Doxorubicin Hydrochloride

1 INDICATIONS AND USAGE 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

DOSAGE AND ADMINISTRATION: When possible, to reduce the risk of developing cardiotoxicity in patients receiving doxorubicin after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, doxorubicin-based therapy should be delayed until the other agents have cleared from the circulation (see WARNINGS and PRECAUTIONS, General ). Care in the administration of doxorubicin will reduce the chance of perivenous infiltration (see WARNINGS ). It may also decrease the chance of local reactions such as urticaria and erythematous streaking. On intravenous administration of doxorubicin, extravasation may occur with or without an accompanying burning or stinging sensation, even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the injection or infusion should be immediately terminated and restarted in another vein. If extravasation is suspected, intermittent application of ice to the site for 15 min. q.i.d. x 3 days may be useful. The benefit of local administration of drugs has not been clearly established. Because of the progressive nature of extravasation reactions, close observation and plastic surgery consultation is recommended. Blistering, ulceration and/or persistent pain are indications for wide excision surgery, followed by split-thickness skin grafting. The most commonly used dose schedule when used as a single agent is 60 to 75 mg/m 2 as a single intravenous injection administered at 21-day intervals. The lower dosage should be given to patients with inadequate marrow reserves due to old age, or prior therapy, or neoplastic marrow infiltration. Doxorubicin has been used concurrently with other approved chemotherapeutic agents. Evidence is available that in some types of neoplastic disease, combination chemotherapy is superior to single agents. The benefits and risks of such therapy continue to be elucidated. When used in combination with other chemotherapy drugs, the most commonly used dosage of doxorubicin is 40 to 60 mg/m 2 given as a single intravenous injection every 21 to 28 days. In a large randomized study (NSABP B-15) of patients with early breast cancer involving axillary lymph nodes (see CLINICAL PHARMACOLOGY , CLINICAL STUDIES and ADVERSE REACTIONS , Adverse Reactions in Patients with Early Breast Cancer Receiving Doxorubicin-Containing Adjuvant Therapy ), the combination dosage regimen of AC (doxorubicin 60 mg/m 2 and cyclophosphamide 600 mg/m 2 ) was administered intravenously on day 1 of each 21-day treatment cycle. Four cycles of treatment were administered. Dose Modifications Patients in the NSABP B-15 study could have dose modifications of AC to 75% of the starting doses for neutropenic fever/infection. When necessary, the next cycle of treatment cycle was delayed until the absolute neutrophil count (ANC) was ≥ 1,000 cells/mm 3 and the platelet count was ≥ 100,000 cells/mm 3 and nonhematologic toxicities had resolved. Doxorubicin dosage must be reduced in case of hyperbilirubinemia as follows: Plasma bilirubin concentration (mg/dL) Dosage reduction (%) 1.2 to 3 50 3.1 to 5 75 Reconstitution Directions It is recommended that doxorubicin be slowly administered into the tubing of a freely running intravenous infusion of Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP. The tubing should be attached to a Butterfly ® needle inserted preferably into a large vein. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. The rate of administration is dependent on the size of the vein and the dosage. However, the dose should be administered in not less than 3 to 5 minutes. Local erythematous streaking along the vein as well as facial flushing may be indicative of too rapid an administration. A burning or stinging sensation may be indicative of perivenous infiltration and, if this occurs, the infusion should be immediately terminated and restarted …

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 )

ADVERSE REACTIONS: Dose limiting toxicities of therapy are myelosuppression and cardiotoxicity. Other reactions reported are: Cardiotoxicity (See WARNINGS ). Cutaneous Reversible complete alopecia occurs in most cases. Hyperpigmentation of nailbeds and dermal creases, primarily in pediatric patients, and onycholysis have been reported in a few cases. Radiation recall reaction has occurred with doxorubicin administration. Rash, itching, or photosensitivity may occur. Gastrointestinal Acute nausea and vomiting occurs frequently and may be severe. This may be alleviated by antiemetic therapy. Mucositis (stomatitis and esophagitis) may occur within 5 to 10 days of beginning therapy, and most patients recover from this adverse event within another 5 to 10 days. The effect may be severe leading to ulceration and represents a site of origin for severe infections. The dosage regimen consisting of administration of doxorubicin on three successive days results in greater incidence and severity of mucositis. Ulceration and necrosis of the colon, especially the cecum, may occur leading to bleeding or severe infections which can be fatal. This reaction has been reported in patients with acute non-lymphocytic leukemia treated with a 3-day course of doxorubicin combined with cytarabine. Anorexia, abdominal pain, dehydration, diarrhea, and hyperpigmentation of the oral mucosa have been occasionally reported. Hematologic (See WARNINGS ). Hypersensitivity Fever, chills and urticaria have been reported occasionally. Anaphylaxis may occur. A case of apparent cross sensitivity to lincomycin has been reported. Neurological Peripheral neurotoxicity in the form of local-regional sensory and/or motor disturbances have been reported in patients treated intra-arterially with doxorubicin, mostly in combination with cisplatin. Animal studies have demonstrated seizures and coma in rodents and dogs treated with intra-carotid doxorubicin. Seizures and coma have been reported in patients treated with doxorubicin in combination with cisplatin or vincristine. Ocular Conjunctivitis, keratitis, and lacrimation occur rarely. Other Malaise/asthenia have been reported. Adverse Reactions in Patients with Early Breast Cancer Receiving Doxorubicin-Containing Adjuvant Therapy Safety data were collected from approximately 2,300 women who participated in a randomized, open-label trial (NSABP B-15) evaluating the use of AC versus CMF in the treatment of early breast cancer involving axillary lymph nodes. In the safety analysis, the follow-up data from all patients receiving AC were combined (N=1,492 evaluable patients) and compared with data from patients receiving conventional CMF (i.e., oral cyclophosphamide; N=739 evaluable patients). The most relevant adverse events reported in this study are provided in Table 2. Table 2. Relevant Adverse Events in Patients with Early Breast Cancer Involving Axillary Lymph Nodes AC* Conventional CMF N=1,492 N=739 Treatment administration Mean number of cycles 3.8 5.5 Total cycles 5,676 4,068 Adverse events, % of patients Leukopenia Grade 3 (1,000 to 1,999 /mm 3 ) 3.4 9.4 Grade 4 (12 hours 36.8 12 Intractable 4.7 1.6 Alopecia 92.4 71.4 Partial 22.9 56.3 Complete 69.5 15.1 Weight loss 5 to 10% 6.2 5.7 >10% 2.4 2.8 Weight gain 5 to 10% 10.6 27.9 >10% 3.8 14.3 Cardiac function Asymptomatic 0.2 0.1 Transient 0.1 0 Symptomatic 0.1 0 Treatment-related death 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

Cardiotoxicity (See WARNINGS ).

Cutaneous Reversible complete alopecia occurs in most cases. Hyperpigmentation of nailbeds and dermal creases, primarily in pediatric patients, and onycholysis have been reported in a few cases. Radiation recall reaction has occurred with doxorubicin administration. Rash, itching, or photosensitivity may occur.

Gastrointestinal Acute nausea and vomiting occurs frequently and may be severe. This may be all …

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 hydrochloride, 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 hydrochloride. 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 hydrochloride 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 hydrochloride 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 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 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. 8.2 Lactation Risk Summary Doxorubicin hydrochloride 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 hydrochloride 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. 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 a …

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 hydrochloride. Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases. The interaction of doxorubicin hydrochloride with topoisomerase II to form DNA-cleavable complexes appears to be an important mechanism of doxorubicin hydrochloride cytocidal activity.

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

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 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.

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