Doxorubicin Hydrochloride Liposome

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

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

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

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

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling. Cardiomyopathy [see Warnings and Precautions ( 5.1 )] Infusion-Related Reactions [see Warnings and Precautions ( 5.2 )] Hand-Foot Syndrome [see Warnings and Precautions ( 5.3 )] Secondary Oral Neoplasms [see Warnings and Precautions ( 5.4 )] Most common adverse reactions (>20%) are asthenia, fatigue, fever, anorexia, nausea, vomiting, stomatitis, diarrhea, constipation, hand-foot syndrome, rash, neutropenia, thrombocytopenia, and anemia ( 6 ). To report SUSPECTED ADVERSE REACTIONS contact Sagent Pharmaceuticals at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice. The safety data reflect exposure to doxorubicin hydrochloride liposome injection in 1,310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi's sarcoma, and 318 patients with multiple myeloma. The most common adverse reactions (>20%) observed with doxorubicin hydrochloride liposome injection are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia. The following tables present adverse reactions from clinical trials of single-agent doxorubicin hydrochloride liposome injection in ovarian cancer and AIDS-Related Kaposi's sarcoma. Patients With Ovarian Cancer The safety data described below are from Trial 4, which included 239 patients with ovarian cancer treated with doxorubicin hydrochloride liposome injection 50 mg/m 2 once every 4 weeks for a minimum of four courses in a randomized, multicenter, open-label study. In this trial, patients received doxorubicin hydrochloride liposome injection for a median number of 3.2 months (range 1 day to 25.8 months). The median age of the patients is 60 years (range 27 to 87), with 91% Caucasian, 6% Black, and 3% Hispanic or Other. Table 3 presents the hematologic adverse reactions from Trial 4. Table 3: Hematologic Adverse Reactions in Trial 4 Doxorubicin Hydrochloride Liposome Injection Topotecan Patients (n=239) Patients (n=235) Neutropenia 500 to <1000/mm3 8% 14% < 500/mm3 4.2% 62% Anemia 6.5 to <8 g/dL 5% 25% <6.5 g/dL 0.4% 4.3% Thrombocytopenia 10,000 to <50,000/mm3 1.3% 17% <10,000/mm3 0.0% 17% Table 4 presents the non-hematologic adverse reactions from Trial 4. Table 4: Non-Hematologic Adverse Reactions in Trial 4 Non-Hematologic Adverse Reaction 10% or Greater Doxorubicin Hydrochloride Liposome Injection (%) treated (n=239) Topotecan (%) treated (n=235) All grades Grades 3-4 All grades Grades 3-4 Body as a Whole Asthenia 40 7 52 8 Fever 21 0.8 31 6 Mucous Membrane Disorder 14 3.8 3.4 0 Back Pain 12 1.7 10 0.9 Infection 12 2.1 6 0.9 Headache 11 0.8 15 0 Digestive Nausea 46 5 63 8 Stomatitis 41 8 15 0.4 Vomiting 33 8 44 10 Diarrhea 21 2.5 35 4.2 Anorexia 20 2.5 22 1.3 Dyspepsia 12 0.8 14 0 Nervous Dizziness 4.2 0 10 0 Respiratory Pharyngitis 16 0 18 0.4 Dyspnea 15 4.1 23 4.3 Cough increased 10 0 12 0 Skin and Appendages Hand-foot syndrome 51 24 0.9 0 Rash 29 4.2 12 0.4 Alopecia 19 N/A 52 N/A The following additional adverse reactions were observed in patients with ovarian cancer with doses administered every four weeks (Trial 4). Incidence 1% to 10% Cardiovascular: vasodilation, tachycardia, deep vein thrombosis, hypotension, cardiac arrest. Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus. Hematologic and Lymphatic: ecchymosis. Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia, hypercalcemia, hyponatremia. Nervous: somnolence, dizziness, depression. Respiratory: rhinitis, pneumonia, sinusitis, epistaxis. Skin and Appe …

7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with doxorubicin hydrochloride liposome injection.

8 USE IN SPECIFIC POPULATIONS Lactation: Discontinue breastfeeding ( 8.2 ). 8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action, doxorubicin hydrochloride liposome injection can cause fetal harm when administered to a pregnant woman; avoid the use of doxorubicin hydrochloride liposome injection during the 1 st trimester. In animal reproduction studies, doxorubicin hydrochloride liposome injection was embryotoxic in rats and abortifacient in rabbits following intravenous administration during organogenesis at doses approximately 0.12 times the recommended clinical dose (see Data ) . Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 2 nd and 3 rd trimesters. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. Data Animal Data Doxorubicin hydrochloride liposome injection was embryotoxic at doses of 1 mg/kg/day in rats and was embryotoxic and abortifacient at 0.5 mg/kg/day in rabbits (both doses are about 0.12 times the recommended dose of 50 mg/m 2 human dose on a mg/m 2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced live litter sizes. 8.2 Lactation Risk Summary It is not known whether doxorubicin hydrochloride liposome injection is present in human milk. Because many drugs, including anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in breastfed infants from doxorubicin hydrochloride liposome injection, discontinue breastfeeding during treatment with doxorubicin hydrochloride liposome injection. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating doxorubicin hydrochloride liposome injection. Contraception Females Doxorubicin hydrochloride liposome injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Advise females of reproductive potential to use effective contraception during and for 6 months after treatment with doxorubicin hydrochloride liposome injection. Males Doxorubicin hydrochloride liposome injection may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during and for 6 months after treatment with doxorubicin hydrochloride liposome injection [see Non-clinical Toxicology ( 13.1 )] . Infertility Females In females of reproductive potential, doxorubicin hydrochloride liposome injection may cause infertility and result in amenorrhea. Premature menopause can occur with doxorubicin hydrochloride. Recovery of menses and ovulation is related to age at treatment. Males Doxorubicin hydrochloride liposome injection may result in oligospermia, azoospermia, and permanent loss of fertility. Sperm counts have been reported to return to normal levels in some men. This may occur several years after the end of therapy [see Non-clinical Toxicology ( 13.1 )] . 8.4 Pediatric Use The safety and effectiveness of doxorubicin hydrochloride liposome injection in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of doxorubicin hydrochloride liposome injection conducted in patients with either epithelial ovarian cancer (Trial 4) or with AIDS-related Kaposi's sarcoma (Trial 5) did not contain sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. In Trial 6, of 318 patients treated with doxorubicin hydrochloride liposome injection in combination with bortezomib for multipl …

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

11 DESCRIPTION The active ingredient in doxorubicin hydrochloride liposome injection is doxorubicin hydrochloride, an anthracycline topoisomerase inhibitor, that is encapsulated in pegylated liposomes for intravenous use. The chemical name of doxorubicin hydrochloride is (8S,10S)-10-[(3-amino-2,3,6‐trideoxy-α-L-lyxo-hexopyranosyl)oxy]-8-glycolyl-7,8,9,10-tetrahydro-6,8,11‐trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride. The molecular formula is C 27 H 29 NO 11 •HCl and the molecular weight is 579.99. The structural formula is: Doxorubicin hydrochloride liposome injection is a sterile, translucent, red liposomal dispersion. Each single-dose vial contains 20 mg or 50 mg doxorubicin hydrochloride at a concentration of 2 mg per mL (equivalent to 1.87 mg per mL of doxorubicin). The pegylated liposome carriers are composed of cholesterol, 3.19 mg per mL; fully hydrogenated soy phosphatidylcholine (HSPC), 9.58 mg per mL; and N-(carbonyl-methoxypolyethylene glycol 2,000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine sodium salt (MPEG-DSPE), 3.19 mg per mL. Each mL also contains ammonium sulfate, approximately 0.6 mg; histidine, 1.55 mg as a buffer; hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (6.0 to 7.0); and sucrose, 94 mg to maintain isotonicity. Greater than 90% of the drug is encapsulated in the pegylated liposomes. MPEG-DSPE has the following structural formula: HSPC has the following structural formula: Representation of a pegylated liposome: Structural Formula MPEG-DSPE Structural Formula HSPC Structural Formula Representation of a Pegylated Liposome

10 OVERDOSAGE Acute overdosage with doxorubicin hydrochloride causes increased risk of severe mucositis, leukopenia, and thrombocytopenia.

16 HOW SUPPLIED/STORAGE AND HANDLING Doxorubicin hydrochloride liposome injection is a sterile, translucent, red liposomal dispersion in 10 mL or 30 mL glass. NDC Doxorubicin Hydrochloride Liposome Package Factor Injection (2 mg per mL) 25021-263-10 20 mg per 10 mL Single-Dose Vial 1 vial per carton 25021-263-25 50 mg per 25 mL Single-Dose Vial 1 vial per carton Storage Conditions Refrigerate unopened vials of doxorubicin hydrochloride liposome injection at 2° to 8°C (36° to 46°F). Do not freeze. Discard unused portion. Sterile, Nonpyrogenic, Preservative-free. The container closure is not made with natural rubber latex. Doxorubicin hydrochloride liposome injection is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1