DOXORUBICIN HYDROCHLORIDE

Doxorubicin hydrochloride is a cytotoxic, anthracycline, topoisomerase II inhibitor isolated from cultures of Streptomyces peucetius var. caesius. Chemically, 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, USP is a clear, red-orange, sterile, isotonic aqueous solution provided in vials containing 50 mg/25 mL or 200 mg/100 mL of doxorubicin hydrochloride. The drug product has demonstrated inherent antimicrobial activity suitable for a multiple dose presentation. Each milliliter of solution contains 2 mg of doxorubicin hydrochloride. Inactive ingredients include sodium chloride 0.9% and water for injection quantity sufficient. The pH of the solution is adjusted to 3 with hydrochloric acid. doxorubicin-chem-str

Doxorubicin hydrochloride (HCl) 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 injection, USP is indicated as a c omponent of multi-a gent adjuvant chemotherapy for treat ment of wo men with axillary lymph node involve ment following resection of pri mary breast cancer [see Clinical Studies (14.1 ) ]. 1.2 Other Cancers DOXOrubicin hydrochloride injection, USP is indicated for the treat ment of acute ly mphoblastic leu ke mia acute m yeloblastic leuke mia Hodgkin lympho ma non-Hodgkin ly mpho ma (NHL) metastatic breast cancer metastatic Wil ms’ tumor metastatic neurobla stoma metastatic s oft tissue sa rco ma metastatic bone sarco ma metastatic o varian car cino ma metastatic t ransitional c ell bladder carcino ma metastatic t hyroid carcinoma metastatic gastric carcinoma metastatic bronchogenic carcinoma

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 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 when used as a single agent is 60 to 75 mg/m 2 intravenously every 21 days. The recommended dose of doxorubicin hydrochloride, 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 is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C or serum bilirubin >5 mg/dL) [see Contraindications (4)] . Decrease the dose of doxorubicin hydrochloride in patients with elevated serum total bilirubin concentrations as follows: Serum bilirubin concentration Doxorubicin Hydrochloride 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 Discontinue doxorubicin hydrochloride [see Warnings and Precautions (5.5) and Use in Specific Population (8.7)] 2.3 Preparation and Administration Preparation for Continuous Intravenous Infusion Dilute doxorubicin hydrochloride solution in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Protect from light following preparation until completion of infusion. 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 injection under refrigerated conditions can result in the formation of a gelled product. Place gelled product at room temperature [15º to 30ºC (59º to 86ºF)] for 2 to 4 hours to return the product to a slightly viscous, mobile solution. Administration by Intravenous Injection: Administer doxorubicin hydrochloride 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 intravenously over 3 to 10 minutes. Decrease the rate of doxorubicin hydrochloride 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 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 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 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 with other drugs. If doxorubicin hydrochloride is mixed with heparin or fluorouracil a precipitate may form. Avoid contact with alkaline solutions which can lead to hydrolysis of doxorubicin hydrochloride. 2.4 Procedures for Proper Handling and Disposal Handle and dispose of doxorubicin hydrochloride 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.

Doxorubicin hydrochloride is contraindicated in patients with: Severe myocardial insufficiency [see Warnings and Precautions (5.1)] Recent (occurring within the past 4 to 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) Hypersensitivity to doxorubicin hydrochloride (4)

The following adverse reactions are discussed in more detail in other sections of the labeling. Cardiomyopathy and Arrhythmias [see Warnings and Precautions (5.1)] Secondary Malignancies [see Warnings and Precautions (5.2)] Extravasation and Tissue Necrosis [see Warnings and Precautions (5.3)] Severe Myelosuppression [see Warnings and Precautions (5.4)] Tumor Lysis Syndrome [see Warnings and Precautions (5.6)] Radiation Sensitization and Radiation Recall [see Warnings and Precautions (5.7)] The most common (>10%) adverse drug reactions are alopecia, nausea and vomiting (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience in Breast Cancer Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety data below were collected from 1492 women who received doxorubicin 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 /mm 3 ) 3.4 9.4 Grade 4 (<1000 /mm 3 ) 0.3 0.3 Thrombocytopenia Grade 3 (25,000 to 49,999 /mm 3 ) 0 0.3 Grade 4 (<25,000 /mm 3 ) 0.1 0 Shock, sepsis 2 1 Systemic infection 2 1 Vomiting Vomiting ≤12 hours 34 25 Vomiting >12 hours 37 12 Intractable 5 2 Alopecia 92 71 Cardiac dysfunction Asymptomatic 0.2 0.1 Transient 0.1 0 Symptomatic 0.1 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

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 hydrochloride­containing 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 to 3 weeks) and doxorubicin hydrochloride (50 mg/m 2 intravenous once per cycle every 2 to 3 weeks) alone or with vincristine and prednisone, all developed hepatic dysfunction manifested by elevations of total serum bilirubin, alkaline phosphatase and aspartate aminotransferase.