. 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 0.91 (95% CI: 0.82, 1.01) and on OS with a HR of 0.91 (95% CI: 0.81, 1.03). Efficacy results are provided in Table 3 and Figures 1 and 2. Table 3. Summary of Randomized Trials Comparing Doxorubicin Hydrochloride-Containing Regimens Versus CMF in Meta-Analysis 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 Figure 1. Meta-analysis of Disease-Free Survival Figure 2. Meta-analysis of Overall Survival Figure 1 Figure 2

<table ID="_RefID0EEUBG" width="90%"><caption>Table 3. Summary of Randomized Trials Comparing Doxorubicin Hydrochloride-Containing Regimens Versus CMF in Meta-Analysis</caption><col width="20%"/><col width="19%"/><col width="13%"/><col width="13%"/><col width="19%"/><col width="17%"/><thead><tr styleCode="Toprule"><th align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">Study </content> <content styleCode="bold">(starting year)</content></th><th align="center" rowspan="2" styleCode="Rrule Botrule Toprule " valign="middle"><content styleCode="bold">Regimens</content></th><th align="center" rowspan="2" styleCode="Rrule Botrule Toprule " valign="middle"><content styleCode="bold">No. of Cycles</content></th><th align="center" rowspan="2" styleCode="Rrule Botrule Toprule " valign="middle"><content styleCode="bold">No. of Patients</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="middle"><content styleCode="bold">Doxorubicin Hydrochloride-Containing Regimens vs.

of Cycles</content></th><th align="center" rowspan="2" styleCode="Rrule Botrule Toprule " valign="middle"><content styleCode="bold">No. of Patients</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="middle"><content styleCode="bold">Doxorubicin Hydrochloride-Containing Regimens vs. CMF</content> <content styleCode="bold">HR</content><footnote ID="_RefID0EZVBG">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.</footnote><content styleCode="bold"> (95% CI)</content></th></tr><tr><th align="center" styleCode="Rrule Botrule " valign="middle"><content styleCode="bold">DFS</content></th><th align="center" styleCode="Rrule Botrule " valign="middle"><content styleCode="bold">OS</content></th></tr></thead><tfoot><tr><td align="left" colspan="6" valign="top"><content styleCode="bold">Abbreviations:</content> 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</td></tr></tfoot><tbody><tr><td rowspan="2" styleCode="Rrule Lrule Toprule " valign="middle"><paragraph>NSABP B-15 (1984)</paragraph></td><td align="center" styleCode="Rrule Toprule " valign="middle"><paragraph>AC</paragraph></td><td align="center" styleCode="Rrule Toprule " valign="middle"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Toprule " valign="middle"><paragraph>1562<footnote ID="_RefID0EZWBG">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.</footnote></paragraph></td><td align="center" styleCode="Rrule Toprule " valign="middle"><paragraph>0.93 (0.82, 1.06)</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>0.97 (0.83, 1.12)</paragraph></td></tr><tr><td align="center" styleCode="Rrule " valign="middle"><paragraph>CMF</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>776</paragraph></td><td styleCode="Rrule " valign="middle"/><td styleCode="Rrule " valign="middle"/></tr><tr><td rowspan="2" styleCode="Rrule Lrule " valign="middle"><paragraph>SECSG 2 (1976)</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>FAC</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>260</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>0.86 (0.66, 1.13)</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>0.93 (0.69, 1.26)</paragraph></td></tr><tr><td align="center" styleCode="Rrule " valign="middle"><paragraph>CMF</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>268</paragraph></td><td styleCode="Rrule " valign="middle"/><td styleCode="Rrule " valign="middle"/></tr><tr><td rowspan="2" styleCode="Rrule Lrule " valign="middle"><paragraph>ONCOFRANCE (1978)</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>FACV</paragraph></td><td align="center" styleCode="Rrule " v

/td><td styleCode="Rrule " valign="middle"/><td styleCode="Rrule " valign="middle"/></tr><tr><td rowspan="2" styleCode="Rrule Lrule " valign="middle"><paragraph>ONCOFRANCE (1978)</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>FACV</paragraph></td><td align="center" styleCode="Rrule " v align="middle"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>138</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>0.71 (0.49, 1.03)</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>0.65 (0.44, 0.96)</paragraph></td></tr><tr><td align="center" styleCode="Rrule " valign="middle"><paragraph>CMF</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>113</paragraph></td><td styleCode="Rrule " valign="middle"/><td styleCode="Rrule " valign="middle"/></tr><tr><td rowspan="2" styleCode="Rrule Lrule " valign="middle"><paragraph>SE Sweden BCG A (1980)</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>AC</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>21</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>0.59 (0.22, 1.61)</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>0.53 (0.21, 1.37)</paragraph></td></tr><tr><td align="center" styleCode="Rrule " valign="middle"><paragraph>CMF</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>22</paragraph></td><td styleCode="Rrule " valign="middle"/><td styleCode="Rrule " valign="middle"/></tr><tr><td rowspan="2" styleCode="Rrule Lrule " valign="middle"><paragraph>NSABC Israel Br0283 (1983)</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>AVbCMF<footnote ID="_RefID0EH1BG">Patients received alternating cycles of AVb and CMF.</footnote></paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>4 6</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>55</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>0.91 (0.53, 1.57)</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>0.88 (0.47, 1.63)</paragraph></td></tr><tr><td align="center" styleCode="Rrule " valign="middle"><paragraph>CMF</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>50</paragraph></td><td styleCode="Rrule " valign="middle"/><td styleCode="Rrule " valign="middle"/></tr><tr><td rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Austrian BCSG 3 (1984)</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>CMFVA</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>121</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>1.07 (0.73, 1.55)</paragraph></td><td align="center" styleCode="Rrule " valign="middle"><paragraph>0.93 (0.64, 1.35)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>CMF</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>124</paragraph></td><td styleCode="Rrule Botrule " valign="middle"/><td s

"center" styleCode="Rrule Botrule " valign="middle"><paragraph>CMF</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>124</paragraph></td><td styleCode="Rrule Botrule " valign="middle"/><td s tyleCode="Rrule Botrule " valign="middle"/></tr><tr><td rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Combined Studies</content></paragraph></td><td colspan="2" styleCode="Rrule Lrule Toprule " valign="middle"><paragraph>Doxorubicin Hydrochloride-Containing Regimen</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="middle"><paragraph> <content styleCode="bold">2157</content></paragraph></td><td align="center" rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">0.91 (0.82, 1.01)</content></paragraph></td><td align="center" rowspan="2" styleCode="Rrule Botrule " valign="middle"><paragraph><content styleCode="bold">0.91 (0.81, 1.03)</content></paragraph></td></tr><tr styleCode="Botrule"><td align="center" styleCode="Botrule Lrule " valign="middle"><paragraph>CMF</paragraph></td><td styleCode="Rrule Botrule " valign="middle"/><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph> <content styleCode="bold">1353</content></paragraph></td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING Doxorubicin Hydrochloride Injection, is available as follows: Doxorubicin Hydrochloride Injection is a sterile, isotonic solution, available in single-dose polypropylene (CYTOSAFE) ® vials, and multiple-dose polypropylene (CYTOSAFE) ® vials: Unit of Sale Total Strength/Total Volume (Concentration) NDC 0069-3030-20 Carton of 1 Single-dose Vial 10 mg/5 mL (2 mg/mL) NDC 0069-3031-20 Carton of 1 Single-dose Vial 20 mg/10 mL (2 mg/mL) NDC 0069-3032-20 Carton of 1 Single-dose Vial 50 mg/25 mL (2 mg/mL) NDC 0069-3033-20 Carton of 1 Multiple-dose Vial 150 mg/75 mL (2 mg/mL) NDC 0069-3034-20 Carton of 1 Multiple-dose Vial 200 mg/100 mL (2 mg/mL) Retain in carton until contents are used. For single-dose vials, discard unused portion. Doxorubicin Hydrochloride Injection is a sterile, isotonic solution, available in single-dose ONCO-TAIN ® glass vials, and multiple-dose ONCO-TAIN ® glass vials: Unit of Sale Total Strength/Total Volume (Concentration) NDC 0069-0358-20 Carton of 1 Single-dose Vial 10 mg/5 mL (2 mg/mL) NDC 0069-0277-02 Carton of 1 Single-dose Vial 20 mg/10 mL (2 mg/mL) NDC 0069-0343-02 Carton of 1 Single-dose Vial 50 mg/25 mL (2 mg/mL) NDC 0069-1542-20 Carton of 1 Multiple-dose Vial 200 mg/100 mL (2 mg/mL) ONCO-TAIN ® is the vial external protection system. Retain in carton until contents are used. For single-dose ONCO-TAIN ® glass vials, discard unused portion. Storage Store all vials at 2°C to 8°C (36°F to 46°F). Protect from light. Storage of Doxorubicin Hydrochloride Injection under refrigerated conditions can result in the formation of a gelled product. Place gelled product at room temperature [15ºC to 30ºC (59ºF to 86ºF)] for 2 to 4 hours to return the product to a slightly viscous, mobile solution. Handling and Disposal Doxorubicin Hydrochloride Injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1

<table width="100%"><col width="50%"/><col width="50%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Unit of Sale</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Total Strength/Total Volume</content></paragraph><paragraph><content styleCode="bold">(Concentration)</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">NDC 0069-3030-20</content></paragraph><paragraph>Carton of 1 Single-dose Vial</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10 mg/5 mL</paragraph><paragraph>(2 mg/mL)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">NDC 0069-3031-20</content></paragraph><paragraph>Carton of 1 Single-dose Vial</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>20 mg/10 mL</paragraph><paragraph>(2 mg/mL)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">NDC 0069-3032-20</content></paragraph><paragraph>Carton of 1 Single-dose Vial</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>50 mg/25 mL</paragraph><paragraph>(2 mg/mL)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">NDC 0069-3033-20</content></paragraph><paragraph>Carton of 1 Multiple-dose Vial</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>150 mg/75 mL</paragraph><paragraph>(2 mg/mL)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">NDC 0069-3034-20</content></paragraph><paragraph>Carton of 1 Multiple-dose Vial</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>200 mg/100 mL</paragraph><paragraph>(2 mg/mL)</paragraph></td></tr></tbody></table>

rule " valign="top"><paragraph><content styleCode="bold">NDC 0069-3034-20</content></paragraph><paragraph>Carton of 1 Multiple-dose Vial</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>200 mg/100 mL</paragraph><paragraph>(2 mg/mL)</paragraph></td></tr></tbody></table> <table width="100%"><col width="48%"/><col width="50%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Unit of Sale</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Total Strength/Total Volume</content></paragraph><paragraph><content styleCode="bold">(Concentration)</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">NDC 0069-0358-20</content></paragraph><paragraph>Carton of 1 Single-dose Vial</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10 mg/5 mL</paragraph><paragraph>(2 mg/mL)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">NDC 0069-0277-02</content></paragraph><paragraph>Carton of 1 Single-dose Vial</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>20 mg/10 mL</paragraph><paragraph>(2 mg/mL)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">NDC 0069-0343-02</content></paragraph><paragraph>Carton of 1 Single-dose Vial</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>50 mg/25 mL</paragraph><paragraph>(2 mg/mL)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">NDC 0069-1542-20</content></paragraph><paragraph>Carton of 1 Multiple-dose Vial</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>200 mg/100 mL</paragraph><paragraph>(2 mg/mL)</paragraph></td></tr></tbody></table>

Storage Store all vials at 2°C to 8°C (36°F to 46°F). Protect from light. Storage of Doxorubicin Hydrochloride Injection under refrigerated conditions can result in the formation of a gelled product. Place gelled product at room temperature [15ºC to 30ºC (59ºF to 86ºF)] for 2 to 4 hours to return the product to a slightly viscous, mobile solution.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Cardiomyopathy Advise patients that Doxorubicin Hydrochloride Injection can cause irreversible myocardial damage and to contact a healthcare provider for symptoms of heart failure during or after treatment [see Warnings and Precautions (5.1) ] . Secondary Malignancy Advise patients of the increased risk of treatment-related leukemia [see Warnings and Precautions (5.2) ] . Myelosuppression Advise patients that Doxorubicin Hydrochloride Injection can reduce the absolute neutrophil count resulting in an increased risk of infection and to contact a healthcare provider for new onset fever or symptoms of infection [see Warnings and Precautions (5.4) ] . Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential of the potential risk to a fetus, and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.8) , Use in Specific Populations (8.1) ] . Advise females of reproductive potential to use effective contraception during treatment with Doxorubicin Hydrochloride Injection and for 6 months after treatment [see Warnings and Precautions (5.8) , Use in Specific Populations (8.3) ] . Advise patients that Doxorubicin Hydrochloride Injection may induce chromosomal damage in sperm, which may lead to loss of fertility and offspring with birth defects. Advise males with female partners of reproductive potential to use effective contraception during treatment with Doxorubicin Hydrochloride Injection and for 3 months after treatment [see Warnings and Precautions (5.8) , Use in Specific Populations (8.3) , Nonclinical Toxicology (13.1) ] . Advise males with pregnant partners to use condoms during treatment with Doxorubicin Hydrochloride Injection and for at least 10 days after the final dose [see Use in Specific Populations (8.3) ] . Lactation Advise females not to breastfeed during treatment with Doxorubicin Hydrochloride Injection and for 10 days after the final dose [see Use in Specific Populations (8.2) ] . Infertility Advise females and males of the potential loss of fertility from Doxorubicin Hydrochloride Injection [see Use in Specific Populations (8.3) ] . Gastrointestinal and Dermatologic Adverse Reactions Advise patients that Doxorubicin Hydrochloride Injection can cause nausea, vomiting, diarrhea, mouth/oral pain and sores and to contact a healthcare provider should they develop any severe symptoms that prevent them from eating and drinking [see Adverse Reactions (6) ] . Advise patients that Doxorubicin Hydrochloride Injection can cause alopecia [see Adverse Reactions (6.1) ] . Administration Advise patients that Doxorubicin Hydrochloride Injection can cause their urine to appear red for 1 to 2 days after administration.

Patient Information DOXORUBICIN (dok-s uh - roo -b uh -sin) HYDROCHLORIDE injection, for intravenous use What is the most important information I should know about Doxorubicin? Doxorubicin may cause serious side effects including: • Heart muscle problems. Doxorubicin can cause heart muscle damage that may lead to heart failure. Heart failure means your heart does not pump blood well. Heart failure is irreversible in some cases and can lead to death. Heart failure can happen during your treatment with Doxorubicin or months to years after stopping treatment. Your risk of heart muscle damage increases with higher total amounts of Doxorubicin that you receive in your lifetime. Your risk of heart failure is higher if you: o have other heart problems o have had or are currently receiving radiation therapy to your chest o have had treatment with certain other anti-cancer medicines o take other medicines that can have severe side effects on your heart Tell your healthcare provider if you get any of these symptoms of heart failure during or after treatment with Doxorubicin: o extreme tiredness or weakness o shortness of breath o fast heartbeat o swelling of your feet and ankles Your healthcare provider will do tests to check the strength of your heart muscle before, during, and after your treatment with Doxorubicin. • Heart rhythm problems. Doxorubicin can cause serious heart rhythm problems that may lead to death. This can happen during your infusion, within a few hours after your infusion or anytime during treatment with Doxorubicin. Tell your healthcare provider if you get any symptoms of heart rhythm problems, such as feeling as if your heart is beating fast, irregular or slow, or you feel lightheaded, dizzy, short of breath, chest discomfort or you faint. • Risk of new cancers. You may have an increased risk of developing certain blood cancers called acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) after treatment with Doxorubicin. Talk with your healthcare provider about your risk of developing new cancers if you receive Doxorubicin. • Skin damage at or near the vein where Doxorubicin is given. Doxorubicin can damage the skin if it leaks out of the vein and might cause blisters, skin sores or severe tissue damage, which may require skin grafts. Tell your healthcare provider if you get burning or stinging during your infusion. • Decreased blood cell counts. Doxorubicin can cause a decrease in neutrophils (a type of white blood cell important in fighting bacterial infections) and platelets (important for clotting and to control bleeding). This may lead to a serious infection, the need for blood transfusions, treatment in a hospital or death. Your healthcare provider will check your blood cell counts before each infusion and during treatment with Doxorubicin. Call your healthcare provider right away if you get a fever (temperature of 100.4°F or higher) or chills with shivering. What is Doxorubicin? Doxorubicin is a prescription medicine used to treat certain types of cancers. Doxorubicin may be used alone or along with other anti-cancer medicines. Do not receive Doxorubicin if: • you have had a recent heart attack (within the past 4 to 6 weeks) or have severe heart problems. • your blood cell counts (platelets, red blood cells, and white blood cells) are very low because of prior chemotherapy. • you have severe liver problems. • you have had a severe allergic reaction to Doxorubicin.

icin if: • you have had a recent heart attack (within the past 4 to 6 weeks) or have severe heart problems. • your blood cell counts (platelets, red blood cells, and white blood cells) are very low because of prior chemotherapy. • you have severe liver problems. • you have had a severe allergic reaction to Doxorubicin. Before you receive Doxorubicin, tell your healthcare provider about all of your medical conditions, including if you: • have heart problems including heart failure. • are currently receiving radiation therapy or plan to receive radiation to the chest. • have liver problems. • have had an allergic reaction to doxorubicin. • are pregnant or plan to become pregnant. Doxorubicin can harm your unborn baby. You should not become pregnant during treatment with Doxorubicin. Tell your healthcare provider right away if you become pregnant or think you may be pregnant. Females who are able to become pregnant : o Your healthcare provider will check to see if you are pregnant before you start treatment with Doxorubicin. o You should use effective birth control (contraception) during treatment with Doxorubicin and for 6 months after treatment. Males : o Doxorubicin can affect your sperm and could cause birth defects. o If you have a female partner who can become pregnant, you should use effective birth control during treatment with Doxorubicin and for 3 months after treatment. o If you have a pregnant partner, you should use condoms during treatment with Doxorubicin and for at least 10 days after the final dose. o Talk to your healthcare provider about birth control methods that may be right for you. • are breastfeeding or plan to breastfeed. Doxorubicin can pass into your breast milk. Do not breastfeed during treatment with Doxorubicin and for 10 days after the final dose. Talk to your healthcare provider about the best way to feed your baby during this time. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How will I receive Doxorubicin? • Doxorubicin will be given to you into your vein through an intravenous (IV) line. • Your healthcare provider will do blood tests to check for side effects during treatment with Doxorubicin. • Your healthcare provider may stop your treatment, change the timing of your treatment, or change the dose of your treatment if you have certain side effects while receiving Doxorubicin. What are the possible side effects of Doxorubicin? Doxorubicin may cause serious side effects, including: • See “ What is the most important information I should know about Doxorubicin? ” The most common side effects of Doxorubicin include: • total hair loss (alopecia). Your hair may re-grow after your treatment. • nausea • vomiting Other side effects: • Red colored urine. You may have red colored urine for 1 to 2 days after your infusion of Doxorubicin. This is normal. Tell your healthcare provider if it does not stop in a few days, or if you see what looks like blood or blood clots in your urine. • Call your healthcare provider if you have severe symptoms that prevent you from eating or drinking, such as: o nausea o vomiting o diarrhea o mouth pain or sores Doxorubicin may cause fertility problems in males. This could affect your ability to father a child. Talk to your healthcare provider if this is a concern for you. Doxorubicin may cause fertility problems in females. Your periods (menstrual cycle) may completely stop when you receive Doxorubicin. Your periods may or may not return following treatment. Early menopause has also happened. Talk to your healthcare provider if this is a concern for you. These are not all of the possible side effects of Doxorubicin. Call your doctor for medical advice about side effects.

y completely stop when you receive Doxorubicin. Your periods may or may not return following treatment. Early menopause has also happened. Talk to your healthcare provider if this is a concern for you. These are not all of the possible side effects of Doxorubicin. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of Doxorubicin. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about Doxorubicin that is written for health professionals. What are the ingredients in Doxorubicin? Active ingredient: doxorubicin hydrochloride Inactive ingredients for Doxorubicin Hydrochloride Injection: sodium chloride, and hydrochloric acid, USP. LAB-0436-5.0 For more information, call 1-800-438-1985 or visit www.pfizer.com . This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 7/2024 Logo

<table width="100%"><col width="3%"/><col width="35%"/><col width="29%"/><col width="34%"/><tbody><tr><td align="center" colspan="4" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Patient Information</content></paragraph></td></tr><tr><td align="center" colspan="4" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">DOXORUBICIN</content> (dok-s<content styleCode="italics">uh</content>-<content styleCode="bold">roo</content>-b<content styleCode="italics">uh</content>-sin) <content styleCode="bold">HYDROCHLORIDE</content> <content styleCode="bold">injection, for intravenous use </content></paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Lrule " valign="top"><paragraph ID="whatisthemostimportantinformation"><content styleCode="bold">What is the most important information I should know about Doxorubicin? </content></paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Doxorubicin may cause serious side effects including:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption><content styleCode="bold">Heart muscle problems.</content> Doxorubicin can cause heart muscle damage that may lead to heart failure. Heart failure means your heart does not pump blood well. Heart failure is irreversible in some cases and can lead to death. Heart failure can happen during your treatment with Doxorubicin or months to years after stopping treatment. Your risk of heart muscle damage increases with higher total amounts of Doxorubicin that you receive in your lifetime. Your risk of heart failure is higher if you: <list listType="unordered"><item><caption>o</caption>have other heart problems</item><item><caption>o</caption>have had or are currently receiving radiation therapy to your chest </item><item><caption>o</caption>have had treatment with certain other anti-cancer medicines</item><item><caption>o</caption>take other medicines that can have severe side effects on your heart <paragraph>Tell your healthcare provider if you get any of these symptoms of heart failure during or after treatment with Doxorubicin:</paragraph></item></list></item></list></td></tr><tr><td styleCode="Lrule " valign="top"/><td valign="top"><list listType="unordered"><item><caption>o</caption>extreme tiredness or weakness</item><item><caption>o</caption>shortness of breath</item></list></td><td valign="top"><list listType="unordered"><item><caption>o</caption>fast heartbeat</item><item><caption>o</caption>swelling of your feet and ankles</item></list></td><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Lrule " valign="top"/><td colspan="3" styleCode="Rrule " valign="top"><paragraph>Your healthcare provider will do tests to check the strength of your heart muscle before, during, and after your treatment with Doxorubicin.</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption>&#x2022;</caption><content styleCode="bold">Heart rhythm problems.</content> Doxorubicin can cause serious heart rhythm problems that may lead to death. This can happen during your infusion, within a few hours after your infusion or anytime during treatment with Doxorubicin.

p"><list listType="unordered"><item><caption>&#x2022;</caption><content styleCode="bold">Heart rhythm problems.</content> Doxorubicin can cause serious heart rhythm problems that may lead to death. This can happen during your infusion, within a few hours after your infusion or anytime during treatment with Doxorubicin. Tell your healthcare provider if you get any symptoms of heart rhythm problems, such as feeling as if your heart is beating fast, irregular or slow, or you feel lightheaded, dizzy, short of breath, chest discomfort or you faint. </item><item><caption>&#x2022;</caption><content styleCode="bold">Risk of new cancers.</content> You may have an increased risk of developing certain blood cancers called acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) after treatment with Doxorubicin. Talk with your healthcare provider about your risk of developing new cancers if you receive Doxorubicin. </item><item><caption>&#x2022;</caption><content styleCode="bold">Skin damage at or near the vein where Doxorubicin is given.</content> Doxorubicin can damage the skin if it leaks out of the vein and might cause blisters, skin sores or severe tissue damage, which may require skin grafts. Tell your healthcare provider if you get burning or stinging during your infusion. </item><item><caption>&#x2022;</caption><content styleCode="bold">Decreased blood cell counts.</content> Doxorubicin can cause a decrease in neutrophils (a type of white blood cell important in fighting bacterial infections) and platelets (important for clotting and to control bleeding). This may lead to a serious infection, the need for blood transfusions, treatment in a hospital or death. Your healthcare provider will check your blood cell counts before each infusion and during treatment with Doxorubicin. Call your healthcare provider right away if you get a fever (temperature of 100.4&#xB0;F or higher) or chills with shivering.</item></list></td></tr><tr><td colspan="4" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">What is Doxorubicin?</content></paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Doxorubicin is a prescription medicine used to treat certain types of cancers. Doxorubicin may be used alone or along with other anti-cancer medicines.</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Do not receive Doxorubicin if: </content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>you have had a recent heart attack (within the past 4 to 6 weeks) or have severe heart problems.</item><item><caption>&#x2022;</caption>your blood cell counts (platelets, red blood cells, and white blood cells) are very low because of prior chemotherapy.</item><item><caption>&#x2022;</caption>you have severe liver problems.</item><item><caption>&#x2022;</caption>you have had a severe allergic reaction to Doxorubicin.</item></list></td></tr><tr><td colspan="4" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Before you receive Doxorubicin, tell your healthcare provider about all of your medical conditions, including if you:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>have heart problems including heart failure.</item><item><caption>&#x2022;</caption>are currently receiving radiation therapy or plan to receive radiation to the chest.</item><item><caption>&#x2022;</caption>have liver problems.</item><item><caption>&#x2022;</caption>have had an allergic reaction to doxorubicin.</item><item><caption>&#x2022;</caption>are pregnant or plan to become pregnant. Doxorubicin can harm your unborn baby. You should not become pregnant during treatment with Doxorubicin.

em><caption>&#x2022;</caption>have liver problems.</item><item><caption>&#x2022;</caption>have had an allergic reaction to doxorubicin.</item><item><caption>&#x2022;</caption>are pregnant or plan to become pregnant. Doxorubicin can harm your unborn baby. You should not become pregnant during treatment with Doxorubicin. Tell your healthcare provider right away if you become pregnant or think you may be pregnant. <content styleCode="bold">Females who are able to become pregnant</content>: <list listType="unordered"><item><caption>o</caption>Your healthcare provider will check to see if you are pregnant before you start treatment with Doxorubicin.</item><item><caption>o</caption>You should use effective birth control (contraception) during treatment with Doxorubicin and for 6 months after treatment.</item></list></item><item><caption> </caption><content styleCode="bold">Males</content>:<list listType="ordered"><item><caption>o</caption>Doxorubicin can affect your sperm and could cause birth defects.</item><item><caption>o</caption>If you have a female partner who can become pregnant, you should use effective birth control during treatment with Doxorubicin and for 3 months after treatment.</item><item><caption>o</caption>If you have a pregnant partner, you should use condoms during treatment with Doxorubicin and for at least 10 days after the final dose.</item><item><caption>o</caption>Talk to your healthcare provider about birth control methods that may be right for you.</item></list></item><item><caption>&#x2022;</caption>are breastfeeding or plan to breastfeed. Doxorubicin can pass into your breast milk. Do not breastfeed during treatment with Doxorubicin and for 10 days after the final dose. Talk to your healthcare provider about the best way to feed your baby during this time. </item></list></td></tr><tr><td colspan="4" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Tell your healthcare provider about all the medicines you take,</content> including prescription and over-the-counter medicines, vitamins, and herbal supplements. </paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How will I receive Doxorubicin? </content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Doxorubicin will be given to you into your vein through an intravenous (IV) line.</item><item><caption>&#x2022;</caption>Your healthcare provider will do blood tests to check for side effects during treatment with Doxorubicin.</item><item><caption>&#x2022;</caption>Your healthcare provider may stop your treatment, change the timing of your treatment, or change the dose of your treatment if you have certain side effects while receiving Doxorubicin. </item></list></td></tr><tr><td colspan="4" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">What are the possible side effects of Doxorubicin? </content></paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Doxorubicin may cause serious side effects, including:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>See <content styleCode="bold">&#x201C;<linkHtml href="#whatisthemostimportantinformation">What is the most important information I should know about Doxorubicin?</linkHtml>&#x201D;</content></item></list></td></tr><tr><td colspan="4" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">The most common side effects of Doxorubicin include:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>total hair loss (alopecia).

oxorubicin?</linkHtml>&#x201D;</content></item></list></td></tr><tr><td colspan="4" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">The most common side effects of Doxorubicin include:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>total hair loss (alopecia). Your hair may re-grow after your treatment.</item><item><caption>&#x2022;</caption>nausea</item><item><caption>&#x2022;</caption>vomiting</item></list></td></tr><tr><td colspan="4" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Other side effects:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Red colored urine. You may have red colored urine for 1 to 2 days after your infusion of Doxorubicin. This is normal. Tell your healthcare provider if it does not stop in a few days, or if you see what looks like blood or blood clots in your urine. </item><item><caption>&#x2022;</caption>Call your healthcare provider if you have severe symptoms that prevent you from eating or drinking, such as:<list listType="unordered"><item><caption>o</caption>nausea</item><item><caption>o</caption>vomiting</item><item><caption>o</caption>diarrhea</item><item><caption>o</caption>mouth pain or sores</item></list></item></list></td></tr><tr><td colspan="4" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Doxorubicin may cause fertility problems in males.</content> This could affect your ability to father a child. Talk to your healthcare provider if this is a concern for you. </paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Doxorubicin may cause fertility problems in females.</content> Your periods (menstrual cycle) may completely stop when you receive Doxorubicin. Your periods may or may not return following treatment. Early menopause has also happened. Talk to your healthcare provider if this is a concern for you. </paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Lrule " valign="top"><paragraph>These are not all of the possible side effects of Doxorubicin.</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. </paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">General information about the safe and effective use of Doxorubicin.</content></paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Lrule " valign="top"><paragraph> Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet.</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>You can ask your pharmacist or healthcare provider for information about Doxorubicin that is written for health professionals.</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">What are the ingredients in Doxorubicin?

le Botrule " valign="top"><paragraph>You can ask your pharmacist or healthcare provider for information about Doxorubicin that is written for health professionals.</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">What are the ingredients in Doxorubicin? </content></paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Active ingredient:</content> doxorubicin hydrochloride </paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Inactive ingredients for Doxorubicin Hydrochloride Injection:</content> sodium chloride, and hydrochloric acid, USP.</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Lrule " valign="top"><renderMultiMedia ID="id2469" referencedObject="MM4a"/></td></tr><tr><td colspan="4" styleCode="Rrule Lrule " valign="top"><paragraph>LAB-0436-5.0</paragraph></td></tr><tr><td colspan="4" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> For more information, call 1-800-438-1985 or visit <linkHtml href="https://www.pfizer.com/">www.pfizer.com</linkHtml>.</paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph>This Patient Information has been approved by the U.S. Food and Drug Administration.</paragraph></td><td align="right" valign="top"><paragraph>Revised: 7/2024</paragraph></td></tr></tbody></table>

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 hydrochloride with incidences from 1% to 20% for cumulative doses from 300 mg/m 2 to 500 mg/m 2 when doxorubicin hydrochloride 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 hydrochloride. ( 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 hydrochloride. ( 5.2 ). • Extravasation and Tissue Necrosis: Extravasation of doxorubicin hydrochloride 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 ). WARNING: CARDIOMYOPATHY, SECONDARY MALIGNANCIES, EXTRAVASATION AND TISSUE NECROSIS and SEVERE MYELOSUPPRESSION • Cardiomyopathy: Myocardial damage, including acute left ventricular failure can occur with doxorubicin hydrochloride. The risk of cardiomyopathy is proportional to the cumulative exposure with incidence rates from 1% to 20% for cumulative doses ranging from 300 mg/m 2 to 500 mg/m 2 when doxorubicin hydrochloride 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 hydrochloride [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 hydrochloride [see Warnings and Precautions (5.2) ]. • Extravasation and Tissue Necrosis: Extravasation of doxorubicin hydrochloride 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) ].

1. INDICATIONS AND USAGE Doxorubicin hydrochloride, USP is an anthracycline topoisomerase II inhibitor indicated: • as a component of multiagent adjuvant chemotherapy for treatment of women with axillary lymph node involvement following resection of primary breast cancer ( 1.1 ). • for the treatment of: acute lymphoblastic leukemia, acute myeloblastic leukemia, Hodgkin lymphoma, Non-Hodgkin lymphoma, metastatic breast cancer, metastatic Wilms' tumor, metastatic neuroblastoma, metastatic soft tissue sarcoma, metastatic bone sarcomas, metastatic ovarian carcinoma, metastatic transitional cell bladder carcinoma, metastatic thyroid carcinoma, metastatic gastric carcinoma, metastatic bronchogenic carcinoma ( 1.2 ). 1.1 Adjuvant Breast Cancer Doxorubicin hydrochloride, USP 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 [see Clinical Studies (14) ] . 1.2 Other Cancers Doxorubicin hydrochloride, USP 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

2. DOSAGE AND ADMINISTRATION • Single agent: 60 to 75 mg/m 2 given intravenously every 21 days ( 2.1 ). • In combination therapy: 40 to 75 mg/m 2 given intravenously every 21 to 28 days ( 2.1 ). • Discontinue doxorubicin hydrochloride in patients who develop signs or symptoms of cardiomyopathy ( 2.2 ). • Reduce dose in patients with hepatic impairment ( 2.2 ). 2.1 Recommended Dose Adjuvant Breast Cancer The recommended dose of doxorubicin hydrochloride, USP 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 [see Clinical Studies (14) ]. Metastatic Disease, Leukemia, or Lymphoma • The recommended dose of doxorubicin hydrochloride, USP when used as a single agent is 60 to 75 mg/m 2 intravenously every 21 days. • The recommended dose of doxorubicin hydrochloride, USP, when administered in combination with other chemotherapy drugs, is 40 to 75 mg/m 2 intravenously every 21 to 28 days. • Consider use of the lower doxorubicin dose in the recommended dose 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 [see Warnings and Precautions (5.1) ]. 2.2 Dose Modifications Cardiac Impairment Discontinue doxorubicin in patients who develop signs or symptoms of cardiomyopathy. Hepatic Impairment Doxorubicin hydrochloride, USP is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C or serum bilirubin >5.0 mg/dL) [see Contraindications (4) ]. Decrease the dose of doxorubicin hydrochloride, USP in patients with elevated serum total bilirubin concentrations as follows: Serum bilirubin concentration Doxorubicin hydrochloride, USP Dose reduction 1.2 to 3 mg/dL 50 % 3.1 to 5 mg/dL 75 % greater than 5 mg/dL Do not initiate doxorubicin hydrochloride, USP Discontinue doxorubicin hydrochloride, USP [see Warnings and Precautions (5.5) and Use in Specific Populations (8.7) ] 2.3 Preparation and Administration Preparation of Doxorubicin Hydrochloride for injection, USP Reconstitute doxorubicin hydrochloride for injection, USP with 0.9% Sodium Chloride Injection, USP to obtain a final concentration of 2 mg per mL as follows: • 5 mL 0.9% Sodium Chloride Injection, USP to reconstitute 10 mg doxorubicin hydrochloride, USP vial. • 25 mL 0.9% Sodium Chloride Injection, USP to reconstitute 50 mg doxorubicin hydrochloride, USP vial. Gently shake vial until the contents have dissolved. Protect reconstituted solution from light. Administration Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if the solution is discolored, cloudy, or contains particulate matter. Storage of vials of Doxorubicin hydrochloride for injection, USP following reconstitution under refrigerated conditions can result in the formation of a gelled product. Place gelled product at room temperature [15 0 to 30 0 C (59 0 to 86 0 F)] for 2 to 4 hours to return the product to a slightly viscous, mobile solution. Administration by Intravenous Injection: • Administer doxorubicin hydrochloride, USP 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.

on. Administration by Intravenous Injection: • Administer doxorubicin hydrochloride, USP 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 doxorubicin hydrochloride, USP intravenously over 3 to 10 minutes. Decrease the rate of doxorubicin hydrochloride, USP administration if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur. Administration by Continuous Intravenous Infusion: Infuse only through a central catheter. Decrease the rate of doxorubicin hydrochloride, USP administration if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur. Protect from light from preparation for infusion until completion of infusion. • Infuse only through a central catheter. Decrease the rate of doxorubicin hydrochloride, USP administration if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur. • Protect from light from preparation for infusion until completion of infusion. Management of Suspected Extravasation Discontinue doxorubicin hydrochloride, USP 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 min 4 times a day for 3 days. • If the extravasation is in an extremity, elevate the extremity. • In adults, consider administration of dexrazoxane [see Warnings and Precautions (5.3)] . Incompatibility with Other Drugs Do not admix doxorubicin hydrochloride, USP with other drugs. If doxorubicin hydrochloride, USP is mixed with heparin or fluorouracil a precipitate may form. Avoid contact with alkaline solutions which can lead to hydrolysis of doxorubicin hydrochloride, USP. 2.4 Procedures for Proper Handling and Disposal Handle and dispose of doxorubicin hydrochloride, USP consistent with recommendations for the handling and disposal of hazardous drugs. 1 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.

3. DOSAGE FORMS AND STRENGTHS • Doxorubicin hydrochloride for injection: Vials contain 10 mg and 50 mg as a lyophilized powder ( 3 ) Doxorubicin hydrochloride for injection, USP: Vials contain 10 mg and 50 mg doxorubicin hydrochloride as a red-orange lyophilized powder.

4. CONTRAINDICATIONS • Severe myocardial insufficiency ( 4 ) • Recent myocardial infarction ( 4 ) • Severe persistent drug-induced myelosuppression ( 4 ) • Severe hepatic impairment ( 4 ) • Hypersensitivity to doxorubicin hydrochloride ( 4 ) Doxorubicin hydrochloride is contraindicated in patients with: • Severe myocardial insufficiency [see Warnings and Precautions (5.1) ] • Recent (occurring within the past 4-6 weeks) myocardial infarction [see Warnings and Precautions (5.1) ] • Severe persistent drug-induced myelosuppression [see Warnings and Precautions (5.4) ] • Severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin level greater than 5 mg/dL) [see Warnings and Precautions (5.5) ] • Severe hypersensitivity reaction to doxorubicin hydrochloride including anaphylaxis [see Adverse Reactions (6.2) ]

5. WARNINGS AND PRECAUTIONS • Radiation-induced toxicity can be increased by the administration of doxorubicin hydrochloride. Radiation recall can occur in patients who receive doxorubicin hydrochloride 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 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). The probability of developing cardiomyopathy is estimated to be 1 to 2% at a total cumulative dose of 300 mg/m 2 of doxorubicin hydrochloride, 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 hydrochloride 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 hydrochloride treatment. Assess left ventricular cardiac function (e.g., MUGA or echocardiogram) prior to initiation of doxorubicin hydrochloride, 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 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 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 hydrochloride. 5.2 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.

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. 5.3 Extravasation and Tissue Necrosis Extravasation of doxorubicin hydrochloride 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 hydrochloride 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 hydrochloride. When doxorubicin hydrochloride 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 hydrochloride in patients with serum bilirubin levels of 1.2 to 5 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 hydrochloride therapy. 5.6 Tumor Lysis Syndrome Doxorubicin hydrochloride 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 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. 5.8 Embryofetal Toxicity Doxorubicin hydrochloride can cause fetal harm when administered to a pregnant woman. Doxorubicin hydrochloride 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) ] .

oxorubicin hydrochloride 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 hydrochloride 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 hydrochloride [see Use in Specific Populations (8.1) and (8.6) ] .

6. ADVERSE REACTIONS The most common (>10%) adverse drug reactions are alopecia, nausea and vomiting ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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) ] 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 hydrochloride 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 AC * 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 Conventional CMF N=1492 N=739 Adverse reactions, % of patients Leukopenia Grade 3 (1,000 to 1,999 /mm3) Grade 4 (<1000 /mm3) 3.4 0.3 9.4 0.3 Thrombocytopenia Grade 3 (25,000 to 49,999 /mm3) 0 0.1 0.3 0 Grade 4 (<25,000 /mm3) 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 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of doxorubicin hydrochloride. 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

<table ID="_RefID450" styleCode="Noautorules" width="100%"><caption>Table 1. Selected Adverse Reactions in Patients with Early Breast Cancer Involving Axillary Lymph Nodes</caption><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph>AC<footnote ID="_Ref151958103">* 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</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>Conventional CMF</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>N=1492</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>N=739</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Adverse reactions, % of patients</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Leukopenia</paragraph><paragraph> Grade 3 (1,000 to 1,999 /mm3)</paragraph><paragraph> Grade 4 (&lt;1000 /mm3)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph> 3.4 0.3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph> 9.4 0.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Thrombocytopenia</paragraph><paragraph> Grade 3 (25,000 to 49,999 /mm3)</paragraph></td><td align="center" rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph> 0 0.1</paragraph></td><td align="center" rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph> 0.3 0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Grade 4 (&lt;25,000 /mm3)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Shock, sepsis</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Systemic infection</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Vomiting</paragraph><paragraph> Vomiting&#x2264;12 hours</paragraph><paragraph> Vomiting &gt;12 hours</paragraph><paragraph> Intractable</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph> 34 37 5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph> 25 12 2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Alopecia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>92</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>71</paragraph></td></tr><tr><td styleCod

><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Alopecia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>92</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>71</paragraph></td></tr><tr><td styleCod e="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Cardiac dysfunction</paragraph><paragraph> Asymptomatic</paragraph><paragraph> Transient</paragraph><paragraph> Symptomatic</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph> 0.2 0.1 0.1</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph> 0.1 0 0</paragraph></td></tr></tbody></table>

7. DRUG INTERACTIONS • Avoid concurrent use of doxorubicin hydrochloride with inhibitors and inducers of CYP3A4, CYP2D6, and/or P-gp ( 7.1 ). • Do not administer doxorubicin hydrochloride in combination with trastuzumab due to increased risk of cardiac dysfunction ( 5.1 , 7.2 ). 7.1 Effect of CYP3A4 Inhibitors, Inducers and P-gp Doxorubicin is a major substrate of cytochrome P450 CYP3A4 and CYP2D6, and P-glycoprotein (P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4, CYP2D6, and/or P-gp (e.g., verapamil), resulting in increased concentration and clinical effect of doxorubicin. Inducers of CYP3A4 (e.g., phenobarbital, phenytoin, St. John's Wort) and P-gp inducers may decrease the concentration of doxorubicin. Avoid concurrent use of doxorubicin hydrochloride with inhibitors and inducers of CYP3A4, CYP2D6, or P-gp. 7.2 Trastuzumab Concurrent use of trastuzumab and doxorubicin hydrochloride results in an increased risk of cardiac dysfunction. Avoid concurrent administration of doxorubicin and trastuzumab. The appropriate interval for administering doxorubicin following trastuzumab therapy has not been determined [see Warnings and Precautions (5.1) ]. 7.3 Paclitaxel Paclitaxel, when given prior to doxorubicin hydrochloride, increases the plasma-concentrations of doxorubicin and its metabolites. Administer doxorubicin hydrochloride prior to paclitaxel if used concomitantly. 7.4 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 than in women who received doxorubicin hydrochloride-based chemotherapy alone. 7.5 6-Mercaptopurine Doxorubicin hydrochloride may potentiate 6-mercaptopurine-induced hepatotoxicity. In 11 patients with refractory leukemia treated with 6-mercaptopurine (500 mg/m 2 intravenously daily for 5 days per cycle every 2-3 weeks) and doxorubicin hydrochloride (50 mg/m 2 intravenous once per cycle every 2-3 weeks) alone or with vincristine and prednisone, all developed hepatic dysfunction manifested by elevations of total serum bilirubin, alkaline phosphatase and aspartate aminotransferase.

8. USE IN SPECIFIC POPULATIONS • Nursing Mothers: Discontinue drug or nursing taking into consideration importance of drug to mother ( 8.3 ). • Pediatric Use: Recommend long-term follow-up cardiac evaluations due to risk of delayed cardiotoxicity ( 8.4 ). • Females and Males of Reproductive Potential: May impair fertility.Counsel female and male patients on pregnancy planning and prevention ( 8.6 ). 8.1 Pregnancy Pregnancy Category D Risk Summary Doxorubicin hydrochloride can cause fetal harm when administered to a pregnant woman. Doxorubicin hydrochloride was teratogenic and embryotoxic in rats and rabbits at doses approximately 0.07 times (based on body surface area) the recommended human dose of 60 mg/m 2 . 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. 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 embryofetal 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. 8.3 Nursing Mothers Doxorubicin has been detected in the milk of at least one lactating patient [see Clinical Pharmacology (12.3) ] . Because of the potential for serious adverse reactions in nursing infants from doxorubicin hydrochloride, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 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 children less than 2 years as compared to adults [see Clinical Pharmacology (12.3) ] . 8.5 Geriatric Use Clinical experience in patients who were 65 years of age and older who received doxorubicin hydrochloride-based chemotherapy regimens for metastatic breast cancer showed no overall differences in safety and effectiveness compared with younger patients. 8.6 Females and Males of Reproductive Potential Contraception Females Doxorubicin hydrochloride can cause fetal harm when administered during pregnancy.

ubicin hydrochloride-based chemotherapy regimens for metastatic breast cancer showed no overall differences in safety and effectiveness compared with younger patients. 8.6 Females and Males of Reproductive Potential Contraception Females Doxorubicin hydrochloride can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment with doxorubicin hydrochloride 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 hydrochloride [see Use in Specific Populations (8.1) ] . Males Doxorubicin hydrochloride may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during and for 6 months after treatment [see Nonclinical Toxicology (13.1) ] . Infertility Females In females of reproductive potential, doxorubicin hydrochloride may cause infertility and result in amenorrhea. Premature menopause can occur. Recovery of menses and ovulation is related to age at treatment [see Nonclinical Toxicology (13.1) ] . Males Doxorubicin hydrochloride may result in oligospermia, azoospermia, and permanent loss of fertility. Sperm counts have been reported to return to normal levels in some men. This may occur several years after the end of therapy. 8.7 Hepatic Impairment The clearance of doxorubicin was reduced in patients with elevated serum bilirubin levels. Reduce the dose of doxorubicin hydrochloride in patients with serum bilirubin levels greater than 1.2 mg/dL [See Dosage and Administration (2.2) and Warnings and Precautions (5.5) ] . Doxorubicin hydrochloride is contraindicated in patients with severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin levels greater than 5 mg/dL) [see Contraindications (4) ] .

8.1 Pregnancy Pregnancy Category D Risk Summary Doxorubicin hydrochloride can cause fetal harm when administered to a pregnant woman. Doxorubicin hydrochloride was teratogenic and embryotoxic in rats and rabbits at doses approximately 0.07 times (based on body surface area) the recommended human dose of 60 mg/m 2 . 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. 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 embryofetal 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.

Risk Summary Doxorubicin hydrochloride can cause fetal harm when administered to a pregnant woman. Doxorubicin hydrochloride was teratogenic and embryotoxic in rats and rabbits at doses approximately 0.07 times (based on body surface area) the recommended human dose of 60 mg/m 2 . 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.

8.3 Nursing Mothers Doxorubicin has been detected in the milk of at least one lactating patient [see Clinical Pharmacology (12.3) ] . Because of the potential for serious adverse reactions in nursing infants from doxorubicin hydrochloride, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 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 children less than 2 years as compared to adults [see Clinical Pharmacology (12.3) ] .

10. OVERDOSAGE 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. A 17-year-old girl with osteogenic sarcoma received 150 mg of doxorubicin hydrochloride daily for 2 days (intended dose was 50 mg per day for 3 days). 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.

11. DESCRIPTION Doxorubicin hydrochloride, USP is a cytotoxic, anthracycline, topoisomerase II inhibitor isolated from cultures of Streptomyces peucetius var. caesius. Chemically, doxorubicin hydrochloride, USP is: 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-α-L- lyx o-hexopyranosyl)oxy]-7,8,9,10 tetrahydro-6,8,11-trihydroxy-8-(hydroxylacetyl)-1-methoxy-, hydrochloride (8S- ci s)-. The chemical structure of doxorubicin hydrochloride is: Doxorubicin Hydrochloride for Injection, USP is a sterile red-orange lyophilized powder, provided in single dose vial containing 10 mg, 50 mg doxorubicin HCl, USP. Doxorubicin Hydrochloride for Injection, USP Each 10 mg lyophilized vial contains 10 mg of Doxorubicin Hydrochloride, USP and 50 mg of Lactose Monohydrate, NF. Each 50 mg lyophilized vial contains 50 mg of Doxorubicin Hydrochloride, USP and 250 mg of Lactose Monohydrate, NF. Chemical Structure

12. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The cytotoxic effect of doxorubicin hydrochloride on malignant cells and its toxic effects on various organs are thought to be related to nucleotide base intercalation and cell membrane lipid binding activities of doxorubicin. Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases. The interaction of doxorubicin with topoisomerase II to form DNA-cleavable complexes appears to be an important mechanism of doxorubicin hydrochloride cytocidal activity. 12.3 Pharmacokinetics Pharmacokinetic studies conducted in patients with various types of tumors have shown that doxorubicin follows multiphasic disposition after intravenous injection. The distribution half-life is approximately 5 minutes, while the terminal half-life is 20 to 48 hours. In four patients, doxorubicin demonstrated dose-independent pharmacokinetics across a dose range of 30 to 70 mg/m2. Distribution Steady-state distribution volume ranges from 809 to 1214 L/m 2 . Binding of doxorubicin and its major metabolite, doxorubicinol, to plasma proteins is about 75% and is independent of plasma concentration of doxorubicin up to 1.1 mcg/mL. Doxorubicin was measured in the milk of one lactating patient after therapy with 70 mg/m 2 of doxorubicin hydrochloride given as a 15-minute intravenous infusion. The peak milk concentration at 24 hours after treatment was 4.4-fold greater than the corresponding plasma concentration. Doxorubicin was detectable in the milk up to 72 hours. 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 hydrochloride. Disposition of doxorubicinol in patients is formation rate limited, with the terminal half-life of doxorubicinol being similar to doxorubicin. The relative exposure of doxorubicinol, i.e., the ratio between the AUC of doxorubicinol and the AUC of doxorubicin is approximately 0.5. 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 doxorubicinol 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. Pediatric patients Following administration of doses ranging from 10 to 75 mg/m 2 of doxorubicin hydrochloride to 60 children and adolescents ranging from 2 months to 20 years of age, doxorubicin clearance averaged 1443 ± 114 mL/min/m2. Further analysis demonstrated that clearance in 52 children greater than 2 years of age (1540 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 [see Use in Specific Populations (8.4) ]. Patient Gender There is no recommended dose adjustment based on gender.

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 [see Use in Specific Populations (8.4) ]. Patient Gender There is no recommended dose adjustment based on gender. A published clinical study involving 6 men and 21 women with no prior anthracycline therapy reported a significantly higher median doxorubicin clearance in men compared to women (1088 mL/min/m 2 versus 433 mL/min/m 2 ). However, the terminal half-life of doxorubicin was longer in men compared to women (54 versus 35 hours). Patients with hepatic impairment The clearance of doxorubicin and doxorubicinol was reduced in patients with elevation in serum bilirubin [see Dosage and Administration (2.2) and Warnings and Precautions (5.5) ] .

12.3 Pharmacokinetics Pharmacokinetic studies conducted in patients with various types of tumors have shown that doxorubicin follows multiphasic disposition after intravenous injection. The distribution half-life is approximately 5 minutes, while the terminal half-life is 20 to 48 hours. In four patients, doxorubicin demonstrated dose-independent pharmacokinetics across a dose range of 30 to 70 mg/m2. Distribution Steady-state distribution volume ranges from 809 to 1214 L/m 2 . Binding of doxorubicin and its major metabolite, doxorubicinol, to plasma proteins is about 75% and is independent of plasma concentration of doxorubicin up to 1.1 mcg/mL. Doxorubicin was measured in the milk of one lactating patient after therapy with 70 mg/m 2 of doxorubicin hydrochloride given as a 15-minute intravenous infusion. The peak milk concentration at 24 hours after treatment was 4.4-fold greater than the corresponding plasma concentration. Doxorubicin was detectable in the milk up to 72 hours. 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 hydrochloride. Disposition of doxorubicinol in patients is formation rate limited, with the terminal half-life of doxorubicinol being similar to doxorubicin. The relative exposure of doxorubicinol, i.e., the ratio between the AUC of doxorubicinol and the AUC of doxorubicin is approximately 0.5. 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 doxorubicinol 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. Pediatric patients Following administration of doses ranging from 10 to 75 mg/m 2 of doxorubicin hydrochloride to 60 children and adolescents ranging from 2 months to 20 years of age, doxorubicin clearance averaged 1443 ± 114 mL/min/m2. Further analysis demonstrated that clearance in 52 children greater than 2 years of age (1540 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 [see Use in Specific Populations (8.4) ]. Patient Gender There is no recommended dose adjustment based on gender. A published clinical study involving 6 men and 21 women with no prior anthracycline therapy reported a significantly higher median doxorubicin clearance in men compared to women (1088 mL/min/m 2 versus 433 mL/min/m 2 ). However, the terminal half-life of doxorubicin was longer in men compared to women (54 versus 35 hours). Patients with hepatic impairment The clearance of doxorubicin and doxorubicinol was reduced in patients with elevation in serum bilirubin [see Dosage and Administration (2.2) and Warnings and Precautions (5.5) ] .

13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Doxorubicin hydrochloride treatment results in an increased risk of secondary malignancies based on postmarketing reports [see Warnings and Precautions (5.2) ] . Doxorubicin hydrochloride was mutagenic in the in vitro Ames assay, and clastogenic in multiple in vitro assays (CHO cell, V79 hamster cell, human lymphoblast, and SCE assays) and the in vivo mouse micronucleus assay. Doxorubicin hydrochloride decreased fertility in female rats at the doses of 0.05 and 0.2 mg/kg/day (approximately 0.005 and 0.02 times the recommended human dose, based on body surface area). A single intravenous dose of 0.1 mg/kg doxorubicin hydrochloride (approximately 0.01 times the recommended human dose based on body surface area) was toxic to male reproductive organs in animal studies, producing testicular atrophy, diffuse degeneration of the seminiferous tubules, and oligospermia/hypospermia in rats. Doxorubicin hydrochloride induces DNA damage in rabbit spermatozoa and dominant lethal mutations in mice.

14. CLINICAL STUDIES The clinical 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). The EBCTCG meta-analyses compared cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) to no chemotherapy (19 trials including 7523 patients) and doxorubicin hydrochloride-containing regimens with CMF as an active control (6 trials including 3510 patients). 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). Of the 3510 women (2157 received doxorubicin hydrochloride-containing regimens and 1353 received CMF treatment) with early breast cancer involving axillary lymph nodes included in the six trials from the meta-analyses, approximately 70% were premenopausal and 30% were postmenopausal. 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 0.91 (95% CI, 0.82 to 1.01) and on OS with a HR of 0.91 (95% CI, 0.81 to 1.03). Results of these analyses for both DFS and OS are provided in Table 2 and Figures 1 and 2. Table 2. Summary of Randomized Trials Comparing Doxorubicin hydrochloride-Containing Regimens Versus CMF in Meta-Analysis Abbreviations: DFS = disease free survival; OS = overall survival; AC = doxorubicin hydrochloride, cyclophosphamide;AVbCMF = doxorubicin hydrochloride, vinblastine, cyclophosphamide, methotrexate, 5-fluorouracil; CMF = cyclophosphamide, methotrexate, 5-fluorouracil; CMFVA = cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, doxorubicin hydrochloride; FAC = 5-fluorouracil, doxorubicin hydrochloride, cyclophosphamide; FACV = 5-fluorouracil, doxorubicin hydrochloride, cyclophosphamide, vincristine; HR = hazard ratio; CI = confidence interval Study (starting year) Regimens No. of Cycles No. of Patients Doxorubicin Hydrochloride-Containing Regimens vs CMF HR a 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 NSABP B-15 (1984) AC CMF 4 6 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. 776 0.93 (0.82 to 1.06) 0.97 (0.83 to 1.12) SECSG 2 (1976) FAC CMF 6 6 260 268 0.86 (0.66 to 1.13) 0.93 (0.69 to 1.26) ONCOFRANCE (1978) FACV CMF 12 12 138 113 0.71 (0.49 to 1.03) 0.65 (0.44 to 0.96) SE Sweden BCG A (1980) AC CMF 6 6 21 22 0.59 (0.22 to 1.61) 0.53 (0.21 to 1.37) NSABC Israel Br0283 (1983) AVbCMF Patients received alternating cycles of AVb and CMF. 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 CMF 6 8 121 124 1.07 (0.73 to 1.55) 0.93 (0.64 to 1.35) Combined Studies Doxorubicin Hydrochloride -Containing Regimens CMF 2157 1353 0.91 (0.82 to 1.01) 0.91 (0.81 to 1.03) Figure 1. Meta-analysis of Disease-Free Survival Figure 2. Meta-analysis of Overall Survival Figure 1 Figure 2

<table ID="_RefID536" width="100%"><caption>Table 2. Summary of Randomized Trials Comparing Doxorubicin hydrochloride-Containing Regimens Versus CMF in Meta-Analysis</caption><col width="23%"/><col width="13%"/><col width="13%"/><col width="13%"/><col width="20%"/><col width="18%"/><tfoot><tr><td align="left" colspan="6" valign="top">Abbreviations: DFS = disease free survival; OS = overall survival; AC = doxorubicin hydrochloride, cyclophosphamide;AVbCMF = doxorubicin hydrochloride, vinblastine, cyclophosphamide, methotrexate, 5-fluorouracil; CMF = cyclophosphamide, methotrexate, 5-fluorouracil; CMFVA = cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, doxorubicin hydrochloride; FAC = 5-fluorouracil, doxorubicin hydrochloride, cyclophosphamide; FACV = 5-fluorouracil, doxorubicin hydrochloride, cyclophosphamide, vincristine; HR = hazard ratio; CI = confidence interval</td></tr></tfoot><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Study (starting year)</content></paragraph></td><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Regimens</content></paragraph></td><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">No. of Cycles</content></paragraph></td><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">No.

</content></paragraph></td><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">No. of Cycles</content></paragraph></td><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">No. of Patients</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Doxorubicin Hydrochloride-Containing Regimens vs CMF HR</content><footnote ID="_Ref151959972">a 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.</footnote><content styleCode="bold"> (95% CI)</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">DFS</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">OS</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="middle"><paragraph>NSABP B-15 (1984)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="middle"><paragraph>AC CMF</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="middle"><paragraph>4 6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="middle"><paragraph>1562<footnote ID="_Ref151959944">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.</footnote> 776</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="middle"><paragraph>0.93 (0.82 to 1.06)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="middle"><paragraph>0.97 (0.83 to 1.12)</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="middle"><paragraph>SECSG 2 (1976)</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="middle"><paragraph>FAC CMF</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="middle"><paragraph>6 6</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="middle"><paragraph>260 </paragraph><paragraph>268</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="middle"><paragraph>0.86 (0.66 to 1.13)</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="middle"><paragraph>0.93 (0.69 to 1.26)</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="middle"><paragraph>ONCOFRANCE (1978)</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="middle"><paragraph>FACV CMF</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="middle"><paragraph>12 12</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="middle"><paragraph>138</paragraph><paragraph> 113</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="middle"><paragraph>0.71 (0.49 to 1.03)</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="middle"><paragraph>0.65 (0.44 to 0.96)</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="middle"><paragraph>SE Sweden BCG A (1980)</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="middle"><paragraph>AC CMF</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="middle"><paragraph>6 6</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="middle"><paragraph>21 22</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="middle"><paragraph>0.59 (0.22 to 1.61)</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="middle"><paragraph>0.53 (0.21 to 1.37)</paragraph></td></tr><tr><td style

lign="center" styleCode="Rrule Lrule " valign="middle"><paragraph>21 22</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="middle"><paragraph>0.59 (0.22 to 1.61)</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="middle"><paragraph>0.53 (0.21 to 1.37)</paragraph></td></tr><tr><td style Code="Rrule Lrule " valign="middle"><paragraph>NSABC Israel Br0283 (1983)</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="middle"><paragraph>AVbCMF<footnote ID="_Ref151959984">Patients received alternating cycles of AVb and CMF.

lign="center" styleCode="Rrule Lrule " valign="middle"><paragraph>21 22</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="middle"><paragraph>0.59 (0.22 to 1.61)</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="middle"><paragraph>0.53 (0.21 to 1.37)</paragraph></td></tr><tr><td style Code="Rrule Lrule " valign="middle"><paragraph>NSABC Israel Br0283 (1983)</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="middle"><paragraph>AVbCMF<footnote ID="_Ref151959984">Patients received alternating cycles of AVb and CMF. </footnote> CMF</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="middle"><paragraph>4 6 6</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="middle"><paragraph>55 50</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="middle"><paragraph>0.91(0.53 to 1.57)</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="middle"><paragraph>0.88 (0.47 to 1.63)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Austrian BCSG 3 (1984)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>CMFVA CMF</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>6 8</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>121 124</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1.07 (0.73 to 1.55)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0.93 (0.64 to 1.35)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Combined Studies</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>Doxorubicin Hydrochloride -Containing Regimens CMF</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">2157 1353</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">0.91 (0.82 to 1.01)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">0.91 (0.81 to 1.03)</content></paragraph></td></tr></tbody></table>

16. HOW SUPPLIED/STORAGE AND HANDLING Doxorubicin Hydrochloride for Injection, USP is supplied as a sterile red-orange lyophilized powder for intravenous use only, is available in single dose flip-top vials in the following package strengths: NDC 67457-478-10: 10 mg vial; individually boxed. NDC 67457-436-50: 50 mg vial; individually boxed. Store unreconstituted vial at controlled room temperature, between 20°C to 25°C (68°F to 77°F). [See USP.] Protect vials from light. Retain in carton until time of use. Discard unused portion. Reconstituted Solution Stability After adding the diluent, the vial should be shaken and the contents allowed to dissolve. The reconstituted solution is stable for 7 days at room temperature and under normal room light (100 foot-candles) and 15 days under refrigeration (2° to 8°C). It should be protected from exposure to sunlight. Discard any unused solution from the 10 mg and 50 mg single dose vials. Handling and Disposal Handle and dispose of Doxorubicin Hydrochloride for Injection, USP consistent with recommendations for the handling and disposal of hazardous drugs. 1

17. PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (Patient Information). Inform patients of the following: • Doxorubicin hydrochloride can cause irreversible myocardial damage. Advise patients to contact a healthcare provider for symptoms of heart failure during or after treatment with doxorubicin hydrochloride [see Warnings and Precautions (5.1) ] . • There is an increased risk of treatment-related leukemia from doxorubicin hydrochloride [see Warnings and Precautions (5.2) ] . • Doxorubicin hydrochloride can reduce the absolute neutrophil count resulting in an increased risk of infection. Advise patients to contact a healthcare provider for new onset fever or symptoms of infection [see Warnings and Precautions (5.4) ] . • Doxorubicin hydrochloride can cause fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment with doxorubicin hydrochloride and for 6 months after treatment, and to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with doxorubicin hydrochloride [see Warnings and Precautions (5.8) and Use in Specific Populations (8.6) ] . • Doxorubicin hydrochloride may induce chromosomal damage in sperm, which may lead to loss of fertility and offspring with birth defects. Advise patients to use effective contraception during and for 6 months after treatment [see Warnings and Precautions (5.8) and Use in Specific Populations (8.6) ] . • Doxorubicin hydrochloride can cause premature menopause in females and loss of fertility in males [see Use in Specific Populations (8.6) ] . • Discontinue nursing while receiving doxorubicin HCl [see Use in Specific Populations (8.3) ] . • Doxorubicin hydrochloride can cause nausea, vomiting, diarrhea, mouth/oral pain and sores. Advise patients to contact a healthcare provider should they develop any severe symptoms that prevent them from eating and drinking [see Adverse Reactions (6) ] . • Doxorubicin hydrochloride causes alopecia [see Adverse Reactions (6.1) ] . • Doxorubicin hydrochloride can cause their urine to appear red for 1 to 2 days after administration. Manufactured for: Mylan Institutional LLC Morgantown, WV 26505 U.S.A. Manufactured by: Mylan Laboratories Limited Bangalore, India Code No.: KR/DRUGS/KTK/28/381/2008 1033608 JULY 2022

Patient Information DOXORUBICIN (dok-suh-roo-buh-sin) HYDROCHLORIDE For Injection, for intravenous use What is the most important information I should know about Doxorubicin? Doxorubicin may cause serious side effects including: • Heart failure . Doxorubicin may cause heart muscle damage that may lead to heart failure, which is a condition in which the heart does not pump well. Heart failure is irreversible in some cases and can lead to death. Heart failure can happen during your treatment with Doxorubicin or months to years after stopping treatment. Your risk of heart muscle damage increases with higher total amounts of doxorubicin hydrochloride that you receive in your lifetime. Your risk of heart failure is higher if you: • already have other heart problems • have had or are currently receiving radiation therapy to your chest • have had treatment with certain other anti-cancer medicines • take other medicines that can have severe side effects on your heart Tell your doctor if you get any of these symptoms of heart failure during or after treatment with Doxorubicin: • extreme tiredness or weakness • fast heartbeat • swelling of your feet and ankles • shortness of breath Your doctor will do tests to check the strength of your heart muscle before, during, and after your treatment with Doxorubicin. • Risk of new cancers. You may have an increased risk of developing certain blood cancers called acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) after treatment with doxorubicin. Talk with your doctor about your risk of developing new cancers if you take Doxorubicin. • Skin damage near the vein where Doxorubicin is given (Injection site reaction). Doxorubicin can damage the skin if it leaks out of the vein. Symptoms of infusion reaction include blisters and skin sores at injection site which may require skin grafts. • Decreased blood cell counts. Doxorubicin can cause a decrease in neutrophils (a type of white blood cells important in fighting bacterial infections) and platelets (important for clotting and to control bleeding). This may lead to a serious infection, the need for blood transfusions, treatment in a hospital and death. Your doctor will check your blood cell count during your treatment with Doxorubicin and after you have stopped your treatment. Call your doctor right away if you get a fever (temperature of 100.4° F or greater) or chills with shivering. What is Doxorubicin? Doxorubicin is a prescription medicine used to treat certain types of cancers. Doxorubicin may be used alone or along with other anti-cancer medicines. Who should not receive Doxorubicin? Do not receive Doxorubicin if: • you have had a recent heart attack or have severe heart problems • your blood cell counts (platelets, red blood cells, and white blood cells) are very low because of prior chemotherapy • you have a severe liver problem • you have had a serious allergic reaction to doxorubicin hydrochloride What should I tell my doctor before receiving Doxorubicin? Before you receive Doxorubicin, tell your doctor if you: • have heart problems including heart failure • are currently receiving radiation therapy or plan to receive radiation to the chest • have severe liver problems • have had an allergic reaction to doxorubicin • have any other medical conditions • are pregnant or plan to become pregnant. Doxorubicin can harm your unborn baby.

e heart problems including heart failure • are currently receiving radiation therapy or plan to receive radiation to the chest • have severe liver problems • have had an allergic reaction to doxorubicin • have any other medical conditions • are pregnant or plan to become pregnant. Doxorubicin can harm your unborn baby. Women who are able to become pregnant and men who take Doxorubicin should use effective birth control (contraception) during treatment and for 6 months after treatment. Talk to your doctor about birth control methods. If you or your partner becomes pregnant, tell your doctor right away. • are breastfeeding or plan to breast feed. Doxorubicin can pass into your breast milk and harm your baby. You and your doctor should decide if you will receive Doxorubicin or breastfeed. You should not do both. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Doxorubicin can interact with other medicines. Do not start any new medicine before you talk with the doctor that prescribed Doxorubicin. Know the medicines you take. Keep a list to show your doctor and pharmacist each time you get a new medicine. How will I receive Doxorubicin? Doxorubicin will be given to you into your vein. What are the possible side effects of Doxorubicin? Doxorubicin may cause serious side effects, including: See "What is the most important information I should know about Doxorubicin?" Doxorubicin may cause lower sperm counts and sperm problems in men. This could affect your ability to father a child and cause birth defects. Talk to your healthcare provider if this is a concern for you. Talk to your healthcare provider about family planning options that might be right for you. Irreversible amenorrhea or early menopause. Your periods (menstrual cycle) may completely stop when you receive Doxorubicin. Your periods may or may not return following treatment. Talk to your healthcare provider about family planning options that might be right for you. The most common side effects of Doxorubicin include: • Total hair loss (alopecia). Your hair may re-grow after your treatment. • nausea • vomiting Other side effects: • Red colored urine. You may have red colored urine for 1 to 2 days after your infusion of Doxorubicin. This is normal. Tell your doctor if it does not stop in a few days, or if you see what looks like blood or blood clots in your urine. • Darkening of your nails or separation of your nails from your nail bed. • Easy bruising or bleeding. Call your doctor if you have severe symptoms that prevent you from eating or drinking, such as: • nausea • vomiting • diarrhea • mouth sores Tell your doctor or nurse if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of Doxorubicin. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of Doxorubicin. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or doctor for information about Doxorubicin that is written for health professionals. For more information, call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX). What are the ingredients of Doxorubicin? Active ingredient: Doxorubicin hydrochloride, USP Inactive ingredients for Doxorubicin hydrochloride For Injection: Lactose Monohydrate This Patient Information has been approved by the U.S. Food and Drug Administration. Manufactured for: Mylan Institutional LLC Morgantown, WV 26505 U.S.A. Manufactured by: Mylan Laboratories Limited Bangalore, India Code No.: KR/DRUGS/KTK/28/381/2008 1033608 JULY 2022

BOXED WARNING WARNING: CARDIOMYOPATHY and INFUSION-RELATED REACTIONS Doxorubicin hydrochloride liposome injection can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy was 11% when the cumulative anthracycline dose was between 450 mg/m 2 to 550 mg/m 2 . Assess left ventricular cardiac function prior to initiation of doxorubicin hydrochloride liposome injection and during and after treatment [see Warnings and Precautions ( 5.1 )] . Serious, life-threatening, and fatal infusion-related reactions can occur with doxorubicin hydrochloride liposome injection. Acute infusion-related reactions occurred in 11% of patients with solid tumors. Withhold doxorubicin hydrochloride liposome injection for infusion-related reactions and resume at a reduced rate. Discontinue doxorubicin hydrochloride liposome injection for serious or life-threatening infusion-related reactions [see Warnings and Precautions ( 5.2 )] . WARNING: CARDIOMYOPATHY and INFUSION-RELATED REACTIONS See full prescribing information for complete boxed warning. Doxorubicin hydrochloride liposome injection can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy was 11% when the cumulative anthracycline dose was between 450 mg/m 2 to 550 mg/m 2 . Assess left ventricular cardiac function prior to initiation of doxorubicin hydrochloride liposome injection, during treatment and after treatment ( 5.1 ). Serious, life-threatening, and fatal infusion-related reactions can occur with doxorubicin hydrochloride liposome injection. Acute infusion-related reactions occurred in 11% of patients with solid tumors. Withhold doxorubicin hydrochloride liposome injection for infusion-related reactions and resume at a reduced rate. Discontinue doxorubicin hydrochloride liposome injection for serious or life-threatening infusion-related reactions ( 5.2 ).

1 INDICATIONS AND USAGE Doxorubicin hydrochloride liposome injection is an anthracycline topoisomerase inhibitor indicated for: Ovarian cancer: After failure of platinum-based chemotherapy ( 1.1 ) AIDS-related Kaposi's Sarcoma: After failure of prior systemic chemotherapy or intolerance to such therapy ( 1.2 ) Multiple Myeloma: In combination with bortezomib in patients who have not previously received bortezomib and have received at least one prior therapy ( 1.3 ) 1.1 Ovarian Cancer Doxorubicin hydrochloride liposome injection is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy. 1.2 AIDS-Related Kaposi's Sarcoma Doxorubicin hydrochloride liposome injection is indicated for the treatment of AIDS-related Kaposi's sarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy. 1.3 Multiple Myeloma Doxorubicin hydrochloride liposome injection, in combination with bortezomib, is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy.

2 DOSAGE AND ADMINISTRATION Administer doxorubicin hydrochloride liposome injection at an initial rate of 1 mg/min to minimize the risk of infusion reactions. If no infusion related reactions occur, increase rate of infusion to complete administration over 1 hour. Do not administer as bolus injection or undiluted solution (2). Ovarian cancer: 50 mg/m 2 intravenously every 4 weeks ( 2.2 ) AIDS-related Kaposi's Sarcoma: 20 mg/m 2 intravenously every 3 weeks ( 2.3 ) Multiple Myeloma: 30 mg/m 2 intravenously on day 4 following bortezomib ( 2.4 ) 2.1 Important Use Information Do not substitute doxorubicin hydrochloride liposome injection for other doxorubicin hydrochloride products. Do not administer as an undiluted suspension or as an intravenous bolus [see Warnings and Precautions ( 5.2 )] . 2.2 Ovarian Cancer The recommended dose of doxorubicin hydrochloride liposome injection is 50 mg/m 2 intravenously over 60 minutes every 28 days until disease progression or unacceptable toxicity. 2.3 AIDS-Related Kaposi's Sarcoma The recommended dose of doxorubicin hydrochloride liposome injection is 20 mg/m 2 intravenously over 60 minutes every 21 days until disease progression or unacceptable toxicity. 2.4 Multiple Myeloma The recommended dose of doxorubicin hydrochloride liposome injection is 30 mg/m 2 intravenously over 60 minutes on day 4 of each 21-day cycle for eight cycles or until disease progression or unacceptable toxicity. Administer doxorubicin hydrochloride liposome injection after bortezomib on day 4 of each cycle [see Clinical Studies ( 14.3 )] . 2.5 Dose Modifications for Adverse Reactions Do not increase doxorubicin hydrochloride liposome injection after a dose reduction for toxicity. Table 1: Recommended Dose Modifications for Hand-Foot Syndrome, Stomatitis, or Hematologic Adverse Reactions Toxicity Dose Adjustment Hand-Foot Syndrome (HFS) Grade 1: Mild erythema, swelling, or desquamation not interfering with daily activities If no previous Grade 3 or 4 HFS: no dose adjustment. If previous Grade 3 or 4 HFS: delay dose up to 2 weeks, then decrease dose by 25%. Grade 2: Erythema, desquamation, or swelling interfering with, but not precluding normal physical activities; small blisters or ulcerations less than 2 cm in diameter Delay dosing up to 2 weeks or until resolved to Grade 0-1. Discontinue doxorubicin hydrochloride liposome injection if no resolution after 2 weeks. If resolved to Grade 0-1 within 2 weeks: o And no previous Grade 3 or 4 HFS: continue treatment at previous dose. o And previous Grade 3 or 4 toxicity: decrease dose by 25%. Grade 3: Blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothing Delay dosing up to 2 weeks or until resolved to Grade 0-1, then decrease dose by 25%. Discontinue doxorubicin hydrochloride liposome injection if no resolution after 2 weeks. Grade 4: Diffuse or local process causing infectious complications, or a bed ridden state or hospitalization Delay dosing up to 2 weeks or until resolved to Grade 0-1, then decrease dose by 25%. Discontinue doxorubicin hydrochloride liposome injection if no resolution after 2 weeks. Stomatitis Grade 1: Painless ulcers, erythema, or mild soreness If no previous Grade 3 or 4 toxicity: no dose adjustment. If previous Grade 3 or 4 toxicity: delay up to 2 weeks then decrease dose by 25%. Grade 2: Painful erythema, edema, or ulcers, but can eat Delay dosing up to 2 weeks or until resolved to Grade 0-1.

Stomatitis Grade 1: Painless ulcers, erythema, or mild soreness If no previous Grade 3 or 4 toxicity: no dose adjustment. If previous Grade 3 or 4 toxicity: delay up to 2 weeks then decrease dose by 25%. Grade 2: Painful erythema, edema, or ulcers, but can eat Delay dosing up to 2 weeks or until resolved to Grade 0-1. Discontinue doxorubicin hydrochloride liposome injection if there is no resolution after 2 weeks. If resolved to Grade 0-1 within 2 weeks: o And no previous Grade 3 or 4 stomatitis: resume treatment at previous dose. o And previous Grade 3 or 4 toxicity: decrease dose by 25%. Grade 3: Painful erythema, edema, or ulcers, and cannot eat Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease dose by 25% and return to original dose interval. If after 2 weeks there is no resolution, discontinue doxorubicin hydrochloride liposome injection. Grade 4: Requires parenteral or enteral support Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease dose by 25% and return to original dose interval. If after 2 weeks there is no resolution, discontinue doxorubicin hydrochloride liposome injection. Neutropenia or Thrombocytopenia Grade 1 No dose reduction Grade 2 Delay until ANC ≥ 1,500 and platelets ≥ 75,000; resume treatment at previous dose Grade 3 Delay until ANC ≥ 1,500 and platelets ≥ 75,000; resume treatment at previous dose Grade 4 Delay until ANC ≥ 1,500 and platelets ≥ 75,000; resume at 25% dose reduction or continue previous dose with prophylactic granulocyte growth factor Table 2: Recommended Dose Modifications of Doxorubicin Hydrochloride Liposome Injection for Toxicity When Administered in Combination With Bortezomib Toxicity Doxorubicin Hydrochloride Liposome Injection Fever ≥38°C and ANC <1,000/mm 3 Withhold dose for this cycle if before Day 4; Decrease dose by 25%, if after Day 4 of previous cycle. On any day of drug administration after Day 1 of each cycle: Platelet count <25,000/mm 3 Hemoglobin <8 g/dL ANC <500/mm 3 Withhold dose for this cycle if before Day 4; Decrease dose by 25%, if after Day 4 of previous cycle AND if bortezomib is reduced for hematologic toxicity. Grade 3 or 4 non-hematologic drug related toxicity Do not dose until recovered to Grade <2, then reduce dose by 25%. For neuropathic pain or peripheral neuropathy, no dosage adjustments are required for doxorubicin hydrochloride liposome injection. Refer to bortezomib manufacturer's prescribing information. 2.6 Preparation and Administration Preparation Dilute doxorubicin hydrochloride liposome injection doses up to 90 mg in 250 mL of 5% Dextrose Injection, USP prior to administration. Dilute doses exceeding 90 mg in 500 mL of 5% Dextrose Injection, USP prior to administration. Refrigerate diluted doxorubicin hydrochloride liposome injection at 2°C to 8°C (36°F to 46°F) and administer within 24 hours. Administration Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if a precipitate or foreign matter is present. Do not use with in-line filters. Administer the first dose of doxorubicin hydrochloride liposome injection at an initial rate of 1 mg/min. If no infusion-related adverse reactions are observed, increase the infusion rate to complete the administration of the drug over one hour [see Warnings and Precautions ( 5.2 )]. Do not rapidly flush the infusion line. Do not mix doxorubicin hydrochloride liposome injection with other drugs. Management of Suspected Extravasation Discontinue doxorubicin hydrochloride liposome injection for burning or stinging sensation or other evidence indicating perivenous infiltration or extravasation.

.2 )]. Do not rapidly flush the infusion line. Do not mix doxorubicin hydrochloride liposome injection with other drugs. Management of Suspected Extravasation Discontinue doxorubicin hydrochloride liposome injection for burning or stinging sensation or other evidence indicating perivenous 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 2.7 Procedure for Proper Handling and Disposal Doxorubicin hydrochloride liposome injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1 If doxorubicin hydrochloride liposome injection comes into contact with skin or mucosa, immediately wash thoroughly with soap and water.

3 DOSAGE FORMS AND STRENGTHS Doxorubicin hydrochloride liposome injection: 20 mg/10 mL (2 mg/mL) and 50 mg/25 mL (2 mg/mL) translucent, red liposomal dispersion in single dose vials. Doxorubicin hydrochloride liposome injection: 20 mg/10 mL (2 mg/mL) and 50 mg/25 mL (2 mg/mL) in single dose vials ( 3 )

4 CONTRAINDICATIONS Doxorubicin hydrochloride liposome injection is contraindicated in patients who have a history of severe hypersensitivity reactions, including anaphylaxis, to doxorubicin hydrochloride [see Warnings and Precautions ( 5.2 )]. Hypersensitivity reactions to doxorubicin hydrochloride or the components of doxorubicin hydrochloride liposome injection ( 4 , 5.2 )

5 WARNINGS AND PRECAUTIONS Hand-Foot Syndrome may occur. Dose modification or discontinuation may be required ( 5.3 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise of potential risk to a fetus. Use effective contraception ( 5.5 , 8.1 , 8.3 ) 5.1 Cardiomyopathy Doxorubicin hydrochloride can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy with doxorubicin hydrochloride is generally proportional to the cumulative exposure. Include prior use of other anthracyclines or anthracenediones in calculations of cumulative dose. The risk of cardiomyopathy may be increased at lower cumulative doses in patients with prior mediastinal irradiation. In a clinical study in 250 patients with advanced cancer who were treated with doxorubicin hydrochloride liposome injection, the risk of cardiomyopathy was 11% when the cumulative anthracycline dose was between 450 mg/m 2 to 550 mg/m 2 . Cardiomyopathy was defined as >20% decrease in resting left ventricular ejection fraction (LVEF) from baseline where LVEF remained in the normal range or a >10% decrease in LVEF from baseline where LVEF was less than the institutional lower limit of normal. Two percent of patients developed signs and symptoms of congestive heart failure without documented evidence of cardiomyopathy. Assess left ventricular cardiac function (e.g. MUGA or echocardiogram) prior to initiation of doxorubicin hydrochloride liposome injection, during treatment to detect acute changes, and after treatment to detect delayed cardiomyopathy. Administer doxorubicin hydrochloride liposome injection to patients with a history of cardiovascular disease only when the potential benefit of treatment outweighs the risk. 5.2 Infusion-Related Reactions Serious, life-threatening, and fatal infusion-related reactions characterized by one or more of the following symptoms can occur with doxorubicin hydrochloride liposome injection: flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. Of 239 patients with ovarian cancer treated with doxorubicin hydrochloride liposome injection in Trial 4, 7% of patients experienced acute infusion-related reactions resulting in dose interruption. All occurred during cycle 1 and none during subsequent cycles. Across multiple studies of doxorubicin hydrochloride liposome injection monotherapy including this and other studies enrolling 760 patients with various solid tumors, 11% of patients had infusion-related reactions. The majority of infusion-related events occurred during the first infusion. Ensure that medications to treat infusion-related reactions and cardiopulmonary resuscitative equipment are available for immediate use prior to initiation of doxorubicin hydrochloride liposome injection. Initiate doxorubicin hydrochloride liposome injections at a rate of 1 mg/min and increase rate as tolerated [see Dosage and Administration ( 2.6 )] . Withhold doxorubicin hydrochloride liposome injection for Grade 1, 2, or 3 infusion-related reactions and resume at a reduced infusion rate. Discontinue doxorubicin hydrochloride liposome injection for serious or life-threatening infusion-related reactions.

se rate as tolerated [see Dosage and Administration ( 2.6 )] . Withhold doxorubicin hydrochloride liposome injection for Grade 1, 2, or 3 infusion-related reactions and resume at a reduced infusion rate. Discontinue doxorubicin hydrochloride liposome injection for serious or life-threatening infusion-related reactions. 5.3 Hand-Foot Syndrome (HFS) In Trial 4, the incidence of HFS was 51% of patients in the doxorubicin hydrochloride liposome injection arm and 0.9% of patients in the topotecan arm, including 24% Grade 3 or 4 cases of HFS in doxorubicin hydrochloride liposome injection-treated patients and no Grade 3 or 4 cases in topotecan-treated patients. HFS or other skin toxicity required discontinuation of doxorubicin hydrochloride liposome injection in 4.2% of patients. HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. Delay doxorubicin hydrochloride liposome injection for the first episode of Grade 2 or greater HFS [see Dosage and Administration ( 2.5 )] . Discontinue doxorubicin hydrochloride liposome injection if HFS is severe and debilitating. 5.4 Secondary Oral Neoplasms Secondary oral cancers, primarily squamous cell carcinoma, have been reported from post-marketing experience in patients with long-term (more than one year) exposure to doxorubicin hydrochloride liposome injection. These malignancies were diagnosed both during treatment with doxorubicin hydrochloride liposome injection and up to 6 years after the last dose. Examine patients at regular intervals for the presence of oral ulceration or with any oral discomfort that may be indicative of secondary oral cancer. The altered pharmacokinetics and preferential tissue distribution of liposomal doxorubicin that contributes to enhanced skin toxicity and mucositis compared to free doxorubicin may play a role in the development of oral secondary malignancies with long-term use. 5.5 Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, doxorubicin hydrochloride liposome injection can cause fetal harm when administered to a pregnant woman; avoid the use of doxorubicin hydrochloride liposome 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. At doses approximately 0.12 times the recommended clinical dose, doxorubicin hydrochloride liposome injection was embryotoxic and abortifacient in rabbits. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during and for 6 months after treatment with doxorubicin hydrochloride liposome injection [see Use in Specific Populations ( 8.1 ), ( 8.3 )] .

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling. Cardiomyopathy [see Warnings and Precautions ( 5.1 )] Infusion-Related Reactions [see Warnings and Precautions ( 5.2 )] Hand-Foot Syndrome [see Warnings and Precautions ( 5.3 )] Secondary Oral Neoplasms [see Warnings and Precautions ( 5.4 )] Most common adverse reactions (>20%) are asthenia, fatigue, fever, anorexia, nausea, vomiting, stomatitis, diarrhea, constipation, hand-foot syndrome, rash, neutropenia, thrombocytopenia, and anemia ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice. The safety data reflect exposure to doxorubicin hydrochloride liposome injection in 1310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi's sarcoma, and 318 patients with multiple myeloma. The most common adverse reactions (>20%) observed with doxorubicin hydrochloride liposome injection are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia. The following tables present adverse reactions from clinical trials of single-agent doxorubicin hydrochloride liposome injection in ovarian cancer and AIDS-Related Kaposi's sarcoma. Patients With Ovarian Cancer The safety data described below are from Trial 4, which included 239 patients with ovarian cancer treated with doxorubicin hydrochloride liposome injection 50 mg/m 2 once every 4 weeks for a minimum of four courses in a randomized, multicenter, open-label study. In this trial, patients received doxorubicin hydrochloride liposome injection for a median number of 3.2 months (range 1 day to 25.8 months). The median age of the patients is 60 years (range 27 to 87), with 91% Caucasian, 6% Black, and 3% Hispanic or Other. Table 3 presents the hematologic adverse reactions from Trial 4. Table 3: Hematologic Adverse Reactions in Trial 4 Doxorubicin Hydrochloride Liposome Injection Patients (n=239) Topotecan Patients (n=235) Neutropenia 500 - <1,000/mm 3 8% 14% <500/mm3 4.2% 62% Anemia 6.5 - <8 g/dL 5% 25% <6.5 g/dL 0.4% 4.3% Thrombocytopenia 10,000 - <50,000/mm 3 1.3% 17% <10,000/mm 3 0.0% 17% Table 4 presents the non-hematologic adverse reactions from Trial 4.

n Hydrochloride Liposome Injection Patients (n=239) Topotecan Patients (n=235) Neutropenia 500 - <1,000/mm 3 8% 14% <500/mm3 4.2% 62% Anemia 6.5 - <8 g/dL 5% 25% <6.5 g/dL 0.4% 4.3% Thrombocytopenia 10,000 - <50,000/mm 3 1.3% 17% <10,000/mm 3 0.0% 17% Table 4 presents the non-hematologic adverse reactions from Trial 4. Table 4: Non-Hematologic Adverse Reactions in Trial 4 Non-Hematologic Adverse Reaction 10% or Greater Doxorubicin Hydrochloride Liposome Injection (%) Treated (n=239) Topotecan (%) Treated (n=235) All grades Grades 3-4 All grades Grades 3-4 Body as a Whole Asthenia 40 7 52 8 Fever 21 0.8 31 6 Mucous Membrane Disorder 14 3.8 3.4 0 Back Pain 12 1.7 10 0.9 Infection 12 2.1 6 0.9 Headache 11 0.8 15 0 Digestive Nausea 46 5 63 8 Stomatitis 41 8 15 0.4 Vomiting 33 8 44 10 Diarrhea 21 2.5 35 4.2 Anorexia 20 2.5 22 1.3 Dyspepsia 12 0.8 14 0 Nervous Dizziness 4.2 0 10 0 Respiratory Pharyngitis 16 0 18 0.4 Dyspnea 15 4.1 23 4.3 Cough increased 10 0 12 0 Skin and Appendages Hand-foot syndrome 51 24 0.9 0 Rash 29 4.2 12 0.4 Alopecia 19 N/A 52 N/A The following additional adverse reactions were observed in patients with ovarian cancer with doses administered every four weeks (Trial 4). Incidence 1% to 10% Cardiovascular: vasodilation, tachycardia, deep vein thrombosis, hypotension, cardiac arrest. Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus. Hematologic and Lymphatic: ecchymosis. Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia, hypercalcemia, hyponatremia. Nervous: somnolence, dizziness, depression. Respiratory: rhinitis, pneumonia, sinusitis, epistaxis. Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne. Special Senses: conjunctivitis, taste perversion, dry eyes. Urinary: urinary tract infection, hematuria, vaginal moniliasis. Patients With AIDS-Related Kaposi's Sarcoma The safety data described is based on the experience reported in 753 patients with AIDS-related Kaposi's sarcoma (KS) enrolled in four open-label, uncontrolled trials of doxorubicin hydrochloride liposome injection administered at doses ranging from 10 to 40 mg/m 2 every 2 to 3 weeks. Demographics of the population were: median age 38.7 years (range 24-70); 99% male; 88% Caucasian, 6% Hispanic, 4% Black, and 2% Asian/other/unknown. The majority of patients were treated with 20 mg/m 2 of doxorubicin hydrochloride liposome injection every 2 to 3 weeks with a median exposure of 4.2 months (range 1 day to 26.6 months). The median cumulative dose was 120 mg/m 2 (range 3.3 to 798.6 mg/m 2 ); 3% received cumulative doses of greater than 450 mg/m 2 . Disease characteristics were: 61% poor risk for KS tumor burden, 91% poor risk for immune system, and 47% poor risk for systemic illness; 36% were poor risk for all three categories; median CD4 count 21 cells/mm 3 (51% less than 50 cells/mm 3 ); mean absolute neutrophil count at study entry approximately 3,000 cells/mm 3 . Of the 693 patients with concomitant medication information, 59% were on one or more antiretroviral medications [35% zidovudine (AZT), 21% didanosine (ddI), 16% zalcitabine (ddC), and 10% stavudine (D4T)]; 85% received PCP prophylaxis (54% sulfamethoxazole/trimethoprim); 85% received antifungal medications (76% fluconazole); 72% received antivirals (56% acyclovir, 29% ganciclovir, and 16% foscarnet) and 48% patients received colony-stimulating factors (sargramostim/filgrastim) during their course of treatment.

ne (D4T)]; 85% received PCP prophylaxis (54% sulfamethoxazole/trimethoprim); 85% received antifungal medications (76% fluconazole); 72% received antivirals (56% acyclovir, 29% ganciclovir, and 16% foscarnet) and 48% patients received colony-stimulating factors (sargramostim/filgrastim) during their course of treatment. Adverse reactions led to discontinuation of treatment in 5% of patients with AIDS-related Kaposi's sarcoma and included myelosuppression, cardiac adverse reactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis, progression of a non-KS tumor, allergy to penicillin, and unspecified reasons. Table 5 and Table 6 summarize adverse reactions reported in patients treated with doxorubicin hydrochloride liposome injection for AIDS-related Kaposi's sarcoma in a pooled analysis of the four trials. Table 5: Hematologic Adverse Reactions Reported in Patients With AIDS-Related Kaposi's Sarcoma *This includes a subset of subjects who were retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least 2 cycles of a regimen containing at least 2 of 3 treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy. **This includes only subjects with AIDS-KS who had available data from the 4 pooled trials. Patients With Refractory or Intolerant AIDS-Related Kaposi's Sarcoma (n=74*) Total Patients With AIDS-Related Kaposi's Sarcoma (n=720 ** ) Neutropenia <1,000/mm 3 46% 49% <500/mm 3 11% 13% Anemia <10 g/dL 58% 55% <8 g/dL 16% 18% Thrombocytopenia <150,000/mm 3 61% 61% <25,000/mm 3 1.4% 4.2% Table 6: Non-Hematologic Adverse Reactions Reported in ≥ 5% of Patients With AIDS-Related Kaposi's Sarcoma *This includes a subset of subjects who were retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least 2 cycles of a regimen containing at least 2 of 3 treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy. ** This includes only subjects with AIDS-KS who had available adverse event data from the 4 pooled trials. Adverse Reactions Patients With Refractory or Intolerant AIDS-Related Kaposi's Sarcoma (n=77*) Total Patients With AIDS-Related Kaposi's Sarcoma (n=705**) Nausea 18% 17% Asthenia 7% 10% Fever 8% 9% Alopecia 9% 9% Alkaline Phosphatase Increase 1.3% 8% Vomiting 8% 8% Diarrhea 5% 8% Stomatitis 5% 7% Oral Moniliasis 1.3% 6% The following additional adverse reactions were observed in 705 patients with AIDS-related Kaposi's sarcoma. Incidence 1% to 5% Body as a Whole: headache, back pain, infection, allergic reaction, chills. Cardiovascular: chest pain, hypotension, tachycardia. Cutaneous: herpes simplex, rash, itching. Digestive: mouth ulceration, anorexia, dysphagia. Metabolic and Nutritional: SGPT increase, weight loss, hyperbilirubinemia. Other: dyspnea, pneumonia, dizziness, somnolence. Incidence Less Than 1% Body As A Whole: sepsis, moniliasis, cryptococcosis. Cardiovascular: thrombophlebitis, cardiomyopathy, palpitation, bundle branch block, congestive heart failure, heart arrest, thrombosis, ventricular arrhythmia. Digestive: hepatitis. Metabolic and Nutritional Disorders: dehydration. Respiratory: cough increase, pharyngitis. Skin and Appendages: maculopapular rash, herpes zoster. Special Senses: taste perversion, conjunctivitis. Patients With Multiple Myeloma The safety data described are from 318 patients treated with doxorubicin hydrochloride liposome injection (30 mg/m 2 ) administered on day 4 following bortezomib (1.3 mg/m 2 i.v. bolus on days 1, 4, 8 and 11) every 3 weeks, in a randomized, open-label, multicenter study (Trial 6).

ivitis. Patients With Multiple Myeloma The safety data described are from 318 patients treated with doxorubicin hydrochloride liposome injection (30 mg/m 2 ) administered on day 4 following bortezomib (1.3 mg/m 2 i.v. bolus on days 1, 4, 8 and 11) every 3 weeks, in a randomized, open-label, multicenter study (Trial 6). In this trial, patients in the doxorubicin hydrochloride liposome injection + bortezomib combination group were treated for a median number of 4.5 months (range 21 days to 13.5 months). The population was 28 to 85 years of age (median age 61), 58% male, 90% Caucasian, 6% Black, and 4% Asian and Other. Table 7 lists adverse reactions reported in 10% or more of patients treated with doxorubicin hydrochloride liposome injection in combination with bortezomib for multiple myeloma. Table 7: Frequency of Treatment-Emergent Adverse Reactions Reported in ≥10% Patients Treated for Multiple Myeloma With Doxorubicin Hydrochloride Liposome Injection in Combination With Bortezomib 1 Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS. 2 Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized. Adverse Reaction Doxorubicin hydrochloride Liposome Injection + bortezomib (n=318) Bortezomib (n=318) Any (%) Grade 3-4 Any (%) Grade 3-4 Blood and lymphatic system disorders Neutropenia 36 32 22 16 Thrombocytopenia 33 24 28 17 Anemia 25 9 21 9 General disorders and administration site conditions Fatigue 36 7 28 3 Pyrexia 31 1 22 1 Asthenia 22 6 18 4 Gastrointestinal disorders Nausea 48 3 40 1 Diarrhea 46 7 39 5 Vomiting 32 4 22 1 Constipation 31 1 31 1 Mucositis/Stomatitis 20 2 5 <1 Abdominal pain 11 1 8 1 Infections and infestations Herpes zoster 11 2 9 2 Herpes simplex 10 0 6 1 Investigations Weight decreased 12 0 4 0 Metabolism and Nutritional disorders Anorexia 19 2 14 <1 Nervous system disorders Peripheral Neuropathy 1 42 7 45 11 Neuralgia 17 3 20 4 Paresthesia/dysesthesia 13 <1 10 0 Respiratory, thoracic and mediastinal disorders Cough 18 0 12 0 Skin and subcutaneous tissue disorders Rash 2 22 1 18 1 Hand-foot syndrome 19 6 <1 0 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post approval use of doxorubicin hydrochloride liposome 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. Musculoskeletal and Connective Tissue Disorders: muscle spasms Respiratory, Thoracic and Mediastinal Disorders: pulmonary embolism (in some cases fatal), interstitial lung disease Hematologic Disorders : Secondary acute myelogenous leukemia Skin and Subcutaneous Tissue Disorders: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, lichenoid keratosis Secondary Oral Neoplasms: [see Warnings and Precautions ( 5.4 )].

<table ID="_RefID65" width="100%"><caption>Table 3: Hematologic Adverse Reactions in Trial 4</caption><col width="45%"/><col width="34%"/><col width="20%"/><tbody><tr styleCode="Toprule"><td styleCode="Botrule Toprule " valign="top"/><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Doxorubicin Hydrochloride Liposome Injection Patients</content> <content styleCode="bold">(n=239)</content> </paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Topotecan Patients</content> <content styleCode="bold">(n=235)</content> </paragraph></td></tr><tr><td valign="top"><paragraph>Neutropenia </paragraph></td><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><paragraph>500 - &lt;1,000/mm ³ </paragraph></td><td align="center" valign="top"><paragraph>8% </paragraph></td><td align="center" valign="top"><paragraph>14% </paragraph></td></tr><tr><td valign="top"><paragraph>&lt;500/mm3 </paragraph></td><td align="center" valign="top"><paragraph>4.2% </paragraph></td><td align="center" valign="top"><paragraph>62% </paragraph></td></tr><tr><td valign="top"><paragraph>Anemia </paragraph></td><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><paragraph>6.5 - &lt;8 g/dL </paragraph></td><td align="center" valign="top"><paragraph>5% </paragraph></td><td align="center" valign="top"><paragraph>25% </paragraph></td></tr><tr><td valign="top"><paragraph>&lt;6.5 g/dL </paragraph></td><td align="center" valign="top"><paragraph>0.4% </paragraph></td><td align="center" valign="top"><paragraph>4.3% </paragraph></td></tr><tr><td valign="top"><paragraph>Thrombocytopenia </paragraph></td><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><paragraph>10,000 - &lt;50,000/mm ³ </paragraph></td><td align="center" valign="top"><paragraph>1.3% </paragraph></td><td align="center" valign="top"><paragraph>17% </paragraph></td></tr><tr styleCode="Botrule"><td styleCode="Botrule " valign="top"><paragraph>&lt;10,000/mm ³ </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>0.0% </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>17% </paragraph></td></tr></tbody></table>

></td></tr><tr styleCode="Botrule"><td styleCode="Botrule " valign="top"><paragraph>&lt;10,000/mm ³ </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>0.0% </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>17% </paragraph></td></tr></tbody></table> <table ID="_RefID67" width="100%"><caption>Table 4: Non-Hematologic Adverse Reactions in Trial 4</caption><col width="36%"/><col width="20%"/><col width="16%"/><col width="14%"/><col width="13%"/><tbody><tr styleCode="Toprule"><td styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Non-Hematologic</content> <content styleCode="bold">Adverse Reaction</content> <content styleCode="bold">10% or Greater</content> </paragraph></td><td colspan="2" align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Doxorubicin Hydrochloride Liposome Injection (%)</content> <content styleCode="bold">Treated</content> <content styleCode="bold">(n=239)</content> </paragraph></td><td colspan="2" align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Topotecan (%)</content> <content styleCode="bold">Treated</content> <content styleCode="bold">(n=235)</content> </paragraph></td></tr><tr><td styleCode="Botrule " valign="top"/><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">All grades</content> </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Grades 3-4</content> </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">All grades</content> </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Grades 3-4</content> </paragraph></td></tr><tr><td colspan="5" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics"> Body as a Whole</content></content> </paragraph></td></tr><tr><td valign="top"><paragraph> Asthenia </paragraph></td><td align="center" valign="top"><paragraph>40 </paragraph></td><td align="center" valign="top"><paragraph>7 </paragraph></td><td align="center" valign="top"><paragraph>52 </paragraph></td><td align="center" valign="top"><paragraph>8 </paragraph></td></tr><tr><td valign="top"><paragraph> Fever </paragraph></td><td align="center" valign="top"><paragraph>21 </paragraph></td><td align="center" valign="top"><paragraph>0.8 </paragraph></td><td align="center" valign="top"><paragraph>31 </paragraph></td><td align="center" valign="top"><paragraph>6 </paragraph></td></tr><tr><td valign="top"><paragraph> Mucous Membrane Disorder </paragraph></td><td align="center" valign="top"><paragraph>14 </paragraph></td><td align="center" valign="top"><paragraph>3.8 </paragraph></td><td align="center" valign="top"><paragraph>3.4 </paragraph></td><td align="center" valign="top"><paragraph>0 </paragraph></td></tr><tr><td valign="top"><paragraph> Back Pain </paragraph></td><td align="center" valign="top"><paragraph>12 </paragraph></td><td align="center" valign="top"><paragraph>1.7 </paragraph></td><td align="center" valign="top"><paragraph>10 </paragraph></td><td align="center" valign="top"><paragraph>0.9 </paragraph></td></tr><tr><td valign="top"><paragraph> Infection </paragraph></td><td align="center" valign="top"><paragraph>12 </paragraph></td><td align="center" valign="top"><paragraph>2.1 </paragraph></td><td align="center" valign="top"><paragraph>6 </paragraph></td><td align="center" valign="top"><paragraph>0.9 </paragraph></td></tr><tr><td valign="top"><paragraph> Headache </paragraph></td><td align="center" valign="top"><paragraph>11 </paragraph></td><td align="center" valign="top"><paragraph>0.8 </paragraph></td><td align="center" valig

lign="top"><paragraph>6 </paragraph></td><td align="center" valign="top"><paragraph>0.9 </paragraph></td></tr><tr><td valign="top"><paragraph> Headache </paragraph></td><td align="center" valign="top"><paragraph>11 </paragraph></td><td align="center" valign="top"><paragraph>0.8 </paragraph></td><td align="center" valig n="top"><paragraph>15 </paragraph></td><td align="center" valign="top"><paragraph>0 </paragraph></td></tr><tr><td colspan="5" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics"> Digestive</content></content> </paragraph></td></tr><tr><td valign="top"><paragraph> Nausea </paragraph></td><td align="center" valign="top"><paragraph>46 </paragraph></td><td align="center" valign="top"><paragraph>5 </paragraph></td><td align="center" valign="top"><paragraph>63 </paragraph></td><td align="center" valign="top"><paragraph>8 </paragraph></td></tr><tr><td valign="top"><paragraph> Stomatitis </paragraph></td><td align="center" valign="top"><paragraph>41 </paragraph></td><td align="center" valign="top"><paragraph>8 </paragraph></td><td align="center" valign="top"><paragraph>15 </paragraph></td><td align="center" valign="top"><paragraph>0.4 </paragraph></td></tr><tr><td valign="top"><paragraph> Vomiting </paragraph></td><td align="center" valign="top"><paragraph>33 </paragraph></td><td align="center" valign="top"><paragraph>8 </paragraph></td><td align="center" valign="top"><paragraph>44 </paragraph></td><td align="center" valign="top"><paragraph>10 </paragraph></td></tr><tr><td valign="top"><paragraph> Diarrhea </paragraph></td><td align="center" valign="top"><paragraph>21 </paragraph></td><td align="center" valign="top"><paragraph>2.5 </paragraph></td><td align="center" valign="top"><paragraph>35 </paragraph></td><td align="center" valign="top"><paragraph>4.2 </paragraph></td></tr><tr><td valign="top"><paragraph> Anorexia </paragraph></td><td align="center" valign="top"><paragraph>20 </paragraph></td><td align="center" valign="top"><paragraph>2.5 </paragraph></td><td align="center" valign="top"><paragraph>22 </paragraph></td><td align="center" valign="top"><paragraph>1.3 </paragraph></td></tr><tr><td valign="top"><paragraph> Dyspepsia </paragraph></td><td align="center" valign="top"><paragraph>12 </paragraph></td><td align="center" valign="top"><paragraph>0.8 </paragraph></td><td align="center" valign="top"><paragraph>14 </paragraph></td><td align="center" valign="top"><paragraph>0 </paragraph></td></tr><tr><td colspan="5" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics"> Nervous</content></content> </paragraph></td></tr><tr><td valign="top"><paragraph> Dizziness </paragraph></td><td align="center" valign="top"><paragraph>4.2 </paragraph></td><td align="center" valign="top"><paragraph>0 </paragraph></td><td align="center" valign="top"><paragraph>10 </paragraph></td><td align="center" valign="top"><paragraph>0 </paragraph></td></tr><tr><td colspan="5" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics"> Respiratory</content></content> </paragraph></td></tr><tr><td valign="top"><paragraph> Pharyngitis </paragraph></td><td align="center" valign="top"><paragraph>16 </paragraph></td><td align="center" valign="top"><paragraph>0 </paragraph></td><td align="center" valign="top"><paragraph>18 </paragraph></td><td align="center" valign="top"><paragraph>0.4 </paragraph></td></tr><tr><td valign="top"><paragraph> Dyspnea </paragraph></td><td align="center" valign="top"><paragraph>15 </paragraph></td><td align="center" valign="top"><paragraph>4.1 </paragraph></td><td align="center" valign="top"><paragraph>23 </paragraph></td><td align="center" valign="top"><paragraph>4.3 </paragraph></td></tr><tr><td valign="top"><paragraph> Cough increased </paragraph></td><td align="center" val

top"><paragraph>15 </paragraph></td><td align="center" valign="top"><paragraph>4.1 </paragraph></td><td align="center" valign="top"><paragraph>23 </paragraph></td><td align="center" valign="top"><paragraph>4.3 </paragraph></td></tr><tr><td valign="top"><paragraph> Cough increased </paragraph></td><td align="center" val ign="top"><paragraph>10 </paragraph></td><td align="center" valign="top"><paragraph>0 </paragraph></td><td align="center" valign="top"><paragraph>12 </paragraph></td><td align="center" valign="top"><paragraph>0 </paragraph></td></tr><tr><td colspan="5" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics"> Skin and Appendages</content></content> </paragraph></td></tr><tr><td valign="top"><paragraph> Hand-foot syndrome </paragraph></td><td align="center" valign="top"><paragraph>51 </paragraph></td><td align="center" valign="top"><paragraph>24 </paragraph></td><td align="center" valign="top"><paragraph>0.9 </paragraph></td><td align="center" valign="top"><paragraph>0 </paragraph></td></tr><tr><td valign="top"><paragraph> Rash </paragraph></td><td align="center" valign="top"><paragraph>29 </paragraph></td><td align="center" valign="top"><paragraph>4.2 </paragraph></td><td align="center" valign="top"><paragraph>12 </paragraph></td><td align="center" valign="top"><paragraph>0.4 </paragraph></td></tr><tr styleCode="Botrule"><td styleCode="Botrule " valign="top"><paragraph> Alopecia </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>19 </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>N/A </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>52 </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>N/A </paragraph></td></tr></tbody></table>

valign="top"><paragraph>19 </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>N/A </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>52 </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>N/A </paragraph></td></tr></tbody></table> <table ID="_RefID69" width="100%"><caption>Table 5: Hematologic Adverse Reactions Reported in Patients With AIDS-Related Kaposi&apos;s Sarcoma</caption><col width="28%"/><col width="37%"/><col width="34%"/><tfoot><tr><td align="left" colspan="3" valign="top">*This includes a subset of subjects who were retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least 2 cycles of a regimen containing at least 2 of 3 treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy.</td></tr><tr><td align="left" colspan="3" valign="top">**This includes only subjects with AIDS-KS who had available data from the 4 pooled trials.</td></tr></tfoot><tbody><tr styleCode="Toprule"><td styleCode="Botrule Toprule " valign="top"/><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Patients With Refractory or Intolerant AIDS-Related Kaposi&apos;s Sarcoma</content> <content styleCode="bold">(n=74*)</content> </paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Total Patients With AIDS-Related Kaposi&apos;s Sarcoma</content> <content styleCode="bold">(n=720</content>** <content styleCode="bold">)</content> </paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph>Neutropenia </paragraph></td></tr><tr><td align="center" valign="top"><paragraph>&lt;1,000/mm ³ </paragraph></td><td align="center" valign="top"><paragraph>46% </paragraph></td><td align="center" valign="top"><paragraph>49% </paragraph></td></tr><tr><td align="center" valign="top"><paragraph>&lt;500/mm ³ </paragraph></td><td align="center" valign="top"><paragraph>11% </paragraph></td><td align="center" valign="top"><paragraph>13% </paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph>Anemia </paragraph></td></tr><tr><td align="center" valign="top"><paragraph>&lt;10 g/dL </paragraph></td><td align="center" valign="top"><paragraph>58% </paragraph></td><td align="center" valign="top"><paragraph>55% </paragraph></td></tr><tr><td align="center" valign="top"><paragraph>&lt;8 g/dL </paragraph></td><td align="center" valign="top"><paragraph>16% </paragraph></td><td align="center" valign="top"><paragraph>18% </paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph>Thrombocytopenia </paragraph></td></tr><tr><td align="center" valign="top"><paragraph>&lt;150,000/mm ³ </paragraph></td><td align="center" valign="top"><paragraph>61% </paragraph></td><td align="center" valign="top"><paragraph>61% </paragraph></td></tr><tr styleCode="Botrule"><td align="center" styleCode="Botrule " valign="top"><paragraph>&lt;25,000/mm ³ </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1.4% </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>4.2% </paragraph></td></tr></tbody></table>

tyleCode="Botrule"><td align="center" styleCode="Botrule " valign="top"><paragraph>&lt;25,000/mm ³ </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1.4% </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>4.2% </paragraph></td></tr></tbody></table> <table ID="_RefID70" width="100%"><caption>Table 6: Non-Hematologic Adverse Reactions Reported in &#x2265; 5% of Patients With AIDS-Related Kaposi&apos;s Sarcoma</caption><col width="23%"/><col width="44%"/><col width="33%"/><tfoot><tr><td align="left" colspan="3" valign="top">*This includes a subset of subjects who were retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least 2 cycles of a regimen containing at least 2 of 3 treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy.</td></tr><tr><td align="left" colspan="3" valign="top"><content styleCode="bold">**</content>This includes only subjects with AIDS-KS who had available adverse event data from the 4 pooled trials. </td></tr></tfoot><tbody><tr styleCode="Toprule"><td styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Adverse Reactions</content> </paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Patients With Refractory or Intolerant AIDS-Related Kaposi&apos;s Sarcoma</content> <content styleCode="bold">(n=77*)</content> </paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Total Patients With AIDS-Related Kaposi&apos;s Sarcoma</content> <content styleCode="bold">(n=705**)</content> </paragraph></td></tr><tr><td valign="top"><paragraph>Nausea </paragraph></td><td align="center" valign="top"><paragraph>18% </paragraph></td><td align="center" valign="top"><paragraph>17% </paragraph></td></tr><tr><td valign="top"><paragraph>Asthenia </paragraph></td><td align="center" valign="top"><paragraph>7% </paragraph></td><td align="center" valign="top"><paragraph>10% </paragraph></td></tr><tr><td valign="top"><paragraph>Fever </paragraph></td><td align="center" valign="top"><paragraph>8% </paragraph></td><td align="center" valign="top"><paragraph>9% </paragraph></td></tr><tr><td valign="top"><paragraph>Alopecia </paragraph></td><td align="center" valign="top"><paragraph>9% </paragraph></td><td align="center" valign="top"><paragraph>9% </paragraph></td></tr><tr><td valign="top"><paragraph>Alkaline Phosphatase Increase </paragraph></td><td align="center" valign="top"><paragraph>1.3% </paragraph></td><td align="center" valign="top"><paragraph>8% </paragraph></td></tr><tr><td valign="top"><paragraph>Vomiting </paragraph></td><td align="center" valign="top"><paragraph>8% </paragraph></td><td align="center" valign="top"><paragraph>8% </paragraph></td></tr><tr><td valign="top"><paragraph>Diarrhea </paragraph></td><td align="center" valign="top"><paragraph>5% </paragraph></td><td align="center" valign="top"><paragraph>8% </paragraph></td></tr><tr><td valign="top"><paragraph>Stomatitis </paragraph></td><td align="center" valign="top"><paragraph>5% </paragraph></td><td align="center" valign="top"><paragraph>7% </paragraph></td></tr><tr styleCode="Botrule"><td styleCode="Botrule " valign="top"><paragraph>Oral Moniliasis </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1.3% </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>6% </paragraph></td></tr></tbody></table>

</paragraph></td></tr><tr styleCode="Botrule"><td styleCode="Botrule " valign="top"><paragraph>Oral Moniliasis </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1.3% </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>6% </paragraph></td></tr></tbody></table> <table ID="_RefID72" width="100%"><caption>Table 7: Frequency of Treatment-Emergent Adverse Reactions Reported in &#x2265;10% Patients Treated for Multiple Myeloma With Doxorubicin Hydrochloride Liposome Injection in Combination With Bortezomib</caption><col width="43%"/><col width="14%"/><col width="16%"/><col width="14%"/><col width="12%"/><tfoot><tr><td align="left" colspan="5" valign="top">¹Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS. </td></tr><tr><td align="left" colspan="5" valign="top">²Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized.

y, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS. </td></tr><tr><td align="left" colspan="5" valign="top">²Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized. </td></tr></tfoot><tbody><tr styleCode="Toprule"><td styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Adverse Reaction</content> </paragraph></td><td colspan="2" align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Doxorubicin hydrochloride Liposome Injection + bortezomib</content> <content styleCode="bold">(n=318)</content> </paragraph></td><td colspan="2" align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Bortezomib</content> <content styleCode="bold">(n=318)</content> </paragraph></td></tr><tr><td styleCode="Botrule " valign="top"/><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Any (%)</content> </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Grade 3-4</content> </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Any (%)</content> </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Grade 3-4</content> </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Blood and lymphatic system disorders</content> </paragraph></td><td valign="top"/><td valign="top"/><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><paragraph>Neutropenia </paragraph></td><td align="center" valign="top"><paragraph>36 </paragraph></td><td align="center" valign="top"><paragraph>32 </paragraph></td><td align="center" valign="top"><paragraph>22 </paragraph></td><td align="center" valign="top"><paragraph>16 </paragraph></td></tr><tr><td valign="top"><paragraph>Thrombocytopenia </paragraph></td><td align="center" valign="top"><paragraph>33 </paragraph></td><td align="center" valign="top"><paragraph>24 </paragraph></td><td align="center" valign="top"><paragraph>28 </paragraph></td><td align="center" valign="top"><paragraph>17 </paragraph></td></tr><tr><td valign="top"><paragraph>Anemia </paragraph></td><td align="center" valign="top"><paragraph>25 </paragraph></td><td align="center" valign="top"><paragraph>9 </paragraph></td><td align="center" valign="top"><paragraph>21 </paragraph></td><td align="center" valign="top"><paragraph>9 </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">General disorders and administration site conditions</content> </paragraph></td><td valign="top"/><td valign="top"/><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><paragraph>Fatigue </paragraph></td><td align="center" valign="top"><paragraph>36 </paragraph></td><td align="center" valign="top"><paragraph>7 </paragraph></td><td align="center" valign="top"><paragraph>28 </paragraph></td><td align="center" valign="top"><paragraph>3 </paragraph></td></tr><tr><td valign="top"><paragraph>Pyrexia </paragraph></td><td align="center" valign="top"><paragraph>31 </paragraph></td><td align="center" valign="top"><paragraph>1 </paragraph></td><td align="center" valign="top"><paragraph>22 </paragraph></td><td align="center" valign="top"><paragraph>1 </paragraph></td></tr><tr><td valign="top"><paragraph>Asthenia </paragraph></td><td align="center" valign="top"><paragraph>22 </paragraph></td><td align="center" valign="top"><paragraph>6 </paragraph></td><td align="center" valign="top"><paragraph>18 </paragraph></td><td align="center" valign="top"><paragraph>4 </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold"

ph></td><td align="center" valign="top"><paragraph>22 </paragraph></td><td align="center" valign="top"><paragraph>6 </paragraph></td><td align="center" valign="top"><paragraph>18 </paragraph></td><td align="center" valign="top"><paragraph>4 </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold" >Gastrointestinal disorders</content> </paragraph></td><td valign="top"/><td valign="top"/><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><paragraph>Nausea </paragraph></td><td align="center" valign="top"><paragraph>48 </paragraph></td><td align="center" valign="top"><paragraph>3 </paragraph></td><td align="center" valign="top"><paragraph>40 </paragraph></td><td align="center" valign="top"><paragraph>1 </paragraph></td></tr><tr><td valign="top"><paragraph>Diarrhea </paragraph></td><td align="center" valign="top"><paragraph>46 </paragraph></td><td align="center" valign="top"><paragraph>7 </paragraph></td><td align="center" valign="top"><paragraph>39 </paragraph></td><td align="center" valign="top"><paragraph>5 </paragraph></td></tr><tr><td valign="top"><paragraph>Vomiting </paragraph></td><td align="center" valign="top"><paragraph>32 </paragraph></td><td align="center" valign="top"><paragraph>4 </paragraph></td><td align="center" valign="top"><paragraph>22 </paragraph></td><td align="center" valign="top"><paragraph>1 </paragraph></td></tr><tr><td valign="top"><paragraph>Constipation </paragraph></td><td align="center" valign="top"><paragraph>31 </paragraph></td><td align="center" valign="top"><paragraph>1 </paragraph></td><td align="center" valign="top"><paragraph>31 </paragraph></td><td align="center" valign="top"><paragraph>1 </paragraph></td></tr><tr><td valign="top"><paragraph>Mucositis/Stomatitis </paragraph></td><td align="center" valign="top"><paragraph>20 </paragraph></td><td align="center" valign="top"><paragraph>2 </paragraph></td><td align="center" valign="top"><paragraph>5 </paragraph></td><td align="center" valign="top"><paragraph>&lt;1 </paragraph></td></tr><tr><td valign="top"><paragraph>Abdominal pain </paragraph></td><td align="center" valign="top"><paragraph>11 </paragraph></td><td align="center" valign="top"><paragraph>1 </paragraph></td><td align="center" valign="top"><paragraph>8 </paragraph></td><td align="center" valign="top"><paragraph>1 </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Infections and infestations</content> </paragraph></td><td valign="top"/><td valign="top"/><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><paragraph>Herpes zoster </paragraph></td><td align="center" valign="top"><paragraph>11 </paragraph></td><td align="center" valign="top"><paragraph>2 </paragraph></td><td align="center" valign="top"><paragraph>9 </paragraph></td><td align="center" valign="top"><paragraph>2 </paragraph></td></tr><tr><td valign="top"><paragraph>Herpes simplex </paragraph></td><td align="center" valign="top"><paragraph>10 </paragraph></td><td align="center" valign="top"><paragraph>0 </paragraph></td><td align="center" valign="top"><paragraph>6 </paragraph></td><td align="center" valign="top"><paragraph>1 </paragraph></td></tr><tr><td valign="top"><paragraph>Investigations </paragraph></td><td valign="top"/><td valign="top"/><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><paragraph>Weight decreased </paragraph></td><td align="center" valign="top"><paragraph>12 </paragraph></td><td align="center" valign="top"><paragraph>0 </paragraph></td><td align="center" valign="top"><paragraph>4 </paragraph></td><td align="center" valign="top"><paragraph>0 </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Metabolism and Nutritional disorders</content> </paragraph></td><td valign="top"/><td valign="top"/><td valign="top"/><td va

aph></td><td align="center" valign="top"><paragraph>4 </paragraph></td><td align="center" valign="top"><paragraph>0 </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Metabolism and Nutritional disorders</content> </paragraph></td><td valign="top"/><td valign="top"/><td valign="top"/><td va lign="top"/></tr><tr><td valign="top"><paragraph>Anorexia </paragraph></td><td align="center" valign="top"><paragraph>19 </paragraph></td><td align="center" valign="top"><paragraph>2 </paragraph></td><td align="center" valign="top"><paragraph>14 </paragraph></td><td align="center" valign="top"><paragraph>&lt;1 </paragraph></td></tr><tr><td valign="top"><paragraph>Nervous system disorders </paragraph></td><td valign="top"/><td valign="top"/><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><paragraph>Peripheral Neuropathy ¹ </paragraph></td><td align="center" valign="top"><paragraph>42 </paragraph></td><td align="center" valign="top"><paragraph>7 </paragraph></td><td align="center" valign="top"><paragraph>45 </paragraph></td><td align="center" valign="top"><paragraph>11 </paragraph></td></tr><tr><td valign="top"><paragraph>Neuralgia </paragraph></td><td align="center" valign="top"><paragraph>17 </paragraph></td><td align="center" valign="top"><paragraph>3 </paragraph></td><td align="center" valign="top"><paragraph>20 </paragraph></td><td align="center" valign="top"><paragraph>4 </paragraph></td></tr><tr><td valign="top"><paragraph>Paresthesia/dysesthesia </paragraph></td><td align="center" valign="top"><paragraph>13 </paragraph></td><td align="center" valign="top"><paragraph>&lt;1 </paragraph></td><td align="center" valign="top"><paragraph>10 </paragraph></td><td align="center" valign="top"><paragraph>0 </paragraph></td></tr><tr><td colspan="5" valign="top"><paragraph><content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content> </paragraph></td></tr><tr><td valign="top"><paragraph>Cough </paragraph></td><td align="center" valign="top"><paragraph>18 </paragraph></td><td align="center" valign="top"><paragraph>0 </paragraph></td><td align="center" valign="top"><paragraph>12 </paragraph></td><td align="center" valign="top"><paragraph>0 </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Skin and subcutaneous tissue disorders</content> </paragraph></td><td valign="top"/><td valign="top"/><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><paragraph>Rash ² </paragraph></td><td align="center" valign="top"><paragraph>22 </paragraph></td><td align="center" valign="top"><paragraph>1 </paragraph></td><td align="center" valign="top"><paragraph>18 </paragraph></td><td align="center" valign="top"><paragraph>1 </paragraph></td></tr><tr styleCode="Botrule"><td styleCode="Botrule " valign="top"><paragraph>Hand-foot syndrome </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>19 </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>6 </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>&lt;1 </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>0 </paragraph></td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS Lactation : Discontinue breastfeeding ( 8.2 ). 8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action, doxorubicin hydrochloride liposome injection can cause fetal harm when administered to a pregnant woman; avoid the use of doxorubicin hydrochloride liposome injection during the 1 st trimester. In animal reproduction studies, doxorubicin hydrochloride liposome injection was embryotoxic in rats and abortifacient in rabbits following intravenous administration during organogenesis at doses approximately 0.12 times the recommended clinical dose (see Data) . 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. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. Data Animal Data Doxorubicin hydrochloride liposome injection was embryotoxic at doses of 1 mg/kg/day in rats and was embryotoxic and abortifacient at 0.5 mg/kg/day in rabbits (both doses are about 0.12 times the recommended dose of 50 mg/m 2 human dose on a mg/m 2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced live litter sizes. 8.2 Lactation Risk Summary It is not known whether doxorubicin hydrochloride liposome injection is present in human milk. Because many drugs, including anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in breastfed infants from doxorubicin hydrochloride liposome injection, discontinue breastfeeding during treatment with doxorubicin hydrochloride liposome injection. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating doxorubicin hydrochloride liposome injection. Contraception Females Doxorubicin hydrochloride liposome injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Advise females of reproductive potential to use effective contraception during and for 6 months after treatment with doxorubicin hydrochloride liposome injection. Males Doxorubicin hydrochloride liposome injection may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during and for 6 months after treatment with doxorubicin hydrochloride liposome injection [see Non-clinical Toxicology (13.1)]. Infertility Females In females of reproductive potential, doxorubicin hydrochloride liposome injection may cause infertility and result in amenorrhea. Premature menopause can occur with doxorubicin hydrochloride. Recovery of menses and ovulation is related to age at treatment . Males Doxorubicin hydrochloride liposome injection may result in oligospermia, azoospermia, and permanent loss of fertility. Sperm counts have been reported to return to normal levels in some men. This may occur several years after the end of therapy [see Non-clinical Toxicology ( 13.1 )] .

elated to age at treatment . Males Doxorubicin hydrochloride liposome injection may result in oligospermia, azoospermia, and permanent loss of fertility. Sperm counts have been reported to return to normal levels in some men. This may occur several years after the end of therapy [see Non-clinical Toxicology ( 13.1 )] . 8.4 Pediatric Use The safety and effectiveness of doxorubicin hydrochloride liposome injection in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of doxorubicin hydrochloride liposome injection conducted in patients with either epithelial ovarian cancer (Trial 4) or with AIDS-related Kaposi's sarcoma (Trial 5) did not contain sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. In Trial 6, of 318 patients treated with doxorubicin hydrochloride liposome injection in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. 8.6 Hepatic Impairment The pharmacokinetics of doxorubicin hydrochloride liposome injection has not been adequately evaluated in patients with hepatic impairment. Doxorubicin is eliminated in large part by the liver. Reduce doxorubicin hydrochloride liposome injection for serum bilirubin of 1.2 mg/dL or higher.

8.5 Geriatric Use Clinical studies of doxorubicin hydrochloride liposome injection conducted in patients with either epithelial ovarian cancer (Trial 4) or with AIDS-related Kaposi's sarcoma (Trial 5) did not contain sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. In Trial 6, of 318 patients treated with doxorubicin hydrochloride liposome injection in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

11 DESCRIPTION Doxorubicin hydrochloride liposome injection is doxorubicin hydrochloride, an anthracycline topoisomerase inhibitor, that is encapsulated in pegylated liposomes for intravenous use. The chemical name of doxorubicin hydrochloride is (8S,10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-8-glycolyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride. The molecular formula is C 27 H 29 NO 11 ∙HCl and the molecular weight is 579.99. The structural formula is: Doxorubicin hydrochloride liposome injection is a sterile, translucent, red liposomal dispersion. Each single-dose vial contains 20 mg or 50 mg doxorubicin hydrochloride at a concentration of 2 mg/mL (equivalent to 1.87 mg/mL of doxorubicin). The pegylated liposome carriers are composed of cholesterol, 3.19 mg/mL; fully hydrogenated soy phosphatidylcholine (HSPC), 9.58 mg/mL; and N-(carbonyl-methoxypolyethylene glycol 2,000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine sodium salt (MPEG-DSPE), 3.19 mg/mL. Each mL also contains ammonium sulfate, approximately 0.6 mg; histidine 1.50 mg as a buffer; hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (6.0 to 7.0); and sucrose, 95.50 mg to maintain isotonicity. Greater than 90% of the drug is encapsulated in the pegylated liposomes. MPEG-DSPE has the following structural formula: HSPC has the following structural formula: Representation of a pegylated liposome: Image Image Image Image

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The active ingredient of doxorubicin hydrochloride liposome injection is doxorubicin hydrochloride. The mechanism of action of doxorubicin hydrochloride is thought to be related to its ability to bind DNA and inhibit nucleic acid synthesis. Cell structure studies have demonstrated rapid cell penetration and perinuclear chromatin binding, rapid inhibition of mitotic activity and nucleic acid synthesis, and induction of mutagenesis and chromosomal aberrations. 12.3 Pharmacokinetics The pharmacokinetic parameters for total doxorubicin following a single dose of doxorubicin hydrochloride liposome injection infused over 30 minutes are presented in Table 8. Table 8: Pharmacokinetic Parameters of Total Doxorubicin from Doxorubicin Hydrochloride Liposome Injection in Patients With AIDS-Related Kaposi's Sarcoma N=23 Mean ± Standard Error Dose Parameter (units) 10 mg/m 2 20 mg/m 2 Peak Plasma Concentration (µg/mL) 4.12 ± 0.215 8.34 ± 0.49 Plasma Clearance (L/h/m 2 ) 0.056 ± 0.01 0.041 ± 0.004 Steady State Volume of Distribution (L/m 2 ) 2.83 ± 0.145 2.72 ± 0.120 AUC (µg/mL∙h) 277 ± 32.9 590 ± 58.7 First Phase (λ1) Half-Life (h) 4.7 ± 1.1 5.2 ± 1.4 Second Phase (λ1) Half-Life (h) 52.3 ± 5.6 55.0 ± 4.8 Doxorubicin hydrochloride liposome injection displayed linear pharmacokinetics over the range of 10 to 20 mg/m 2 . Relative to doxorubicin hydrochloride liposome injection doses at or below 20 mg/m 2 , the pharmacokinetics of total doxorubicin following a 50 mg/m 2 doxorubicin hydrochloride liposome injection dose are nonlinear. At this dose, the elimination half-life of doxorubicin hydrochloride liposome injection is longer and the clearance lower compared to a 20 mg/m 2 dose. Distribution Direct measurement of liposomal doxorubicin shows that at least 90% of the drug (the assay used cannot quantify less than 5-10% free doxorubicin) remains liposome-encapsulated during circulation. In contrast to doxorubicin, which displays a large volume of distribution (range 700 to 1,100 L/m 2 ), the small steady state volume of distribution of liposomal doxorubicin suggests that doxorubicin hydrochloride liposome injection is largely confined to vascular fluid. Doxorubicin becomes available after the liposomes are extravasated. Plasma protein binding of doxorubicin hydrochloride liposome injection has not been determined; the plasma protein binding of doxorubicin is approximately 70%. Metabolism Doxorubicinol, the major metabolite of doxorubicin, was detected at concentrations of 0.8 to 26.2 ng/mL in the plasma of patients who received 10 or 20 mg/m 2 doxorubicin hydrochloride liposome injection. Elimination The plasma clearance of total doxorubicin from doxorubicin hydrochloride liposome injection was 0.041 L/h/m 2 at a dose of 20 mg/m 2 . Following administration of doxorubicin hydrochloride, the plasma clearance of doxorubicin is 24 to 35 L/h/m 2 .

12.1 Mechanism of Action The active ingredient of doxorubicin hydrochloride liposome injection is doxorubicin hydrochloride. The mechanism of action of doxorubicin hydrochloride is thought to be related to its ability to bind DNA and inhibit nucleic acid synthesis. Cell structure studies have demonstrated rapid cell penetration and perinuclear chromatin binding, rapid inhibition of mitotic activity and nucleic acid synthesis, and induction of mutagenesis and chromosomal aberrations.

12.3 Pharmacokinetics The pharmacokinetic parameters for total doxorubicin following a single dose of doxorubicin hydrochloride liposome injection infused over 30 minutes are presented in Table 8. Table 8: Pharmacokinetic Parameters of Total Doxorubicin from Doxorubicin Hydrochloride Liposome Injection in Patients With AIDS-Related Kaposi's Sarcoma N=23 Mean ± Standard Error Dose Parameter (units) 10 mg/m 2 20 mg/m 2 Peak Plasma Concentration (µg/mL) 4.12 ± 0.215 8.34 ± 0.49 Plasma Clearance (L/h/m 2 ) 0.056 ± 0.01 0.041 ± 0.004 Steady State Volume of Distribution (L/m 2 ) 2.83 ± 0.145 2.72 ± 0.120 AUC (µg/mL∙h) 277 ± 32.9 590 ± 58.7 First Phase (λ1) Half-Life (h) 4.7 ± 1.1 5.2 ± 1.4 Second Phase (λ1) Half-Life (h) 52.3 ± 5.6 55.0 ± 4.8 Doxorubicin hydrochloride liposome injection displayed linear pharmacokinetics over the range of 10 to 20 mg/m 2 . Relative to doxorubicin hydrochloride liposome injection doses at or below 20 mg/m 2 , the pharmacokinetics of total doxorubicin following a 50 mg/m 2 doxorubicin hydrochloride liposome injection dose are nonlinear. At this dose, the elimination half-life of doxorubicin hydrochloride liposome injection is longer and the clearance lower compared to a 20 mg/m 2 dose. Distribution Direct measurement of liposomal doxorubicin shows that at least 90% of the drug (the assay used cannot quantify less than 5-10% free doxorubicin) remains liposome-encapsulated during circulation. In contrast to doxorubicin, which displays a large volume of distribution (range 700 to 1,100 L/m 2 ), the small steady state volume of distribution of liposomal doxorubicin suggests that doxorubicin hydrochloride liposome injection is largely confined to vascular fluid. Doxorubicin becomes available after the liposomes are extravasated. Plasma protein binding of doxorubicin hydrochloride liposome injection has not been determined; the plasma protein binding of doxorubicin is approximately 70%. Metabolism Doxorubicinol, the major metabolite of doxorubicin, was detected at concentrations of 0.8 to 26.2 ng/mL in the plasma of patients who received 10 or 20 mg/m 2 doxorubicin hydrochloride liposome injection. Elimination The plasma clearance of total doxorubicin from doxorubicin hydrochloride liposome injection was 0.041 L/h/m 2 at a dose of 20 mg/m 2 . Following administration of doxorubicin hydrochloride, the plasma clearance of doxorubicin is 24 to 35 L/h/m 2 .

<table ID="_RefID110" width="100%"><caption>Table 8: Pharmacokinetic Parameters of Total Doxorubicin from Doxorubicin Hydrochloride Liposome Injection in Patients With AIDS-Related Kaposi&apos;s Sarcoma</caption><col width="62%"/><col width="18%"/><col width="19%"/><tfoot><tr><td align="left" colspan="3" valign="top">N=23</td></tr><tr><td align="left" colspan="3" valign="top">Mean &#xB1; Standard Error</td></tr></tfoot><tbody><tr styleCode="Toprule"><td styleCode="Toprule " valign="top"/><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Dose</content> </paragraph></td><td styleCode="Botrule Toprule " valign="top"/></tr><tr><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Parameter (units)</content> </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>10 mg/m ² </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>20 mg/m ² </paragraph></td></tr><tr><td valign="top"><paragraph>Peak Plasma Concentration (&#xB5;g/mL) </paragraph></td><td align="center" valign="top"><paragraph>4.12 &#xB1; 0.215 </paragraph></td><td align="center" valign="top"><paragraph>8.34 &#xB1; 0.49 </paragraph></td></tr><tr><td valign="top"><paragraph>Plasma Clearance (L/h/m ²) </paragraph></td><td align="center" valign="top"><paragraph>0.056 &#xB1; 0.01 </paragraph></td><td align="center" valign="top"><paragraph>0.041 &#xB1; 0.004 </paragraph></td></tr><tr><td valign="top"><paragraph>Steady State Volume of Distribution (L/m ²) </paragraph></td><td align="center" valign="top"><paragraph>2.83 &#xB1; 0.145 </paragraph></td><td align="center" valign="top"><paragraph>2.72 &#xB1; 0.120 </paragraph></td></tr><tr><td valign="top"><paragraph>AUC (&#xB5;g/mL&#x2219;h) </paragraph></td><td align="center" valign="top"><paragraph>277 &#xB1; 32.9 </paragraph></td><td align="center" valign="top"><paragraph>590 &#xB1; 58.7 </paragraph></td></tr><tr><td valign="top"><paragraph>First Phase (&#x3BB;1) Half-Life (h) </paragraph></td><td align="center" valign="top"><paragraph>4.7 &#xB1; 1.1 </paragraph></td><td align="center" valign="top"><paragraph>5.2 &#xB1; 1.4 </paragraph></td></tr><tr styleCode="Botrule"><td styleCode="Botrule " valign="top"><paragraph>Second Phase (&#x3BB;1) Half-Life (h) </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>52.3 &#xB1; 5.6 </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>55.0 &#xB1; 4.8 </paragraph></td></tr></tbody></table>

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Mutagenicity or carcinogenicity studies have not been conducted with doxorubicin hydrochloride liposome injection, however doxorubicin was shown to be mutagenic in the in vitro Ames assay, and clastogenic in multiple in vitro assays (CHO cell, V79 hamster cell, human lymphoblast, and SCE assays) and the in vivo mouse micronucleus assay. The possible adverse effects on fertility in animals have not been adequately evaluated. Doxorubicin hydrochloride liposome injection resulted in mild to moderate ovarian and testicular atrophy in mice after administration of a single dose of 36 mg/kg (about 2 times the 50 mg/m 2 human dose on a mg/m 2 basis). Decreased testicular weights and hypospermia were observed in rats after repeat doses ≥ 0.25 mg/kg/day (about 0.03 times the 50 mg/m 2 human dose on a mg/m 2 basis), and diffuse degeneration of the seminiferous tubules and a marked decrease in spermatogenesis were observed in dogs after repeat doses of 1 mg/kg/day (about 0.4 times the 50 mg/m 2 human dose on a mg/m 2 basis).

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Mutagenicity or carcinogenicity studies have not been conducted with doxorubicin hydrochloride liposome injection, however doxorubicin was shown to be mutagenic in the in vitro Ames assay, and clastogenic in multiple in vitro assays (CHO cell, V79 hamster cell, human lymphoblast, and SCE assays) and the in vivo mouse micronucleus assay. The possible adverse effects on fertility in animals have not been adequately evaluated. Doxorubicin hydrochloride liposome injection resulted in mild to moderate ovarian and testicular atrophy in mice after administration of a single dose of 36 mg/kg (about 2 times the 50 mg/m 2 human dose on a mg/m 2 basis). Decreased testicular weights and hypospermia were observed in rats after repeat doses ≥ 0.25 mg/kg/day (about 0.03 times the 50 mg/m 2 human dose on a mg/m 2 basis), and diffuse degeneration of the seminiferous tubules and a marked decrease in spermatogenesis were observed in dogs after repeat doses of 1 mg/kg/day (about 0.4 times the 50 mg/m 2 human dose on a mg/m 2 basis).

14 CLINICAL STUDIES 14.1 Ovarian Cancer Doxorubicin hydrochloride liposome injection was studied in three open-label, single-arm, clinical studies of 176 patients with metastatic ovarian cancer (Trials 1, 2, and 3). One hundred forty-five of these patients were refractory to both paclitaxel- and platinum-based chemotherapy regimens, defined as disease progression while on treatment or relapse within 6 months of completing treatment. Patients received doxorubicin hydrochloride liposome injection at 50 mg/m 2 every 3 or 4 weeks for 3-6+ cycles in the absence of dose-limiting toxicity or disease progression. The median age at diagnosis ranged from 52 to 64 years in the 3 studies, and the range was 22 to 85. Most patients had International Federation of Obstetricians and Gynecologists (FIGO) stage III or IV disease (ranging from 83% to 93%). Approximately one third of the patients had three or more prior lines of therapy (ranging from 22% to 33%). The primary outcome measure was confirmed response rate based on Southwestern Oncology Group (SWOG) criteria for patients refractory to both paclitaxel- and a platinum-containing regimen. Secondary efficacy parameters were time to response, duration of response, and time to progression. The response rates for the individual single arm trials are given in Table 9 below. Table 9: Response Rates in Patients With Refractory Ovarian Cancer From Single Arm Ovarian Cancer Trials Trial 1 (U.S.) N=27 Trial 2 (U.S.) N=82 Trial 3 (non-U.S.) N=36 Response Rate 22.2% 17.1% 0% 95% Confidence Interval 8.6% - 42.3% 9.7% - 27.0% 0.0% - 9.7% In a pooled analysis of Trials 1-3, the response rate for all patients refractory to paclitaxel and platinum agents was 13.8% (95% CI 8.1% to 19.3%). The median time to progression was 15.9 weeks, the median time to response was 17.6 weeks, and the duration of response was 39.4 weeks. In Trial 4, a randomized, multicenter, open-label, trial in 474 patients with epithelial ovarian cancer after platinum-based chemotherapy, patients were randomized to receive either doxorubicin hydrochloride liposome injection 50 mg/m 2 every 4 weeks (n=239) or topotecan 1.5 mg/m 2 daily for 5 consecutive days every 3 weeks (n=235). Patients were stratified according to platinum sensitivity (response to initial platinum-based therapy and a progression-free interval of greater than 6 months off treatment) and the presence of bulky disease (tumor mass greater than 5 cm in size). The primary outcome measure was time to progression (TTP). Other endpoints included overall survival and objective response rate. Of the 474 patients, the median age at diagnosis was 60 years (range 25 to 87), 90% were FIGO stage III and IV; 46% were platinum sensitive; and 45% had bulky disease. There was no statistically significant difference in TTP between the two arms. Results are provided in Table 10. Table 10: Results of Efficacy Analyses 1 1 Analysis based on investigators' strata for protocol defined ITT population. 2 Kaplan-Meier estimates. 3 p-value is based on the stratified log-rank test. 4 Hazard ratio is based on Cox proportional-hazard model with the treatment as single independent variable. A hazard ratio less than 1 indicates an advantage for doxorubicin hydrochloride liposome injection. 5 p-value not adjusted for multiple comparisons.

estimates. 3 p-value is based on the stratified log-rank test. 4 Hazard ratio is based on Cox proportional-hazard model with the treatment as single independent variable. A hazard ratio less than 1 indicates an advantage for doxorubicin hydrochloride liposome injection. 5 p-value not adjusted for multiple comparisons. Protocol Defined ITT Population Doxorubicin Hydrochloride Liposome Injection (n=239) Topotecan (n=235) TTP (Protocol Specified Primary Endpoint) Median (Months) 2 4.1 4.2 p-value 3 0.62 Hazard Ratio 4 0.96 95% CI for Hazard Ratio (0.76, 1.20) Overall Survival Median (Months) 2 14.4 13.7 p-value 5 0.05 Hazard Ratio 4 0.82 95% CI for Hazard Ratio (0.68, 1.00) Response Rate Overall Response n (%) 47 (19.7) 40 (17.0) Complete Response n (%) 9 (3.8) 11 (4.7) Partial Response n (%) 38 (15.9) 29 (12.3) Median Duration of Response (Months) 2 6.9 5.9 14.2 AIDS-Related Kaposi's Sarcoma Doxorubicin hydrochloride liposome injection was studied in an open-label, single-arm, multicenter study at a dose of 20 mg/m 2 every 3 weeks, until disease progression or unacceptable toxicity (Trial 5). Data is described for a cohort of 77 patients retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least two cycles of a regimen containing at least two of three treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy. Forty-nine of the 77 (64%) patients had received prior doxorubicin hydrochloride. The median time on study was 5.1 months (range 1 day to 15 months). The median cumulative dose of doxorubicin hydrochloride liposome injection was 154 mg/m 2 (range 20 to 620 mg/m 2 ). Among the 77 patients, mean age was 38 years (range 24 to 54); 87% were Caucasian, 5% Hispanic, 4% Black, and 4% Asian/Other/Unknown; median CD4 count was 10 cells/mm 3 ; ACTG staging criteria were 78% poor risk for tumor burden, 96% poor risk for immune system, and 58% poor risk for systemic illness at baseline; and mean Karnofsky status score was 74%. All patients had cutaneous or subcutaneous lesions, 40% also had oral lesions, 26% pulmonary lesions, and 14% had lesions of the stomach/intestine. Two analyses of tumor response were used: one based on investigator assessment of changes in lesions based on modified ACTG criteria (partial response defined as no new lesions, sites of disease, or worsening edema; flattening of ≥50% of previously raised lesions or area of indicator lesions decreasing by ≥50%; and response lasting at least 21 days with no prior progression), and one based on changes in up to five prospectively indentified representative indicator lesions (partial response defined as flattening of ≥50% of previously raised indicator lesions, or >50% decrease in the area of indicator lesions and lasting at least 21 days with no prior progression). Of the 77 patients, 34 were evaluable for investigator assessment and 42 were evaluable for indicator lesion assessment; analyses of tumor responses are shown in Table 11. Table 11: Response in Patients with Refractory 1 AIDS-Related Kaposi's Sarcoma 1 Patients with disease that progressed on prior combination chemotherapy or who were intolerant to such therapy. 2 There were no complete responses in this population.

or lesion assessment; analyses of tumor responses are shown in Table 11. Table 11: Response in Patients with Refractory 1 AIDS-Related Kaposi's Sarcoma 1 Patients with disease that progressed on prior combination chemotherapy or who were intolerant to such therapy. 2 There were no complete responses in this population. Investigator Assessment All Evaluable Patients (n=34) Evaluable Patients Who Received Prior Doxorubicin (n=20) Response 2 Partial (PR) 27% 30% Stable 29% 40% Progression 44% 30% Duration of PR (Days) Median 73 89 Range 42+ to 210+ 42+ to 210+ Time to PR (Days) Median 43 53 Range 15 to 133 15 to 109 Indicator Lesion Assessment All Evaluable Patients (n=42) Evaluable Patients Who Received Prior Doxorubicin (n=23) Response 2 Partial (PR) 48% 52% Stable 26% 30% Progression 26% 17% Duration of PR (Days) Median 71 79 Range 22+ to 210+ 35 to 210+ Time to PR (Days) Median 22 48 Range 15 to 109 15 to 109 Retrospective efficacy analyses were performed in two trials that had subsets of patients who received single-agent doxorubicin hydrochloride liposome injection and who were on stable antiretroviral therapy for at least 60 days prior to enrollment and until a response was demonstrated. In one trial, 7 of 17 (40%) patients had a durable response (median duration not reached but was longer than 11.6 months). In the second trial, 4 of 11 patients (40%) on a stable antiretroviral therapy demonstrated durable responses. 14.3 Multiple Myeloma The efficacy of doxorubicin hydrochloride liposome injection in combination with bortezomib was evaluated in Trial 6, a randomized, open-label, international, multicenter study in 646 patients who had not previously received bortezomib and whose disease progressed during or after at least one prior therapy. Patients were randomized (1:1) to receive either doxorubicin hydrochloride liposome injection (30 mg/m 2 ) administered intravenous on day 4 following bortezomib (1.3 mg/m 2 intravenous on days 1, 4, 8 and 11) or bortezomib alone every 3 weeks for up to 8 cycles or until disease progression or unacceptable toxicity. Patients who maintained a response were allowed to receive further treatment. The median number of cycles in each treatment arm was 5 (range 1-18). The baseline demographics and clinical characteristics of the patients with multiple myeloma were similar between treatment arms (Table 12). Table 12: Summary of Baseline Patient and Disease Characteristics Patient Characteristics Doxorubicin Hydrochloride Liposome Injection + bortezomib n=324 bortezomib n=322 Median age in years (range) 61 (28, 85) 62 (34, 88) % Male/female 58 / 42 54 / 46 % Caucasian/Black/other 90 / 6 / 4 94 / 4 / 2 Disease Characteristics % with IgG/IgA/Light chain 57 / 27 / 12 62 / 24 / 11 % β2-microglobulin group ≤2.5 mg/L 14 14 >2.5 mg/L and ≤5.5 mg/L 56 55 >5.5 mg/L 30 31 Serum M-protein (g/dL): Median (Range) 2.5 (0-10.0) 2.7 (0-10.0) Urine M-protein (mg/24 hours): Median (Range) 107 (0-24883) 66 (0-39657) Median Months Since Diagnosis 35.2 37.5 % Prior Therapy One 34 34 More than one 66 66 Prior Systemic Therapies for Multiple Myeloma Corticosteroid (%) 99 >99 Anthracyclines 68 67 Alkylating agent (%) 92 90 Thalidomide/lenalidomide (%) 40 43 Stem cell transplantation (%) 57 54 The primary outcome measure was time to progression (TTP). TTP was defined as the time from randomization to the first occurrence of progressive disease or death due to progressive disease. The combination arm demonstrated significant improvement in TTP. As the prespecified primary objective was achieved at the interim analysis, patients in the bortezomib monotherapy group were then allowed to receive the doxorubicin hydrochloride liposome injection + bortezomib combination. Efficacy results are as shown in Table 13 and Figure 1 .

trated significant improvement in TTP. As the prespecified primary objective was achieved at the interim analysis, patients in the bortezomib monotherapy group were then allowed to receive the doxorubicin hydrochloride liposome injection + bortezomib combination. Efficacy results are as shown in Table 13 and Figure 1 . Table 13: Efficacy of Doxorubicin Hydrochloride Liposome Injection in Combination With Bortezomib in the Treatment of Patients With Multiple Myeloma 1 Kaplan Meier estimate. 2 Hazard ratio based on stratified Cox proportional hazards regression. A hazard ratio <1 indicates an advantage for doxorubicin hydrochloride liposome injection + bortezomib. 3 Stratified log-rank test. 4 RR as per EBMT criteria. 5 Cochran-Mantel-Haenszel test adjusted for the stratification factors. Endpoint Doxorubicin Hydrochloride Liposome Injection + bortezomib n=324 Bortezomib n=322 Time to Progression 1 Progression or death due to progression (n) 99 150 Censored (n) 225 172 Median in days (months) 282 (9.3) 197 (6.5) 95% CI 250; 338 170; 217 Hazard ratio 2 0.55 (95% CI) (0.43, 0.71) p-value 3 <0.001 Response (n) 4 303 310 % Complete Response (CR) 5 3 % Partial Response (PR) 43 40 % CR + PR 48 43 p-value 5 0.25 Median Duration of Response (months) 10.2 7.0 (95% CI) (10.2; 12.9) (5.9; 8.3) Figure 1- Time to Progression Kaplan-Meier Curve At the final analysis of survival, 78% of subjects in the doxorubicin hydrochloride liposome injection and bortezomib combination therapy group and 80% of subjects in the bortezomib monotherapy group had died after a median follow up of 8.6 years. The median survival was 33 months in the doxorubicin hydrochloride liposome injection and bortezomib combination therapy group and 31 months in the bortezomib monotherapy group. There was no difference observed in overall survival at the final analysis [HR for doxorubicin hydrochloride liposome injection + bortezomib vs. bortezomib = 0.96 (95% CI 0.80, 1.14)]. Seventy-eight percent of subjects in the doxorubicin hydrochloride liposome injection and bortezomib combination therapy group and 80% of subjects in the bortezomib monotherapy group had received subsequent therapy. Image

<table ID="_RefID118" width="100%"><caption>Table 9: Response Rates in Patients With Refractory Ovarian Cancer From Single Arm Ovarian Cancer Trials</caption><col width="35%"/><col width="22%"/><col width="22%"/><col width="22%"/><tbody><tr styleCode="Toprule"><td styleCode="Botrule Toprule " valign="top"/><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Trial 1 (U.S.)</content> <content styleCode="bold">N=27</content> </paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Trial 2 (U.S.)</content> <content styleCode="bold">N=82</content> </paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Trial 3 (non-U.S.)</content> <content styleCode="bold">N=36</content> </paragraph></td></tr><tr><td valign="top"><paragraph>Response Rate </paragraph></td><td align="center" valign="top"><paragraph>22.2% </paragraph></td><td align="center" valign="top"><paragraph>17.1% </paragraph></td><td align="center" valign="top"><paragraph>0% </paragraph></td></tr><tr styleCode="Botrule"><td styleCode="Botrule " valign="top"><paragraph>95% Confidence Interval </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>8.6% - 42.3% </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>9.7% - 27.0% </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>0.0% - 9.7% </paragraph></td></tr></tbody></table>

</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>8.6% - 42.3% </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>9.7% - 27.0% </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>0.0% - 9.7% </paragraph></td></tr></tbody></table> <table ID="_RefID120" width="100%"><caption>Table 10: Results of Efficacy Analyses ¹</caption><col width="43%"/><col width="28%"/><col width="28%"/><tfoot><tr><td align="left" colspan="3" valign="top">¹Analysis based on investigators&apos; strata for protocol defined ITT population. </td></tr><tr><td align="left" colspan="3" valign="top">²Kaplan-Meier estimates. </td></tr><tr><td align="left" colspan="3" valign="top">³p-value is based on the stratified log-rank test. </td></tr><tr><td align="left" colspan="3" valign="top">⁴Hazard ratio is based on Cox proportional-hazard model with the treatment as single independent variable. A hazard ratio less than 1 indicates an advantage for doxorubicin hydrochloride liposome injection. </td></tr><tr><td align="left" colspan="3" valign="top">⁵p-value not adjusted for multiple comparisons.

Hazard ratio is based on Cox proportional-hazard model with the treatment as single independent variable. A hazard ratio less than 1 indicates an advantage for doxorubicin hydrochloride liposome injection. </td></tr><tr><td align="left" colspan="3" valign="top">⁵p-value not adjusted for multiple comparisons. </td></tr></tfoot><tbody><tr styleCode="Toprule"><td styleCode="Toprule " valign="top"/><td colspan="2" align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Protocol Defined ITT Population</content> </paragraph></td></tr><tr><td styleCode="Botrule " valign="top"/><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Doxorubicin Hydrochloride Liposome Injection</content> <content styleCode="bold">(n=239)</content> </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Topotecan</content> <content styleCode="bold">(n=235)</content> </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">TTP</content>(Protocol Specified Primary Endpoint) </paragraph></td><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><paragraph> Median (Months) ² </paragraph></td><td align="center" valign="top"><paragraph>4.1 </paragraph></td><td align="center" valign="top"><paragraph>4.2 </paragraph></td></tr><tr><td valign="top"><paragraph> p-value ³ </paragraph></td><td colspan="2" align="center" valign="top"><paragraph>0.62 </paragraph></td></tr><tr><td valign="top"><paragraph> Hazard Ratio ⁴ </paragraph></td><td colspan="2" align="center" valign="top"><paragraph>0.96 </paragraph></td></tr><tr><td valign="top"><paragraph> 95% CI for Hazard Ratio </paragraph></td><td colspan="2" align="center" valign="top"><paragraph>(0.76, 1.20) </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Overall Survival</content> </paragraph></td><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><paragraph> Median (Months) ² </paragraph></td><td align="center" valign="top"><paragraph>14.4 </paragraph></td><td align="center" valign="top"><paragraph>13.7 </paragraph></td></tr><tr><td valign="top"><paragraph> p-value ⁵ </paragraph></td><td colspan="2" align="center" valign="top"><paragraph>0.05 </paragraph></td></tr><tr><td valign="top"><paragraph> Hazard Ratio ⁴ </paragraph></td><td colspan="2" align="center" valign="top"><paragraph>0.82 </paragraph></td></tr><tr><td valign="top"><paragraph> 95% CI for Hazard Ratio </paragraph></td><td colspan="2" align="center" valign="top"><paragraph>(0.68, 1.00) </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Response Rate</content> </paragraph></td><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><paragraph> Overall Response n (%) </paragraph></td><td align="center" valign="top"><paragraph>47 (19.7) </paragraph></td><td align="center" valign="top"><paragraph>40 (17.0) </paragraph></td></tr><tr><td valign="top"><paragraph> Complete Response n (%) </paragraph></td><td align="center" valign="top"><paragraph>9 (3.8) </paragraph></td><td align="center" valign="top"><paragraph>11 (4.7) </paragraph></td></tr><tr><td valign="top"><paragraph> Partial Response n (%) </paragraph></td><td align="center" valign="top"><paragraph>38 (15.9) </paragraph></td><td align="center" valign="top"><paragraph>29 (12.3) </paragraph></td></tr><tr styleCode="Botrule"><td styleCode="Botrule " valign="top"><paragraph> Median Duration of Response (Months) ² </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>6.9 </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>5.9 </paragraph></td></tr></tbody></table>

e="Botrule"><td styleCode="Botrule " valign="top"><paragraph> Median Duration of Response (Months) ² </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>6.9 </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>5.9 </paragraph></td></tr></tbody></table> <table ID="_RefID123" width="100%"><caption>Table 11: Response in Patients with Refractory ¹AIDS-Related Kaposi&apos;s Sarcoma </caption><col width="30%"/><col width="22%"/><col width="48%"/><tfoot><tr><td align="left" colspan="3" valign="top">¹Patients with disease that progressed on prior combination chemotherapy or who were intolerant to such therapy. </td></tr><tr><td align="left" colspan="3" valign="top">²There were no complete responses in this population.

2%"/><col width="48%"/><tfoot><tr><td align="left" colspan="3" valign="top">¹Patients with disease that progressed on prior combination chemotherapy or who were intolerant to such therapy. </td></tr><tr><td align="left" colspan="3" valign="top">²There were no complete responses in this population. </td></tr></tfoot><tbody><tr styleCode="Toprule"><td styleCode="Botrule Toprule " valign="top"><paragraph>Investigator Assessment </paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph>All Evaluable Patients (n=34) </paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph>Evaluable Patients Who Received Prior Doxorubicin (n=20) </paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Response ² </paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/></tr><tr><td valign="top"><paragraph>Partial (PR) </paragraph></td><td align="center" valign="top"><paragraph>27% </paragraph></td><td align="center" valign="top"><paragraph>30% </paragraph></td></tr><tr><td valign="top"><paragraph>Stable </paragraph></td><td align="center" valign="top"><paragraph>29% </paragraph></td><td align="center" valign="top"><paragraph>40% </paragraph></td></tr><tr><td valign="top"><paragraph>Progression </paragraph></td><td align="center" valign="top"><paragraph>44% </paragraph></td><td align="center" valign="top"><paragraph>30% </paragraph></td></tr><tr><td valign="top"><paragraph>Duration of PR (Days) </paragraph></td><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><paragraph>Median </paragraph></td><td align="center" valign="top"><paragraph>73 </paragraph></td><td align="center" valign="top"><paragraph>89 </paragraph></td></tr><tr><td valign="top"><paragraph>Range </paragraph></td><td align="center" valign="top"><paragraph>42+ to 210+ </paragraph></td><td align="center" valign="top"><paragraph>42+ to 210+ </paragraph></td></tr><tr><td valign="top"><paragraph>Time to PR (Days) </paragraph></td><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><paragraph>Median </paragraph></td><td align="center" valign="top"><paragraph>43 </paragraph></td><td align="center" valign="top"><paragraph>53 </paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Range </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>15 to 133 </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>15 to 109 </paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Indicator Lesion Assessment </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>All Evaluable Patients (n=42) </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>Evaluable Patients Who Received Prior Doxorubicin (n=23) </paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Response ² </paragraph></td><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"/></tr><tr><td valign="top"><paragraph>Partial (PR) </paragraph></td><td align="center" valign="top"><paragraph>48% </paragraph></td><td align="center" valign="top"><paragraph>52% </paragraph></td></tr><tr><td valign="top"><paragraph>Stable </paragraph></td><td align="center" valign="top"><paragraph>26% </paragraph></td><td align="center" valign="top"><paragraph>30% </paragraph></td></tr><tr><td valign="top"><paragraph>Progression </paragraph></td><td align="center" valign="top"><paragraph>26% </paragraph></td><td align="center" valign="top"><paragraph>17% </paragraph></td></tr><tr><td valign="top"><paragraph>Duration of PR (Days) </paragraph></td><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><paragraph>Median </paragraph><

ssion </paragraph></td><td align="center" valign="top"><paragraph>26% </paragraph></td><td align="center" valign="top"><paragraph>17% </paragraph></td></tr><tr><td valign="top"><paragraph>Duration of PR (Days) </paragraph></td><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><paragraph>Median </paragraph>< /td><td align="center" valign="top"><paragraph>71 </paragraph></td><td align="center" valign="top"><paragraph>79 </paragraph></td></tr><tr><td valign="top"><paragraph>Range </paragraph></td><td align="center" valign="top"><paragraph>22+ to 210+ </paragraph></td><td align="center" valign="top"><paragraph>35 to 210+ </paragraph></td></tr><tr><td valign="top"><paragraph>Time to PR (Days) </paragraph></td><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><paragraph>Median </paragraph></td><td align="center" valign="top"><paragraph>22 </paragraph></td><td align="center" valign="top"><paragraph>48 </paragraph></td></tr><tr styleCode="Botrule"><td styleCode="Botrule " valign="top"><paragraph>Range </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>15 to 109 </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>15 to 109 </paragraph></td></tr></tbody></table>

/paragraph></td></tr><tr styleCode="Botrule"><td styleCode="Botrule " valign="top"><paragraph>Range </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>15 to 109 </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>15 to 109 </paragraph></td></tr></tbody></table> <table ID="_RefID127" width="100%"><caption>Table 12: Summary of Baseline Patient and Disease Characteristics</caption><col width="50%"/><col width="34%"/><col width="16%"/><tbody><tr styleCode="Toprule"><td styleCode="Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Patient Characteristics</content> </paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Doxorubicin Hydrochloride Liposome Injection + bortezomib</content> <content styleCode="bold">n=324</content> </paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">bortezomib</content> <content styleCode="bold">n=322</content> </paragraph></td></tr><tr><td valign="top"><paragraph>Median age in years (range) </paragraph></td><td align="center" valign="top"><paragraph>61 (28, 85) </paragraph></td><td align="center" valign="top"><paragraph>62 (34, 88) </paragraph></td></tr><tr><td valign="top"><paragraph>% Male/female </paragraph></td><td align="center" valign="top"><paragraph>58 / 42 </paragraph></td><td align="center" valign="top"><paragraph>54 / 46 </paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>% Caucasian/Black/other </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>90 / 6 / 4 </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>94 / 4 / 2 </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Disease Characteristics</content> </paragraph></td><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><paragraph>% with IgG/IgA/Light chain </paragraph></td><td align="center" valign="top"><paragraph>57 / 27 / 12 </paragraph></td><td align="center" valign="top"><paragraph>62 / 24 / 11 </paragraph></td></tr><tr><td valign="top"><paragraph>% &#x3B2;2-microglobulin group </paragraph></td><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><paragraph>&#x2264;2.5 mg/L </paragraph></td><td align="center" valign="top"><paragraph>14 </paragraph></td><td align="center" valign="top"><paragraph>14 </paragraph></td></tr><tr><td valign="top"><paragraph>&gt;2.5 mg/L and &#x2264;5.5 mg/L </paragraph></td><td align="center" valign="top"><paragraph>56 </paragraph></td><td align="center" valign="top"><paragraph>55 </paragraph></td></tr><tr><td valign="top"><paragraph>&gt;5.5 mg/L </paragraph></td><td align="center" valign="top"><paragraph>30 </paragraph></td><td align="center" valign="top"><paragraph>31 </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Serum M-protein (g/dL): Median (Range)</content> </paragraph></td><td align="center" valign="top"><paragraph>2.5 (0-10.0) </paragraph></td><td align="center" valign="top"><paragraph>2.7 (0-10.0) </paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Urine M-protein (mg/24 hours): Median (Range)</content> </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>107 (0-24883) </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>66 (0-39657) </paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Median Months Since Diagnosis</content> </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>35.2 </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>37.5 </paragraph></td></tr><t

</tr><tr><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Median Months Since Diagnosis</content> </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>35.2 </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>37.5 </paragraph></td></tr><t r><td valign="top"><paragraph><content styleCode="bold">% Prior Therapy</content> </paragraph></td><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><paragraph>One </paragraph></td><td align="center" valign="top"><paragraph>34 </paragraph></td><td align="center" valign="top"><paragraph>34 </paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>More than one </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>66 </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>66 </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Prior Systemic Therapies for Multiple Myeloma</content> </paragraph></td><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><paragraph>Corticosteroid (%) </paragraph></td><td align="center" valign="top"><paragraph>99 </paragraph></td><td align="center" valign="top"><paragraph>&gt;99 </paragraph></td></tr><tr><td valign="top"><paragraph>Anthracyclines </paragraph></td><td align="center" valign="top"><paragraph>68 </paragraph></td><td align="center" valign="top"><paragraph>67 </paragraph></td></tr><tr><td valign="top"><paragraph>Alkylating agent (%) </paragraph></td><td align="center" valign="top"><paragraph>92 </paragraph></td><td align="center" valign="top"><paragraph>90 </paragraph></td></tr><tr><td valign="top"><paragraph>Thalidomide/lenalidomide (%) </paragraph></td><td align="center" valign="top"><paragraph>40 </paragraph></td><td align="center" valign="top"><paragraph>43 </paragraph></td></tr><tr styleCode="Botrule"><td styleCode="Botrule " valign="top"><paragraph>Stem cell transplantation (%) </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>57 </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>54 </paragraph></td></tr></tbody></table>

></td></tr><tr styleCode="Botrule"><td styleCode="Botrule " valign="top"><paragraph>Stem cell transplantation (%) </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>57 </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>54 </paragraph></td></tr></tbody></table> <table ID="_RefID129" width="100%"><caption>Table 13: Efficacy of Doxorubicin Hydrochloride Liposome Injection in Combination With Bortezomib in the Treatment of Patients With Multiple Myeloma</caption><col width="51%"/><col width="24%"/><col width="24%"/><tfoot><tr><td align="left" colspan="3" valign="top">¹Kaplan Meier estimate. </td></tr><tr><td align="left" colspan="3" valign="top">²Hazard ratio based on stratified Cox proportional hazards regression. A hazard ratio &lt;1 indicates an advantage for doxorubicin hydrochloride liposome injection + bortezomib. </td></tr><tr><td align="left" colspan="3" valign="top">³Stratified log-rank test. </td></tr><tr><td align="left" colspan="3" valign="top">⁴RR as per EBMT criteria. </td></tr><tr><td align="left" colspan="3" valign="top">⁵Cochran-Mantel-Haenszel test adjusted for the stratification factors.

></tr><tr><td align="left" colspan="3" valign="top">³Stratified log-rank test. </td></tr><tr><td align="left" colspan="3" valign="top">⁴RR as per EBMT criteria. </td></tr><tr><td align="left" colspan="3" valign="top">⁵Cochran-Mantel-Haenszel test adjusted for the stratification factors. </td></tr></tfoot><tbody><tr styleCode="Toprule"><td styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Endpoint</content> </paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Doxorubicin Hydrochloride Liposome Injection + bortezomib</content> <content styleCode="bold">n=324</content> </paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Bortezomib</content> <content styleCode="bold">n=322</content> </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Time to Progression</content>¹ </paragraph></td><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><paragraph>Progression or death due to progression (n) </paragraph></td><td align="center" valign="top"><paragraph>99 </paragraph></td><td align="center" valign="top"><paragraph>150 </paragraph></td></tr><tr><td valign="top"><paragraph> Censored (n) </paragraph></td><td align="center" valign="top"><paragraph>225 </paragraph></td><td align="center" valign="top"><paragraph>172 </paragraph></td></tr><tr><td valign="top"><paragraph> Median in days (months) </paragraph></td><td align="center" valign="top"><paragraph>282 (9.3) </paragraph></td><td align="center" valign="top"><paragraph>197 (6.5) </paragraph></td></tr><tr><td valign="top"><paragraph> 95% CI </paragraph></td><td align="center" valign="top"><paragraph>250; 338 </paragraph></td><td align="center" valign="top"><paragraph>170; 217 </paragraph></td></tr><tr><td valign="top"><paragraph> Hazard ratio ² </paragraph></td><td colspan="2" align="center" valign="top"><paragraph>0.55 </paragraph></td></tr><tr><td valign="top"><paragraph> (95% CI) </paragraph></td><td colspan="2" align="center" valign="top"><paragraph>(0.43, 0.71) </paragraph></td></tr><tr><td valign="top"><paragraph> p-value ³ </paragraph></td><td colspan="2" align="center" valign="top"><paragraph>&lt;0.001 </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Response (n)</content>⁴ </paragraph></td><td align="center" valign="top"><paragraph>303 </paragraph></td><td align="center" valign="top"><paragraph>310 </paragraph></td></tr><tr><td valign="top"><paragraph> % Complete Response (CR) </paragraph></td><td align="center" valign="top"><paragraph>5 </paragraph></td><td align="center" valign="top"><paragraph>3 </paragraph></td></tr><tr><td valign="top"><paragraph> % Partial Response (PR) </paragraph></td><td align="center" valign="top"><paragraph>43 </paragraph></td><td align="center" valign="top"><paragraph>40 </paragraph></td></tr><tr><td valign="top"><paragraph> % CR + PR </paragraph></td><td align="center" valign="top"><paragraph>48 </paragraph></td><td align="center" valign="top"><paragraph>43 </paragraph></td></tr><tr><td valign="top"><paragraph> p-value ⁵ </paragraph></td><td colspan="2" align="center" valign="top"><paragraph>0.25 </paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Median Duration of Response (months)</content> </paragraph></td><td align="center" valign="top"><paragraph>10.2 </paragraph></td><td align="center" valign="top"><paragraph>7.0 </paragraph></td></tr><tr styleCode="Botrule"><td valign="top"><paragraph>(95% CI) </paragraph></td><td align="center" valign="top"><paragraph>(10.2; 12.9) </paragraph></td><td align="center" valign="top"><paragraph>(5.9; 8.3) </pa

gn="top"><paragraph>10.2 </paragraph></td><td align="center" valign="top"><paragraph>7.0 </paragraph></td></tr><tr styleCode="Botrule"><td valign="top"><paragraph>(95% CI) </paragraph></td><td align="center" valign="top"><paragraph>(10.2; 12.9) </paragraph></td><td align="center" valign="top"><paragraph>(5.9; 8.3) </pa ragraph></td></tr></tbody></table> <table width="100%" styleCode="Noautorules"><col width="100%"/><tbody><tr><td align="center" valign="top"><paragraph><content styleCode="bold">Figure 1- Time to Progression Kaplan-Meier Curve</content> </paragraph></td></tr><tr><td valign="top"><renderMultiMedia ID="id2842" referencedObject="A17CBE7A-472B-40B6-A596-F131896AA824"/> </td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING Doxorubicin hydrochloride liposome injection is a sterile, translucent, red liposomal dispersion in 10 mL or 30 mL glass, single dose vials. The following individually cartoned vials are available: Table 14 Vial Concentration Vial Size NDC number 20 mg/10 mL (2 mg/ mL) 10 mL 68001-703-36 50 mg/25 mL (2 mg/mL) 30 mL 68001-704-26 Refrigerate unopened vials of doxorubicin hydrochloride liposome injection at 2° to 8°C (36° to 46°F). Do not freeze. Discard unused portion. Doxorubicin hydrochloride liposome injection is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1

<table ID="_RefID135" width="68.52%"><caption>Table 14</caption><col width="34%"/><col width="16%"/><col width="29%"/><tbody><tr styleCode="Toprule"><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Vial Concentration</content> </paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Vial Size</content> </paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">NDC number</content> </paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20 mg/10 mL (2 mg/ mL) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>10 mL </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>68001-703-36 </paragraph></td></tr><tr styleCode="Botrule"><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>50 mg/25 mL (2 mg/mL) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>30 mL </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>68001-704-26 </paragraph></td></tr></tbody></table>

17 PATIENT COUNSELING INFORMATION Cardiomyopathy Advise patients to contact their healthcare provider if they develop symptoms of heart failure [see Warnings and Precautions ( 5.1 )] . Infusion-Related Reactions Advise patients about the symptoms of infusion related reactions and to seek immediate medical attention if they develop any of these symptoms [see Warnings and Precautions ( 5.2 )] . Myelosuppression Advise patients to contact their healthcare provider for a new onset fever or symptoms of infection. Hand-Foot Syndrome Advise patients to notify their healthcare provider if they experience tingling or burning, redness, flaking, bothersome swelling, small blisters, or small sores on the palms of their hands or soles of their feet (symptoms of Hand-Foot Syndrome) [see Warnings and Precautions ( 5.3 )] . Stomatitis Advise patients to notify their healthcare provider if they develop painful redness, swelling, or sores in the mouth (symptoms of stomatitis). Embryo-Fetal Toxicity Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider with a known or suspected pregnancy [see Warnings and Precautions (5.5) and Use in Specific Populations ( 8.1 )]. Advise females and males of reproductive potential to use effective contraception during and for 6 months following treatment with doxorubicin hydrochloride liposome injection [see Use in Specific Populations ( 8.3 )] . Lactation Advise females not to breastfeed during treatment with doxorubicin hydrochloride liposome injection [see Use in Specific Populations ( 8.2 )]. Infertility Advise females and males of reproductive potential that doxorubicin hydrochloride liposome injection may cause temporary or permanent infertility [see Use in Specific Populations ( 8.3 )]. Discoloration of Urine and Body Fluids Inform patients that following doxorubicin hydrochloride liposome injection administration, a reddish-orange color to the urine and other body fluids may be observed. This nontoxic reaction is due to the color of the product and will dissipate as the drug is eliminated from the body.