Doxorubicin Hydrochloride

1 INDICATIONS AND USAGE Doxorubicin hydrochloride for injection is an anthracycline topoisomerase 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 for 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 for 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 ( 2.1 ). In combination: 40 to 75 mg/m 2 given intravenously every 21 to 28 days ( 2.1 ). Discontinue doxorubicin hydrochloride for injection in patients who develop signs or symptoms of cardiomyopathy ( 2.2 ). Reduce dose in patients with hepatic impairment ( 2.3 ). 2.1 Recommended Dosage for Adjuvant Breast Cancer The recommended dosage of doxorubicin hydrochloride for 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 for 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 for 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 for 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 for 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 for 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 for 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 to 3 mg/dL 50% 3.1 to 5 mg/dL 75% greater than 5 mg/dL Do not initiate doxorubicin hydrochloride for injection; discontinue doxorubicin hydrochloride for injection 2.5 Preparation and Administration Doxorubicin hydrochloride for injection is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1 Preparation Reconstitution of Doxorubicin Hydrochloride for Injection Reconstitute doxorubicin hydrochloride for injection with 0.9% Sodium Chloride Injection to obtain a final concentration of 2 mg per mL as follows: 10 mL 0.9% Sodium Chloride Injection, USP to reconstitute 20 mg vial 25 mL 0.9% Sodium Chloride Injection, USP to reconstitute 50 mg vial Gently shake vial until the contents have dissolved. Protect reconstituted solution from light. Dilution of Reconstituted Doxorubicin Hydrochloride for Injection Dilute reconstituted doxorubicin hydrochloride for 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 reconstituted doxorubicin hydrochloride for 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 infusio…

5 WARNINGS AND PRECAUTIONS Radiation-Induced Toxicity: Can be increased by the administration of doxorubicin hydrochloride for injection. Radiation recall can occur in patients who receive doxorubicin hydrochloride for 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 for 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 for 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. 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 cons…

4 CONTRAINDICATIONS Doxorubicin hydrochloride for injection 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 ). Severe hypersensitivity to doxorubicin hydrochloride ( 4 ).

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 for 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 for 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 for 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 for 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 for 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 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 increased total serum bilirubin, alkaline phosphatase and aspartate aminotransferase.

8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action, doxorubicin hydrochloride for injection can cause fetal harm when administered to a pregnant woman; avoid the use of doxorubicin hydrochloride for 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 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 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating doxorubicin hydrochloride for injection. Contraception Females Doxorubicin hydrochloride for 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 for 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 for 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) ] .

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 Amneal Pharmaceuticals at 1-877-835-5472 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 1,492 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* N=1,492 Conventional CMF N=739 % % Alopecia 92 71 Vomiting Vomiting ≤ 12 hours Vomiting > 12 hours Intractable 34 37 5 25 12 2 Leukopenia Grade 3 (1,000 to 1,999 /mm 3 ) Grade 4 (< 1,000 /mm 3 ) 3.4 0.3 9.4 0.3 Shock, sepsis 2 1 Systemic infection 2 1 Cardiac dysfunction Asymptomatic Transient Symptomatic 0.2 0.1 0.1 0.1 0 0 Thrombocytopenia Grade 3 (25,000 to 49,999 /mm 3 ) Grade 4 (< 25,000 /mm 3 ) 0 0.1 0.3 0 AC = doxorubicin hydrochloride, cyclophosphamide; CMF = cyclophosphamide, methotrexate, fluorouracil * Includes pooled data from patients who received either AC for 4 cycles or AC for 4 cycles followed by CMF for 3 cycles 6.2 Post-marketing Experience The following adverse reactions have been identified during post-approval use of doxorubicin hydrochloride for 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