Doxorubicin Hydrochloride

1 INDICATIONS AND USAGE Doxorubicin 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 HCl Injection, 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 )]. 1.2 Other Cancers Doxorubicin 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

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling. Cardiomyopathy and Arrhythmias [see Warnings and Precautions (5.1) ] Secondary Malignancies [see Warnings and Precautions (5.2) ] Extravasation and Tissue Necrosis [see Warnings and Precautions (5.3) ] Severe Myelosuppression [see Warnings and Precautions (5.4) ] Tumor Lysis Syndrome [see Warnings and Precautions (5.6) ] Radiation Sensitization and Radiation Recall [see Warnings and Precautions (5.7) ] The most common (>10%) adverse drug reactions are alopecia, nausea and vomiting ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceutical Corp. at 1-877-845-0689, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience in Breast Cancer Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety data below were collected from 1492 women who received doxorubicin at a dose of 60 mg/m 2 and cyclophosphamide at a dose of 600 mg/m 2 (AC) every 3 weeks for 4 cycles for the adjuvant treatment of axillary lymph node positive breast cancer. The median number of cycles received was 4. Selected adverse reactions reported in this study are provided in Table 1. No treatment-related deaths were reported in patients on either arm of the study. Table 1. Selected Adverse Reactions in Patients with Early Breast Cancer Involving Axillary Lymph Nodes Adverse reactions, % of patients AC* N=1492 Conventional CMF N=739 Leukopenia Grade 3 (1,000 to 1,999 /mm 3 ) Grade 4 (<1000 /mm 3 ) 3.4 0.3 9.4 0.3 Thrombocytopenia Grade 3 (25,000 to 49,999 /mm 3 ) Grade 4 (<25,000 /mm 3 ) 0 0.1 0.3 0 Shock, sepsis 2 1 Systemic infection 2 1 Vomiting Vomiting ≤12 hours Vomiting >12 hours Intractable 34 37 5 25 12 2 Alopecia 92 71 Cardiac dysfunction Asymptomatic Transient Symptomatic 0.2 0.1 0.1 0.1 0 0 * Includes pooled data from patients who received either AC alone for 4 cycles, or who were treated with AC for 4 cycles followed by 3 cycles of CMF 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of doxorubicin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac – cardiogenic shock Cutaneous – Skin and nail hyperpigmentation, oncolysis, rash, itching, photosensitivity, urticaria, acral erythema, palmar plantar erythrodysesthesia Gastrointestinal – Nausea, mucositis, stomatitis, necrotizing colitis, typhlitis, gastric erosions, gastrointestinal tract bleeding, hematochezia, esophagitis, anorexia, abdominal pain, dehydration, diarrhea, hyperpigmentation of the oral mucosa Hypersensitivity – Anaphylaxis Laboratory Abnormalities –Increased alanine aminotransferase, increased aspartate aminotransferase Neurological – Peripheral sensory and motor neuropathy, seizures, coma Ocular – Conjunctivitis, keratitis, lacrimation Vascular – Phlebosclerosis, phlebitis/thrombophlebitis, hot flashes, thromboembolism Other – Malaise/asthenia, fever, chills, weight gain

4 CONTRAINDICATIONS Doxorubicin 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 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 HCl ( 4 )

11 DESCRIPTION Doxorubicin is a cytotoxic anthracycline antibiotic isolated from cultures of Streptomyces peucetius var. caesius . Doxorubicin consists of a naphthacenequinone nucleus linked through a glycosidic bond at ring atom 7 to an amino sugar, daunosamine. Chemically, doxorubicin hydrochloride is (8S,10S)-10-[(3-Amino-2,3,6-trideoxy-a-L-lyxo-hexopyranosyl)-oxy]-8-glycoloyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride. The structural formula is as follows: Doxorubicin binds to nucleic acids, presumably by specific intercalation of the planar anthracycline nucleus with the DNA double helix. The anthracycline ring is lipophilic, but the saturated end of the ring system contains abundant hydroxyl groups adjacent to the amino sugar, producing a hydrophilic center. The molecule is amphoteric, containing acidic functions in the ring phenolic groups and a basic function in the sugar amino group. It binds to cell membranes as well as plasma proteins. It is supplied in the hydrochloride form as a sterile parenteral, isotonic solution with sodium chloride for intravenous use only. DOXOrubicin HCI Injection, USP: Each 2 mg/mL, 5 mL (10 mg) vial contains 10 mg Doxorubicin Hydrochloride, USP; Sodium Chloride 0.9% (to adjust tonicity) and Water for Injection q.s.; pH adjusted to 3 using Hydrochloric Acid. Each 2 mg/mL, 10 mL (20 mg) vial contains 20 mg Doxorubicin Hydrochloride, USP; Sodium Chloride 0.9% (to adjust tonicity) and Water for Injection q.s.; pH adjusted to 3 using Hydrochloric Acid. Each 2 mg/mL, 25 mL (50 mg) vial contains 50 mg Doxorubicin Hydrochloride, USP; Sodium Chloride 0.9% (to adjust tonicity) and Water for Injection q.s.; pH adjusted to 3 using Hydrochloric Acid. Each 2 mg/mL, 100 mL (200 mg) multiple dose vial contains 200 mg Doxorubicin Hydrochloride, USP; Sodium Chloride 0.9% (to adjust tonicity) and Water for Injection q.s.; pH adjusted to 3 using Hydrochloric Acid. structure

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 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 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 when used as a single agent is 60 to 75 mg/m 2 intravenously every 21 days. The recommended dose of doxorubicin, 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 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 in patients with elevated serum total bilirubin concentrations as follows: Serum bilirubin concentration Doxorubicin 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 Discontinue doxorubicin [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 solution or reconstituted solution in 0.9% Sodium Chloride Injection 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 HCl Injection, USP following reconstitution 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 as an intravenous injection through a central intravenous line or a secure and free-flowing peripheral venous line containing 0.9% Sodium Chloride Injection, 0.45% Sodium Chloride Injection, or 5% Dextrose Injection. Administer doxorubicin intravenously over 3 to 10 minutes. Decrease the rate of doxorubicin 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 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 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 with other drugs. If doxorubicin is mixed with heparin or fluorouracil a precipitate may form. Avoid contact with alkaline solutions which can lead to hydrolysis of doxorubicin. 2.4 Procedures for Proper Handling and Disposal Handle and dispose of doxorubicin 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.

10 OVERDOSAGE Few cases of overdose have been described. A 58-year-old man with acute lymphoblastic leukemia received 10-fold overdose of doxorubicin (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 daily for 2 days (intended dose was 50 mg per day for 3 days). The patient developed severe mucositis on days 4 to 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.

7 DRUG INTERACTIONS Avoid concurrent use of doxorubicin with inhibitors and inducers of CYP3A4, CYP2D6, and/or P-gp ( 7.1 ). Do not administer doxorubicin 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 with inhibitors and inducers of CYP3A4, CYP2D6, or P-gp. 7.2 Trastuzumab Concurrent use of trastuzumab and doxorubicin 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, increases the plasma-concentrations of doxorubicin and its metabolites. Administer doxorubicin prior to paclitaxel if used concomitantly. 7.4 Dexrazoxane Do not administer dexrazoxane as a cardioprotectant at the initiation of doxorubicin containing chemotherapy regimens. In a randomized trial in women with metastatic breast cancer, initiation of dexrazoxane with doxorubicin 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 based chemotherapy alone. 7.5 6-Mercaptopurine Doxorubicin 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 (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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The cytotoxic effect of doxorubicin 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 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/m 2 . 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 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. 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 to 60 children and adolescents ranging from 2 months to 20 years of age, doxorubicin clearance averaged 1443 ± 114 mL/min/m 2 . 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 )] .

12.1 Mechanism of Action The cytotoxic effect of doxorubicin 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 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/m 2 . 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 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. 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 to 60 children and adolescents ranging from 2 months to 20 years of age, doxorubicin clearance averaged 1443 ± 114 mL/min/m 2 . 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 )] .

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3 DOSAGE FORMS AND STRENGTHS DOXOrubicin HCl Injection, USP: Vials contain 10 mg/5 mL, 20 mg/10 mL, 50 mg/25 mL, and 200 mg/100 mL doxorubicin hydrochloride as a clear red solution. DOXOrubicin HCl Injection, USP: Vials contain 10 mg/5 mL, 20 mg/10 mL, 50 mg/25 mL, and 200 mg/100 mL as a solution ( 3 )

Doxorubicin Hydrochloride Doxorubicin Hydrochloride DOXORUBICIN HYDROCHLORIDE DOXORUBICIN HYDROCHLORIC ACID SODIUM CHLORIDE WATER Doxorubicin Hydrochloride Doxorubicin Hydrochloride DOXORUBICIN HYDROCHLORIDE DOXORUBICIN HYDROCHLORIC ACID SODIUM CHLORIDE WATER Doxorubicin Hydrochloride Doxorubicin Hydrochloride DOXORUBICIN HYDROCHLORIDE DOXORUBICIN HYDROCHLORIC ACID SODIUM CHLORIDE WATER Doxorubicin Hydrochloride Doxorubicin Hydrochloride DOXORUBICIN HYDROCHLORIDE DOXORUBICIN HYDROCHLORIC ACID SODIUM CHLORIDE WATER

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Doxorubicin treatment results in an increased risk of secondary malignancies based on postmarketing reports [see Warnings and Precautions (5.2) ] . Doxorubicin 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 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 (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 induces DNA damage in rabbit spermatozoa and dominant lethal mutations in mice.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Doxorubicin treatment results in an increased risk of secondary malignancies based on postmarketing reports [see Warnings and Precautions (5.2) ] . Doxorubicin 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 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 (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 induces DNA damage in rabbit spermatozoa and dominant lethal mutations in mice.

ANDA062975

Doxorubicin Hydrochloride

Doxorubicin Hydrochloride

0143-9084

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

Package/Label Display Panel NDC 0143- 9084 -01 Rx only DOXOrubicin HCl Injection, USP 10 mg per 5 mL (2 mg/mL) For IV use ONLY Preservative Free STERILE ISOTONIC SOLUTION 5 mL Single Dose Vial vial

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (Patient Information). Inform patients of the following: Doxorubicin can cause irreversible myocardial damage. Advise patients to contact a healthcare provider for symptoms of heart failure during or after treatment with doxorubicin [see Warnings and Precautions (5.1) ] . There is an increased risk of treatment-related leukemia from doxorubicin [see Warnings and Precautions (5.2) ] . Doxorubicin 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 can cause fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment with doxorubicin 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 [see Warnings and Precautions (5.8) and Use in Specific Populations (8.6)] . Doxorubicin 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 can cause premature menopause in females and loss of fertility in males [see Use in Specific Populations (8.6 )] . Discontinue nursing while receiving doxorubicin [see Use in Specific Populations (8.3)]. Doxorubicin 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 causes alopecia [see Adverse Reactions (6.1) ] . Doxorubicin can cause their urine to appear red for 1 to 2 days after administration. Manufactured by: THYMOORGAN PHARMAZIE GmbH Schiffgraben 23, 38690 Goslar, Germany Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 Revised March 2021 127.207.042/00

14 CLINICAL STUDIES The clinical efficacy of doxorubicin 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 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 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 containing regimens retained at least 75% of the historical CMF adjuvant effect on DFS with a hazard ratio (HR) of 0.91 (95% CI, 0.8 to 1.01 ) and on OS with a HR of 0.91 (95% CI, 0.8 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 Containing Regimens Versus CMF in Meta-Analysis Study (starting year) Regimens No. of Cycles No. of Patients Doxorubicin Containing Regimens vs. CMF HR** (95% CI) DFS OS NSABP B-15 (1984) AC CMF 4 6 1562* 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† 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 Containing Regimens CMF 2157 1353 0.91 (0.82 to 1.01) 0.91 (0.81 to 1.03) Abbreviations: DFS = disease free survival; OS = overall survival; AC = doxorubicin, cyclophosphamide; AVbCMF = doxorubicin, vinblastine, cyclophosphamide, methotrexate, 5-fluorouracil; CMF = cyclophosphamide, methotrexate, 5-fluorouracil; CMFVA = cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, doxorubicin; FAC = 5-fluorouracil, doxorubicin, cyclophosphamide; FACV = 5-fluorouracil, doxorubicin, cyclophosphamide, vincristine; HR = hazard ratio; CI = confidence interval * 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. ** a hazard ratio of less than 1 indicates that the treatment with doxorubicin containing regimens is associated with lower risk of disease recurrences or death compared to the treatment with CMF. † Patients received alternating cycles of AVb and CMF. fig. 1 fig. 2

15 REFERENCES 1. “Hazardous Drugs”. OSHA . http://www.osha.gov/SLTC/hazardousdrugs/index.html

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

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, 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 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. Doxorubicin, 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)].

8.1 Pregnancy Pregnancy Category D Risk Summary Doxorubicin can cause fetal harm when administered to a pregnant woman. Doxorubicin 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 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 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 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 can cause fetal harm when administered to a pregnant woman. Doxorubicin 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 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 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, 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 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. Doxorubicin, 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 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 can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment with doxorubicin and for 6 months after treatment. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking doxorubicin [see Use in Specific Populations (8.1) ] . Males Doxorubicin 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 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 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 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 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) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING DOXOrubicin HCI Injection, USP is supplied in single-dose, flip-top vials, as a red-orange solution containing Doxorubicin Hydrochloride, USP 2 mg/mL in the following package strengths: NDC 0143-9084-01 : 10 mg in 5 mL; individually boxed. NDC 0143-9085-01 : 20 mg in 10 mL; individually boxed. NDC 0143-9086-01 : 50 mg in 25 mL; individually boxed. Store refrigerated, 2° to 8°C (36° to 46°F). Protect from light. Retain in carton until time of use. Discard unused portion. DOXOrubicin HCI Injection, USP is supplied in a sterile, multiple dose, flip-top vial, as a red-orange solution containing Doxorubicin Hydrochloride, USP 2 mg/mL in the following package strength: NDC 0143-9087-01 : 200 mg in 100 mL; individually boxed. Store refrigerated, 2° to 8°C (36° to 46°F). Protect from light. Retain in carton until contents are used. Storage of vials of DOXOrubicin HCl Injection, USP following reconstitution 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. Handling and Disposal Handle and dispose of DOXOrubicin HCl Injection, USP consistent with recommendations for the handling and disposal of hazardous drugs. 1

WARNING: CARDIOMYOPATHY, SECONDARY MALIGNANCIES, EXTRAVASATION AND TISSUE NECROSIS, and SEVERE MYELOSUPPRESSION Cardiomyopathy: Myocardial damage, including acute left ventricular failure can occur with doxorubicin. The risk of cardiomyopathy is proportional to the cumulative exposure with incidences from 1% to 20% for cumulative doses from 300 mg/m 2 to 500 mg/m 2 when doxorubicin is administered every 3 weeks. The risk of cardiomyopathy is further increased with concomitant cardiotoxic therapy. Assess LVEF before and regularly during and after treatment with doxorubicin [see Warnings and Precautions ( 5.1 )]. Secondary Malignancies: Secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) occur at a higher incidence in patients treated with anthracyclines, including doxorubicin [see Warnings and Precautions ( 5.2 )]. Extravasation and Tissue Necrosis: Extravasation of doxorubicin can result in severe local tissue injury and necrosis requiring wide excision of the affected area and skin grafting. Immediately terminate the drug, and apply ice to the affected area [see Warnings and Precautions ( 5.3 )]. Severe myelosuppression resulting in serious infection, septic shock, requirement for transfusions, hospitalization, and death may occur [see Warnings and Precautions ( 5.4 )]. WARNING: CARDIOMYOPATHY, SECONDARY MALIGNANCIES, EXTRAVASATION AND TISSUE NECROSIS, and SEVERE MYELOSUPPRESSION See full prescribing information for complete boxed warning. Cardiomyopathy: Myocardial damage can occur with doxorubicin with incidences from 1% to 20% for cumulative doses from 300 mg/m 2 to 500 mg/m 2 when doxorubicin is administered every 3 weeks. The risk of cardiomyopathy is further increased with concomitant cardiotoxic therapy. Assess left ventricular ejection fraction (LVEF) before and regularly during and after treatment with doxorubicin HCl. ( 5.1 ) Secondary Malignancies: Secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) occur at a higher incidence in patients treated with anthracyclines, including doxorubicin. ( 5.2 ) Extravasation and Tissue Necrosis: Extravasation of doxorubicin can result in severe local tissue injury and necrosis requiring wide excision and skin grafting.Immediately terminate the drug, and apply ice to the affected area. ( 5.3 ) Severe myelosuppression resulting in serious infection, septic shock, requirement for transfusions, hospitalization, and death may occur. ( 5.4 )